Processes and intermediates for preparation of MCL1 inhibitors

Abstract

The present disclosure provides processes for the preparation of MCL1 inhibitors or salts thereof and related key intermediates.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of November 20, 2020, application number 202080085451.3 (PCT / US2020 / 061517), and invention name: "Methods and intermediates for preparing MCL1 inhibitors".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 940,387, filed on November 26, 2019. The entire contents of that application are incorporated herein by reference in their entirety. Technical Field

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

[0005] Apoptosis (programmed cell death) is a process used to eliminate unwanted or potentially dangerous cells of an organism. Avoiding apoptosis is essential for the development and continued growth of tumors. Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic member of the Bcl-2 protein family. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Studies have shown that MCL1 inhibitors can be used to treat cancer. Compounds that inhibit MCL1 have been disclosed, but there is still a need for synthetic methods for preparing such compounds on a production scale.

[0006] PCT application number PCT / US2019 / 032053 (WO 2019 / 222112) discloses novel compounds that can be used as MCL1 inhibitors. The patent publication discloses compounds according to formula (A),

[0007]

[0008] The invention relates to a pharmaceutically acceptable salt thereof and is effective as an inhibitor of MCL1 and can be used for treating cancer.

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

[0010] The present disclosure provides methods for preparing compounds according to formula (A), as shown above. In some embodiments, the present disclosure provides compounds according to formula (I),

[0011]

[0012] in: is a single bond or a double bond;

[0013] R 12 is hydrogen or -C(O)R 1 ;

[0014] R 1 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 or -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 group substitution;

[0015] R 2 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 group substitution;

[0016] R 3 It is hydrogen, C 1-6 Alkyl, -OR 7 , C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R 7 or -CN, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 group substitution;

[0017] R 4 It is hydrogen;

[0018] R 5 It is C 1-6 Alkyl, -(CH 2 CH2 O) p R 7 , C 1-6 Haloalkyl or C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 The cycloalkyl group is optionally substituted with 1 to 5 R 10 Group substitution;

[0019] R 6 is hydrogen or a halogen;

[0020] Each R 7 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substitution;

[0021] Each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substitution;

[0022] Each R 10 Independently C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a 、-C(O)R a 、-C(O)OR a 、-C(O)NRa R b 、-OC(O)NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR a C(O)OR b 、-S(O) q R a 、-S(O) 2 NR a R b 、-NR a S(O) 2 R b 、-N 3 , -CN or -NO 2 , or two R 10 The groups form fused, spiro or bridged C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl are optionally substituted with 1-5 R 20 Group substitution;

[0023] Each R a and R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, or R a and R b Together with the atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted with 1-5 R 20 Group substitution;

[0024] Each R 20 Independently C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C6 -C 10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1-6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH 2 、-C(O)NH(C- 1-6 alkyl), -C(O)N(C- 1-6 alkyl) 2 、-COOH、-C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or halogen;

[0025] p is 0, 1, or 2; and

[0026] q is 0, 1, or 2;

[0027] and pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula I is a compound according to formula I(a):

[0028]

[0029] In a specific embodiment, the present disclosure provides a method for preparing Compound 1:

[0030]

[0031] The compounds of formula A (as well as formula I and I(a)) can be schematically divided into four functional regions, as shown below, each separated by one of the four key synthetic bonds (dashed lines):

[0032]

[0033] Thus, the compounds of Formula A (as well as Formulas I and I(a)) can be considered to contain four major sub-parts: a tetracyclic core (TC), and specifically, a 6'-substituted-3,4-dihydro-2H,2'H,4H-5λ 2 -spiro[benzo[b][1,4]oxazepane-3,1'-naphthene-7-yl moiety; a disubstituted cyclobutane moiety (CB); a polysubstituted sulfonimide moiety (SNO); and an N-linked side chain (SC).

[0034] In this structure, the TC and CB moieties are linked by a single N-C alkylamine bond (numbered 1), the TC and SNO moieties are linked by a single N-C amide bond (numbered 2), the CB and SNO moieties are linked by a C-C alkyl or C=C alkenyl bond (numbered 3), and the SC and SNO moieties are linked by either an NH or N-C single bond (numbered 4), depending on R. 12 characteristics.

[0035] WO 2019 / 222112 discloses a method for preparing a compound of formula A (including formula I and I(a)). In this method, the key synthetic bonds are formed in the order of 1, 2, 4 and then 3.

[0036] It should be understood that in this nomenclature, when discussing synthetic routes that build and connect key fragments in a step-wise manner, there may be protecting groups and other temporary substituents in further intermediates that will not match the final substituents or structural motifs in the final Formula A compound.

[0037] Method disclosed in WO 2019 / 222112

[0038]

[0039] Disclosed herein are methods for preparing compounds of formula A (e.g., compounds of formula I or I(a)), and methods for preparing key intermediates thereof. Specifically, in some embodiments, disclosed herein are methods for preparing compounds of formula A (e.g., compounds of formula I or I(a)), wherein the key synthetic bond is formed in one or more of the following orders: 1, 2, 3 then 4; 2, 1, 3 then 4; 1, 2, 4 then 3; 2, 1, 4 then 3; 2, 3, 1 then 4; or 3, 2, 1 then 4; provided that if the order of the key synthetic bond formation steps is 1, 2, 3, 4, then the method does not include the use of intermediates 1-J or 1-K as defined herein, wherein R 5 It's H.

[0040] In some embodiments, the fragment TC is fully formed before being incorporated into the above method steps. In other embodiments, the fragment TC is initially prepared as a bicyclic phenoxy fragment and carried out one or more steps in a protected state, followed by deprotection and ring closure to form a tetracyclic TC fragment. For example:

[0041]

[0042] Wherein PG represents a protected aldehyde, for example, PG is CH(OC 1-6 Alkyl)(OC 1-6 alkyl) or -O(C 2-10 Alkyl)O-. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The method for preparing compounds of formula A (including formula I and I(a)) disclosed in WO 2019 / 222112 is schematically abbreviated. DETAILED DESCRIPTION

[0044] Thus, in a first aspect, the present disclosure provides a method (Method A) for preparing a compound of formula A (e.g., a compound of formula I or I(a)), as described above, wherein the method comprises the following steps:

[0045] (a) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) connecting fragment TC (or BC) to fragment CB by forming bond 1, (4) synthesizing fragment SNO, (5) connecting fragment TC-CB (or BC-CB) to fragment SNO by forming bond 2, (6) connecting the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 within the molecule, and (7) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A;

[0046] Provided that at no time during the process is the TC-CB fragment a compound of formula intermediate 1-J or 1-K, as defined herein, wherein R 5 is H; or

[0047] (b) (1) synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) connecting fragment SNO to fragment TC (or BC) by forming bond 2, (4) synthesizing fragment CB, (5) connecting fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1, (6) connecting the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 within the molecule, and (7) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or

[0048] (c) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) connecting fragment TC (or BC) to fragment CB by forming bond 1, (4) synthesizing fragment CNO, (5) connecting fragment TC-CB (or BC-CB) to fragment CNO by forming bond 2, (6) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4, and (7) connecting the CB portion and the SNO portion of the SC-SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 within the molecule to form a compound of formula A; or

[0049] (d) (1) synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) connecting fragment SNO to fragment TC (or BC) by forming bond 2, (4) synthesizing fragment CB, (5) connecting fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1, (6) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4, and (7) connecting the CB portion and the SNO portion of the SC-SNO-TC-CB (or SC-SNO-BC-CB) fragment by forming bond 3 within the molecule to form a compound of formula A; or

[0050] (e) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment SNO, (3) connecting fragment TC (or BC) to fragment SNO by forming bond 2, (4) synthesizing fragment CB, (5) connecting fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 3, (6) connecting the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) portion by forming bond 2 within the molecule, and (7) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or

[0051] (f) (1) synthesizing fragment SNO, (2) synthesizing fragment CB, (3) connecting fragment SNO to fragment CB by forming bond 3, (4) synthesizing fragment TC (or BC), (5) connecting fragment SNO-CB to fragment TC (or BC) by forming bond 2, (6) connecting the CB portion and the TC (or BC) portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 1 within the molecule, and (7) connecting the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A;

[0052] Optionally wherein any of the aforementioned methods further comprises the step of converting any intermediate comprising fragment BC into the same intermediate comprising fragment TC, for example,

[0053] If step (3) links fragment SNO to fragment BC by forming bond 2, step (3') may convert fragment SNO-BC to fragment SNO-TC, followed by the remaining steps (eg, in method (b) or method (d)); or

[0054] If step (5) connects fragment SNO-CB to fragment BC to form fragment SNO-BC-CB, step (5') can convert fragment SNO-BC-CB to fragment SNO-TC-CB (without bond 1) and then perform the remaining steps, or alternatively, step (6') can convert fragment SNO-BC-CB to fragment SNO-TC-CB (with bond 1) and then perform the remaining steps (e.g., in method (f));

[0055] Among them, fragment BC is: The fragment TC is: The fragment CB is: The fragment SNO is: Fragment SC is R 12 ; and PG is a protecting group (e.g., CH(OC 1-6 Alkyl)(OC 1-6 alkyl) or -O(C 2-10 alkyl)O-); and

[0056] wherein all other substituents are as defined herein for compounds of formula A.

[0057] In some embodiments, the product of Method A is Compound 1, Compound 1(a), or Compound 1, as defined herein. In some embodiments, Method A can include one or more steps, in any order and in any combination, as provided in any embodiment of Method 1, Method 2, Method 3, Method 4, and Method 5 described herein.

[0058] In a second aspect, the present disclosure provides a method for preparing a compound selected from compounds 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, 1-K, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 9-A, 9-B, 9-C, 9-D, 9-E and one or more compounds of compounds I or I (a) (Method 1), as described above, wherein the method includes the step of reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 1 generally involves the formation of a cyclobutyl moiety (CB), including advanced intermediates 1-I, 1-J and 1-K, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 1 may include any of the steps shown in Schemes 1, 2 and 3.

[0059]

[0060]

[0061] In a specific embodiment, the present disclosure provides the following method 1:

[0062] 1.1 Method 1, wherein the method comprises the step of reacting compound 1-A with a suitable protecting agent in a suitable solvent (optionally with a suitable base and / or catalyst) and under conditions effective to produce compound 1-B for a period of time; wherein R' is C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl), optionally R' is methyl;

[0063] 1.2 Method 1.1, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1-6 alkyl groups such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 an alkyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl), a tert-alkyl group (e.g., tert-butyl or trityl), an alkoxyalkyl group (e.g., methoxymethyl or ethoxymethyl), or a C 1-6 alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl);

[0064] 1.3 Method 1.2, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl) and a triarylsilyl group (e.g., triphenylsilyl);

[0065] 1.4 Method 1.3, wherein the substituent PG is a tert-butyldiphenylsilyl group, optionally wherein the protecting agent is tert-butyldiphenylsilyl chloride;

[0066] 1.5 Any of methods 1.1-1.4, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl chloride), bromides, tert-butyldimethylsilyl bromide, dimethylphenylsilane bromide, triphenylsilane bromide), 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), acid 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);

[0067] 1.6 Any of methods 1.1-1.5, wherein the reaction comprises a base;

[0068] 1.7 Method 1.6, wherein the base is selected from tertiary amines (e.g., triethylamine, 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) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0069] 1.8 Method 1.7, wherein the base is triethylamine;

[0070] 1.9 Any of methods 1.1-1.8, wherein the reaction comprises a catalyst;

[0071] 1.10 Method 1.9, wherein the catalyst is selected from 4-(dimethylamino)pyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine and 9-azajulonidine;

[0072] 1.11 Method 1.10, wherein the catalyst is 4-(dimethylamino)pyridine;

[0073] 1.12 Any of methods 1.1-1.11, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0074] 1.13 Method 1.12, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0075] 1.14 Method 1.12, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0076] 1.15 Method 1.12, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0077] 1.16 Any of methods 1.1-1.15, wherein the reaction temperature is -30°C to 40°C, for example, -10°C to 30°C or about 0°C to 25°C;

[0078] 1.17 Any of Method 1 or 1.1-1.16, wherein the method comprises the step of reacting compound 1-B with an organometallic reagent in a suitable solvent and under conditions effective to form 1-hydroxycyclopropane compound 1-C for a period of time, wherein R' is as defined in Method 1.1, and PG is as defined as provided in Method 1.2, 1.3 or 1.4;

[0079] 1.18 Method 1.17, wherein the substituent R x Selected from H, C 1-6 Alkyl (e.g., methyl) and C 6-10 Aryl (eg phenyl), wherein the alkyl group is optionally replaced by C 6-10 Aryl (e.g., phenyl) substitution;

[0080] 1.19 Method 1.18, where R x It is H;

[0081] 1.20 Method 1.17, 1.18 or 1.19, wherein the organometallic reagent is an organolithium reagent (e.g., C 1-6 alkyl lithium) or Grignard reagents (e.g., C 1-6 Alkyl magnesium halides);

[0082] 1.21 Method 1.20, wherein the organometallic reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, n-propylmagnesium bromide and 2-phenylethylmagnesium bromide, each optionally in an ether solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dimethicone ... alkane) in the form of a solution;

[0083] 1.22 Any of methods 1.17-1.21, wherein the reaction further comprises a transition metal promoter, such as a titanium (IV) compound;

[0084] 1.23 Method 1.22, wherein the promoter is titanium (IV) alkoxide (e.g., titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, or titanium (IV) butoxide);

[0085] 1.24 Any of methods 1.20-1.23, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide;

[0086] 1.25 Any of methods 1.17-1.24, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0087] 1.26 Method 1.25, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0088] 1.27 Method 1.25, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0089] 1.28 Method 1.25, wherein the non-polar solvent is an ether solvent, optionally wherein the solvent is tetrahydrofuran;

[0090] 1.29 Any of methods 1.17-1.28, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or about 0°C to 5°C;

[0091] 1.30 Method 1 or any of Methods 1.1-1.29, wherein the method comprises the step of reacting Compound 1-C with a halogenating agent in a suitable solvent and under conditions effective to form a β-haloketone compound 1-D for a period of time, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0092] 1.31 Method 1.30, wherein the substituent X is selected from bromine, chlorine and iodine;

[0093] 1.32 Method 1.31, wherein X is bromine;

[0094] 1.33 Method 1.30, 1.31 or 1.32, wherein the halogenating agent is selected from N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide and iodine;

[0095] 1.34 Method 1.33, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin and hypobromous acid;

[0096] 1.35 Method 1.34, wherein the halogenating agent is N-bromosuccinimide;

[0097] 1.36 Any of methods 1.30-1.35, wherein the suitable solvent is a non-polar solvent;

[0098] 1.37 Method 1.36, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0099] 1.38 Method 1.37, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0100] 1.39 Any of methods 1.30-1.38, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or about 0°C to 5°C;

[0101] 1.40 Any of methods 1.30-1.39, wherein compound 1-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.25 hours to 5 hours, such as 0.5 hours to 3 hours, or 1 hour to 2 hours, or about 1.5 hours;

[0102] 1.41 Method 1 or any of Methods 1.1-1.40, wherein the method comprises the step of reacting Compound 1-D with a base in a suitable solvent and under conditions effective to form an α,β-unsaturated ketone Compound 1-E for a period of time, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R xAs defined in method 1.18 or 1.19, and wherein X is chloro, bromo or iodo;

[0103] 1.42 Method 1.41, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO) and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole);

[0104] 1.43 Method 1.42, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0105] 1.44 Method 1.43 wherein the base is triethylamine;

[0106] 1.45 Any of methods 1.41-1.44, wherein the suitable solvent is a non-polar solvent;

[0107] 1.46 Method 1.45, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0108] 1.47 Method 1.46, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0109] 1.48 Any of methods 1.41-1.47, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or about 0°C to 5°C;

[0110] 1.49 Any of methods 1.30 to 1.48, wherein the conversion of compound 1-C to compound 1-D and the conversion of compound 1-D to compound 1-E occur continuously in the same container without isolating compound 1-D;

[0111] 1.50 Method 1 or any one of methods 1.1-1.49, wherein the method comprises the step of reducing an α,β-unsaturated ketone compound 1-E to an allylic alcohol compound 1-F and its stereoisomer 1-F', wherein PG is defined as provided in method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0112] 1.51 Method 1.50, wherein the reduction is carried out by reacting compound 1-E with a reducing agent and a Lewis acid catalyst in a suitable solvent;

[0113] 1.52 Method 1.51, wherein the reducing agent is selected from a borane agent (e.g., borane, a borane complex [e.g., BH 3 -THF, BH 3 -DMS, BH 3 -CBS], 9-BBN), a borohydride reagent (e.g., sodium borohydride, lithium borohydride, lithium triethylborohydride), an aluminum hydride reagent (e.g., lithium aluminum hydride, diisobutylaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenation agent (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene)), an alcohol aluminum reagent in an alcohol solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase (e.g., ketoreductase);

[0114] 1.53 Method 1.52, wherein the reducing agent is sodium borohydride;

[0115] 1.54 Method 1.51, 1.52 or 1.53, wherein the Lewis acid is selected from cerium (III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide and calcium iodide;

[0116] 1.55 Method 1.54, wherein the Lewis acid is cerium (III) chloride, such as cerium (III) chloride heptahydrate or anhydrous cerium (III) chloride;

[0117] 1.56 Any of methods 1.50-1.55, wherein the suitable solvent is a polar protic solvent or a non-polar solvent;

[0118] 1.57 Method 1.56, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol, butanol);

[0119] 1.58 Method 1.56 wherein the nonpolar solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) or halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0120] 1.59 Method 1.56, wherein the solvent is ethanol;

[0121] 1.60 Any of methods 1.50-1.59, wherein the reaction temperature is -30°C to 30°C, for example, -20°C to 20°C or -10°C to 0°C;

[0122] 1.61 Any of methods 1.50-1.60, wherein the products 1-F and 1-F' are not separated prior to the next step of the method;

[0123] 1.62 Any of methods 1.50-1.60, wherein the products 1-F and 1-F' are separated prior to the next step in the method;

[0124] 1.63 Method 1 or any of Methods 1.1-1.62, wherein the method comprises the step of treating a mixture of allyl alcohol compounds 1-F and 1-F' with an acyl donor and an esterase, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in method 1.18 or 1.19, wherein the acyl donor is an ester of an acid of formula RCOOH;

[0125] 1.64 Method 1.63, wherein the esterase selectively esterifies the (R)-allyl alcohol portion of compound 1-F' to form ester 1-F";

[0126] 1.65 Method 1.64, wherein the esterase is a bacterial esterase, for example, Pseudomonas stutzeri lipase;

[0127] 1.66 Method 1.63, 1.64 or 1.65, wherein R is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 Alkyl (e.g., trifluoromethyl, trichloromethyl), C 1-6 alkylcarboxylates (eg, 3-propionate, 4-butyrate), optionally substituted aryl (eg, phenyl, 4-bromophenyl), and optionally substituted heteroaryl (eg, 2-pyridyl);

[0128] 1.67 Any of methods 1.63-1.66, wherein the acyl donor is a vinyl ester, isopropenyl ester, methyl ester, ethyl ester, 2,2,2-trifluoroethyl ester, 2,2,2-trichloroethyl ester or a methoxyvinyl ester of an acid RCOOH, or an anhydride of an acid RCOOH (including mixed and unmixed linear anhydrides and cyclic anhydrides of dicarboxylic acids), wherein R is as defined in method 1.66;

[0129] 1.68 Method 1.67, wherein the acyl donor is selected from succinic anhydride, vinyl acetate, isopropylene acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, 4-vinyl bromoacetate, vinyl picolinate, glutaric anhydride, vinyl formate, vinyl butyrate and butyric anhydride;

[0130] 1.69 Any of methods 1.63-1.68, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0131] 1.70 Method 1.69, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane);

[0132] 1.71 Method 1.69, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0133] 1.72 Method 1.69, wherein the non-polar solvent is an ether solvent, optionally wherein the solvent is methyl tert-butyl ether;

[0134] 1.73 Any of methods 1.63-1.72, wherein the reaction temperature is 0°C to 50°C, for example, 10°C to 30°C or about 20°C;

[0135] 1.74 Any of methods 1.63-1.73, wherein after the reaction is complete, the product mixture is purified to isolate compound 1-F and / or compound 1-F is removed and discarded;

[0136] 1.75 Method 1 or any of Methods 1.1-1.74, wherein the method comprises the step of reacting Compound 1-F with an alkylating agent and optionally a base in a suitable solvent and under conditions effective for a period of time to form an ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in method 1.18 or 1.19, and wherein R 5 Selected from C 1-6 Alkyl, -(CH 2 CH 2 O) p R 7 , C 1-6 Haloalkyl and C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 The cycloalkyl group is optionally substituted with 1 to 5 R 10 Group substitution (R 7 and R 10 As defined for compounds of formula I);

[0137] 1.76 method 1.75, where R 5 Selected from C1-6 Alkyl and C 1-6 haloalkyl, each optionally substituted by 1-3 groups selected from halogen, oxo, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl radical substitution;

[0138] 1.77 method 1.76, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0139] 1.78 method 1.77, where R 5 It is methyl;

[0140] 1.79 Any of methods 1.75-1.78, wherein the alkylating agent is of formula R 5 -X compound, wherein X is selected from Cl, Br, I, OS(O) 2 OR 5 and OSO 2 -L, where L is C 1-6 Alkyl, optionally substituted aryl or halogenated C 1-6 alkyl;

[0141] 1.80 Method 1.79, wherein the alkylating agent is selected from the group consisting of alkyl bromides, alkyl chlorides, alkyl iodides, alkyl trifluoromethanesulfonates, alkyl toluenesulfonates, alkyl methanesulfonates, alkyl nitrobenzenesulfonates, alkyl benzenesulfonates, and dialkyl sulfates;

[0142] 1.81 Method 1.80, wherein the alkylating agent is selected from methyl iodide, methyl trifluoromethanesulfonate, methyl toluenesulfonate and dimethyl sulfate;

[0143] 1.82 Any of methods 1.75-1.81, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide), and an amide base (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide);

[0144] 1.83 Method 1.82, wherein the base is sodium tert-butoxide;

[0145] 1.84 Any of methods 1.75-1.83, wherein the suitable solvent is a non-polar solvent, a polar protic solvent or a polar aprotic solvent;

[0146] 1.85 Method 1.84, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene);

[0147] 1.86 Method 1.84, wherein the polar protic solvent is an alcohol solvent (e.g., tert-butyl alcohol or tert-amyl alcohol), optionally in combination with water;

[0148] 1.87 Method 1.84, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0149] 1.88 Method 1.84 wherein the suitable solvent is tetrahydrofuran;

[0150] 1.89 Any of methods 1.75-1.88, wherein the reaction temperature is -80°C to 50°C, for example, -45°C to 10°C, or -10°C to 10°C or about 0°C;

[0151] 1.90 Method 1 or any of Methods 1.1-1.89, wherein the method comprises the step of treating Compound 1-G with a deprotecting agent in a suitable solvent and for a period of time under conditions effective to form alcohol Compound 1-H, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.75-1.78;

[0152] 1.91 Method 1.90, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0153] 1.92 Method 1.91, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is methyl;

[0154] 1.93 Any of methods 1.90-1.92, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent;

[0155] 1.94 Methods 1.90-1.93, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric 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, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complexes, Pd complexes, Ir complexes) and combinations of ammonium formate with palladium or platinum catalysts (e.g., Pd, Pd / C, Pt, PtO 2 )

[0156] 1.95 Any of methods 1.90-1.94, wherein the substituent PG is a silyl group and the deprotecting agent is a fluoride agent;

[0157] 1.96 Method 1.95, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl) and a triarylsilyl group (e.g., triphenylsilyl), and the deprotecting agent is selected from hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride and tetrabutylammonium fluoride;

[0158] 1.97 Method 1.96, wherein the substituent PG is tert-butyldiphenylsilyl and the deprotecting agent is selected from tetramethylammonium fluoride, tetraethylammonium fluoride and tetrabutylammonium fluoride;

[0159] 1.98 Any of methods 1.90-1.97, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0160] 1.99 Method 1.98, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0161] 1.100 Method 1.98, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol), optionally in combination with water, or wherein the polar protic solvent is water;

[0162] 1.101 Method 1.98, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0163] 1.102 Method 1.98 wherein the suitable solvent is tetrahydrofuran;

[0164] 1.103 Any of methods 1.90-1.102, wherein the reaction temperature is -15°C to 50°C, for example, -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C;

[0165] 1.104 Method 1 or any one of methods 1.1-1.103, wherein the method comprises the step of treating compound 1-H with an oxidizing agent in a suitable solvent to form an aldehyde compound 1-I, wherein R x As defined in method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.75-1.78;

[0166] 1.105 Method 1.104, wherein the reaction further comprises an additive, a catalyst and / or a base;

[0167] 1.106 Method 1.104 or 1.105, wherein the oxidant is selected from sodium hypochlorite, pyridine sulfur trioxide, dimethyl sulfoxide / oxalyl chloride, DMSO / acetic anhydride, DMSO / trifluoroacetic anhydride, diacetoxyiodobenzene (DAIB), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate , N-chlorosuccinimide / dimethyl sulfide, iodophenyl, DMSO / dicyclohexylcarbodiimide, bis(trifluoroacetoxy)iodobenzene, and manganese dioxide;

[0168] 1.107 Method 1.106, wherein the oxidizing agent is selected from diacetoxyiodobenzene (DAIB), Dess-Martin periodinane, iodosobenzene and bis(trifluoroacetoxy)iodobenzene;

[0169] 1.108 Method 1.107, wherein the oxidizing agent is diacetoxyiodobenzene (DAIB);

[0170] 1.109 Any of methods 1.104-1.108, wherein the reaction further comprises a catalyst selected from TEMPO((2,2,6,6-tetramethylpiperidin-1-yl)oxy), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl and 9-azaadamantane N-oxyl;

[0171] 1.110 Any of methods 1.104-1.109, wherein the reaction further comprises an additive selected from the group consisting of sodium bromide, lithium bromide and potassium bromide;

[0172] 1.111 Any of methods 1.104-1.110, wherein the reaction further comprises a base selected from an inorganic base (e.g., disodium hydrogen phosphate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide) and an organic amine base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, DBU, DBN);

[0173] 1.112 Any of methods 1.104-1.109, wherein the oxidant is diacetoxyiodobenzene and the catalyst is TEMPO, wherein the reaction does not contain a base or an additive;

[0174] 1.113 Any of methods 1.104-1.112, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0175] 1.114 Method 1.113, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0176] 1.115 Method 1.113, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0177] 1.116 Method 1.113 wherein the suitable solvent is dichloromethane;

[0178] 1.117 Any of methods 1.104-1.116, wherein the reaction temperature is -80°C to 50°C, for example, -40°C to 40°C or 10°C to 30°C;

[0179] 1.118 Method 1 or any of methods 1.1-1.117, wherein the method comprises the step of treating compound 1-I with a reducing agent and compound 5-I in a suitable solvent for a period of time under conditions effective to form tertiary amine compound 1-J, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, and wherein R z As defined in any of Methods 2.129-2.131, and wherein R 6 is hydrogen or halogen. In one embodiment, R x is H. In one embodiment, R 5 It is methyl;

[0180] 1.119 Method 1.118, where R 6 is selected from chlorine, bromine, fluorine and iodine;

[0181] 1.120 Method 1.119, where R 6 It is chlorine;

[0182] 1.121 Any of methods 1.118-1.120, wherein the reducing agent is selected from the group consisting of a hydride reducing agent, a silane reducing agent, and a zinc acid solution (e.g., a zinc acetic acid solution);

[0183] 1.122 Method 1.121, wherein the reducing agent is a hydride reducing agent;

[0184] 1.123 Method 1.122, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride and tetramethylammonium triacetoxyborohydride;

[0185] 1.124 Method 1.123, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[0186] 1.125 Any of methods 1.122-1.124, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride);

[0187] 1.126 Method 1.121, the reducing agent is selected from silane (triisopropylsilane, triphenylsilane, diethylsilane, etc.), 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;

[0188] 1.127 Any of methods 1.121 to 1.126 wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid and hydrochloric acid). In one embodiment, the acid is trifluoroacetic acid;

[0189] 1.128 Any of methods 1.118-1.128, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0190] 1.129 Method 1.128, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), acetonitrile, and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0191] 1.130 Method 1.128, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide;

[0192] 1.131 Method 1.128 wherein the suitable solvent is dichloromethane. In one embodiment, the solvent is acetonitrile;

[0193] 1.132 Any of methods 1.118-1.131, wherein the temperature of the reaction is from -30°C to 50°C, for example, from -30°C to 0°C, or from -30°C to -10°C or about -20°C. In one embodiment, the temperature is from -10°C to 30°C;

[0194] 1.133 Method 1 or any of Methods 1.1-1.132, wherein the method comprises the step of hydrolyzing Compound 1-J in a suitable solvent and under conditions effective for a period of time to form Carboxylic Acid Compound 1-K, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, and wherein R z As defined in any of Methods 2.129-2.131, and wherein R 6 is hydrogen or a halogen;

[0195] 1.134 Method 1.133, wherein the reaction comprises treating Compound 1-J with an acid or base aqueous solution in an organic and / or aqueous solvent; or treating Compound 1-J with an enzyme (e.g., a bacterial or fungal lipase, such as a lipase from a Rhizopus species); or treating Compound 1-J with magnesium dibromide in a non-polar solvent; or treating Compound 1-J with a fluoride source (e.g., hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride) in a non-polar solvent; or treating Compound 1-J with hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complex, Pd complex, Ir complex) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO 2 ) of the combination treatment compound 1-J;

[0196] 1.135 Method 1.134, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid;

[0197] 1.136 Method 1.134 wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide, alkoxides (lithium, sodium, potassium, magnesium or calcium salts of methanol, ethanol, isopropanol, tert-butyl alcohol or tert-amyl alcohol), trimethyltin hydroxide, sodium trimethylsilanolate, potassium trimethylsilanolate and pyridine;

[0198] 1.137 Any of methods 1.133-1.136, wherein the solvent is selected from water, alcohols (e.g., methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, tert-amyl alcohol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile), ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dimethyl ether, one or more of alkane), hydrocarbon solvents (e.g., toluene, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0199] 1.138 Any of methods 1.133-1.137, wherein the temperature of the reaction is from -10°C to 100°C, for example, from 10°C to 80°C, or from 20°C to 80°C, or from 20°C to 50°C. In one embodiment, the temperature is from 20°C to 100°C. In one embodiment, the temperature is from 50°C to 70°C;

[0200] 1.139 Method 1 or any of Methods 1.1-1.138, wherein the method comprises treating (1S,5R)-3-oxabicyclo[3.2.0]heptan-2-one (Compound 2-A) with an organometallic reagent in a suitable solvent and for a period of time under conditions effective to form 1-hydroxycyclopropane Compound 2-B, wherein the substituent R x Selected from H, C 1-6 Alkyl (e.g., methyl) and C 6-10 Aryl (eg, phenyl), wherein alkyl is an optionally substituted aryl (eg, phenyl);

[0201] 1.140 Method 1.139, where R x It is H;

[0202] 1.141 Method 1.139 or 1.140, wherein the organometallic reagent is an organolithium reagent (e.g., C 1-6 alkyl lithium) or Grignard reagents (e.g., C 1-6 Alkyl magnesium halides);

[0203] 1.142 Method 1.141, wherein the organometallic reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium iodide, n-propylmagnesium bromide and 2-phenylethylmagnesium bromide, each optionally in an ether solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dimethicone ... alkane) in the form of a solution;

[0204] 1.143 Any of methods 1.139-1.142, wherein the reaction further comprises a transition metal promoter, such as a titanium (IV) compound;

[0205] 1.144 Method 1.143, wherein the promoter is titanium (IV) alkoxide (e.g., titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, titanium (IV) n-butoxide, titanium (IV) tert-butoxide, titanium (IV) benzyl alcoholate);

[0206] 1.145 Any of methods 1.139-1.144, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide;

[0207] 1.146 Any of methods 1.139-1.145, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0208] 1.147 Method 1.146, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene); or wherein the polar aprotic solvent is a nitrile (e.g., acetonitrile);

[0209] 1.148 Method 1.147, wherein the non-polar solvent is an ethereal solvent, optionally wherein the solvent is tetrahydrofuran;

[0210] 1.149 Any of methods 1.139-1.148, wherein the reaction temperature is -20°C to 50°C, for example, -10°C to 10°C or about 0°C to 5°C;

[0211] 1.150 Method 1 or any one of 1.1-1.149, wherein the method comprises the step of reacting compound 2-B with a suitable protecting agent in a suitable solvent (optionally with a suitable base and / or catalyst) and under conditions effective to produce compound 2-C for a period of time, wherein R x As defined in Method 1.139 or 1.140;

[0212] 1.151 Method 1.150, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1-6 alkyl groups such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tert-alkyl groups (e.g., tert-butyl or trityl), alkoxyalkyl groups (e.g., methoxymethyl or ethoxymethyl), and C 1-6 alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl);

[0213] 1.152 Method 1.151, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl) and a triarylsilyl group (e.g., triphenylsilyl);

[0214] 1.153 Method 1.152 wherein the substituent PG is a tert-butyldiphenylsilyl group, optionally wherein the protecting agent is TBDPS-chloride;

[0215] 1.154 Any of methods 1.150-1.153, wherein the protecting agent is selected from a silyl chloride (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, or triphenylsilyl chloride), a silyl triflate (e.g., trimethylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, tert-butyldimethylsilyl triflate, dimethylphenylsilyl triflate, or triphenylsilyl triflate), a silyl bromide (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl triflate, or triphenylsilyl triflate). silyl bromide, tert-butyldimethylsilyl bromide, dimethylphenylsilane bromide or triphenylsilane bromide), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halide (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chloride (e.g., pivaloyl chloride or 1-adamantanecarbonyl chloride), acid anhydride (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate or phenyl chloroformate), alkyl chlorides (e.g., trityl chloride) and alkoxymethyl chlorides (e.g., methoxymethyl chloride);

[0216] 1.155 Any of methods 1.150-1.154, wherein the reaction comprises a base;

[0217] 1.156 Method 1.155, wherein the base is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine, imidazole or 1-methylimidazole) and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium hydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate) or sodium phosphate (monosodium hydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0218] 1.157 Method 1.156 wherein the base is triethylamine;

[0219] 1.158 Any of methods 1.150-1.157, wherein the reaction comprises a catalyst;

[0220] 1.159 Method 1.158 wherein the catalyst is selected from the group consisting of 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine and 9-azajulonidine;

[0221] 1.160 Method 1.159 wherein the catalyst is 4-(dimethylamino)pyridine;

[0222] 1.161 Any of methods 1.150-1.160, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0223] 1.162 Method 1.161, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrogen ether) alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0224] 1.163 Method 1.161, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0225] 1.164 Method 1.161 wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0226] 1.165 Any of methods 1.150-1.161, wherein the reaction temperature is -30°C to 40°C, for example, -10°C to 30°C or 0°C to 25°C;

[0227] 1.166 Method 1 or any of Methods 1.1-1.165, wherein the method comprises the step of reacting Compound 2-C with a halogenating agent in a suitable solvent and under conditions and for a period of time effective to form a β-haloketone compound 2-D, wherein PG is as defined in any of Methods 1.151-1.153, and R x As defined in Method 1.139 or 1.140;

[0228] 1.167 Method 1.166 wherein the substituent X is selected from bromine, chlorine and iodine;

[0229] 1.168 Method 1.167, wherein X is bromine;

[0230] 1.169 Method 1.166, 1.167 or 1.168, wherein the halogenating agent is selected from N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide and iodine;

[0231] 1.170 Method 1.169, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin and hypobromous acid;

[0232] 1.171 Method 1.169, wherein the halogenating agent is N-bromosuccinimide;

[0233] 1.172 Any of methods 1.166-1.171, wherein the suitable solvent is a non-polar solvent;

[0234] 1.173 Method 1.172, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0235] 1.174 Method 1.172, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0236] 1.175 Any of methods 1.166-1.174, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or 0°C to 5°C;

[0237] 1.176 Any of methods 1.166-1.175, wherein compound 2-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.1 hour to 3 hours, e.g., 0.2 hour to 2 hours, or 0.3 hour to 1 hour, or about 0.5 hour;

[0238] 1.177 Method 1 or any one of Methods 1.1-1.176, wherein the method comprises the step of reacting Compound 2-D with a base in a suitable solvent and under conditions effective to form an α,β-unsaturated ketone Compound 2-E for a period of time, wherein PG is defined as provided in any one of Methods 1.151-1.153, and R x As defined in method 1.139 or 1.140, and wherein X is chloro, bromo or iodo;

[0239] 1.178 Method 1.177 wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, 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) and inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, alkali metal phosphates such as sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate, or lithium dihydrogen phosphate, dilithium hydrogen phosphate or trilithium phosphate);

[0240] 1.179 Method 1.178 wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0241] 1.180 Method 1.179 wherein the base is triethylamine;

[0242] 1.181 Any of methods 1.177-1.180, wherein the suitable solvent is a non-polar solvent;

[0243] 1.182 Method 1.181, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrofuran) alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0244] 1.183 Method 1.182, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0245] 1.184 Any of methods 1.177-1.183, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or 0°C to 5°C;

[0246] 1.185 Any of methods 1.166 to 1.184, wherein the conversion of compound 2-C to compound 2-D and the conversion of compound 2-D to compound 2-E occur continuously in the same vessel without isolating compound 2-D;

[0247] 1.186 Method 1 or any of Methods 1.1-1.185, wherein the method comprises the step of reacting Compound 2-E with a promoter in a suitable solvent and under conditions effective to form an epimerized α,β-unsaturated ketone Compound 1-E for a period of time, wherein PG is defined as provided in any of Methods 1.151-1.153, and R xAs defined in Method 1.139 or 1.140;

[0248] 1.187 Method 1.186, wherein the promoter is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane or DABCO), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine or 1-methylimidazole), an inorganic base (e.g., an alkali metal carbonate such as sodium carbonate, potassium carbonate and lithium carbonate, or an alkali metal phosphate such as sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate, or lithium dihydrogen phosphate, dilithium hydrogen phosphate or trilithium phosphate), an inorganic halide (e.g., lithium chloride, magnesium bromide, magnesium chloride) and an acid (e.g., titanium tetraisopropoxide, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid);

[0249] 1.188 Method 1.187, wherein the promoter is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);

[0250] 1.189 Method 1.188, wherein the promoter is DBU;

[0251] 1.190 Any of methods 1.186-1.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, or a polar protic solvent;

[0252] 1.191 Method 1.190, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkanes) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0253] 1.192 Method 1.190, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0254] 1.193 Method 1.190, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol or isopropanol);

[0255] 1.194 Method 1.190, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0256] 1.195 Any of methods 1.186-1.194, wherein the reaction temperature is -10°C to 50°C, for example, 0°C to 40°C, or 10°C to 30°C or about 25°C;

[0257] 1.196 Method 1 or any of Methods 1.1-1.195, wherein the method comprises the step of thiolation of Compound 1-E by reacting Compound 1-E with a thiol and a base in a suitable solvent under conditions and for a period of time effective to form Compound 3-A, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0258] 1.197 Method 1.196, where R S Selected from optionally substituted C 1-6 alkyl (eg, methyl) and optionally substituted aryl (eg, phenyl);

[0259] 1.198 Method 1.197, where R S is optionally one or more selected from C 1-6 Alkoxy, halogen, C 1-6 Alkyl and aryl (e.g., phenyl) groups substituted with C 1-6 Alkyl, optionally wherein R S is methyl, ethyl or isopropyl;

[0260] 1.199 Method 1.197, where R S is optionally one or more selected from C 1-6 Alkoxy, halogen, C 1-6 alkyl and aryl (eg, phenyl) substituted aryl, optionally wherein R S is phenyl or tolyl;

[0261] 1.200 method 1.197, where R S is 4-tolyl;

[0262] 1.201 Any of methods 1.196-1.200, wherein the thiol is R S -SH (e.g., methyl mercaptan, benzenethiol or 4-methylbenzenethiol);

[0263] 1.202 Any of methods 1.196-1.201, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]octane) and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, imidazole or 1-methylimidazole);

[0264] 1.203 Method 1.202, wherein the base is triethylamine or N,N-diisopropylethylamine;

[0265] 1.204 Any of methods 1.196-1.203, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0266] 1.205 Method 1.204, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrogen ether). alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene);

[0267] 1.206 Method 1.204, wherein the polar aprotic solvent is selected from an ester (e.g., ethyl acetate, methyl acetate, or isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0268] 1.207 Method 1.204, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0269] 1.208 Any of methods 1.196-1.207, wherein the reaction temperature is -20°C to 50°C, for example, 0°C to 30°C, or 10°C to 20°C or about 25°C;

[0270] 1.209 Method 1 or any of Methods 1.1-1.208, wherein the method comprises the step of reducing the unsaturated thio compound 3-A to the thio alcohol compound 3-B, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, R x As defined in Method 1.18 or 1.19, and R S As defined in any of Methods 1.197-1.200;

[0271] 1.210 Method 1.209, wherein the reduction is carried out by reacting compound 3-A with a reducing agent and a Lewis acid catalyst in a suitable solvent;

[0272] 1.211 Method 1.210, wherein the reducing agent is selected from a borane agent (e.g., borane, a borane complex [e.g., BH 3 -THF, BH 3 -DMS, BH 3 -CBS] or 9-BBN), a borohydride reagent (e.g., sodium borohydride, lithium borohydride or lithium triethylborohydride), an aluminum hydride reagent (e.g., lithium aluminum hydride, diisobutylaluminum hydride or lithium tri-tert-butoxyaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenation agent (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene)), an aluminum alkoxide reagent in an alcohol solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase (e.g., ketoreductase);

[0273] 1.212 Method 1.211, wherein the reducing agent is sodium borohydride;

[0274] 1.213 Any of methods 1.209-1.212, wherein the Lewis acid is selected from cerium (III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide and calcium iodide;

[0275] 1.214 Method 1.213, wherein the Lewis acid is cerium (III) chloride, such as cerium (III) chloride heptahydrate or anhydrous cerium (III) chloride;

[0276] 1.215 Any of methods 1.209-1.214, wherein the suitable solvent is a polar protic solvent or a non-polar solvent;

[0277] 1.216 Method 1.215, wherein the suitable solvent is a polar protic solvent such as an alcohol (eg, methanol, ethanol, propanol, isopropanol or butanol);

[0278] 1.217 Method 1.215, wherein the suitable solvent is a non-polar solvent such as an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen peroxide, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) or halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0279] 1.218 Method 1.215, wherein the solvent is ethanol;

[0280] 1.219 Any of methods 1.209-1.218, wherein the reaction temperature is -30°C to 30°C, for example, -20°C to 20°C or -10°C to 10°C;

[0281] 1.220 Method 1 or any of Methods 1.1-1.219, wherein the method comprises the step of reacting compound 3-B with an alkylating agent and optionally a base in a suitable solvent and under conditions effective for a period of time to form ether compound 3-C, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19, R S As defined in any of Methods 1.197-1.200, and wherein R 5 Selected from C 1-6 Alkyl, -(CH 2 CH 2 O) p R 7 , C 1-6 Haloalkyl or C 3-10Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 The cycloalkyl group is optionally substituted with 1 to 5 R 10 Group substitution (R 7 and R 10 As defined for compounds of formula I);

[0282] 1.221 Method 1.220, where R 5 Selected from C 1-6 Alkyl and C 1-6 haloalkyl, each optionally substituted by 1-3 groups selected from halogen, oxo, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl radical substitution;

[0283] 1.222 Method 1.221, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0284] 1.223 Method 1.222, where R 5 It is methyl;

[0285] 1.224 Any of methods 1.220-1.223, wherein the alkylating agent is of formula R 5 -X compound, wherein X is selected from Cl, Br, I, OS(O) 2 OR 5 and OSO 2 -L, where L is C 1-6 Alkyl, optionally substituted aryl or halogenated C 1-6 alkyl;

[0286] 1.225 Method 1.224 wherein the alkylating agent is selected from the group consisting of alkyl bromides, alkyl chlorides, alkyl iodides, alkyl trifluoromethanesulfonates, alkyl toluenesulfonates, alkyl methanesulfonates, alkyl nitrobenzenesulfonates, alkyl benzenesulfonates, and dialkyl sulfates;

[0287] 1.226 Method 1.224 wherein the alkylating agent is selected from the group consisting of methyl iodide, methyl trifluoromethanesulfonate, methyl toluenesulfonate and dimethyl sulfate;

[0288] 1.227 Any of methods 1.220-1.226, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), and an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide);

[0289] 1.228 Method 1.227 wherein the base is sodium hydride;

[0290] 1.229 Any of methods 1.220-1.228, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0291] 1.230 Method 1.229, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0292] 1.231 Method 1.229, wherein the polar protic solvent is an alcohol solvent (e.g., tert-butyl alcohol, tert-amyl alcohol), optionally in combination with water;

[0293] 1.232 Method 1.229, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0294] 1.233 Method 1.229 wherein the suitable solvent is tetrahydrofuran;

[0295] 1.234 Any of methods 1.220-1.233, wherein the reaction temperature is -80°C to 50°C, for example, -45°C to 10°C, or -10°C to 10°C, or 10°C to 20°C;

[0296] 1.235 Method 1 or any of Methods 1.1-1.234, wherein the method comprises the step of treating Compound 3-C with an S-oxidant in a suitable solvent and for a period of time under conditions effective to form N-tosylsulfinylimidoyl Compound 3-D, wherein R s As defined in any of Methods 1.197-1.200, wherein PG is as defined in Methods 1.2, 1.3 or 1.4, and R xAs defined in method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.220-1.223;

[0297] 1.236 method 1.235, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0298] 1.237 method 1.236, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is methyl;

[0299] 1.238 Any of methods 1.235-1.237, wherein the S-oxidant is selected from N-chloro-4-methylbenzenesulfonamide or a salt thereof, N-chlorobenzenesulfonamide or a salt thereof, (tosylimido)iodobenzene and p-toluenesulfonamide / phenyliododiacetate;

[0300] 1.239 Method 1.238, wherein the reagent is N-chloro-4-methylbenzenesulfonamide (chloramine-T);

[0301] 1.240 Any of methods 1.235-1.239, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0302] 1.241 Method 1.240, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0303] 1.242 Method 1.240, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, or tert-amyl alcohol);

[0304] 1.243 Method 1.240, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0305] 1.244 Method 1.240, wherein the suitable solvent is acetonitrile;

[0306] 1.245 Any of methods 1.235-1.244, wherein the reaction temperature is 0°C to 50°C, e.g., 10°C to 30°C or about 25°C;

[0307] 1.246 Method 1 or any of Methods 1.1-1.245, wherein the method comprises the step of pyrolyzing compound 3-D in a suitable solvent to form allyl ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.220-1.223;

[0308] 1.247 method 1.246, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl or tert-butyl);

[0309] 1.248 method 1.247, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is methyl;

[0310] 1.249 Any of methods 1.246-1.248, wherein heat is applied without any chemical agent;

[0311] 1.250 Any of methods 1.246-1.249, wherein the suitable solvent is a non-polar solvent, a polar protic solvent or a polar aprotic solvent, optionally wherein the boiling point of the solvent is at least 60°C;

[0312] 1.251 Method 1.250, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0313] 1.252 Method 1.250, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, or any mixture thereof);

[0314] 1.253 Method 1.250 wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a nitrile (e.g., acetonitrile) and an ester (e.g., ethyl acetate, methyl acetate or isopropyl acetate);

[0315] 1.254 Method 1.250 wherein the suitable solvent is isopropyl acetate;

[0316] 1.255 Any of methods 1.246-1.254, wherein the reaction temperature is 70°C to 150°C, for example, 80°C to 100°C or about 90°C;

[0317] 1.256 Any of Method 1 or Method 1.255, wherein the method produces a compound according to any one or more of Compound 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J or 1-K;

[0318] 1.257 Method 1.256 wherein in one or more of said compounds, R' is methyl, R x is H, X is Cl or Br (e.g., Br), PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), R z It is C 1-3 Alkyl (e.g., methyl), R 5 It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0319] 1.258 Method 1 or any of Methods 1.1-1.257, wherein the method produces a compound according to any one or more of Compounds 2-B, 2-C, 2-D or 2-E;

[0320] 1.259 Method 1.258 wherein in one or more of said compounds, R x is H, PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), and / or X is Cl or Br (e.g., Br);

[0321] 1.260 Method 1 or any of methods 1.1-1.259, wherein the method produces a compound according to any one or more of compounds 3-A, 3-B, 3-C or 3-D;

[0322] 1.261 Method 1.260, wherein in one or more of said compounds, R x is H, PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), R S is aryl (e.g., 4-tolyl), and / or R 5 It is C 1-3 Alkyl (e.g., methyl);

[0323] 1.262 Method 1 or any of methods 1.1-1.261, wherein the method produces a compound according to any one or more of compounds 9-A, 9-B, 9-C, 9-D, 9-E;

[0324] 1.263 Method 1.262, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D or 9-E are prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0325] 1.264 Method 1.262 or 1.263 wherein in one or more of the compounds, R x It is H, R y It is H, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (eg, (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (eg, 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0326] 1.265 Method 1.264, wherein in one or more of said compounds, R x Yes H, R y Yes H, R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0327] 1.266 Method 1.265, wherein in one or more of said compounds, R 2 and R 3 It is H or R 2 and R 3

[0328] 1.267 is methyl, or R 2 is H and R 3 It is methyl;

[0329] 1.268 Method 1.266 wherein in one or more of said compounds, R 2 is H and R 3 It is methyl;

[0330] 1.269 Any of methods 1.262-1.267, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NRa R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0331] 1.270 Method 1.268, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0332] 1.271 Method 1.269, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0333] 1.272 Method 1.269, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0334] 1.273 Method 1 or any of methods 1.1-1.271, wherein the method produces a compound according to Compound I;

[0335] 1.274 Method 1.272, wherein Compound I is Compound I(a);

[0336] 1.275 Method 1.272 or 1.273, wherein compound I or I(a) is prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0337] 1.276 Any of methods 1.272-1.274, wherein in compound I or I(a), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0338] 1.277 Method 1.275 wherein in compound I or I(a), R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0339] 1.278 Method 1.276 wherein in compound I or I(a), R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0340] 1.279 Method 1.277 wherein in compound I or I(a), R 2 is H and R 3 It is methyl;

[0341] 1.280 Any of methods 1.275-1.278, wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C1-6 Alkoxy and halogen;

[0342] 1.281 Method 1.279 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0343] 1.282 Method 1.280 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0344] 1.283 Any of methods 1.262-1.281, wherein in one or more of compound 9-E, compound I, or compound I(a), It is a double bond;

[0345] 1.284 Method 1 or any of Methods 1.1-1.282, wherein the method produces Compound 1;

[0346] 1.285 Method 1 or any of Methods 1.1-1.283, wherein the method further comprises any of the steps described in any of Method 2 et seq., Method 3 et seq., Method 4 et seq. and Method 5 et seq.

[0347] In a third aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 4-B, 4-C, 4-D, 4-E, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-I, 1-J, 1-K, 9-A, 9-B, 9-C, 9-D, 9-E and compounds I or I(a) (Method 2), as described herein, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 2 generally involves the formation of a tetracyclic moiety (TC), including advanced intermediates 5-F and 5-I, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 2 may include any of the steps shown in Schemes 4 and 5.

[0348] In a specific embodiment, the present disclosure provides the following method 2:

[0349] 2.1 Method 2, wherein the method comprises the step of reacting compound 4-A (6-hydroxy-3,4-dihydronaphthalen-1(2H)-one) with a suitable triflation agent in a suitable solvent (with a suitable base) for a period of time and under conditions effective to produce compound 4-B;

[0350] 2.2 Method 2.1, wherein the triflation agent is selected from trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonic acid, N-trifluoromethanesulfonyl imidazole and N-phenyltrifluoromethanesulfonimide;

[0351] 2.3 Method 2.1 or 2.2, wherein the base is selected from tertiary amines (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 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) and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic sodium phosphate, disodium hydrogen phosphate or tribasic sodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic potassium phosphate, dibasic potassium phosphate or tripotassium phosphate), potassium fluoride, lithium carbonate, cesium carbonate);

[0352]

[0353]

[0354] 2.4 Any of methods 2.1-2.3, wherein the reagent is trifluoromethanesulfonyl anhydride and the base is pyridine;

[0355] 2.5 Any of methods 2.1-2.4, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0356] 2.6 Method 2.5, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0357] 2.7 Method 2.5, wherein the polar aprotic solvent is selected from nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0358] 2.8 Method 2.5, wherein the non-polar solvent is dichloromethane;

[0359] 2.9 Any of methods 2.1-2.8, wherein the reaction temperature is -80°C to 40°C, for example, -30°C to 20°C, or -10°C to 10°C or about 0°C;

[0360] 2.10 Method 2 or any of methods 2.1-2.9, wherein the method comprises the step of reacting compound 4-B with a halide source under conditions effective for a period of time to form compound 4-C, wherein R6 is fluorine, chlorine, bromine or iodine;

[0361] 2.11 Method 2.10, where R 6 is selected from chlorine and bromine (for example, wherein R 6 is chlorine);

[0362] 2.12 Method 2.10 or 2.11, wherein the halide source is selected from a chloride salt (e.g., lithium chloride, potassium chloride, cesium chloride, tetrabutylammonium chloride), triphenylphosphine dichloride, copper (II) chloride, copper (I) chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, cyanuric chloride, methanesulfonyl chloride, phosgene, triphosgene, a bromide salt (e.g., lithium bromide, potassium bromide, cesium bromide, tetrabutylammonium bromide), triphenylphosphine dibromide, copper (II) bromide, copper (I) bromide, phosphorus tribromide, phosphorus oxybromide, thionyl bromide, sulfuryl bromide, an iodide salt (e.g., potassium iodide, cesium iodide, tetrabutylammonium iodide), copper (II) iodide, copper (I) iodide, a fluoride salt (e.g., lithium fluoride, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride), copper (II) fluoride, and copper (I) fluoride;

[0363] 2.13 Method 2.12, wherein the halide source is a chloride salt, such as lithium chloride;

[0364] 2.14 Any of methods 2.10-2.13, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0365] 2.15 Method 2.14, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0366] 2.16 Method 2.14, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0367] 2.17 Method 2.14, wherein the polar aprotic solvent is N-methyl-2-pyrrolidone;

[0368] 2.18 Any of methods 2.10-2.17, wherein the reaction temperature is 50°C to 250°C, for example, 100°C to 220°C, or 130°C to 150°C or about 140°C;

[0369] 2.19 Method 2 or any one of methods 2.1-2.18, wherein the method comprises the step of converting compound 4-C into compound 4-D, wherein R 6 As defined in Method 2.10 or 2.11;

[0370] 2.20 Method 2.19, where R 6 It is chlorine;

[0371] 2.21 Method 2.19 or 2.20, wherein the reaction comprises treating compound 4-C with a trimethylsulfonium salt and a base in a polar aprotic solvent;

[0372] 2.22 Method 2.21, wherein the trimethylsulfonium salt is trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide, trimethylsulfonium tetrafluoroborate or trimethylsulfonium methylsulfate;

[0373] 2.23 Method 2.21 or 2.22, wherein the base is an inorganic base (e.g., sodium hydroxide, potassium hydroxide or lithium hydroxide);

[0374] 2.24 Any of methods 2.21-2.23, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0375] 2.25 Any of methods 2.21-2.24, wherein the reaction temperature is 0°C to 50°C, for example, 10°C to 40°C or 20°C to 30°C;

[0376] 2.26 Any of methods 2.19-2.25, wherein the stereoisomers of compound 4-D are not separated prior to the next step of the method;

[0377] 2.27 Method 2 or any of Methods 2.1-2.26, wherein the method comprises the step of rearranging compound 4-D for a period of time under conditions effective to form compound 4-E, wherein R 6 As defined in Method 2.10 or 2.11;

[0378] 2.28 Method 2.27, where R 6 It is chlorine;

[0379] 2.29 Method 2.27 or 2.28, wherein the reaction comprises treating compound 4-D with a Lewis acid in a nonpolar solvent;

[0380] 2.30 Method 2.29, wherein the Lewis acid is selected from boron trifluoride, boron trichloride reagent, boron tribromide, magnesium dibromide, indium chloride, bismuth trifluoromethanesulfonate and copper trifluoromethanesulfonate;

[0381] 2.31 Method 2.30, wherein the boron trifluoride is boron trifluoride diethyl ether, boron trifluoride dimethyl sulfide or boron trifluoride tetrahydrofuran complex;

[0382] 2.32 Any of methods 2.29-2.31, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0383] 2.33 Method 2.32, wherein the non-polar solvent is tetrahydrofuran;

[0384] 2.34 Any of methods 2.27-2.33, wherein the reaction temperature is -10°C to 50°C, for example, 0°C to 30°C or 0°C to 10°C;

[0385] 2.35 Any of methods 2.27-2.34, wherein the stereoisomers of compound 4-E are not separated prior to the next step of the method;

[0386] 2.36 Method 2 or any one of methods 2.1-2.35, wherein the method comprises the step of converting compound 4-E into compound 5-A, wherein R 6 As defined in Method 2.10 or 2.11;

[0387] 2.37 Method 2.36, where R6 It is chlorine;

[0388] 2.38 Method 2.35 or 2.36, wherein the reaction comprises treating compound 4-E with formaldehyde and a base in a polar protic solvent;

[0389] 2.39 Method 2.38, wherein the formaldehyde is provided in the form of an aqueous solution;

[0390] 2.40 Method 2.38 or 2.39, wherein the base is a hydroxide base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, zinc hydroxide or aluminum hydroxide);

[0391] 2.41 Any of methods 2.38-2.40, wherein the solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butyl alcohol, tert-amyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol and water or a combination thereof;

[0392] 2.42 Method 2.41, wherein the solvent further comprises tetrahydrofuran, 2-methyltetrahydrofuran, dihydrofuran alkyl, methyl tert-butyl ether, cyclopentyl methyl ether and di One or more of alkanes;

[0393] 2.43 Any of methods 2.38-2.42, wherein the reaction comprises aqueous formaldehyde, aqueous sodium hydroxide or potassium hydroxide, and diethylene glycol solvent;

[0394] 2.44 Any of methods 2.36-2.43, wherein the reaction temperature is 0°C to 90°C, for example, 5°C to 50°C or 10°C to 40°C;

[0395] 2.45 Method 2 or any of Methods 2.1-2.44, wherein the method comprises the step of acylating compound 5-A with an acylating agent in a suitable solvent and under conditions effective to form compound 5-B for a period of time, wherein R 6 As defined in Method 2.10 or 2.11;

[0396] 2.46 Method 2.45, where R 6 It is chlorine;

[0397] 2.47 Method 2.45 or 2.46, where R m Selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 Alkyl (e.g., trifluoromethyl, trichloromethyl), carboxyl C 1-6alkyl (eg, 3-carboxypropyl), optionally substituted aryl (eg, phenyl, 4-halophenyl), or optionally substituted heteroaryl (eg, pyridyl, such as 2-pyridyl);

[0398] 2.48 Method 2.47, where R m It is C 1-6 Alkyl, optionally wherein R m It is methyl;

[0399] 2.49 Any of methods 2.45-2.48, wherein the acylation is asymmetric, for example, the acylation produces a product with greater than 50% ee (e.g., greater than 75% ee, or greater than 85% ee, or greater than 90% ee, or greater than 95% ee) prior to any purification;

[0400] 2.50 Any of methods 2.45-2.49, wherein the acylation is enzymatic and the acylating agent is a combination of an enzyme and an acyl donor;

[0401] 2.51 Method 2.50, wherein the acyl donor is of formula R m -C(=O)-OZ ester or formula R m -C(=O)-OC(=O)-R m anhydride, wherein Z is selected from C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl), C 2-6 Alkenyl (e.g., vinyl, allyl, methoxyvinyl, isopropenyl) and halogenated C 1-6 Alkyl (e.g., trifluoromethyl, 2,2,2-trichloroethyl);

[0402] 2.52 Method 2.50, wherein the acyl donor is selected from the group consisting of vinyl acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, isopropenyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, 4-vinyl bromoacetate, vinyl picolinate, glutaric anhydride and vinyl formate;

[0403] 2.53 Any of methods 2.50-2.52, wherein the enzyme is a lipase, e.g., a bacterial or fungal lipase, such as from a Candida species (e.g., Lipozyme TL IM or Novozym 435);

[0404] 2.54 Any of methods 2.45-2.53, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0405] 2.55 Method 2.54, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane);

[0406] 2.56 Method 2.54, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0407] 2.57 Method 2.54, wherein the polar aprotic solvent is ethyl acetate;

[0408] 2.58 Any of methods 2.45-2.57, wherein the reaction temperature is -10°C to 110°C, for example, 10°C to 80°C or 0°C to 40°C; or 20°C to 30°C;

[0409] 2.59 Method 2 or any of Methods 2.1-2.58, wherein the method comprises the step of treating compound 5-B with an oxidizing agent in a suitable solvent and for a period of time under conditions effective to form aldehyde compound 5-C, wherein R 6 As defined in Method 2.10 or 2.11, and R m As defined in Method 2.47 or 2.48;

[0410] 2.60 method 2.59, where R 6 is chlorine and R m It is methyl;

[0411] 2.61 Method 2.59 or 2.60, wherein the reaction further comprises an additive, a catalyst and / or a base;

[0412] 2.62 Any of methods 2.59-2.61, wherein the oxidant is selected from sodium hypochlorite, sulfur trioxide-pyridine, dimethyl sulfoxide and an activator (e.g., oxalyl chloride), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate , N-chlorosuccinimide / dimethyl sulfide, iodobenzoyl, chromium trioxide, 2-iodooxybenzoic acid, bis(trifluoroacetoxy)iodobenzene, diacetoxyiodobenzene (DAIB), and manganese dioxide;

[0413] 2.63 Method 2.62, wherein the DMSO activator is selected from the group consisting of oxalyl chloride, trifluoroacetic anhydride, cyanuric chloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolinium chloride, polyphosphoric acid, phosphorus trichloride, phosphorus pentoxide, triphenylphosphine dichloride, triphenylphosphine dibromide, phosphorus oxychloride, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate and ethoxyacetylene;

[0414] 2.64 Any of methods 2.61-2.63, wherein the reaction further comprises a catalyst selected from TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxy), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl and 9-azaadamantane N-oxyl;

[0415] 2.65 Any of methods 2.61-2.64, wherein the reaction further comprises an additive selected from the group consisting of sodium bromide, lithium bromide and potassium bromide;

[0416] 2.66 Any of methods 2.61-2.65, wherein the reaction further comprises a base selected from a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, disodium hydrogen or tribasic), sodium acetate, potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tripotassium phosphate), potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate) and a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide);

[0417] 2.67 Any of methods 2.59-2.66, wherein the oxidizing agent is sulfur trioxide-pyridine;

[0418] 2.68 Method 2.67 wherein the base is N,N-diisopropylethylamine;

[0419] 2.69 Any of methods 2.59-2.68, wherein the suitable solvent is water, a non-polar solvent and / or a polar aprotic solvent;

[0420] 2.70 Method 2.69, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0421] 2.71 Method 2.69, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), nitriles (e.g., acetonitrile) and ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone);

[0422] 2.72 Method 2.69, wherein the suitable solvent is a mixture of ethyl acetate and dimethyl sulfoxide;

[0423] 2.73 Any of methods 2.59-2.72, wherein the reaction temperature is -80°C to 50°C, for example, -40°C to 40°C or -10°C to 10°C;

[0424] 2.74 Method 2 or any of Methods 2.1-2.73, wherein the method comprises the step of treating compound 5-C with a protecting agent in a suitable solvent and for a period of time under conditions effective to form acetal compound 5-D, wherein R 6 As defined in Method 2.10 or 2.11, and R m As defined in Method 2.47 or 2.48;

[0425] 2.75 method 2.74, where R 6 is chlorine and R m It is methyl;

[0426] 2.76 Method 2.74 or 2.75, where each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an acetal bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted by one to four C 1-6 Alkyl, halogen or aryl substituted; or two of R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[0427] 2.77 Method 2.76, where each R n Independently C 1-6 Alkyl, optionally wherein each Rn is methyl;

[0428] 2.78 Method 2.76, where two Rs n moieties are joined together to form a group selected from -CH 2 CH 2 -, -CH(CH 3 )CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH(Ph)-, -C(CH 3 ) 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CBr 2 CH 2 -, -CH 2 (C=CH)CH 2 -, -CH 2 CH(Ph)CH 2 -, -CH(CH 3 )CH 2 CH(CH 3 )-, -CH 2 CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 2 CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH(C 6 H 5 )CH(C 6 H 5 ), -CH 2 CH(C 6 H 5 )CH 2 - and -(o-C 6 H4 )-bridge;

[0429] 2.79 Method 2.78, where two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、CH 2 C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH(C 6 H 5 )CH(C 6 H 5 ) and -CH 2 CH(C 6 H 5 )CH 2 - bridge;

[0430] 2.80 method 2.76, where each R n is the same as C 1-6 alkyl moiety (e.g., methyl, ethyl, or isopropyl), and the protecting agent is C 1-6 Alcohol or tri(C 1-6 alkyl) esters, for example, wherein each R n is methyl, and the protecting agent is methanol or trimethyl orthoformate;

[0431] 2.81 method 2.76, where two R n Partially formed C 2-10 Alkyl or C 2-10 olefinic bridge, and the protecting agent is C 2-10 Alkyl-diol or C 2-10 Alkenyl-diols (e.g., ethylene glycol, propylene glycol);

[0432] 2.82 Method 2.81, wherein the protecting agent is selected from trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, triethyl orthoformate, an alcohol (e.g., MeOH) or a diol (e.g., ethylene glycol, pinacol, propylene glycol, butanediol, 2,2-dimethyl-1,3-propanediol, catechol, HOCH 2 CH 2 OH, HOCH(CH 3 )CH(CH 3 )OH、HOCH 2 CH(CH 3 )OH、HOCH 2 CH(Ph)OH, HOC(CH 3 ) 2 C(CH 3 ) 2 OH, HOCH 2 CH 2 CH 2 OH, HOCH 2 CBr 2 CH 2 OH, HOCH 2 (C=CH)CH 2 OH, HOCH 2 CH(Ph)CH 2 OH, HOCH(CH 3 )CH 2 CH(CH 3 )OH、HOCH 2 CH(CH 3 )CH 2 OH, HOCH 2 C(CH 3 ) 2 CH 2 OH, HOCH 2 C(CH 2 CH 3 ) 2 CH 2 OH, HOCH 2 CH 2 CH 2 CH 2 OH, HOCH 2 CH 2 CH 2 CH 2 CH 2 OH);

[0433] 2.83 Any of methods 2.74-2.82, wherein the reaction further comprises, for example, a catalytic amount (e.g., 0.001 to 0.10 equivalents or 0.01 to 0.05 equivalents) of an acid;

[0434] 2.84 Method 2.83, wherein the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate , sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid and formic acid; or an acidic resin in which the acid is fixed (e.g., Amberlyst resin);

[0435] 2.85 Any of methods 2.74 to 2.84, wherein each R n is methyl, the protecting agent is trimethyl orthoformate, and the acid catalyst is p-toluenesulfonic acid;

[0436] 2.86 Any of methods 2.74 to 2.85, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0437] 2.87 Method 2.86, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0438] 2.88 Method 2.86, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and diols (e.g., ethylene glycol, propylene glycol) or combinations thereof, optionally wherein the solvent alcohol is the same as the protecting reagent;

[0439] 2.89 Method 2.86, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0440] 2.90 Method 2.86, wherein the suitable solvent is methanol;

[0441] 2.91 Any of methods 2.74-2.87, wherein the reaction comprises refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water;

[0442] 2.92 Any of methods 2.74-2.91, wherein the reaction temperature is 0°C to 150°C, for example, 25°C to 120°C, 0°C to 60°C or 35°C to 55°C;

[0443] 2.93 Method 2 or any of Methods 2.1-2.92, wherein the method comprises the step of hydrolyzing compound 5-D in water with a base, optionally with a suitable co-solvent, for a period of time and under conditions effective to form acetal compound 5-E, wherein R 6 As defined in Method 2.10 or 2.11, R m As defined in Method 2.47 or 2.48, and R n As defined in any of Methods 2.76-2.79;

[0444] 2.94 Method 2.93, where R 6 is chlorine, R m is a methyl group, and R n is each methyl group;

[0445] 2.95 Method 2.93 or 2.94, wherein the base is an inorganic base such as a hydroxide, bicarbonate or carbonate base;

[0446] 2.96 Method 2.95, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; in one embodiment, the base is potassium carbonate;

[0447] 2.97 Any of methods 2.93-2.96, wherein the suitable co-solvent is selected from a non-polar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0448] 2.98 Method 2.97, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0449] 2.99 Method 2.98, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol);

[0450] 2.100 Method 2.98, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0451] 2.101 Method 2.97, wherein the suitable solvent is a combination of tetrahydrofuran and water;

[0452] 2.102 Any of methods 2.93-2.101, wherein the reaction further comprises a phase transfer catalyst, such as a quaternary ammonium halide salt (e.g., a chloride or bromide salt of tetrabutylammonium, tetraethylammonium, benzyltriethylammonium, methyltrioctylammonium, methyltributylammonium, or methyltrioctylammonium);

[0453] 2.103 Any of methods 2.93-2.102, wherein the reaction temperature is -10°C to 70°C, for example, 10°C to 30°C or 20°C to 30°C;

[0454] 2.104 Any of methods 2.74-2.103, wherein compound 5-C is converted to compound 5-E in two steps without isolating or purifying the intermediate compound 5-D;

[0455] 2.105 Method 2 or any of Methods 2.1-2.104, wherein the method comprises the step of treating compound 5-E with a transcondensation reagent in a suitable solvent and for a period of time under conditions effective to form acetal compound 5-E', wherein R 6 As defined in method 2.10 or 2.11, and wherein each R of compound 5-E n Independently C 1-6 alkyl (eg, methyl, ethyl or isopropyl), and wherein both R n R of compound 5-E n different;

[0456] 2.106 Method 2.105, where R 6 It is chlorine;

[0457] 2.107 Method 2.105 or 2.106, wherein both R n It is methyl;

[0458] 2.108 Any of methods 2.105-2.107, wherein each R of compound 5-E' n Independently C 2-6 alkyl (eg, ethyl or isopropyl), or wherein both R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups; or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[0459] 2.109 Method 2.108, wherein each R of compound 5-E' n Independently C2-6 alkyl, optionally wherein each R n It is ethyl;

[0460] 2.110 Method 2.108, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 CH(Ph)-、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CBr 2 CH 2 -、-CH 2 (C=CH)CH 2 -、-CH 2 CH(Ph)CH 2 -、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH(C 6 H 5 )CH(C 6 H 5 ),-CH 2 CH(C 6 H 5 )CH2 -and-(oC 6 H 4 )-bridge;

[0461] 2.111 Method 2.110, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、CH 2 C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH(C 6 H 5 )CH(C 6 H 5 ) and -CH 2 CH(C 6 H 5 )CH 2 - bridge;

[0462] 2.112 Method 2.108, wherein each R of compound 5-E' n is the same as C 2-6 alkyl moiety (e.g., ethyl or isopropyl), and the transamination agent is C 2-6 alcohol, for example, where each R n is ethyl, and the reagent is ethanol;

[0463] 2.113 Method 2.108, wherein both R n Partially formed C 2-10 Alkyl or C 2-10 The alkenyl bridge, and the transversion reagent is C 2-10 Alkyl-diol or C 2-10Alkenyl-diols (e.g., ethylene glycol, propylene glycol);

[0464] 2.114 Method 2.113, wherein the transcondensation agent is selected from alcohols (e.g., ethanol and propanol) or diols (e.g., ethylene glycol, 2,3-butanediol, pinacol, propylene glycol, 2,4-pentanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-diethyl-1,3-propanediol, 2-phenyl-1,3-propanediol, meso-1,2-diphenyl-1,2-ethanediol, and catechol);

[0465] 2.115 Any of methods 2.105-2.114, wherein the reaction further comprises a Lewis acid (eg, boron trifluoride, titanium isopropoxide) or a Bronsted acid (eg, p-toluenesulfonic acid);

[0466] 2.116 Method 2.115, wherein the Lewis acid is selected from boron trifluoride, boron trichloride, boron tribromide, magnesium dibromide, indium chloride, aluminum chloride, tin(IV) chloride, zinc chloride, bismuth trifluoromethanesulfonate, copper trifluoromethanesulfonate, titanium(IV) chloride, and titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide);

[0467] 2.117 Method 2.116, wherein the boron trifluoride is boron trifluoride diethyl ether, boron trifluoride dimethyl sulfide or boron trifluoride tetrahydrofuran complex;

[0468] 2.118 Method 2.115, wherein the Bronsted acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate , sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid and formic acid; or wherein the acid is an immobilized acidic resin (e.g., Amberlyst resin); in one embodiment, the acid is boron trifluoride diethyl etherate (BF 3 ·OEt 2 );

[0469] 2.119 Any of methods 2.105 to 2.118, wherein the suitable solvent is a non-polar solvent, a polar protic solvent or a polar aprotic solvent, a non-polar solvent or a polar aprotic solvent optionally in combination with a trace amount of a polar protic solvent (e.g., less than 10% v / v);

[0470] 2.120 Method 2.119, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0471] 2.121 Method 2.119, wherein the polar protic solvent is selected from alcohols (e.g., ethanol, propanol, isopropanol) and glycols (e.g., ethylene glycol, propylene glycol), or combinations thereof, optionally wherein the solvent alcohol is the same as the transduction reagent;

[0472] 2.122 Method 2.119, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0473] 2.123 Method 2.119 wherein the suitable solvent is 2-methyltetrahydrofuran;

[0474] 2.124 Any of methods 2.105-2.120, wherein the reaction comprises refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water;

[0475] 2.125 Any of methods 2.105-2.124, wherein the reaction temperature is 0°C to 100°C, for example, 25°C to 120°C, or 50°C to 100°C or 70°C to 80°C;

[0476] 2.126 Method 2 or any of methods 2.1-2.125, wherein the method comprises the step of treating compound 5-E or 5-E' with 4-fluoro-3-nitrobenzoic acid or ester in a suitable solvent and for a period of time under conditions effective to form the ether adduct compound 5-F, wherein R 6 As defined in Method 2.10 or 2.11, and wherein each R n as defined in any of Methods 2.76-2.79 or 2.108-2.111;

[0477] 2.127 Method 2.126, where R 6 It is chlorine;

[0478] 2.128 Method 2.126 or 2.127, wherein both R n The moiety is methyl or ethyl, or the two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2-、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[0479] 2.129 Any of methods 2.126-2.128, where R z is H or optionally substituted C 1-6 alkyl;

[0480] 2.130 Method 2.129, where R z is selected from H, unsubstituted C 1-6 Alkyl (e.g., methyl), C 1-6 Alkoxy substituted C 1-6 Alkyl (e.g., methoxyethyl, methoxymethyl), C 1-6 Alkoxy substituted C 1-6 Alkoxy substituted C 1-6 C substituted with alkyl (e.g., methoxyethoxyethyl, methoxyethoxymethyl), 5-6 membered heterocycloalkyl 1-6 Alkyl (e.g., 2-N-(morpholino)ethyl, 2-tetrahydropyranyl), aryloxy substituted C 1-6 Alkyl (e.g., benzyloxymethyl), halogen-substituted C 1-6 Alkyl (e.g., 2,2,2-trichloroethyl), trialkylsilyl substituted C 1-6 Alkyl (e.g., 2-(trimethylsilyl)ethyl, triisopropylsilylmethyl), trialkylsilyl-substituted C 1-6 Alkoxy substituted C 1-6 Alkyl (e.g., 2-(trimethylsilyl)ethoxymethyl) and aryl substituted C 1-6 Alkyl (e.g., benzyl, 4-methylbenzyl, 4-nitrobenzyl);

[0481] 2.131 Method 2.130, where R z is H or unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl);

[0482] 2.132 Any of methods 2.126-2.131, wherein compound 5-E or 5-E' is dissolved or suspended in a suitable solvent and treated with a strong base, and optionally with a promoter (eg, sodium iodide, tetrabutylammonium iodide);

[0483] 2.133 Method 2.132, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0484] 2.134 Method 2.133 wherein the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide and potassium diisopropylamide; optionally wherein the base is potassium tert-butoxide;

[0485] 2.135 Method 2.132, 2.133 or 2.134 wherein the 4-fluoro-3-nitrobenzoic acid or ester is added to the reaction about 1 to 60 minutes, e.g., about 1 to 30 minutes, or 1 to 20 minutes, or 1 to 15 minutes, or 1 to 10 minutes, or 1 to 5 minutes after the addition of the base;

[0486] 2.136 Any of methods 2.126-2.135, wherein the 4-fluoro-3-nitrobenzoic acid or ester has the formula 4-F-3-NO 2 -C 6 H 4 -COOR z ;

[0487] 2.137 Any of methods 2.126-2.136, wherein the suitable solvent is a non-polar solvent;

[0488] 2.138 Method 2.137, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0489] 2.139 Method 2.138 wherein the nonpolar solvent is tetrahydrofuran;

[0490] 2.140 Any of methods 2.126-2.139, wherein the reaction temperature is -80°C to 100°C, for example, -45°C to 10°C, or -30°C to 10°C, or -10°C to 5°C, or about 0°C, or -10°C to 50°C, or -10°C to 30°C, or 10°C to 30°C, or 30°C to 80°C;

[0491] 2.141 Method 2 or any of Methods 2.1-2.140, wherein the method comprises the step of treating the nitro compound 5-F or 5-G' with a reducing agent in a suitable solvent and for a period of time under conditions effective to produce the aniline compound 5-G or 5-H, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, and wherein R z As defined in any of Methods 2.129 to 2.131;

[0492] 2.142 Method 2.141, where R 6 It is chlorine;

[0493] 2.143 Method 2.141 or 2.142, wherein both R n The moiety is methyl or ethyl, or the two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[0494] 2.144 Any of methods 2.141-2.143, wherein R z is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl);

[0495] 2.145 Any of methods 2.141-2.144, wherein the reducing agent is selected from a solution of an acid of zinc, tin or iron (e.g., formic acid or acetic acid or HCl in a suitable solvent);

[0496] 2.146 Any of methods 2.141-2.144, wherein the reducing agent is a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system);

[0497] 2.147 Method 2.146, wherein the hydrogenating agent is hydrogen gas and a palladium, platinum, rhodium, iridium, ruthenium or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc) 2 、Pt / C、PtO 2 , Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complex, Pd complex, Ir complex) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO 2 )

[0498] 2.148 Method 2.147, wherein the hydrogenating agent is hydrogen with Pd, Pd / C, Pd(OAc) 2 , Pt / C or PtO 2 a combination of catalysts, optionally at a pressure of 1-5 bar (e.g., 1-2 bar);

[0499] 2.149 Method 2.145, wherein the reducing agent is a solution of iron in acetic acid;

[0500] 2.150 Any of methods 2.141 to 2.149, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0501] 2.151 Method 2.150, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0502] 2.152 Method 2.150, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0503] 2.153 Method 2.150 wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0504] 2.154 Method 2.150 wherein the suitable solvent is ethyl acetate or isopropyl acetate or acetic acid;

[0505] 2.155 Any of methods 2.141-2.154, wherein the reaction temperature is 0°C to 100°C, for example, 20°C to 50°C, or 20°C to 30°C, or 50°C to 80°C;

[0506] 2.156 Method 2 or any of methods 2.1-2.155, wherein the method comprises the step of treating the acetal compound 5-F or 5-G' with a deprotecting agent in a suitable solvent and for a period of time under conditions effective to produce the aldehyde compound 5-G or 5-H, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, and wherein R z As defined in any of Methods 2.129 to 2.131;

[0507] 2.157 Method 2.156, where R 6 It is chlorine;

[0508] 2.158 Method 2.156 or 2.157, where both R n is methyl or ethyl, or two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[0509] 2.159 Any of the methods 2.156-2.158, where R z is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl);

[0510] 2.160 Any of methods 2.156-2.159, wherein the deprotecting agent comprises an acid;

[0511] 2.161 Method 2.160, wherein the acid is selected from HCl (e.g., aqueous HCl or HCl / methanol, HCl / isopropanol or HCl / dihydrochloric acid). alkane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium toluenesulfonate , trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium trifluoromethanesulfonate), and acidic resins (e.g., Amberlyst);

[0512] 2.162 Method 2.161, wherein the acid is selected from HCl (e.g., HCl / dihydrochloric acid) alkane), p-toluenesulfonic acid, methanesulfonic acid, and acidic resins (e.g., Amberlyst);

[0513] 2.163 Any of methods 2.156 to 2.162, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0514] 2.164 Method 2.163, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0515] 2.165 Method 2.163, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0516] 2.166 Method 2.163, wherein the polar aprotic solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0517] 2.167 Method 2.163, wherein the suitable solvent is acetone or distilled water. alkyl;

[0518] 2.168 Any of methods 2.156-2.167, wherein the reaction temperature is 0°C to 100°C, for example, 20°C to 50°C or 20°C to 30°C;

[0519] 2.169 Any of methods 2.141-2.168, as appropriate, wherein the desired product compound 5-H undergoes spontaneous condensation partially or completely to form the intermediate imine 5-H', and the mixture of 5-H and 5-H' is subjected to the next step, or the isolated product is 5-H' for the next step;

[0520] 2.170 Method 2 or any of Methods 2.1-2.169, wherein the method comprises the step of treating the aniline / acetal compound 5-H (and / or 5-H') with a reducing agent in a suitable solvent and for a period of time under conditions effective to produce the secondary amine compound 5-I, wherein R 6 As defined in method 2.10 or 2.11, and wherein R z As defined in any of Methods 2.129 to 2.131;

[0521] 2.171 Method 2.170, where R 6 It is chlorine;

[0522] 2.172 Method 2.170 or 2.171, where R z is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl);

[0523] 2.173 Any of methods 2.170-2.172, wherein the reducing agent is selected from the group consisting of a hydride reducing agent, a silane reducing agent, and a zinc acid solution (e.g., a zinc acetic acid solution);

[0524] 2.174 Method 2.173, wherein the reducing agent is a hydride reducing agent;

[0525] 2.175 Method 2.174, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride and tetramethylammonium triacetoxyborohydride;

[0526] 2.176 Method 2.175, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[0527] 2.177 Any of methods 2.174-2.176, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride);

[0528] 2.178 Method 2.173, wherein the silane reducing agent is triethylsilane;

[0529] 2.179 Any of methods 2.173 to 2.178 wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid and hydrochloric acid);

[0530] 2.180 Any of methods 2.170-2.179, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0531] 2.181 Method 2.180, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0532] 2.182 Method 2.180, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide;

[0533] 2.183 Method 2.180, wherein the suitable solvent is dichloromethane or dichloroethane;

[0534] 2.184 Any of methods 2.170-2.183, wherein the reaction temperature is -30°C to 80°C, for example, 0°C to 50°C, or 20°C to 30°C or about 20°C;

[0535] 2.185 Method 2 or any of Methods 2.1-2.184, wherein the method produces a compound according to any one or more of Compounds 4-B, 4-C, 4-D, and 4-E;

[0536] 2.186 Method 2.185, wherein in any one or more of said compounds, R 6 is a halogen (e.g., chlorine);

[0537] 2.187 Method 2 or any of Methods 2.1-2.186, wherein the method produces a compound according to any one or more of Compounds 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H and 5-I;

[0538] 2.188 Method 2.187, wherein in one or more of said compounds, R m It is C 1-3 Alkyl (e.g., methyl), two R n is methyl or ethyl, or two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH2 - Bridge, R z It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0539] 2.189 Method 2 or any of Methods 2.1-2.188, wherein the method produces a compound according to any one or more of Compounds 1-J or 1-K;

[0540] 2.190 Method 2.189, wherein in one or more of said compounds, R x It is H, R z Is H or C 1-3 Alkyl (e.g., methyl), R 5 It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0541] 2.191 Method 2 or any of Methods 2.1-2.190, wherein the method produces a compound according to any one or more of Compounds 9-A, 9-B, 9-C, 9-D or 9-E;

[0542] 2.192 Method 2.191, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D or 9-E are prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0543] 2.193 Method 2.191 or 2.192, wherein in one or more of the compounds, R x It is H, R y It is H, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (eg, (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (eg, 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0544] 2.194 Method 2.193, wherein in one or more of said compounds, R x Yes H, R y Yes H, R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0545] 2.195 Method 2.194, wherein in one or more of said compounds, R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0546] 2.196 Method 2.195, wherein in one or more of said compounds, R 2 is H and R 3 It is methyl;

[0547] 2.197 Any of methods 2.191-2.196, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0548] 2.198 Method 2.197, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0549] 2.199 Method 2.198, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C1-6 Alkoxy (e.g., methoxy);

[0550] 2.200 Method 2.198, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0551] 2.201 Method 2 or any of methods 2.1-2.200, wherein the method produces a compound according to Compound I;

[0552] 2.202 Method 2.201, wherein Compound I is Compound I(a);

[0553] 2.203 Method 2.201 or 2.202, wherein compound I or I(a) is prepared according to any one or more of method 4 or method 4.1 etc. or method 5 or method 5.1 etc.;

[0554] 2.204 Any of methods 2.201-2.203, wherein in compound I or I(a), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0555] 2.205 Method 2.204 wherein in compound I or I(a), R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0556] 2.206 Method 2.205 wherein in compound I or I(a), R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0557] 2.207 Method 2.206 wherein in compound I or I(a), R 2 is H and R 3 It is methyl;

[0558] 2.208 Any of methods 2.204-2.207, wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0559] 2.209 Method 2.208 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0560] 2.210 Method 2.209 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0561] 2.211 Any of methods 2.191-2.210, wherein in one or more of compound 9-E, compound I, or compound I(a), It is a double bond;

[0562] 2.212 Method 2 or any of methods 2.1-2.211, wherein the method produces compound 1;

[0563] 2.213 Method 2 or any of methods 2.1-2.212, wherein the method further comprises any steps described in any of method 1 etc., method 3 etc., method 4 etc. and method 5 etc.

[0564] In a fourth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E and compounds I or I(a) (Method 3), as described herein, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 3 generally involves the formation of a sulfonimide moiety (SNO), including advanced intermediates 6-H, 6-L and 8-B, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 3 may include any of the steps shown in Schemes 6, 7 and 8.

[0565]

[0566] In a specific embodiment, the present disclosure provides the following method 3:

[0567] 3.1 Method 3, wherein the method comprises the step of reacting alcohol compound 6-A with an activating agent in a suitable solvent (with a suitable base) and under conditions effective to produce activated compound 6-B for a period of time;

[0568] 3.2 Method 3.1, where R y Selected from H, C 1-6 alkyl (eg, methyl) and optionally substituted aryl (eg, phenyl);

[0569] 3.3 Method 3.2, where R y It is H;

[0570] 3.4 Any of the methods 3.1-3.3, where R 2 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 Group substitution (R 10 As defined for Compound 1);

[0571] 3.5 Method 3.4, where R 2 is hydrogen or C 1-6 Alkyl (e.g., methyl);

[0572] 3.6 Any of the methods 3.1-3.5, wherein R 3 It is hydrogen, C 1-6 Alkyl, -OR 7 , C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R 7 or -CN, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 Group substitution (R 7 and R 10 As defined for Compound 1);

[0573] 3.7 Method 3.6, where R 3 It is hydrogen, C 1-6 Alkyl (eg, methyl) or -OR 7 , where R 7 It is C 1-6 Alkyl (e.g. methyl);

[0574] 3.8 Method 3.7, where R 3 is hydrogen or C 1-6 Alkyl (e.g., methyl);

[0575] 3.9 Any of the methods 3.1-3.9, wherein R 2 and R 3 are all hydrogen, or R 2 is hydrogen and R 3 It is C 1-6 Alkyl (eg, methyl), or wherein R 2 and R 3 All C 1-6 Alkyl (e.g., methyl);

[0576] 3.10 Method 3.9, where R 2 is hydrogen and R 3 It is C 1-6 Alkyl (e.g., methyl);

[0577] 3.11 Any of methods 3.1-3.10, wherein the group X of compound 6-B is selected from the group consisting of halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate) and oxy (For example, oxytriphenyl ), optionally wherein the group X is 4-toluenesulfonate;

[0578] 3.12 Any of methods 3.1-3.11, wherein the activating agent is selected from p-toluenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonic anhydride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenyltrifluorocarbonimide, triphenylphosphine dihalide, triphenylphosphine with tetrahalomethane (e.g., tetrabromomethane), and combinations thereof with metal halide salts (e.g., sodium bromide, potassium iodide);

[0579] 3.13 Method 3.12, wherein the activating agent is p-toluenesulfonyl chloride;

[0580] 3.14 Any of methods 3.1-3.13, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 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, picoline, indole, isoindole, quinoline, isoquinoline) and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic sodium phosphate, disodium hydrogen phosphate or tribasic sodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic potassium phosphate, dibasic potassium phosphate or tripotassium phosphate), potassium fluoride, lithium carbonate, cesium carbonate);

[0581] 3.15 Method 3.14, wherein the base is triethylamine;

[0582] 3.16 Any of methods 3.1-3.15, wherein the reaction further comprises a catalyst;

[0583] 3.17 Method 3.16, wherein the catalyst is selected from 4-dimethylaminopyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine and 9-azajulonidine, optionally wherein the catalyst is 4-dimethylaminopyridine;

[0584] 3.18 Any of methods 3.1-3.17, wherein the activator is p-toluenesulfonyl chloride, the base is triethylamine, and the catalyst is 4-dimethylaminopyridine;

[0585] 3.19 Any of methods 3.1-3.18, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0586] 3.20 Method 3.19, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0587] 3.21 Method 3.19, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0588] 3.22 Method 3.19, wherein the nonpolar solvent is dichloromethane;

[0589] 3.23 Any of methods 3.1-3.22, wherein the reaction temperature is -20°C to 80°C, for example, -10°C to 30°C or 0°C to 20°C;

[0590] 3.24 Method 3 or any of 3.1-3.23, wherein the method comprises the step of reacting compound 6-B with a thiol in a suitable solvent (optionally with a suitable base) and under conditions effective for a period of time to form thioether 6-C, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 as defined in any of Methods 3.4-3.10, and X is as defined in Method 3.11;

[0591] 3.25 Method 3.24, where R e is selected from an optionally substituted 5-10 membered heteroaryl (eg, optionally substituted pyridinyl or pyrimidinyl), -C(=NH)NH(C 1-6 alkyl), -C(=NH)N(C 1-6 alkyl) 2 and -C(=NH)NH 2 ;

[0592] 3.26 Method 3.25, where R e is a 5-10 membered heteroaryl, such as a 6 membered heteroaryl (e.g., 2-pyridyl or 2-pyrimidinyl);

[0593] 3.27 Any of methods 3.24-3.26, wherein the thiol is a thiol having the formula R e -SH compound, optionally in the form of a salt thereof (e.g., lithium, sodium or potassium) or a tautomeric equivalent thereof (e.g., thiourea or thiopyridone);

[0594] 3.28 Method 3.27, wherein the thiol is selected from 2-mercaptopyrimidine, 2-mercaptopyridine, thiourea, N-methylthiourea, N,N-dimethylthiourea, each optionally in the form of a salt (eg, a sodium or potassium salt);

[0595] 3.29 Any of methods 3.24-3.28, wherein the reaction comprises an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, bases such as sodium diisopropylamide, potassium diisopropylamide), tertiary amines (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, quinoline, isoquinoline), and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic sodium phosphate, disodium hydrogen phosphate, or tribasic sodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic potassium phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate));

[0596] 3.30 Method 3.29, wherein the base is an inorganic hydride (e.g., sodium hydride or potassium hydride) or an alkoxide base (e.g., sodium ethoxide or sodium methoxide);

[0597] 3.31 Any of methods 3.27-3.29, wherein the thiol is 2-mercaptopyrimidine and the base is sodium ethoxide;

[0598] 3.32 Any of methods 3.24-3.31, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0599] 3.33 Method 3.32, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0600] 3.34 Method 3.32, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol);

[0601] 3.35 Method 3.32, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0602] 3.36 Method 3.32, wherein the suitable solvent is methanol or ethanol, optionally wherein the suitable solvent is ethanol;

[0603] 3.37 Any of methods 3.24-3.36, wherein the reaction temperature is 0°C to 100°C, for example, 20°C to 80°C, or 55°C to 75°C or about 65°C;

[0604] 3.38 Method 3 or any of Methods 3.1-3.37, wherein the method comprises the step of oxidizing the sulfide compound 6-C with an oxidizing agent in a suitable solvent and under conditions effective to form the sulfone compound 6-D for a period of time, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10, and R e As defined in Method 3.25 or 3.26;

[0605] 3.39 Method 3.38, wherein the oxidizing agent is selected from peroxides (e.g., hydrogen peroxide, sodium peroxide, potassium peroxide), organic peroxides and peroxy compounds (e.g., tert-butyl hydroperoxide, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, magnesium monoperoxyphthalate), hypochlorites (e.g., sodium hypochlorite, potassium hypochlorite, calcium hypochlorite), periodates (e.g., sodium periodate, potassium periodate), perborates (e.g., sodium perborate), peroxymonosulfates (e.g., potassium peroxymonosulfate, potassium hydrogen persulfate), permanganates (e.g., potassium permanganate), tetramethyl perruthenate (TPAP), and any combination thereof;

[0606] 3.40 Method 3.39, wherein the oxidizing agent is a peroxide (e.g., hydrogen peroxide);

[0607] 3.41 Any of methods 3.38-3.40, wherein the reaction further comprises a catalyst, for example selected from sodium tungstate, tungsten tetrachloride, tetrabutylammonium hexafluorotungstate, ammonium molybdate, vanadium acetylacetonate, manganese sulfate, phosphotungstic acid, cerium ammonium nitrate, ruthenium trichloride, methylrhenium trioxide, scandium trifluoromethanesulfonate, iron, and any combination thereof;

[0608] 3.42 Any of methods 3.38-3.41, wherein the oxidant is hydrogen peroxide and the catalyst is sodium tungstate;

[0609] 3.43 Any of methods 3.38-3.42, wherein the reaction further comprises an optional catalytic amount (e.g., 0.01 equivalents to 0.1 equivalents) of an acid such as phosphoric acid;

[0610] 3.44 Method 3.43, wherein the phosphoric acid is selected from the group consisting of phenylphosphonic acid, methylphosphonic acid, phenylphosphinic acid, methylphosphinic acid, phosphoric acid, polyphosphoric acid (PPA), phosphonic acid, phosphinic acid, and combinations thereof;

[0611] 3.45 Any of methods 3.38-3.44, wherein the reaction further comprises an optional catalytic amount (e.g., 0.01 eq. to 0.1 eq.) of a phase transfer reagent, such as a tetraalkylammonium salt (e.g., tetraethylammonium or tetrabutylammonium salt);

[0612] 3.46 Method 3.45, wherein the phase transfer reagent is selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride and tetrabutylammonium iodide;

[0613] 3.47 Any of methods 3.42-3.46, wherein the reaction further comprises phenylphosphonic acid and tetrabutylammonium hydrogen sulfate each in an optionally catalytic amount (e.g., 0.01 eq. to 0.1 eq.);

[0614] 3.48 Any of methods 3.38-3.47, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0615] 3.49 Method 3.48, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0616] 3.50 Method 3.48, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), water, or a combination thereof;

[0617] 3.51 Method 3.48, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0618] 3.52 Method 3.48, wherein the suitable solvent is toluene;

[0619] 3.53 Any of methods 3.38-3.52, wherein the reaction temperature is 0°C to 100°C, for example, 0°C to 60°C or 10°C to 30°C;

[0620] 3.54 Method 3 or any of methods 3.1-3.53, wherein the method comprises the step of reacting compound 6-D with a base in a suitable solvent and under conditions effective for a period of time to form compound 6-E, wherein Ry As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10, and R e As defined in Method 3.25 or 3.26;

[0621] 3.55 Method 3.54, wherein M is selected from hydrogen and an alkali metal or an alkaline earth metal, for example, wherein M is selected from H, Li, Na, K, Mg and Ca;

[0622] 3.56 Method 3.54 or 3.55, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), an organic lithium base (e.g., methyllithium, ethyllithium, propyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium) and an inorganic carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate);

[0623] 3.57 Method 3.56, wherein the base is selected from the group consisting of an inorganic hydride, an alkoxide and an inorganic hydroxide;

[0624] 3.58 Method 3.57, wherein the base is selected from sodium methoxide and potassium methoxide;

[0625] 3.59 Any of methods 3.54-3.58, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0626] 3.60 Method 3.59, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0627] 3.61 Method 3.59, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or water or a mixture of the two; optionally wherein the base is an alkoxide corresponding to the alcohol (e.g., a methoxide base and a methanol solvent), or the base is a hydroxide base and the solvent is water;

[0628] 3.62 Method 3.59, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0629] 3.63 Any of methods 3.58 to 3.61 wherein the base is sodium methoxide or potassium methoxide and the solvent is methanol;

[0630] 3.64 Any of methods 3.54-3.63, wherein the reaction temperature is 0°C to 100°C, for example, 0°C to 60°C or 10°C to 30°C;

[0631] 3.65 Any of methods 3.54-3.64, wherein the solvent is removed from the reaction and the crude compound 6-E is washed with water and / or an organic solvent and then used in the next step without further purification;

[0632] 3.66 Method 3 or any one of 3.1-3.65, wherein the method comprises the step of oxidizing compound 6-E with a suitable oxidant and a base in a suitable solvent to form a sulfonamide compound 6-F, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 as defined in any of Methods 3.4-3.10, and M is as defined in Method 3.55;

[0633] 3.67 Method 3.66, wherein the oxidant is hydroxylamine-O-sulfonic acid, or the oxidant is a mixture of ammonia and an oxidant selected from iodine, N-chlorosuccinimide, N-bromosuccinimide, tert-butyl hydroperoxide and m-chloroperbenzoic acid;

[0634] 3.68 Method 3.67, wherein the oxidizing agent is hydroxylamine-O-sulfonic acid;

[0635] 3.69 Any of methods 3.66-3.68, wherein the base is selected from alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide), inorganic bases (e.g., lithium acetate, sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic sodium phosphate, disodium hydrogen phosphate or tribasic sodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic potassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), lithium carbonate, cesium carbonate), other alkali metal carboxylates (e.g., potassium propionate), and combinations thereof;

[0636] 3.70 Method 3.69, wherein the base is sodium acetate or potassium acetate;

[0637] 3.71 Any of methods 3.66-3.70, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0638] 3.72 Method 3.71, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0639] 3.73 Method 3.71, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or water or a mixture of the two;

[0640] 3.74 Method 3.71, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0641] 3.75 Method 3.71, wherein the suitable solvent is water;

[0642] 3.76 Any of methods 3.66-3.71, wherein the reaction temperature is 0°C to 100°C, for example, 20°C to 80°C, or 35°C to 55°C or about 45°C;

[0643] 3.77 Method 3 or any of Methods 3.1-3.76, wherein the method comprises the step of reacting compound 6-F with a protecting agent in a suitable solvent and under conditions effective to form N-protected compound 6-G for a period of time, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10;

[0644] 3.78 Method 3.77, wherein the protecting group R k Selected from silyl groups, alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl (aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., tert-butyl or trityl), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., C 1-6 alkoxymethyl, such as methoxymethyl or ethoxymethyl), C 1-6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1-6 Alkyl(aryl) (aryl), such as diphenylmethyl), alkylsulfonyl groups (e.g., SO 2 C 1-6 alkyl, such as methylsulfonyl or isopropylsulfonyl) and arylsulfonyl groups (e.g., SO 2 -aryl, such as benzenesulfonyl, toluenesulfonyl);

[0645] 3.79 Method 3.78, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0646] 3.80 method 3.79, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0647] 3.81 Method 3.80, where R k is tert-butyldimethylsilyl;

[0648] 3.82 Any of methods 3.77-3.81, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, dimethylphenylsilyl bromide, triphenylsilyl bromide), 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, acetyl chloride, benzoyl chloride), acid anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride);

[0649] 3.83 Any of methods 3.77-3.82, wherein the reaction further comprises a base;

[0650] 3.84 Method 3.83, wherein 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), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), Inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0651] 3.85 Method 3.84 wherein the protecting agent is tert-butyldimethylsilyl chloride and the base is triethylamine;

[0652] 3.86 Any of methods 3.77-3.85, wherein the reaction further comprises a catalyst selected from 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulonidine;

[0653] 3.87 Any of methods 3.77-3.86, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0654] 3.88 Method 3.87, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0655] 3.89 Method 3.87, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0656] 3.90 Method 3.87, wherein the nonpolar solvent is an ether, optionally wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran;

[0657] 3.91 Any of methods 3.77-3.90, wherein the reaction temperature is -30°C to 100°C, e.g., -10°C to 30°C, 0°C to 25°C, 0°C to 100°C, e.g., 20°C to 80°C, or 35°C to 55°C or about 45°C;

[0658] 3.92 Method 3 or any of Methods 3.1-3.91, wherein the method comprises the steps of treating the protected sulfonamide 6-G with (1) a chlorinating agent and a base in a suitable solvent, and then treating with (2) an ammonia source in a suitable solvent and for a period of time under conditions effective to form compound 6-H, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k As defined in any of Methods 3.78-3.81;

[0659] 3.93 Method 3.92, wherein the chlorinating agent is selected from triphenylphosphine dichloride (Ph 3 PCl2 ) (optionally prepared in situ from triphenylphosphine and oxalyl chloride), phosphorus oxychloride (optionally prepared in situ from phosphorus pentoxide and a chloride salt such as sodium chloride, potassium chloride or tetrabutylammonium chloride), phenyldichlorophosphate, triphenyldichlorophosphorane, phenylphosphine dichloride, oxalyl chloride, thionyl chloride, sulfuryl chloride, triphenylphosphite dichloride complex ((PhO) 3 PCl 2 ) (optionally prepared in situ from chlorine and triphenylphosphite), phosphorus(V) oxychloride, phosphorus trichloride, phosphorus pentachloride and hydrogen chloride;

[0660] 3.94 Method 3.93 wherein the chlorinating agent is triphenylphosphine dichloride, optionally wherein the triphenylphosphine dichloride is prepared in situ from triphenylphosphine oxide and oxalyl chloride;

[0661] 3.95 Any of methods 3.92-3.94, wherein 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) and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine);

[0662] 3.96 Method 3.95 wherein the base is N,N-diisopropylethylamine;

[0663] 3.97 Any of methods 3.92-3.96, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0664] 3.98 Method 3.97, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0665] 3.99 Method 3.97, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0666] 3.100 Method 3.97 wherein the nonpolar solvent is dichloromethane;

[0667] 3.101 Any of methods 3.92-3.100, wherein the ammonia source is selected from ammonia gas, aqueous ammonia, inorganic ammonium salts (e.g., ammonium chloride, ammonium bromide, ammonium sulfate, ammonium acetate), ammonia substitutes (e.g., hexamethyldisilazane), amides (e.g., acetamide), and carbamates (e.g., tert-butyl carbamate) dissolved in any of the solvents provided in methods 3.97-3.100;

[0668] 3.102 Method 3.101, wherein the ammonia source is ammonia dissolved in a solvent, optionally wherein the solvent is the same solvent as the reaction solvent from step (1) (e.g., wherein the reaction solvent is dichloromethane and the ammonia source is ammonia gas dissolved in dichloromethane);

[0669] 3.103 Any of methods 3.92-3.102, wherein the reaction temperature of step (1) and step (2) is independently selected from -40°C to 60°C, -25°C to 30°C, -20°C to 30°C, -20°C to 10°C, -10°C to 30°C, -10°C to 10°C, -20°C to 0°C, -10°C to 0°C, and 0°C to 30°C;

[0670] 3.104 Any of methods 3.92-3.103, wherein step (1) comprises mixing compound 6-G with a base and a suitable solvent at a temperature of -20°C to 0°C, then adding a chlorinating agent (or forming a chlorinating agent in situ), stirring the reaction for a period of 0.5 hour to 10 hours (e.g., 1 to 5 hours), and then performing step (2), which comprises cooling the reaction to -40°C to -10°C, adding an ammonia source and stirring the reaction at a temperature in the range of -10 to 10°C for a period of 0.1 to 5 hours (e.g., 0.1 to 2 hours);

[0671] 3.105 Method 3 or any one of methods 3.1-3.104, wherein the method comprises the step of reacting the mono-protected sulfonyl imide compound 6-H with a protecting agent in a suitable solvent and under conditions effective for a period of time to produce the di-protected sulfonyl imide compound 6-I, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k As defined in any of Methods 3.78-3.81, provided that R p With R k different;

[0672] 3.106 Method 3.105, where R kis selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0673] 3.107 Method 3.106, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0674] 3.108 Method 3.107, where R k is tert-butyldimethylsilyl;

[0675] 3.109 Any of methods 3.105-3.108, wherein the protecting group R p Selected from silyl groups, alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl (aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., tert-butyl or trityl), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., C 1-6 alkoxymethyl, such as methoxymethyl or ethoxymethyl), C 1-6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1-6 Alkyl(aryl) (aryl), such as diphenylmethyl), alkylsulfonyl groups (e.g., SO 2 C 1-6 alkyl, such as methylsulfonyl or isopropylsulfonyl) and arylsulfonyl groups (e.g., SO 2 -aryl, such as benzenesulfonyl, toluenesulfonyl);

[0676] 3.110 Method 3.109, where R p Selected from -C(=O)-C1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[0677] 3.111 Method 3.110, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0678] 3.112 Method 3.111, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0679] 3.113 Any of methods 3.105-3.112, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide) , dimethylphenylsilyl bromide, triphenylsilyl bromide), 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, acetyl chloride, benzoyl chloride), acid anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane) and alkoxymethyl halides (e.g., methoxymethyl chloride);

[0680] 3.114 Any of methods 3.105-3.112, wherein the protecting agent is 1H-imidazole-1-carboxylic acid C 1-6 Alkyl or C 1-6 Alkyl (aryl) esters, optionally by reacting the corresponding C 1-6 Alkyl alcohol or C 1-6 Alkyl (aryl) alcohol reacts with carbonyl diimidazole (CDI) in a suitable solvent, and then compound 6-H is added to prepare in situ;

[0681] 3.115 Method 3.113 or 3.114, wherein the protecting agent is selected from symmetrical or unsymmetrical carbonates (eg, di-tert-butyl dicarbonate or 4-nitrophenyl (1-phenylethyl) carbonate), C 1-6 Alkyl or C 1-6 Alkyl (aryl) chloroformate (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate) or 1H-imidazole-1-carboxylic acid C 1-6 Alkyl or C 1-6 Alkyl (aryl) esters;

[0682] 3.116 Method 3.115, wherein the protecting reagent is selected from 1-phenylethyl-1H-imidazole-1-carboxylate (optionally prepared in situ from 1-phenylethanol and CDI), 4-nitrophenyl-(1-phenylethyl) carbonate and 1-phenylethyl chloroformate, wherein each of said reagents is optionally in the (R) or (S) form;

[0683] 3.117 Any of methods 3.105-3.116, wherein the reaction further comprises a base;

[0684] 3.118 Method 3.117, wherein the base is selected from a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine) , inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0685] 3.119 Method 3.118, wherein the base is an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) or an organic lithium base (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium);

[0686] 3.120 Method 3.119, wherein the protecting agent is (S)-1H-imidazole-1-carboxylic acid 1-phenylethyl ester (optionally prepared in situ from (S)-1-phenylethanol and CDI), and the base is lithium hexamethyldisilazide;

[0687] 3.121 Any of methods 3.105-3.120, wherein the reaction further comprises a mixture selected from 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-

[0688] Catalysts for pyrrolidine pyridine, 4-piperidinyl pyridine and 9-azajulonidine;

[0689] 3.122 Any of methods 3.105-3.121, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0690] 3.123 Method 3.122, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0691] 3.124 Method 3.122, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0692] 3.125 Method 3.122 wherein the nonpolar solvent is an ether, optionally wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran;

[0693] 3.126 Any of methods 3.105-3.125, wherein the reaction temperature is -30°C to 100°C, for example, -20°C to 60°C, -20°C to 10°C, 0°C to 25°C, 0°C to 100°C, for example, 20°C to 80°C, or 35°C to 55°C;

[0694] 3.127 Method 3 or one of methods 3.1-3.126, wherein the method comprises the step of reacting compound 6-I with a deprotecting agent in a suitable solvent and under conditions effective to form compound 6-J for a period of time, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R k As defined in any of Methods 3.78-3.81, and wherein R p As defined in any of Methods 3.109-3.112, provided that R p With R k different;

[0695] 3.128 Method 3.127, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0696] 3.129 Method 3.128, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0697] 3.130 Method 3.129, where R k is tert-butyldimethylsilyl;

[0698] 3.131 Any of the methods 3.127-3.130, R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[0699] 3.132 Method 3.131, where R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0700] 3.133 Method 3.132, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0701] 3.134 Method 3.133, where R k is tert-butyldimethylsilyl, and R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0702] 3.135 Any of methods 3.127-3.134, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent;

[0703] 3.136 Method 3.135, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (monobasic sodium phosphate, disodium hydrogen phosphate or tribasic sodium phosphate), potassium phosphate (monobasic potassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenyl silicate, hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complexes, Pd complexes, Ir complexes) and combinations of ammonium formate with palladium or platinum catalysts (e.g., Pd, Pd / C, Pt, PtO 2 )

[0704] 3.137 Any of methods 3.127-3.136, where R k is a silyl group, and the deprotecting agent is a fluoride agent or an inorganic base;

[0705] 3.138 Method 3.137, where R kis a trialkylsilyl group (e.g., tripropylsilyl, triisopropylsilyl, tert-butyldiethylsilyl, tert-butyldimethylsilyl), and the deprotecting agent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, lithium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine trihydrofluoride, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenyl silicate, and tetrabutylammonium difluorotriphenyl silicate;

[0706] 3.139 Method 3.138, where R k is tert-butyldimethylsilyl, and the deprotecting agent is selected from sodium carbonate, potassium carbonate and cesium carbonate;

[0707] 3.140 Any of methods 3.127-3.139, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, or a combination thereof;

[0708] 3.141 Method 3.140, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0709] 3.142 Method 3.140, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol), optionally in combination with water, or wherein the polar protic solvent is water;

[0710] 3.143 Method 3.140, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile), optionally in combination with water;

[0711] 3.144 Method 3.140 wherein the suitable solvent is tetrahydrofuran or 2-methyltetrahydrofuran, optionally in combination with water;

[0712] 3.145 Any of methods 3.127-3.144, wherein the reaction temperature is -15°C to 70°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C, or 20°C to 70°C, 40°C to 60°C, or about 50°C;

[0713] 3.146 Method 3 or any of Methods 3.1-3.145, wherein the method comprises the step of acylating compound 6-J with an acylating agent and a base under conditions and for a period of time effective to form compound 6-K, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0714] 3.147 Method 3.146, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0715] 3.148 Method 3.147, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0716] 3.149 Any of methods 3.146-3.148, wherein R" is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl);

[0717] 3.150 Method 3.149, where R' is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0718] 3.151 Method 3.150, wherein R" is methyl;

[0719] 3.152 Any of methods 3.146-3.151, wherein the acylating agent is an acyl chloride (e.g., R"-C(=O)-Cl), an anhydride (e.g., R"-C(=O)-O-(C=O)-R"), or a carboxylic acid (e.g., R"-COOH) in combination with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0720] 3.153 Method 3.152, where R' is C 1-6alkyl (e.g., methyl), and the acylating agent is an acid chloride (e.g., R"-C(=O)-Cl) or an acid anhydride (e.g., R"-C(=O)-O-(C=O)-R");

[0721] 3.154 Any of methods 3.146-3.153, wherein 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) and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine);

[0722] 3.155 Method 3.154 wherein the base is pyridine;

[0723] 3.156 Any of methods 3.146-3.155, wherein the reaction further comprises a catalyst, for example selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole and N,N-dimethylformamide;

[0724] 3.157 Any of methods 3.146-3.156, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0725] 3.158 Method 3.157, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0726] 3.159 Method 3.157, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0727] 3.160 Method 3.157 wherein the nonpolar solvent is dichloromethane;

[0728] 3.161 Any of methods 3.146-3.160, wherein the reaction temperature is -20°C to 60°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C or about 25°C;

[0729] 3.162 Method 3 or any of Methods 3.1-3.161, wherein the method comprises the step of stereoselectively (e.g., enantioselectively or diastereoselectively) hydrolyzing compound 6-K in a suitable solvent for a period of time and under conditions effective to produce a mixture of hydrolyzed stereoisomer 6-L and unreacted stereoisomer 6-L', wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0730] 3.163 Method 3.162, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0731] 3.164 Method 3.163, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0732] 3.165 Method 3.164, where R' is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0733] 3.166 Method 3.165, wherein R" is methyl;

[0734] 3.167 Any of methods 3.162-3.166, wherein the reacting comprises treating compound 6-K with an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease;

[0735] 3.168 Method 3.167, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas stutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei);

[0736] 3.169 Any of methods 3.162-3.168, wherein the reaction further comprises an aqueous buffer, such as a sodium phosphate buffer or a potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0737] 3.170 Any of methods 3.162-3.169, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof;

[0738] 3.171 Method 3.170, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0739] 3.172 Method 3.170, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and nitriles (e.g., acetonitrile);

[0740] 3.173 Method 3.170, wherein the nonpolar solvent is methyl isobutyl ketone, in combination with an aqueous sodium phosphate buffer (pH about 7);

[0741] 3.174 Any of methods 3.162-3.173, wherein the reaction temperature is 0°C to 50°C, for example, 10°C to 40°C, or 10°C to 30°C or about 20°C;

[0742] 3.175 Any of methods 3.162-3.174, wherein compound 6-L and compound 6-L' are purified and separately isolated;

[0743] 3.176 Method 3 or any of methods 3.1-3.175, wherein the method comprises the step of converting compound 6-B to compound 6-B' by replacing group X with a different group X, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of methods 3.4-3.10, wherein the group X of compound 6-B is a sulfonate (eg, 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate);

[0744] 3.177 Method 3.176 wherein the group X of compound 6-B' is a halide ion (eg, chloride ion, bromide ion or iodide ion);

[0745] 3.178 Method 3.177 wherein the group X of compound 6-B is 4-toluenesulfonate and the group X of compound 6-B' is bromide;

[0746] 3.179 Method 3.176, 3.177 or 3.178, wherein the method comprises treating compound 6-B with an inorganic halide salt (e.g., a lithium, sodium, potassium or cesium salt of chloride, bromide or iodide) in a suitable solvent;

[0747] 3.180 Method 3.179, wherein the inorganic halide is lithium bromide;

[0748] 3.181 Any of methods 3.176-3.180, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0749] 3.182 Method 3.181, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0750] 3.183 Method 3.181, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0751] 3.184 Method 3.181, wherein the polar aprotic solvent is N-methyl-2-pyrrolidone;

[0752] 3.185 Any of methods 3.176-3.184, wherein the reaction temperature is 20°C to

[0753] 120°C, for example, 20°C to 100°C, or 40°C to 60°C;

[0754] 3.186 Method 3 or any of 3.1 to 3.185, wherein the method comprises the step of treating compound 6-B or 6-B' with a sulfite source for a period of time and under conditions effective to produce sulfonic acid 7-A, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any one of methods 3.4-3.10, wherein the group X of compound 6-B is selected from halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate) and oxy (For example, oxytriphenyl ), or the group X of compound 6-B' is a halide ion (eg, bromide ion, chloride ion or iodide ion);

[0755] 3.187 Method 3.186, wherein the group X of compound 6-B or 6-B' is a halide ion, optionally wherein the halide ion is bromide or iodide;

[0756] 3.188 Method 3.186 or 3.187, wherein the sulfite source is an inorganic sulfite or bisulfite, such as a lithium, sodium, potassium or cesium salt of sulfite or bisulfite;

[0757] 3.189 Method 3.188, wherein the sulfite source is sodium sulfite;

[0758] 3.190 Any of methods 3.186-3.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, water, or a combination thereof;

[0759] 3.191 Method 3.190, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0760] 3.192 Method 3.190, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0761] 3.193 Method 3.190, wherein the solvent is a mixture of acetone and water;

[0762] 3.194 Any of methods 3.186-3.193, wherein the reaction temperature is 20°C to 120°C, for example, 40°C to 100°C or 50°C to 70°C;

[0763] 3.195 Method 3 or any of Methods 3.1-3.194, wherein the method comprises the steps of treating the sulfonic acid 7-A with (1) a chlorinating agent and optionally a catalyst in a suitable solvent, and then treating with (2) an ammonia source in a suitable solvent and for a period of time under conditions effective to form the sulfonamide compound 6-F, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10;

[0764] 3.196 Method 3.195, wherein the chlorinating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus(V) oxychloride, phosphorus trichloride and phosphorus pentachloride;

[0765] 3.197 Method 3.196, wherein the chlorinating agent is oxalyl chloride;

[0766] 3.198 Any of methods 3.195-3.197, wherein the reaction step (1) further comprises a catalyst, such as 4-dimethylaminopyridine or N,N-dimethylformamide;

[0767] 3.199 Any of methods 3.195-3.198, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, or wherein the solvent is a pure chlorinating agent (e.g., thionyl chloride);

[0768] 3.200 Method 3.199, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0769] 3.201 Method 3.199, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0770] 3.202 Method 3.199, wherein the solvent is tetrahydrofuran;

[0771] 3.203 Any of methods 3.195-3.302, wherein the ammonia source is selected from ammonia gas, gaseous ammonia, aqueous ammonia, and an ammonia substitute (e.g., hexamethyldisilazane) dissolved in any of the solvents provided in methods 3.199-3.202;

[0772] 3.204 Method 3.203, wherein the ammonia source is aqueous ammonia;

[0773] 3.205 Any of methods 3.195-3.204, wherein the reaction temperature of step (1) and step (2) is independently selected from -10°C to 100°C, 0°C to 50°C, 0°C to 30°C, and 20°C to 30°C;

[0774] 3.206 Any of methods 3.195-3.205, wherein step (1) comprises mixing compound 7-A with a catalyst and a suitable solvent at a temperature of 0°C to 30°C, then adding a chlorinating agent, stirring the reaction for a period of 0.1 hour to 2 hours (e.g., 0.5 to 1 hour), and then performing step (2), which comprises adding the reaction mixture from step (1) to a reactor containing an ammonia source and stirring the reaction at a temperature in the range of 10°C to 30°C for a period of 0.1 to 2 hours (e.g., 0.1 to 0.5 hours);

[0775] 3.207 Method 3 or any of Methods 3.1-3.206, wherein the method comprises the step of acylating compound 6-H with an acylating agent and a base in a suitable solvent and for a period of time under conditions effective to form diacyl compound 8-A, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k is a silyl group;

[0776] 3.208 Method 3.207, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0777] 3.209 Method 3.208, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0778] 3.210 Method 3.209, where R k is tert-butyldimethylsilyl;

[0779] 3.211 Any of methods 3.207-3.210, wherein R" is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl),

[0780] 3.212 Method 3.211, where R' is C1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0781] 3.213 Method 3.212, wherein R" is methyl;

[0782] 3.214 Any of methods 3.207-3.213, wherein the acylating agent is a combination of an acyl chloride (e.g., R"-C(=O)-Cl), an anhydride (e.g., R"-C(=O)-O-(C=O)-R"), or a carboxylic acid (e.g., R"-COOH) with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0783] 3.215 Method 3.214, where R' is C 1-6 alkyl (e.g., methyl), and the acylating agent is an acid chloride (e.g., R"-C(=O)-Cl), an acid anhydride (e.g., R"-C(=O)-O-(C=O)-R");

[0784] 3.216 Method 3.215 wherein R" is methyl and the acylating agent is acetyl chloride;

[0785] 3.217 Any of methods 3.207-3.216, wherein 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), aromatic amines (e.g., pyridine, pyrimidine, pyridazine, pyrazine, 2,6-lutidine, picoline, colloidal pyridine, imidazole), , 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), amide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) and alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylalkoxide, sodium tert-amylalkoxide, lithium tert-amylalkoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide);

[0786] 3.218 Method 3.217, wherein the base is an aromatic amine selected from pyridine, pyrimidine, pyridazine and pyrazine;

[0787] 3.219 Any of methods 3.207-3.218, wherein the reaction further comprises a catalyst, for example selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole and N,N-dimethylformamide;

[0788] 3.220 Any of methods 3.207-3.219, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0789] 3.221 Method 3.220, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0790] 3.222 Method 3.220, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0791] 3.223 Method 3.220 wherein the solvent is acetonitrile;

[0792] 3.224 Any of methods 3.207-3.223, wherein the reaction temperature is -20°C to 50°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C or about 20°C;

[0793] 3.225 Method 3 or any of Methods 3.1-3.224, wherein the method comprises the step of stereoselectively (e.g., enantioselectively or diastereoselectively) hydrolyzing compound 8-A in a suitable solvent for a period of time and under conditions effective to produce the hydrolyzed stereoisomer 8-B, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of methods 3.4-3.10, and wherein R" is as defined in any of methods 3.211-3.213;

[0794] 3.226 Method 3.225, where R' is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0795] 3.227 Method 3.226, wherein R" is methyl;

[0796] 3.228 Any of methods 3.225-3.227, wherein the reacting comprises treating compound 8-B with an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease;

[0797] 3.229 Method 3.228 wherein the lipase or protease is derived from a Carica species (e.g., Carica papaya);

[0798] 3.230 Any of methods 3.225-3.229, wherein the reaction further comprises an aqueous buffer, such as a sodium phosphate buffer or a potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0799] 3.231 Any of methods 3.225-3.230, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof;

[0800] 3.232 Method 3.231, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0801] 3.233 Method 3.231, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and nitriles (e.g., acetonitrile);

[0802] 3.234 Method 3.231, wherein the nonpolar solvent is methyl isobutyl ketone, combined with an aqueous sodium phosphate buffer (pH about 7);

[0803] 3.235 Any of methods 3.225-3.234, wherein the temperature of the reaction is 0°C to 50°C, e.g., 10°C to 40°C, or 20°C to 40°C or about 30°C;

[0804] 3.236 Method 3 or any of methods 3.1-3.235, wherein the method produces a compound according to any one or more of compounds 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A and 8-B;

[0805] 3.237 Method 3.236, wherein in any one or more of said compounds, R y Yes H, R 2 Is H or C 1-3 Alkyl (e.g., methyl), R 3 Is H or C 1-3 alkyl (e.g., methyl), X is 4-toluenesulfonyl or bromine, R eis 2-pyrimidinyl, M is Na, R k is a trialkylsilyl group (e.g., tert-butyldimethylsilyl), R p Yes -C(=O)-OC 1-6 alkyl(aryl) (e.g., 1-phenylethoxycarbonyl, optionally in the form of (R) or (S)), and R" is C 1-3 Alkyl (e.g., methyl);

[0806] 3.238 Method 3.237, wherein in one or more of said compounds, R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0807] 3.239 Method 3.238, wherein in one or more of said compounds, R 2 is H and R 3 It is methyl;

[0808] 3.240 Method 3 or any of methods 3.1-3.239, wherein the method produces a compound according to any one or more of compounds 9-A, 9-B, 9-C, 9-D or 9-E;

[0809] 3.241 Method 3.240, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D or 9-E are prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0810] 3.242 Method 3.240 or 3.241 wherein in one or more of the compounds, R x It is H, R y It is H, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6alkoxy (eg, (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (eg, 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0811] 3.243 Method 3.242, wherein in one or more of said compounds, R x Yes H, R y Yes H, R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0812] 3.244 Method 3.243, wherein in one or more of said compounds, R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0813] 3.245 Method 3.244, wherein in one or more of said compounds, R 2 is H and R 3 It is methyl;

[0814] 3.246 Any of methods 3.240-3.245, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0815] 3.247 Method 3.246, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0816] 3.248 Method 3.247, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0817] 3.249 Method 3.247, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0818] 3.250 Method 3 or any of methods 3.1-3.249, wherein the method produces a compound according to Compound I;

[0819] 3.251 Method 3.250 wherein Compound I is Compound I(a);

[0820] 3.252 Method 3.251 or 3.251, wherein compound I or I(a) is prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0821] 3.253 Any of methods 3.250-3.252, wherein in compound I or I(a), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0822] 3.254 Method 3.253 wherein in compound I or I(a), R 2 and R 3 are independently H or methyl, R 4 Yes H, R 5 is a methyl group, and R 6 It is chlorine;

[0823] 3.255 Method 3.254 wherein in compound I or I(a), R 2 and R3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0824] 3.256 Method 3.255 wherein in compound I or I(a), R 2 is H and R 3 It is methyl;

[0825] 3.257 Any of methods 3.253-3.256 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0826] 3.258 Method 3.257 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0827] 3.259 Method 3.258 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0828] 3.260 Any of methods 3.240-3.259, wherein in one or more of compound 9-E, compound I, or compound I(a), It is a double bond;

[0829] 3.261 Method 3 or any of methods 3.1-3.260, wherein the method produces compound 1;

[0830] 3.262 Method 3 or any of Methods 3.1-3.261, wherein the method further comprises any of the steps described in any of Method 1 et seq., Method 2 et seq., Method 4 et seq., and Method 5 et seq.

[0831] In a fifth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 9-A, 9-B, 9-C, 9-D, 9-E and compounds I or I(a) (Method 4), as described herein, wherein the method includes the step of reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 4 generally involves the formation of SNO-CB-TC cyclic fragments (including a ring-closing metathesis step) and the attachment of side chain fragments (SC), including advanced intermediates 9-B, 9-C and 9-E, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 4 may include any of the steps shown in Scheme 9.

[0832]

[0833] In a specific embodiment, the present disclosure provides the following method 4:

[0834] 4.1 Method 4, wherein the method comprises the step of deprotecting compound 6-L' with a deprotecting agent in a suitable solvent and under conditions effective to produce the reverse stereoisomer 8-B for a period of time, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, and wherein R" is as defined in any of Methods 3.211-3.213;

[0835] 4.2 Method 4.1, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0836] 4.3 Method 4.2, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0837] 4.4 Any of methods 4.1-4.3, wherein R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0838] 4.5 Method 4.4, wherein R" is methyl;

[0839] 4.6 Any of methods 4.1-4.5, wherein the deprotecting agent is selected from an inorganic base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), optionally in the form of their aqueous solutions), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., hydrofluoric acid, fluorine The invention can be prepared by mixing with a prepolymer such as pyridine hydrogen, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, optionally in an organic solvent), a hydrogenating agent (e.g., hydrogen gas with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) such as Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO 2 , Pt complexes, Pd complexes, Ir complexes, or phase transfer hydrogenation systems such as ammonium formate with palladium or platinum catalysts (e.g., Pd, Pd / C, Pt, PtO 2 )), optionally further comprising a phase transfer agent or an enzyme;

[0840] 4.7 Method 4.6, wherein the deprotecting agent is an acid, for example selected from trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate , sulfuric acid, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), hydrobromic acid, acetic acid, formic acid, phosphoric acid, and oxalic acid, optionally wherein the acid is trifluoroacetic acid;

[0841] 4.8 Any of methods 4.1-4.7, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0842] 4.9 Method 4.8, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0843] 4.10 Method 4.8, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0844] 4.11 Method 4.8, wherein the solvent is dichloromethane;

[0845] 4.12 Any of methods 4.1-4.11, wherein the reaction temperature is -50°C to 50°C, for example, 0°C to 40°C, or 10°C to 30°C or about 20°C;

[0846] 4.13 Method 4 or any one of 4.1-4.12, wherein the method comprises the step of condensing sulfonimide compound 8-B or sulfonimide compound 6-L with carboxylic acid 1-K using an acid activator, a base and an optional promoter in a suitable solvent and under conditions effective to form N-acylsulfonimide compound 9-A for a period of time, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of methods 3.4-3.10, and wherein R of compound 6-L p As defined in any of Methods 3.109-3.112, wherein R" of Compound 8-B is as defined in any of Methods 3.211-3.213, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0847] 4.14 Method 4.13, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0848] 4.15 Method 4.14, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0849] 4.16 Any of methods 4.13-4.15, wherein R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0850] 4.17 Method 4.16, wherein R" is methyl;

[0851] 4.18 Any of methods 4.13-4.17, wherein the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholine Chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethylimine chloride, isobutyl chloroformate, N,N,N,N'N'-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (PhO) 2 POCl, oxalyl chloride ((COCl) 2 ) and thionyl chloride (SOCl 2 );

[0852] 4.19 Method 4.18, wherein the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl);

[0853] 4.20 Any of methods 4.13-4.19, wherein 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, imidazole, 1-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and bicarbonate derivatives, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and tripotassium phosphate, and sodium dihydrogen phosphate, disodium hydrogen phosphate and trisodium phosphate);

[0854] 4.21 Method 4.20, wherein the base is imidazole; or in one embodiment, the base is 1-methylimidazole;

[0855] 4.22 Any of methods 4.13-4.21, wherein the reaction comprises a promoter selected from 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt) and 1-hydroxybenzotriazole (HOBt);

[0856] 4.23 Any of methods 4.13-4.22, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the promoter is DMAP;

[0857] 4.24 Any of methods 4.13-4.23, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent, or a combination thereof with water;

[0858] 4.25 Method 4.24, wherein the solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0859] 4.26 Method 4.24, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP)), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), ketones (acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (2-propanol); halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0860] 4.27 Method 4.24, wherein the solvent is N,N-dimethylformamide. In one embodiment, the solvent is acetonitrile;

[0861] 4.28 Any of methods 4.13-4.27, wherein the reaction temperature is -50°C to 50°C, for example, 0°C to 40°C, or 10°C to 30°C, or 0°C to 80°C or about 20°C;

[0862] 4.29 Method 4 or any of methods 4.1-4.28, wherein the method comprises the step of deprotecting compound 9-A for a period of time under conditions effective to form compound 9-B or deprotecting compound 9-D for a period of time under conditions effective to form compound 9-E using a deprotecting agent in a suitable solvent, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R pAs defined in any one of Methods 3.109-3.112 or as -C(=O)-R", wherein R" is as defined in any one of Methods 3.211-3.213, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0863] 4.30 Method 4.29, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0864] 4.31 Method 4.30, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0865] 4.32 Any of the methods 4.31, where R p is -C(=O)-R", and R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0866] 4.33 Method 4.32, wherein R" is methyl;

[0867] 4.34 Any of methods 4.29-4.33, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent or an enzyme;

[0868] 4.35 Method 4.34, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), 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, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), methanesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenyl silicate, hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complexes, Pd complexes, Ir complexes) and combinations of ammonium formate with palladium or platinum catalysts (e.g., Pd, Pd / C, Pt, PtO 2 ) combination; in one embodiment, the deprotecting agent is sodium isopropoxide; in one embodiment, the deprotecting agent is trifluoroacetic acid;

[0869] 4.36 Method 4.34, wherein the deprotecting agent is an enzyme, such as a lipase or a protease, for example a bacterial or fungal lipase or protease;

[0870] 4.37 Method 4.36, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas astutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei);

[0871] 4.38 Method 4.37, wherein the enzyme is a lipase from Pseudomonas stutzeri;

[0872] 4.39 Methods 4.36-4.38, wherein the reaction further comprises an aqueous buffer, such as a sodium phosphate buffer or a potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0873] 4.40 Any of methods 4.29-4.39, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, a polar protic solvent, water, or a combination thereof;

[0874] 4.41 Method 4.40, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the non-polar solvent is toluene;

[0875] 4.42 Method 4.40, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and nitriles (e.g., acetonitrile);

[0876] 4.43 Method 4.40, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol) and water or a combination thereof;

[0877] 4.44 Method 4.40, wherein the nonpolar solvent is methyl tert-butyl ether, combined with an aqueous sodium phosphate buffer (pH about 7). In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and 2-propanol (IPA);

[0878] 4.45 Any of methods 4.29-4.44, wherein the reaction temperature is 0°C to 100°C, for example, 10°C to 80°C, or 20°C to 60°C, or 20°C to 40°C, or 40°C to 80°C, or 60°C to 80°C or about 30°C; in one embodiment, the reaction temperature is 10°C-30°C. In one embodiment, the reaction temperature is 60°C-80°C;

[0879] 4.46 Method 4 or any one of 4.1-4.45, wherein the method includes the step of acylating compound 9-B for a period of time under conditions effective to form compound 9-C or acylating compound 9-E for a period of time under conditions effective to form compound I, the step comprising treating the starting material compound with a suitable acylating agent and a base in a suitable solvent, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0880] 4.47 Method 4.46, where R 12 As defined in Compound I or I(a);

[0881] 4.48 Method 4.46, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0882] 4.49 Method 4.48, where R 12 Yes-C(O)-R 1 , and R 1is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0883] 4.50 Method 4.49, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0884] 4.51 Method 4.50, where R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with alkoxy (e.g., methoxy);

[0885] 4.52 Method 4.51, where R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0886] 4.53 Any of methods 4.46-4.52, wherein R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl, and the acylating agent is an acyl chloride (e.g., R 1 -C(=O)-Cl), anhydrides (e.g., R 1 -C(=O)-O-(C=O)-R 1 ) or carboxylic acid (e.g., R1 -COOH) in combination with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0887] 4.54 Method 4.53, wherein the activating agent is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholine chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethylimine chloride, isobutyl chloroformate, N,N,N,N'N'-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT);

[0888] 4.55 Method 4.54, wherein the activating agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl);

[0889] 4.56 Any of methods 4.46-4.52, wherein R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted -OR 7 , and the acylating agent is a chloroformate (e.g., R 7 -OC(=O)-Cl) or carbonate (e.g., R 7 -OC(=O)-OR 7 ).

[0890] 4.57 Any of methods 4.46-4.52, wherein R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted -NR 8 R 9 , and the acylating agent is an isocyanate (e.g., R 8 R 9 -NC(=O));

[0891] 4.58 Any of methods 4.46-4.57, wherein the base is selected from a tertiary amine (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), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an inorganic base (lithium carbonate, 1-methylimidazole;

[0892] 4.59 Any of methods 4.46-4.58, wherein the reaction further comprises a catalyst / promoter, for example selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, N,N-dimethylformamide, N,N-dimethylacetamide and dichloromethylene-dimethylimine chloride; in one embodiment, the catalyst / promoter is 4-dimethylaminopyridine;

[0893] 4.60 Any of methods 4.46-4.59, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent, optionally further comprising water;

[0894] 4.61 Method 4.60, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene);

[0895] 4.62 Method 4.60, wherein the solvent is selected from esters (e.g., ethyl acetate, isopropyl acetate), carbonates (e.g., dimethyl carbonate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform), hydrocarbon solvents (e.g., toluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone) and nitriles (e.g., propionitrile);

[0896] 4.63 Method 4.60, wherein the solvent is acetonitrile;

[0897] 4.64 Any of methods 4.46-4.63, wherein the reaction temperature is -20°C to 60°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C or about 20°C;

[0898] 4.65 Method 4 or any of Methods 4.1-4.64, wherein the reaction comprises the step of subjecting Compound 9-A to ring-closing metathesis for a period of time under conditions effective to form Compound 9-D, or subjecting Compound 9-B to ring-closing metathesis for a period of time under conditions effective to form Compound 9-E, or subjecting Compound 9-C to ring-closing metathesis for a period of time under conditions effective to form Compound I, using a suitable catalyst in a suitable solvent, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R x As defined in Method 1.18 or 1.19, where R 5 As defined in any of Methods 1.75-1.78, wherein R 6 is hydrogen or a halogen, and wherein It is a double bond;

[0899] 4.66 Method 4.65, where R x and R y It's all hydrogen;

[0900] 4.67 Method 4.65 or 4.66, where R 12 As defined in Compound I or I(a);

[0901] 4.68 Method 4.67, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0902] 4.69 Method 4.68, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C1-6 Alkoxy and halogen;

[0903] 4.70 method 4.69, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0904] 4.71 Method 4.70, R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with alkoxy (e.g., methoxy);

[0905] 4.72 Method 4.71, where R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0906] 4.73 Any of methods 4.65-4.72, wherein the catalyst is a ruthenium catalyst or a molybdenum catalyst;

[0907] 4.74 Method 4.73, wherein the catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) , dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][3-(2-pyridyl)propylene]ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro(phenylmethylene)bis(3-bromopyridine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro[3-(2-pyridyl)propylidene]ruthenium(II), (1,3-dimesityl-2-imidazolidinyl)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl][2-thienylmethylene]ruthenium(II) dichloride 1H-inden-1-yl]ruthenium(II) dichloride, tricyclohexylphosphino[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-yl]ruthenium(II) dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) and bis(tricyclohexylphosphino)-3-phenyl-1H-inden-1-ylruthenium(II) dichloride;

[0908] 4.75 Method 4.73, wherein the catalyst is selected from 2,6-diisopropyl-phenylimino-neophenylene [(S)-(-)-BIPHEN] molybdenum (VI), dichlorobis[(2,6-diisopropylphenyl)imino](1,2-dimethoxyethane) molybdenum (VI) and (T-4)-chloro(2,2-dimethylpropylene)[2,2",4,4',6,6'-hexa(1-methylethyl)[1,1':3',1-terphenyl]-2'olate][2-methyl-2-propylaminoester(2-)] molybdenum (VI);

[0909] 4.76 Method 4.73, wherein the suitable catalyst is Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II));

[0910] 4.77 Any of methods 4.65-4.76, wherein the solvent is a nonpolar solvent or a polar aprotic solvent;

[0911] 4.78 Method 4.77, wherein the solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the solvent is toluene;

[0912] 4.79 Method 4.77, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone) and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate);

[0913] 4.80 Any of methods 4.65-4.79, wherein the reaction temperature is 0°C to 150°C, for example, 20°C to 90°C, or 40°C to 90°C, or 20°C to 60°C, or 40°C to 80°C or about 80°C; in one embodiment, the reaction temperature is 70°C to 90°C;

[0914] 4.81 Method 4 or any of Methods 4.1-4.80, wherein the method further comprises a step of forming a compound 9-D, 9-E, I or I(a) (wherein is a double bond) for a period of time, wherein is a double bond, the step comprising treating the compound with hydrogen in a suitable solvent (e.g., acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene) over a suitable catalyst (e.g., Pd / C, Pt, PtO2, Raney nickel, nickel boride, RhCl(Ph3P)3);

[0915] 4.82 Method 4 or any of Methods 4.1-4.81, wherein the method produces a compound according to one or more of Compound 8-B, 9-A, 9-B, 9-C, 9-D, 9-E or Compound I or I(a);

[0916] 4.83 Method 4.82, wherein in any one or more of said compounds, R x Yes H, R y Yes H, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), R p Yes -C(=O)-OC 1-6 alkyl(aryl) (eg, 1-phenylethoxycarbonyl, optionally in the form of (R) or (S)), R' is C 1-3 Alkyl (eg, methyl), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (eg, (S)-1-phenethoxy) or optionally substituted 5-10 membered heteroaryl (eg, 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0917] 4.84 Method 4.83, wherein in one or more of the compounds, R 2 and R 3 It is H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is methyl;

[0918] 4.85 Method 4.84, wherein in one or more of the compounds, R 2 is H and R 3 It is methyl;

[0919] 4.86 Any of methods 4.82-4.85, wherein in one or more of compound 9-C, compound I and compound I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[0920] 4.87 method 4.86, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[0921] 4.88 Method 4.87, where R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0922] 4.89 Any of methods 4.82-4.88, wherein in one or more of compound 9-D, 9-E, compound I, or compound I(a), It is a double bond;

[0923] 4.90 Method 4 or any of Methods 4.1-4.89, wherein the product of the method is Compound 1;

[0924] 4.91 Method 4 or any of Methods 4.1-4.90, wherein the method further comprises any of the steps described in any of Method 1 et seq., Method 2 et seq., Method 3 et seq., and Method 5 et seq.

[0925] In a sixth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 5-F, 5-F', 10-A, 10-B, 10-C, 10-C', 10-D, 10-E, 9-A and 9-D (Method 5), as described herein, wherein the method includes the step of reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 5 generally involves alternative routes to form SNO-CB-TC cyclic fragments (including a ring-closing metathesis step) and to attach side chain fragments, including advanced intermediates 10-C, 10-C' and 10-E, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 5 may include any of the steps shown in Scheme 10.

[0926]

[0927] In a specific embodiment, the present disclosure provides the following method 5:

[0928] 5.1 Method 5, wherein the method includes any steps described in any one of Method 1, etc., Method 2, etc., Method 3, etc., and Method 4, etc.;

[0929] 5.2 Method 5 or 5.1, wherein the method comprises the following steps: (1) reacting compound 5-E or 5-E' with 4-fluoro-3-nitrobenzoic acid or ester under conditions and for a period of time effective to form compound 5-F, as defined in any one of methods 2.126-2.2.140, wherein R 6 , R n and R z As defined in any of Methods 2.126-2.131, and optionally (2) in an amount effective to form compound 5-F' (wherein R z Compound 5-F (wherein R is H) is treated with a compound 5-F as provided in any one of Methods 1.134-1.138 for a period of time under conditions of z is not H) hydrolyzed to the corresponding compound 5-F'; in one embodiment, R n Each is independently CH 3 , or two of them R n The moieties are linked together to form a -CH 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 CH(Ph)-、-C(CH 3 ) 2C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CBr 2 CH 2 -、-CH 2 (C=CH)CH 2 -、-CH 2 CH(Ph)CH 2 -、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH(C 6 H 5 )CH(C 6 H 5 ),-CH 2 CH(C 6 H 5 )CH 2 -and-(oC 6 H 4 )-bridge;

[0930] 5.3 Method 5.2, wherein R of compound 5-F is z is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl);

[0931] 5.4 Method 5.3, wherein R of compound 5-F or 5-F' is z It is H;

[0932] 5.5 Method 5 or any of Methods 5.1 or 5.2, wherein the method comprises the step of acylating compound 6-L with 4-fluoro-3-nitrobenzoic acid for a period of time under conditions effective to form compound 10-A or acylating compound 6-L with benzoic acid compound 5-F / 5-F' for a period of time under conditions effective to form compound 10-B using an acid activating agent and a base in a suitable solvent, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of methods 2.76-2.79 or 2.108-2.111, wherein R of compound 5-F or 5-F' is z is H, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0933] 5.6 Method 5.5, where R 6 It is chlorine;

[0934] 5.7 Method 5.5 or 5.6, where both R n is methyl or ethyl, or two R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、CH 2 C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH(C 6 H 5 )CH(C6 H 5 ) and -CH 2 CH(C 6 H 5 )CH 2 - bridge;

[0935] 5.8 Any of the methods 5.5-5.7, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0936] 5.9 Method 5.8, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0937] 5.10 Any of methods 5.5-5.9, wherein the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl), (PhO) 2 POCl, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholine chlorides (DMTMM), thionyl chloride, oxalyl chloride, and sulfuryl chloride;

[0938] 5.11 Method 5.10, wherein the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl);

[0939] 5.12 Any of methods 5.5-5.11, wherein 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), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0940] 5.13 Method 5.12, wherein the base is imidazole or 1-methylimidazole;

[0941] 5.14 Any of methods 5.5-5.13, wherein the reaction further comprises a promoter selected from 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt) and 1-hydroxybenzotriazole (HOBt);

[0942] 5.15 Any of methods 5.5-5.14, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the promoter is DMAP;

[0943] 5.16 Any of methods 5.5-5.15, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0944] 5.17 Method 5.16, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0945] 5.18 Method 5.16, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0946] 5.19 Method 5.16, wherein the solvent is acetonitrile;

[0947] 5.20 Any of methods 5.5-5.19, wherein the reaction temperature is -50°C to 50°C, for example, 0°C to 40°C, or 10°C to 30°C or about 20°C;

[0948] 5.21 Method 5 or any of methods 5.1-5.20, wherein the method comprises the step of treating a fluorophenyl compound 10-A with an alcohol compound 5-E or 5-E' in a suitable solvent for a period of time and under conditions effective to form an ether adduct compound 10-B, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0949] 5.22 Method 5.21, where R 6 It is chlorine;

[0950] 5.23 Method 5.21 or 5.22, wherein both R n is methyl or ethyl, or both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[0951] 5.24 Any of the methods 5.21-5.23, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0952] 5.25 Method 5.24, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0953] 5.26 Any of methods 5.21-5.25, wherein compound 5-E or 5-E' is dissolved or suspended in a suitable solvent and treated with a strong base, and optionally with a promoter (eg, sodium iodide, tetrabutylammonium iodide);

[0954] 5.27 Method 5.26, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0955] 5.28 Method 5.27, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide and potassium diisopropylamide; optionally wherein the base is potassium tert-butoxide;

[0956] 5.29 Any of methods 5.21-5.28, wherein compound 10-A is added to the reaction about 1 to 60 minutes, e.g., about 1 to 30 minutes, or 1 to 20 minutes, or 1 to 15 minutes, or 1 to 10 minutes, or 1 to 5 minutes after the addition of the base;

[0957] 5.30 Any of methods 5.21-5.29, wherein the suitable solvent is a non-polar solvent;

[0958] 5.31 Method 5.30, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0959] 5.32 Method 5.30, wherein the nonpolar solvent is tetrahydrofuran;

[0960] 5.33 Any of methods 5.21-5.32, wherein the reaction temperature is -80°C to 100°C, for example, -45°C to 10°C, or -30°C to 10°C, or -10°C to 5°C, or about 0°C, or -10°C to 50°C, or -10°C to 30°C, or 10°C to 30°C, or 30°C to 80°C;

[0961] 5.34 Method 5 or any of 5.1-5.33, wherein the method comprises the step of treating the acetal compound 10-B or 10-C' with a deprotecting agent in a suitable solvent and for a period of time under conditions effective to form the aldehyde compound 10-C or 10-D, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0962] 5.35 Method 5.34, where R6 It is chlorine;

[0963] 5.36 Method 5.34 or 5.35, wherein both R n is methyl or ethyl, or both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[0964] 5.37 Any of the methods 5.34-5.36, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0965] 5.38 Method 5.37, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0966] 5.39 Any of methods 5.34-5.38, wherein the acid is selected from HCl (e.g., aqueous HCl or HCl / methanol, HCl / isopropanol or HCl / dihydrochloric acid). alkane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium toluenesulfonate , trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium trifluoromethanesulfonate), and acidic resins (e.g., Amberlyst);

[0967] 5.40 Method 5.39, wherein the acid is methanesulfonic acid;

[0968] 5.41 Any of methods 5.34-5.40, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0969] 5.42 Method 5.41, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0970] 5.43 Method 5.41, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0971] 5.44 Method 5.41, wherein the polar aprotic solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0972] 5.45 Method 5.41, wherein the suitable solvent is tetrahydrofuran and water;

[0973] 5.46 Any of methods 5.34-5.45, wherein the reaction temperature is 0°C to 100°C, for example, 20°C to 50°C, or 20°C to 30°C, or 60°C to 70°C;

[0974] 5.47 Any of methods 5.34-5.46, wherein the method results in R p The cleavage of the protecting group makes the reaction R p The product compound 10-C or 10-D is hydrogen;

[0975] 5.48 Method 5 or any of 5.1-5.47, wherein the method includes the step of reducing the nitro / aldehyde compound 10-C to the aniline / aldehyde compound 10-D or reducing the nitro / acetal 10-B to the aniline / acetal 10-C', wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, or R p is hydrogen; and wherein each R n as defined in any of Methods 2.76-2.79 or 2.108-2.111;

[0976] 5.49 Method 5.48, where R 6 It is chlorine;

[0977] 5.50 Method 5.48 or 5.49, where Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0978] 5.51 Method 5.50, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0979] 5.52 Method 5.48 or 5.49, where R p It is hydrogen;

[0980] 5.53 Any of methods 5.48-5.52, wherein the reducing agent is selected from a solution of an acid (e.g., formic acid or acetic acid or HCl, or ammonium chloride in a suitable solvent) of zinc, tin or iron;

[0981] 5.54 Method 5.53, wherein the reducing agent is a solution of iron (e.g., powder) in acetic acid;

[0982] 5.55 Any of methods 5.48-5.52, wherein the reducing agent is a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer

[0983] Hydrogenation system);

[0984] 5.56 Method 5.55, wherein the hydrogenating agent is hydrogen gas and a palladium, platinum, rhodium, iridium, ruthenium or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc) 2 、Pt / C、PtO 2 , Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complex, Pd complex, Ir complex) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO 2 )

[0985] 5.57 Method 5.56, wherein the hydrogenating agent is hydrogen with Pd, Pd / C, Pd(OAc) 2 , Pt / C or PtO 2 a combination of catalysts, optionally at a pressure of 1-5 bar (e.g., 1-2 bar);

[0986] 5.58 Any of methods 5.48-5.57, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0987] 5.59 Method 5.58, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0988] 5.60 Method 5.58, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid) or an aqueous acid solution (e.g., aqueous HCl);

[0989] 5.61 Method 5.58, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0990] 5.62 Method 5.58, wherein the suitable solvent is acetic acid;

[0991] 5.63 Any of methods 5.48-5.62, wherein the reaction temperature is 0°C to 100°C,

[0992] For example, 20°C to 50°C, or 20°C to 30°C, or 50°C to 90°C, or 65°C to 85°C;

[0993] 5.64 Any of methods 5.34-5.63, wherein the desired product compound 10-D of this step undergoes spontaneous condensation to partially or completely form the intermediate imine 10-D', and the mixture of 10-D and 10-D' is subjected to the next step, or the isolated product is 10-D' for the next step;

[0994] 5.65 Method 5 or any of 5.1-5.64, wherein the method comprises the step of treating the aniline / acetal compound 10-D (and / or 10-D') with a reducing agent in a suitable solvent and for a period of time under conditions effective to produce the secondary amine compound 10-E, wherein R 6 As defined in Method 2.10 or 2.11, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, or R p It is hydrogen;

[0995] 5.66 Method 5.65, where R 6 It is chlorine;

[0996] 5.67 Method 5.65 or 5.66, where R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0997] 5.68 Method 5.67, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[0998] 5.69 Method 5.65 or 5.66, where R p It is hydrogen;

[0999] 5.70 Any of methods 5.65-5.69, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, a hydrogenating agent, iron powder (Fe) and sodium triacetoxyborohydride (NaBH(OAc) 3 ), combinations of tin or zinc with an acid (e.g., hydrochloric acid, acetic acid, ammonium chloride), combinations of transition metals (e.g., Pd, Pt, or Rh) with H 2 or formate, poisoned heterogeneous catalysts (e.g., Pt / S / C), silanes (triisopropylsilane, triphenylsilane, diethylsilane, etc.), sodium borohydride, sodium borohydride / acetic acid, 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 iron powder (Fe) and sodium triacetoxyborohydride (NaBH(OAc) 3 )

[1000] 5.71 Method 5.70, wherein the reducing agent is a hydride reducing agent;

[1001] 5.72 Method 5.71, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride and tetramethylammonium triacetoxyborohydride;

[1002] 5.73 Method 5.72, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[1003] 5.74 Any of methods 5.71-5.73, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, a borate, magnesium perchlorate, or zinc chloride);

[1004] 5.75 Method 5.70, wherein the silane reducing agent is triethylsilane;

[1005] 5.76 Any of methods 5.70-5.75, wherein the reaction further comprises an acid (e.g.,

[1006] from formic acid, acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid and hydrochloric acid);

[1007] 5.77 Any of methods 5.65-5.76, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[1008] 5.78 Method 5.77, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[1009] 5.79 Method 5.77, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid);

[1010] 5.80 Method 5.77, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[1011] 5.81 Method 5.77, wherein the suitable solvent is acetic acid;

[1012] 5.82 Any of methods 5.65-5.81, wherein the reaction temperature is -30°C to 100°C, for example, 0°C to 80°C, or 20°C to 30°C, 20°C to 50°C, 50°C to 90°C, or 60°C to 80°C;

[1013] 5.83 Method 5 or any of methods 5.1-5.82, wherein the method comprises the step of treating compound 10-E with a reducing agent and compound 1-I in a suitable solvent for a period of time under conditions effective to form tertiary amine compound 9-A, wherein R 6 As defined in Method 2.10 or 2.11, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R p As defined in any of Methods 3.109-3.112, or R p is hydrogen, where R x As defined in method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.75-1.78;

[1014] 5.84 Method 5.83, where R 6 It is chlorine;

[1015] 5.85 Method 5.83 or 5.84, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1016] 5.86 method 5.85, where R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1017] 5.87 Method 5.83 or 5.84, where R p It is hydrogen;

[1018] 5.88 Any of methods 5.83-5.87, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent;

[1019] 5.89 Method 5.88, wherein the reducing agent is a hydride reducing agent;

[1020] 5.90 Method 5.89, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride and tetramethylammonium triacetoxyborohydride;

[1021] 5.91 Method 5.90, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[1022] 5.92 Any of methods 5.89-5.91, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, a borate, magnesium perchlorate, or zinc chloride);

[1023] 5.93 Method 5.88, wherein the silane reducing agent is triethylsilane;

[1024] 5.94 Any of methods 5.83-5.93, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid);

[1025] 5.95 Any of methods 5.83-5.94, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[1026] 5.96 Method 5.95, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrofuran, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[1027] 5.97 Method 5.95, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid);

[1028] 5.98 Method 5.95, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., methyl acetate, ethyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[1029] 5.99 Method 5.95, wherein the suitable solvent is dichloromethane;

[1030] 5.100 Any of methods 5.83-5.95, wherein the reaction temperature is -30°C to 80°C, e.g., 0°C to 80°C or 10°C to 30°C;

[1031] 5.101 Method 5 or any of Methods 5.1-5.100, wherein the method produces a compound according to one or more of Compounds 10-A, 10-B, 10-C, 10-C', 10-D, 10-E, or 9-A;

[1032] 5.102 Any of Method 5 or 5.1-5.101, wherein the product Compound 9-A is further refined to Compound I, Compound I(a) or Compound 1, as provided by any step described in Method 4.

[1033] In another aspect, the disclosure provides compounds 1-A, 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 2-A, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 4-A, 4-B, 4-C, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-I, 6-A, 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6- Each of the compounds of -G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, 10-A, 10-B, 10-C, 10-C', 10-D or 10-E, in each of their disclosed embodiments for all purposes, and methods for making Compound 1, Compound 1(a) or Compound 1, and methods for making any other compound disclosed herein. In specific embodiments, the disclosure provides:

[1034] 6.1 Compound 9-A, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 5 It is C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1035] 6.2 Compound 9-A, as provided in Formula 6.1, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1036] 6.3 Compound 9-A, as provided in Formula 6.2, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1037] 6.4 Compound 9-A, as provided in Formula 6.3, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1038] 6.5 Compound 9-A, as provided in Formula 6.4, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1039] 6.6 Compound 9-A, as provided in Formula 6.5, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1040] 6.7 Compound 9-A, as provided by any one of Formulas 6.1-6.6, wherein R x and R y Each is H;

[1041] 6.8 Compound 9-A, as provided by any one of Formulas 6.1-6.7, wherein R 2 is H and R 3 It is methyl;

[1042] 6.9 Compound 9-A, as provided by any one of Formulas 6.1-6.8, wherein R 5 It is methyl;

[1043] 6.10 Compound 9-A, as provided by any one of Formulas 6.1-6.9, wherein R 6 It is chlorine;

[1044] 6.11 Compound 9-B, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 It is H, R 5 It is C 1-6 alkyl (eg, methyl), and R 6 is a halogen (e.g., chlorine);

[1045] 6.12 Compound 9-B, as provided in Formula 6.11, wherein R x and R y Each is H;

[1046] 6.13 Compound 9-B, as provided in Formula 6.11 or 6.12, wherein R 2 is H and R 3 It is methyl;

[1047] 6.14 Compound 9-B, as provided by any one of Formulas 6.11-6.13, wherein R 5 It is methyl;

[1048] 6.15 Compound 9-B, as provided by any one of Formulas 6.11-6.14, wherein R 6 It is chlorine;

[1049] 6.16 Compound 9-C, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the 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 are optionally substituted with 1-5 R 10 Group substitution; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and-NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[1050] 6.17 Compound 9-C, as provided in Formula 6.16, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and halogen;

[1051] 6.18 Compound 9-C, as provided in Formula 6.17, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted pyrazolyl or imidazolyl; wherein R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (e.g., methoxy);

[1052] 6.19 Compound 9-C, as provided in Formula 6.18, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with alkoxy (e.g., methoxy);

[1053] 6.20 Compound 9-C, as provided in Formula 6.19, wherein R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[1054] 6.21 Compound 9-C, provided by any one of Formulas 6.16-6.20, wherein R x and R y Each is H;

[1055] 6.22 Compound 9-C, as provided by any one of Formulas 6.16-6.21, wherein R 2 is H and R 3 It is methyl;

[1056] 6.23 Compound 9-C, provided by any one of Formulas 6.16-6.22, wherein R 5 It is methyl;

[1057] 6.24 Compound 9-C, provided by any one of Formulas 6.16-6.23, wherein R 6 It is chlorine;

[1058] 6.25 Compound 9-E, wherein R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 4 Yes H, R 5 It is C 1-6 alkyl (eg, methyl), and R 6 is a halogen (e.g., chlorine);

[1059] 6.26 Compound 9-E, as provided in Formula 6.25, wherein It is a double bond;

[1060] 6.27 Compound 9-E, as provided in Formula 6.25 or 6.26, wherein R 2 is H and R 3 It is methyl;

[1061] 6.28 Compound 9-E, provided by any one of Formulas 6.25-6.27, wherein R 5 It is methyl;

[1062] 6.29 Compound 9-E, provided by any one of Formulas 6.25-6.28, wherein R 6 It is chlorine;

[1063] 6.30 Compound 10-E, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1064] 6.31 Compound 10-E, as provided in Formula 6.30, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1065] 6.32 Compound 10-E, as provided in Formula 6.30 or 6.31, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1066] 6.33 Compound 10-E, provided by any one of Formulas 6.30-6.32, wherein R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1067] 6.34 Compound 10-E, as provided in Formula 6.33, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1068] 6.35 Compound 10-E, as provided in Formula 6.34, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1069] 6.36 Compound 10-E, as provided by any one of Formulas 6.30-6.35, wherein R y It is H;

[1070] 6.37 Compound 10-E, provided by any one of Formulas 6.30-6.36, wherein R 2 is H and R 3 It is methyl;

[1071] 6.38 Compound 10-E, provided by any one of Formulas 6.30-6.37, wherein R 6 It is chlorine;

[1072] 6.39 Compound 10-B or 10-C', wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an alkylene bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (eg, a catechol bridge), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1073] 6.40 Compound 10-B or 10-C', as provided in Formula 6.39, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1074] 6.41 Compound 10-B or 10-C', as provided in Formula 6.39 or 6.40, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1075] 6.42 Compound 10-B or 10-C', as provided by any one of Formulas 6.39-6.41, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1076] 6.43 Compound 10-B or 10-C', as provided in Formula 6.42, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1077] 6.44 Compound 10-B or 10-C', as provided in Formula 6.43, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1078] 6.45 Compound 10-B or 10-C', as provided by any one of Formulas 6.39-6.44, wherein R y It is H;

[1079] 6.46 Compound 10-B or 10-C', as provided by any one of Formulas 6.39-6.45, wherein R 2 is H and R 3 It is methyl;

[1080] 6.47 Compound 10-B or 10-C', as provided by any one of Formulas 6.39-6.46, wherein each R n Independently C 1-6 Alkyl, optionally wherein each R n It is methyl;

[1081] 6.48 Compound 10-B or 10-C', as provided in Formula 6.47, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 CH(Ph)-、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CBr 2 CH 2 -、-CH 2 (C=CH)CH 2 -、-CH 2 CH(Ph)CH 2 -、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH2 CH 2 CH 2 CH 2 -and-(oC 6 H 4 )-bridge;

[1082] 6.49 Compound 10-B or 10-C', as provided in Formula 6.48, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[1083] 6.50 Compound 10-B or 10-C', as provided by any one of Formulas 6.39-6.49, wherein R 6 It is chlorine;

[1084] 6.51 Compound 10-C or 10-D, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1085] 6.52 Compound 10-C or 10-D, as provided in Formula 6.51, wherein R p Selected from -C(=O)-C1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1086] 6.53 Compound 10-C or 10-D, as provided in Formula 6.51 or 6.52, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1087] 6.54 Compound 10-C or 10-D, as provided by any one of Formulas 6.51-6.53, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1088] 6.55 Compound 10-C or 10-D, as provided in Formula 6.54, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1089] 6.56 Compound 10-C or 10-D, as provided in Formula 6.55, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1090] 6.57 Compound 10-C or 10-D, as provided by any one of Formulas 6.51-6.56, wherein R y It is H;

[1091] 6.58 Compound 10-C or 10-D, as provided by any one of Formulas 6.51-6.57, wherein R 2 is H and R 3 It is methyl;

[1092] 6.59 Compound 10-C or 10-D, as provided by any one of Formulas 6.51-6.58, wherein R 6 It is chlorine;

[1093] 6.60 Compound 10-A, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C1-6 alkyl (eg, methyl), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1094] 6.61 Compound 10-A, as provided in Formula 6.60, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1095] 6.62 Compound 10-A, as provided in Formula 6.61, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1096] 6.63 Compound 10-A, as provided in Formula 6.62, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1097] 6.64 Compound 10-A, as provided in Formula 6.63, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1098] 6.65 Compound 10-A, as provided in Formula 6.64, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1099] 6.66 Compound 10-A, as provided by any one of Formulas 6.60-6.65, wherein R y It is H;

[1100] 6.67 Compound 10-A, as provided by any one of Formulas 6.60-6.66, wherein R 2 is H and R 3 It is methyl;

[1101] 6.68 Compound 5-F, wherein R 6 is a halogen (e.g., chlorine), each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an alkylene bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (eg, a catechol bridge), and R z is selected from H and unsubstituted C 1-6 Alkyl (e.g., methyl or ethyl) and a C 1-6 Alkoxy, aryloxy, trialkylsilyl, aryl or halogenated C 1-6 Alkyl substituted C 1-6 Alkyl (e.g., methyl or ethyl);

[1102] 6.69 Compound 5-F, as provided in Formula 6.68, wherein each R n Independently C 1-6 alkyl, optionally wherein each R n It is methyl;

[1103] 6.70 Compound 5-F, as provided in Formula 6.69, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 CH(Ph)-、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2CBr 2 CH 2 -、-CH 2 (C=CH)CH 2 -、-CH 2 CH(Ph)CH 2 -、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -and-(oC 6 H 4 )-bridge;

[1104] 6.71 Compound 5-F, as provided in Formula 6.70, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[1105] 6.72 Compound 5-F, provided by any one of Formulas 6.68-6.71, wherein R z It is H;

[1106] 6.73 Compound 5-F, provided by any one of Formulas 6.68-6.72, wherein R z is unsubstituted C 1-6Alkyl (e.g., methyl or ethyl);

[1107] 6.74 Compound 5-F, provided by any one of Formulas 6.68-6.73, wherein R 6 It is chlorine;

[1108] 6.75 Compound 5-E, wherein R 6 is a halogen (e.g., chlorine), and both R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an alkylene bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[1109] 6.76 Compound 5-E, as provided in Formula 6.75, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 CH(Ph)-、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CBr 2 CH 2 -、-CH 2 (C=CH)CH 2 -、-CH 2 CH(Ph)CH 2 -、-CH(CH 3 )CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 2 CH 3 ) 2 CH 2-、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -and-(oC 6 H 4 )-bridge;

[1110] 6.77 Compound 5-E, as provided in Formula 6.76, wherein both R n The moieties are linked together to form a -CH 2 CH 2 -、-C(CH 3 ) 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 - and CH 2 C(CH 3 ) 2 CH 2 - bridge;

[1111] 6.78 Compound 5-E, provided by any one of Formulas 6.75-6.77, wherein R 6 It is chlorine;

[1112] 6.79 Compound 8-A or 8-B, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[1113] 6.80 Compound 8-A or 8-B, as provided in Formula 6.79, wherein R y It is H;

[1114] 6.81 Compound 8-A or 8-B, as provided in Formula 6.79 or 6.80, wherein R 2 is H and R 3 It is methyl;

[1115] 6.82 Compound 8-A or 8-B, as provided by any of Formulas 6.79-6.81, wherein R" is methyl;

[1116] 6.83 Compound 6-K, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 Alkyl (e.g., methyl), R" is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1117] 6.84 Compound 6-K, as provided in Formula 6.83, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1118] 6.85 Compound 6-K, as provided in Formula 6.84, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1119] 6.86 Compound 6-K, as provided in Formula 6.85, wherein R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1120] 6.87 Compound 6-K, as provided in Formula 6.86, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1121] 6.88 Compound 6-K, as provided in Formula 6.87, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1122] 6.89 Compound 6-K, provided by any one of Formulas 6.83-6.88, wherein R y It is H;

[1123] 6.90 Compound 6-K, provided by any one of Formulas 6.83-6.89, wherein R 2 is H and R 3 It is methyl;

[1124] 6.91 Compound 6-K, provided by any one of Formulas 6.83-6.90, wherein R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[1125] 6.92 Compound 6-K, as provided by any one of Formulas 6.83-6.91, wherein R" is methyl;

[1126] 6.93 Compound 6-L, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 alkyl (eg, methyl), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1127] 6.94 Compound 6-L, as provided in Formula 6.93, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1128] 6.95 Compound 6-L, as provided in Formula 6.94, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1129] 6.96 Compound 6-L, as provided in Formula 6.95, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1130] 6.97 Compound 6-L, as provided in Formula 6.96, wherein R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form;

[1131] 6.98 Compound 6-L, as provided in Formula 6.97, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1132] 6.99 Compound 6-L, provided by any one of Formulas 6.93-6.98, wherein R y It is H;

[1133] 6.100 Compound 6-L, as provided by any one of Formulas 6.93-6.99, wherein R 2 is H and R 3 It is methyl;

[1134] 6.101 Compound 6-J, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 independently H or C 1-6 alkyl (eg, methyl), and R p Select from alkylcarbonyl groups (e.g., -C(=O)-C 1-6Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1135] 6.102 Compound 6-J, as provided in Formula 6.101, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1136] 6.103 Compound 6-J, as provided in Formula 6.102, wherein R p Yes -C(=O)-OC 1-6 Alkyl(aryl);

[1137] 6.104 ...

Claims

1. A compound selected from: Wherein PG is selected from tri-C 1-6 Alkylsilyl group, di-C 1-6 Alkyl-phenylsilyl group, C 1-6 Alkyl-diphenylsilyl groups and triphenylsilyl groups; R' is C 1-6 alkyl; R x Is H or C 1-6 alkyl; X is Br, Cl or I; and R 5 It is C 1-6 alkyl.

2. The compound according to claim 1, selected from:

3. A compound selected from: or its salts; Where R 6 It is a halogen; R m Is H or C 1-6 alkyl; Each R n Independently C 1-6 Alkyl, or two R n The parts are connected together to form C 2-4 An alkyl bridge, wherein the bridge is optionally composed of one to four independently selected C 1-3 Alkyl and phenyl radical substitution; R z Is H or C 1-6 Alkyl; and R c It is C 2-6 alkyl.

4. The compound according to claim 3, selected from: or a salt thereof.

5. A compound selected from: or its salts; Where R y Is H or C 1-6 alkyl; R 2 and R 3 independently H or C 1-6 alkyl; R e is optionally substituted heteroaryl; R p Selected from H, -C(=O)-C 1-6 alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-phenyl, wherein each phenyl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl radical substitution; wherein each heteroaryl group has from one to four heteroatoms, and each heteroatom is independently selected from N, O and S; and wherein each heteroaryl group has 5 to 10 ring members.

6. The compound according to claim 5, selected from: or a salt thereof.

7. A compound selected from: or its salt; wherein R y Is H or C 1-6 alkyl; R 2 and R 3 independently H or C 1-6 alkyl; R 6 It is a halogen; Each R n Independently C 1-6 Alkyl, or two R n The parts are connected together to form C 2-4 An alkyl bridge, wherein the bridge is optionally composed of one to four independently selected C 1-3 Alkyl and phenyl radicals are substituted; and R p Selected from H, -C(=O)-C 1-6 alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-phenyl, wherein each phenyl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl radical substitution; wherein each heteroaryl has from one to four heteroatoms, and each heteroatom is independently selected from N, O, and S; and wherein each heteroaryl has from 5 to 10 ring members.

8. The compound according to claim 7, selected from: or a salt thereof.

9. A compound selected from: or its salts; Where R x and R y independently H or C 1-6 alkyl; R 2 and R 3 independently H or C 1-6 alkyl; R 5 It is C 1-6 alkyl; R 6 It is a halogen; R p Selected from H, -C(=O)-C 1-6 alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-phenyl, wherein each phenyl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl radical substitution; and wherein each heteroaryl has from one to four heteroatoms; wherein each heteroatom is independently selected from N, O and S; and wherein each heteroaryl has from 5 to 10 ring members.

10. The compound according to claim 9, selected from: or a salt thereof.

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