Methods for the preparation of 3-bicylco[3.lo]hexan-6-YL derivatives and intermediates therefor

Abstract

Methods for preparing 3-bicyclo[3.1.0]hexan-6-yl derivatives, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives and useful intermediates are disclosed herein. Such intermediates and methods may be used to synthesize useful biological compounds, such as SSTR4 agonists.

Description

NOVEL METHODS FOR THE PREPARATION OF 3-BICYLCO[3.1.0]HEXAN-6-YL DERIVATIVES AND INTERMEDIATES FIELD

[0001] The present disclosure novel includes methods for the preparation of 3-bicyclo[3. I.0]hexan-6-yl derivatives, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which can be useful as biologically active compounds, such as SSTR4 agonists. Also included are novel methods for the preparation of various intermediate compounds, which can be used for the preparation of various 3-bicyclo[3.1.0]hexan-6-yl derivatives, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives.BACKGROUND

[0002] Somatostatin, or somatotropin-release inhibitory factor (SRIF), is a cyclic peptide found in humans. It is produced widely in the human body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors and neurotransmitters. The effects of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes are known. These subtypes are divided into two subfamilies, the first comprising SSTR2, SSTR3 and SSTR5 and the second SSTR1 and SSTR4.

[0003] Somatostatin is involved in the regulation of processes such as for example cellular proliferation, glucose homeostasis, inflammation, and pain. In this aspect, somatostatin or other members of the somatostatin peptide family are believed to inhibit nociceptive and inflammatory processes via the SSTR4 pathway.

[0004] WO 2014 / 184275 discloses 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which are useful as SSTR4 agonists, and which are useful for preventing or treating medical disorders related to SSTR4. However, it can be challenging to synthesize 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives with sufficient enantiomeric and diastereomeric purity. Lab scale synthetic pathways are known, but many steps used in previous synthetic pathways can be impractical and / or too expensive to utilize at commercial scale.

[0005] While methods for the preparation of certain SSTR4 compounds are disclosed in WO 2014 / 184275, WO 2021 / 233427, and WO 2022 / 012534, these compounds were produced at laboratory scale, which can include numerous synthetic steps that are impractical at commercial scale. In these previous preparations, the synthetic pathways used high levels of expensive catalysts, including palladium and / or rhodium, which can increase the overall cost ofthe preparation and add additional purification steps to remove trace amounts of Pd, Rh, and / or undesirable diastereomers with lower activity, and have low yields, such as those described in WO 2021 / 233427 and WO 2022 / 012534.

[0006] Thus, there remains a need for improved synthesis methods of useful compounds (such as SSTR4 inhibitors) that are more suitable for commercial scale up and manufacture. Similarly, there remains a need for improved synthesis methods that avoid unwanted isomers, improving yields and reducing the amount purification needed for commercially acceptable pharmaceutical products. Also, there remains a need for new and novel intermediates, which may help facilitate new and improved synthesis methods.

[0007] Similarly, there remains a need for improved synthesis methods and novel intermediates for other useful biologically active compounds, such biologically active 3-bicyclo[3.1.0]hexan-6-yl derivatives, such as (i) antivirals active against the hepatitis B virus (HBV) disclosed in U. S. Patent Application Publication No. 2020 / 354379, (ii) antibiotics disclosed in U. S. Patent Application Publication No. 2023 / 373978, and (iii) retinoid related orphan receptor RORy modulators disclosed in U. S. Patent Application Publication No.2016 / 326195.

[0008] Thus, there is a present need for new methods that may allow for a more costefficient production of these aforementioned useful biologically active compounds, such as 3-bicyclo[3.1.0]hexan-6-yl derivatives. Also, there remains a need for new and novel intermediates, which may help facilitate new and improved synthesis methods.SUMMARY

[0009] Thus, disclosed herein are novel compounds and synthesis methods that are useful for manufacturing such useful biologically compounds, such as SSTR4 inhibitors, antivirals, antibiotics, and RORy modulators. Such novel compounds and disclosed methods of preparation allow for a more cost-effective way of preparing such biologically active and useful compounds.

[0010] The various methods and compounds disclosed herein can be used to make 3-bicyclo[3.1.0]hexan-6-yl derivatives, such as additional useful diazo-acetamides.

[0011] Thus, various methods for preparing a compound of the formula:Formula I or a salt thereof, include:Formula Acombining a compound of the Formula Awith a compound of the Formula Formula BB N2in the presence of from about 0.0001 to about 1 mol% Rh or Ru catalyst, wherein W is C-H, N-A, SO2, O,A is H, or an organic protecting group,each Rxis independently C1-C6alkyl, optionally substituted with from 1 to 6 halogens,Y is covalent bond, O, S, C1to C6ether, or C1to C6thioether,Z is absent, a covalent bond, CH2, or CH2CH2,an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6to C10aryl,k— ' is substituted with one or more Rn, andeach Rnis independently OH, F, Cl, Br, I, NH2, CF3, Ci to Ce alkyl, C3 to C7 cycloalkyl, Ci tC1to C7ether, or Ci to C7 thioether.

[0012] Various aspects also include compounds of Formula I where in the compound of Formula I are:Formula la

[0013] Some aspects include methods where the compound of Formula I is:Formula lb

[0014] Other aspects include methods where the compound of Formula I is:Formula Ic

[0015] As described herein various methods may include differing compounds of Formula B, is as where the compound of Formula B is the compound of Formula B2:, wherein R is chosen from C1-C12 alkyl and C1-C12 aryl alkyl.ects, the compound of Formula B is the compound of Formula B4:Formula B4, wherein, the compound of Formula B4 is made by mixing the compoundof Formula B3:Formula B3, with the compound of Formula

[0017] Also disclosed herein are compounds of Formula I is the compound of Formulathe compound of Formula B is the compound of Formula B3Formula B3

[0018] In many aspects, W may be N-A. In some methods, A may be chosen from tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), and fluorenylmethyloxycarbonyl Boc Tos (Fmoc). Thus, exemplary compounds of Formula A, where W is N-A include

[0019] Further, in some aspects, X may be chosen from:

[0021] Also disclosed herein are aspects where X may be chosen from:

[0022] In other aspects, X may be OH, O-Rx, where Rxis C2 alkyl.

[0023] Also disclosed herein are compounds of Formula B, that are chosen from:acceptable salts thereof.

[0024] Also disclosed herein are various Ru and Rh catalysts. Such catalysts include Rh2catalysts of the formula Rh2(L)2or Rh2(L)4, and L is a ligand, such as acetate (OAc), pivalate (OPiv), octanoate (Oct), triphenylacetate (TPA), or 3-[3-(2-carboxy-2-methylpropyl)phenyl]-2,2-dimethylpropanoic acid (esp). Specific catalyst of various aspects include Rh or Ru catalysts chosen from the group:, and combinations thereof.

[0025] The amount of catalyst is not particularly limited and may be present in an amount of from about 0.0001 to about 0.1 mol%, in an amount of from about 0.001 to about 0.01 mol%, or in an amount of about 0.005 mol%.

[0026] Also included herein are methods that further comprises isomerizing the compound of Formula I:, or a salt thereof, by exposing the compound of Formula I with a base to yield the compound of Formula Ic:This may be done in the presence of a strong base, such as a base that has a pH of about 12 or greater. Exemplary specific bases include sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), triazabicyclodecene (TBD), or 2-tert-Butyl- 1, 1, 3, 3 -tetramethy Iguanidine (BTMG).

[0027] Specific various methods also preparing a compound of the Formula III:pharmaceutically acceptable salts thereof,whereinY is covalent bond, O, S, Ci to Ce ether, or Ci to Ce thioether.Z is absent, a covalent bond, CH2, or CH2CH2,A )'-' / is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or Ce to C10 aryl,substituted with one or more Rn, andeach Rn is independently OH, F, Cl, Br, I, NH2, CF3, C1to C6alkyl, C3 to C7 cycloalkyl, Ci tC1to C7ether, or Ci to C7 thioether,the method comprising:A / (i) mixing a compound of the formulaa compound of the formulathe presence of from about 0.0001 to about 1 mol% of an Rh or Ru catalyst, whereinA is H or an organic protecting group,halogen, each Rxis independently C1-C6alkyl, optionally substituted with from 1 to 6 halogens,Y is covalent bond, O, S, Ci to C, ether, or Ci to C<, thioether, Z is absent, a covalent bond, CH2, or CH2CH2,(A)— ' is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6 to C10 aryl,(A)— ' is substituted with one or more Rn, andeach Rnis independently OH, F, Cl, Br, I, NH2, CF3, C1to C6alkyl, C3 to C7 cycloalkyl, Ci tC1 tC1to C7ether, or Ci to C7 thioether, andRxis Ci-Ce alkyl, optionally substituted with from 1 to 6 halogens.

[0028] In some aspects, the methods may further include isomerizing the compound ofnt as described herein. Thus, specific compounds may include compounds chosen from:pharmaceutically acceptable salts thereof.

[0029] Other compounds that may be made by the various methods disclosed herein include compounds chosen from the group of:acceptable salts thereof.

[0030] The pharmaceutically acceptable salts are not particularly limited and may also include polymorphs and / or hydrates. Exemplary salts include:BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The above mentioned and other features and objects of this disclosure, and the manner of attaining them, will become more apparent and the disclosure itself will be better understood by reference to the following description of various aspects of this disclosure taken in conjunction with the accompanying drawings, wherein:

[0032] FIG. 1 illustrates the exemplary stability data of 2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide, an exemplary compound disclosed herein;

[0033] FIG. 2 shows exemplary reaction data with altering various reaction conditions in accordance with various aspects of this disclosure; and

[0034] FIG. 3 shows exemplary1H NMR data of an exemplary endo-amide showing isomerization in the presence of a base.

[0035] The exemplification set out herein illustrates many aspects of the disclosure, in various forms, and such exemplifications are not to be construed as limiting the scope of the disclosure in any manner.DETAILED DESCRIPTION

[0036] Disclosed herein, are new stereoselective methods or synthesis routes for azabicyclo[3.1.0]hexanes-6-carboxamides, including both em / o-azabicyclo[3.1.0]hexanes-6-carboxamides and exo-azabicyclo[3.1.0]hexanes-6-carboxamides. Also included with these new methods are new compounds that, in some aspects, may be used as intermediates or precursors to make such azabicyclo[3.1.0]hexanes-6-carboxamides. Such methods and intermediates have the improvement of reducing costs and allowing for the synthetic route to be performed at a commercial scale with a reduction in Rh catalyst needed and with a reduction in further processing steps.

[0037] Thus, the various methods and compounds disclosed herein can be used to make commercial scale to produce useful biologically active compounds, such as SSTR4 agonists, antivirals active against the hepatitis B virus (HBV), antibiotics, and retinoid-related orphan receptor RORy modulators.

[0038] Such useful biologically active compounds include, for example, the following compounds and their pharmaceutically acceptable salts:

[0039] Pharmaceutically acceptable salts also include the various polymorphs and hydrates of such compounds. Thus, exemplary salts of useful biologically active compounds that can be produced by the methods and compounds disclosed herein also include, by way of example:

[0040] These novel routes present disclosure includes new stereoselective route to certain compounds, such as certain SSTR4 compounds, such as 3-azabicyclo[3.1.0]hexane-6- carboxamide derivatives, which can be performed at commercial scale with minimal use of a Rh or Ru metal catalyst to form the compound of Formula I:Formula I

[0041] Methods disclosed herein for compounds of Formula I or salts thereof, can be obtained from various methods, such as the methods exemplified herein by combining a Formula A Formula Bcompound of the Formula Awith a compound of the Formula B N2in the presence and Rh or Ru catalyst.

[0042] The compounds of Formula A may be obtained by various methods or obtained commercially. In various aspects, W may be N-A, where A may be chosen from H, or a protecting group, such as tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), and fluorenylmethyloxycarbonyl (Fmoc). Thus, exemplary compounds of Formula A, where W is

[0043] The compounds of Formula B may be obtained from the various methods disclosed herein.Formula B - Example 1: 2,5-dioxopyrrolidin-l-yl 2-diazoacetate

[0044] First, (E)-2-(2-tosylhydrazineylidene)acetic acid was obtained from the following reaction:As a solidH2O, HCI [2.5 M],65 °C 30 min, 65Tos0to 25 °C 3 h89% yield

[0045] To a 500 mL RBF charged with a stir-bar was added 2-oxoacetic acid hydrate (18.41 g, 1 equivalent, 200 mmol) and water (3.60 g, 200 mL, 1 molar, mmol). The solution was heated to 65 °C and stirred vigorously. The homogenous clear pale -yellow solution was stirred at 65 °C for at least 10 minutes. To the stirring solution was added 4-methylbenzenesulfonohydrazide (37.25 g, 200 mmol) in small portions to allow for even stirring.

[0046] In some embodiments, addition of the hydrazide could be done gradually to help prevent clumping and / or inadequate stirring or mixing. After complete addition of the hydrazide, HCI [2.5 M] (9.480 g, 104 mL, 2.5 molar, 260 mmol) was added to the reaction mixture and the solution was added to stir at 65 °C for 30 min. After the elapsed time, the reaction mixture was slowly cooled to room temperature by turning off the heating and allowing it to cool and sit for 3 hours while stirring.

[0047] The precipitate was vacuum filtered using a buchner funnel and filter paper, the filter cake washed with excess water and then vacuum dried to afford (E)-2-(2-tosylhydrazineylidene)acetic acid (44.8 g, 89%) as a white solid. The 1H NMR matches to literature characterizations. 1H NMR (DMSO-d6) δ 12.31 (brs, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.18 (s, 1H), 2.38 (s, 3H).

[0048] Then 2,5-dioxopyrrolidin-l-yl 2-diazoacetate was obtained from the (E)-2-(2-tosylhydrazineylidene)acetic acid was obtained from the following reaction:55% yield

[0049] A flame-dried 500 mL RBF was charged with a stir-bar was added (E)-2-(2-tosylhydrazineylidene)acetic acid (3.2299 g, 1 equivalent, 13.333 mmol) and N-Hydroxysuccinimide ( 1.688 g, 1.1 equivalent, 14.66). To the RBF was added dichloromethane (133.3 mL) and cooled to 0 °C. A solution of DCC (4.127 g, 1.5 equivalent, 20 mmol) in dichloromethane (20.0 mL) was then added dropwise to the reaction and stirred at 0 °C for 1 hour. The reaction solution was allowed to slowly warm to room temperature and stirred for a total for 18 hours.

[0050] After the elapsed time, the reaction was then quenched by filtering through a plug of diatomaceous earth and the filtrate concentrated in vacuo. The filtrate was diluted with saturated sodium bicarbonate solution and EtOAc, extracted with EtOAc three times, the combined organics washed with saturated bicarbonate three times, and then washed with saturated aqueous NaCl solution. The combined organics were dried with Na2SC>4, vacuum filtered through a plug of diatomaceous earth, and the filtrate concentrated in vacuo.

[0051] The crude was then purified by SiO2 flash chromatography eluting with 6:4: 1 hexanes: EtOAc: DCM. The collected fractions were concentrated in vacuo to afford 2,5-dioxopyrrolidin-l-yl 2-diazoacetate (1405.6 mg, 55%) as a light-yellow solid. When the solids were powdered, the product was an off-white powder. The following1H NMR was obtained:1H NMR (CDCh) 55.12 (brs, 1H), 2.85 (s, 4H).

[0052] The obtained 2,5-dioxopyrrolidin-l-yl 2-diazoacetate obtained was observed to be bench-top stable.Formula B - Example 2:2-diazo-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0053] Yet another example of a compound of Formula B according to an aspect of this disclosure is 2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide. Here,2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide was then obtained from the 2,5-dioxopyrrolidin-l-yl 2-diazoacetate using the following method:

[0054] To a flame-dried RBF charged with a stir-bar was added 2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-amine (2.0 g, 1.2 equivalent, 11 mmol), THF (0.65 g, 36 mL, 0.25 molar, 1 equivalent, 9.1 mmol), and then 2,5-dioxopyrrolidin-l-yl 2-diazoacetate (2.0 g, 83% wt, 1.0 equivalent, 9.1 mmol) topped with a nitrogen balloon. The reaction solution was stirred at room temperature for at least 5 minutes. Afterwards, triethylamine (1.0 g, 1.4 mL, 1.1 equivalent, 10 mmol) was added to the mixture. The reaction was stirred at room temperature for 24 hours.

[0055] After the elapsed time, the reaction solution was quenched with saturated ammonium chloride solution, the solution diluted with ether, extracted with ether three times, the combined organics dried with MgSO4. vacuum filtered through a diatomaceous earth plug, and the filtrate concentrated in vacuo at 50 °C. The crude was dry-loaded onto SiO2and subjected to SiO2flash chromatography using hexanes / ether (Biotage Sfar DLV Sfar 100 g column as the running-column and Biotage Sfar DLV 50 g column as the loading-column; 0% 5CV 5% 5CV 10% 5CV 20% 5CV 40% 5CV 60% 5CV 70% 5CV 80% 5CV —> 100% 10 CV; 200 mL / min flow-rate; 210 / 230 nm detector; POI elutes at 60 to 100% ether).

[0056] The collected fractions were concentrated in vacuo at 50 °C, redissolved in dichloromethane, filtered through a plug of neutral alumina, and the filtrate concentrated in vacuo to afford 2-diazo-N-(2- methyl- l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide (1.5 g, 51%) as a yellow solid. 1H NMR (CDCl3) 58.08 - 7.87 (m, 1H), 7.42 (dd, J = 7.1, 1.0 Hz, 1H), 6.83 (dd, J = 7.2, 5.0 Hz, 1H), 6.25 (brs, 1H), 4.57 (s, 1H), 4.31 (s, 2H), 2.21 (s, 3H), 1.52 (s, 6H).

[0057] The obtained 2,5-dioxopyrrolidin-l-yl 2-diazoacetate obtained was observed to be bench-top stable.

[0058] FIG. 1 illustrates 28-day stability data for the obtained 2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide. As can be seen from FIG.l, the 2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide was stable for 28 days. Due to their stability, such intermediates can be useful in large scale processes, especially if needing to be stored or transported.

[0059] Using the aforementioned examples and teachings of compounds of Formula A and Formula B, the compounds of Formula I, or pharmaceutical salts thereof, may be obtained. Such methods include combining the compounds of Formula A with a compound of Formula B in the presence of an Rh or Ru catalyst, such as shown as Methods 2 and 3 below:Method 2Formula A Formula B Formula I

[0060] In various embodiments, conditions or catalysts may be optimized to obtain the desired isomer, such as the endo or exo isomer of Formula 1, as illustrated below:Method 2 - EndoFormula A Formula B Formula IdorMethod 2 - ExoFormula A Formula B Formula le

[0061] Also, in some embodiments, a different isomer than the desired isomer may be first obtained, then the compound of Formula I (Formula la or Formula lb) may be subjected to an isomerization reaction to obtain the desired isomer.

[0062] For example, if the exo-isomer is desired, then the endo-isomer may first be obtained:Formula A Formula B Formula IdThen the endo-isomer may be subjected to an isomerization reaction, such as exposure to a base, such as a strong base (a base having a pH greater than about 12):Method 3Formula la Formula le

[0063] Also disclosed herein, are various compositions comprising a stereochemically pure, or substantially pure, intermediate, which can be isolated with an isomerization step without the need for any chromatography purification steps.

[0064] Additionally disclosed herein, are compositions comprising a stereochemically pure, or substantially pure, intermediate that can be isolated through the selected hydrolysis, for example in some aspects, the endo stereoisomer can be isolated through the selected hydrolysis of the exo stereoisomer followed by extraction, without the need for any chromatography purification steps.Catalysts

[0065] Any catalyst suitable for the cyclopropanation reaction may be used. Such catalysts include rhodium and ruthenium catalysts, such as Rh2, Rh4, and Ru(II) catalysts.

[0066] Table 1 below shows exemplary cyclopropanation reactions with succinimyl diazoacetate, in accordance with various embodiments, for various catalysts shown on Table 1. The cyclopropanation was performed using 1 mol% catalyst, which in some aspects, showed a higher exo diastereomer yield, and specifically higher yield using Ru(II)-(S)-Pheox catalyst.Table 1: Cvclopropanation with Diazo Amide

[0067] Table 1 above shows cyclopropanation reactions using diazo amide with various ruthenium or rhodium catalysts. The cyclopropanation reactions exemplified in Table 1 were performed using 1 mol% catalyst and, in some aspects, showed a higher endo diastereomer yield, and specifically higher yield using Rh2(S-NTTL)4 and Rh2(S-2-Cl,5-BrTPCP)4 catalyst.

[0068] The reported yields in Table 1 were QNMR yields. The data was obtained using 1 mol% catalyst and, in some aspects, showed a higher endo diastereomer yield.

[0069] Also, Table 2 below shows catalyst loading below 1 mol %. The cyclopropanation with diazoacetamide was performed using the catalysts as shown on Table 2 below. The reported yields were QNMR yields. The optimization using 1 mol% catalyst shows a higher endo diastereomer yield.Table 2: Cyclopropanation with DiazoacetamideSSTR4 Agonists

[0070] As described somewhat previously, the disclosed methods can be used to prepare useful compounds, such the compounds of Formula I, Formula II, or Formula III (e.g., Formula Illa and Formula IIIb).

[0071] The disclosed methods can also be used to prepare salts, pharmaceutically acceptable salts, solvates, hydrates, and / or combinations thereof of Formula la, including Formula lb and Formula Ic, where W is N-A:

[0072] Formula la, Formula lb,andFormula Ic,with Aand X being further described as below.

[0073] As used herein, A may be H, or an organic protecting group. Exemplary organic protecting groups include tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc).

[0074] Below are some further examples of synthesis of such useful compounds, such as SSTR4 agonists of Formula Illa and Formula Illb, that will further the understanding of this disclosure to a person of ordinary skill in the art.Formula Illb SSTR4 Agonist

[0075] As used herein, in some aspects,can be a Ce to Cio aryl or a 5-member to 10-member heteroaryl with from 1 to 4 heteroatoms selected from O, N, or S. In some (Aembodiments, ' — ' can be an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms (A)selected from O, N, or S. In some embodiments, can be a monocyclic, bicyclic, or (A) (A)polycyclic system. If is a monocyclic system,7can be a Cs to C7 aryl or five-member (A) to six-member heteroaryl with 1 or 2 heteroatoms selected from O, N, or S. If is a bicyclic system, each of the ring systems can include a Cs to Ce aryl or five-member to six-member heteroaryl with 1 or 2 heteroatoms selected from O, N, or S.(A)

[0076] In some embodiments, can be substituted with one or more Rn. Rn can be independently selected from OH, F, Cl, Br, I, NH2, Ci to Ce alkyl, C3 to C7 cycloalkyl, Ci tC1to C7ether, Ci to C7 thioether, or combinatio, and combinations thereof. In some embodiments, n can represent the(A) number of substitutions on. For example, Ri can be a first substitution onMR2can be a second substitution on, etc.

[0077] In some embodiments, Y can be covalent bond, O, S, Ci to Ce ether, or Ci to Ce fAJthioether. When Y is absent, — is connected via a covalent bond to the dimethyl substituted carbon atom immediately adjacent to the amide functional group.

[0078] In some embodiments Z can be absent, a covalent bond, CH2, or CH2CH2.When Z is absent, there no connection between the two methyl substituents at the alpha carbon atom. When Z is a covalent bond, the alpha carbon atom forms a cyclopropyl functional group. When Z is CH2, the alpha carbon atom forms a cyclobutyl functional group. When Z is CH2CH2, the alpha carbon atom forms a cyclopentyl functional group.

[0079] In some embodiments, the Ci to C7 thioether can be a thioether selected from the following:

[0080] Certain abbreviations are as follows: “I” refers to acetonitrile; “Boc” refers to tert-butyloxycarbonyl; “BTMG” refers to 2-tert-butyl-l,l,3,3-tetramethylguanidine; “cbz” refers to carbobenzyloxy; “DBU” refers to l,8-diazabicyclo[5.4.0]undec-7-ene “DCM” refers to dichloromethane; “DI P” refers to 4-dimethylaminopyridine; DMC refers to dimethyl carbonate; “EtOH” refers to ethanol; “Fmoc” refers to fluorenylmethyloxycarbonyl; “hr / hrs” refers to hour / s; “KOtBu” refers to potassium tert-butoxide; MeOH refers to methanol; “min” refers to minute / s; “NaOtBu” refers to sodium tert-butoxide; “TBD refers to triazabicyclodecene; and “THF” refers to tetrahydrofuranExample 1[2+1] Cycloaddition with Succinimyl Diazoacetate

[0081] The [2+1] cycloaddition of cyclopropane derivative to succinimyl diazoacetate in a reaction taking about 18 hours at 25 °C, and in the presence of 4 Å molecular sieves, a ruthenium or rhodium catalyst gave a mixture of endo and exo cyclopropanated carboxylates.After optimization of the catalysts, Ru(II)-(S)-Pheox was found to give a higher yield of exo cyclopropanated carboxylate, and such it was selected for this reaction (Table 1).

[0082] The exo cyclopropane was then subjected to amide coupling to give exo cyclopropanated amide. The amide coupling reaction was performed in the presence of a base such as DCC, triethylamine, and such, a solvent such as THF, and at about 25 °C. One skilled in the art will also recognize that there are other variations of a base, organic solvent combinations, and conditions that may be used to perform this transformation.Example 2[2+1] Cycloaddition with Diazo Amide1 mol % Ru or Rh2 CatalystCH2Cl2[0.25M]Endo-amide

[0083] The [2+1] reaction to form a cyclopropane derivative from an alkene compound and a diazo amide takes place in about 18 hours at 25 °C, and in the presence of 4 Å molecular sieves, a ruthenium or rhodium catalyst give. After optimization of the catalysts, Rh2(S-NTTL)4 and Rh2(S-2-Cl,5-BrTPCP)4 were found to give a higher yield of cyclopropanated amide, and as such were selected for this reaction (Table 2).

[0084] Also, it will be appreciated by a person of skill in the art with the benefit of this disclosure to combine various aspects of methods and / or intermediates to come with a general synthetic scheme to manufacture the useful biologically active compounds previously described.

[0085] Below is Exemplary General Scheme 1 exemplifying how an ordinary skilled artisan might combine various methods and intermediates to synthesize a useful biologically active compound, such as an SSTR4 agonist.

[0086] Exemplary General Scheme 1Step 3cyclopropane derivative,56

[0087] X and W as shown in General Exemplary Scheme 1 above, may be as previously defined. Furthermore, in some aspects, X may be an amine derivative that can be selected from any of the derivatives on the following Table 3, Table, 4, or Table 6, with exemplary cyclopropane derivatives being shown in Table 5 below:Table 3-Amine Derivatives

[0088] Other amines that can be used include, for example, those listed in Table 4 below:Table 4

[0089] The cyclopropane derivatives used in Exemplary General Scheme 1, step 4, can be chosen from any of the compounds shown on the following table:Table 5: Cyclopropane Derivatives

[0090] In the synthetic scheme 1, Step 1 shows an acetylation reaction in which acetic acid such as 2-oxoacetic acid hydrate is reacted with hydrazide compound 1 in the presence of hydrochloric acid, and at a suitable temperature to give an acetic acid compound 2.

[0091] Step 2 depicts conversion of compound 2 to give the diazoacetate compound 3. The reaction takes place in the presence of N-hydroxysuccinimide, DCM as a solvent, and at a suitable temperature to give compound 3.

[0092] Step 3 depicts an amine coupling reaction to give compound 4. The diazoacetate compound 3 is reacted with an amine derivative compound such as the ones listed on Table 1 or Table 2, in the presence of DCC as a coupling agent, triethylamine as a base, and THF as the solvent, and at a suitable temperature to give the diazoamide compound 4. One skilled in art will also recognize that there are many catalysts, ligands, base, and solvent combinations that may be used to perform this transformation.

[0093] For example, FIG. 2 shows Endo yield data for varying conditions, such as molar amount, solvent, trap, temperature, and rate of addition.

[0094] Step 4 depicts a cyclopropanation reaction to give compound 5. The diazoamide compound 4 is reacted with a cyclopropane derivative such as tert-butyl 2,5-dihydro-lH-pyrrole-1 -carboxylate, or any other derivative listed on Table 3 and in the presence of a chiral selective rhodium or ruthenium catalyst such as the ones listed on Table 4, molecular sieves, and a solvent such as DCM, and at a suitable temperature to selectively give the endo-amide compound 5.

[0095] Step 5 depicts conversion of the endo-amide compound 5 to a preferred exoamide compound 6. The endo-amide compound 5 reacts with sodium tert-pentoxide in the presence of toluene as a solvent, and at a temperature of about 55 °C for about 16-20 hours to give the exo-amide compound 6.Amine Derivatives with an Alkyne Substitution

[0096] Also, using this disclosure, one of skill in the art will recognize that various amine derivatives with alkyne substitutions may also be used. For example, Table 6 below contains exemplary amine derivatives with alkyne substitutions that can be used in various aspects of this disclosure. Table 6 below shows examples of X, when X, as disclosed herein, is an amine derivative with an alkyne substitution.Table 6: Additional Amine Derivatives

[0097] The amine derivatives shown on Table 6 with an alkyne group substitution can also be used to perform the reaction shown on Step 3 as described in general scheme 1. A person skilled in the art will recognize there may be several processes used in adding alkyne to these compounds.

[0098] For example, such processes may include, according to various aspects, an elimination reaction in which a halogen such as iodide, bromine or chlorine is used to form a halide, and the halide is eliminated to form an alkyne. The reaction may involve use of a base,such as a strong base or a base having a pH of about 12 or greater, and a metal catalyst such as Cu, or Pd.

[0099] One skilled in the art will also recognize, with the benefit of this disclosure, that there are many metal catalysts, ligands, strong base, and organic solvent combinations that may be used to perform this transformation. An example of such transformation is as shown in the reactions below:metal catalyst, ligandstrong base, solvent

[0100] Rj can be selected from hydrogen, oxetane, 3-5 cycloalkyl, or a 1-5 alkyl group that can be substituted with OH, or a halogen.Example 3Synthesis of / wt -Butyl (lR,5S,6r)-6-((2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2- yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Preparation 1(E)-2-(2-Tosylhydrazineylidene)acetic acid

[0101] Water (3.604 g, 200 mL) was added to 2-oxoacetic acid hydrate (18.41 g, 200 mmol). The solution was heated to 65 °C and stirred vigorously for at least 10 minutes. 4-Methylbenzenesulfonohydrazide (37.25 g, 200 mmol) was added in small portions while stirring. After complete addition of the hydrazide, 2.5 M HC1 (9.480 g, 104 mL, 260 mmol) was added to the reaction mixture and the solution stirred at 65 °C for 30 minutes. The reaction mixture was slowly cooled to ambient temperature by turning off the heating and allowing it to cool and sit for 3 hours while stirring. The precipitate was vacuum filtered, the filter cake washed with excess water and then vacuum dried to give the title compound (44.8 g, 89 %) as a white solid.

[0102] NMR (DMSO) δ 12.31 (brs, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.18 (s, 1H), 2.38 (s, 3H).Preparation 22, 5-Dioxo-l-pyrrolidinyl 2-diazoacetate

[0103] A mixture of (E)-2-(2-tosylhydrazineylidene)acetic acid (3.33 g, 13.33 mmol) and N-hydroxysuccinimide (1.688 g, 14.66 mmol) was diluted with DCM (133.3 mL, dry distilled over CaH2and stored over 4 Å molecular sieves. The mixture was then cooled to 0 °C. A solution of DCC (4.127 g, 20 mmol) in DCM (20 mL, dry distilled over CaH2over 4 Å molecular sieves) was then added dropwise to the reaction and stirred at 0 °C for 1 hour. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was then quenched by filtering, and the filtrate concentrated in vacuum. The reaction mixture was then diluted with saturated aqueous NaHCO3and extracted with EtOAc three times, then washed with saturated aqueous NaHCO3three times, followed by saturated aqueous sodium chloride. The organic phases were separated, dried over Na2SO4, filtered, and concentrated in vacuum. The crude residue was purified by flash column chromatography, eluting with 6:4:1 hexanes: EtOAc: DCM to give the title compound (1.41 g, 55 %) as a lightyellow solid.

[0104] ‘H NMR (CDCh) 55.12 (brs, 1H), 2.85 (s, 4H).Preparation 32-Diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0105] A mixture of 2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-amine (2.0 g, 11 mmol), THF (0.65 g, 36 mL, 9.1 mmol), and 2,5-dioxopyrrolidin-l-yl 2-diazoacetate (2.0 g, 83% Wt, 9.1 mmol) was added to a vial topped with a nitrogen balloon. The reaction solution was stirred at ambient temperature for at least 5 minutes. Afterwards, tri ethylamine (1.0 g, 1.4 mL, 10 mmol) was added to the mixture. The reaction was stirred at ambient temperature for 24 hours. The reaction solution was then quenched with saturated ammonium chloride solution, the solution diluted with ether, extracted with ether three times, the combined organics dried with MgSO4, filtered, and the filtrate concentrated in vacuum at 50 °C. The crude was dry-loaded onto SiO2and subjected to SiO2flash chromatography using hexanes in ether (Biotage DLV Sfar 100 g column as the running-column and Biotage DLV Sfar 50 g column as the loading-column; 0% 5CV -> 5% 5CV -> 10% 5CV -> 20% 5CV -> 40% 5CV -> 60% 5CV --> 70% 5CV; 80% 5CV --> 100% 10 CV; 200 mL / minute flow-rate; 210 / 230 nm detector; product of interest elutes at 60 to 100% EtOAc). The collected fractions were concentrated in vacuum at 50 °C, redissolved in DCM, filtered through a plug of neutral alumina, and the filtrate concentrated in vacuum to give the title compound (1.5 g, 67 %) as a yellow solid.

[0106] NMR (CDCl3) δ 8.08 - 7.87 (m, 1H), 7.42 (dd, J = 7.1, 1.0 Hz, 1H), 6.83 (dd, J = 7.2, 5.0 Hz, 1H), 6.25 (brs, 1H), 4.57 (s, 1H), 4.31 (s, 2H), 2.21 (s, 3H), 1.52 (s, 6H).Preparation 4Endo-Amidefert-Butyl (lR,5S,6s)-6-((2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3- azabicyclo[3.1.0]hexane-3 -carboxylate

[0107] ferr-Butyl 2,5-dihydro-lH-pyrrole-l -carboxylate (846 mg, 5.00 mmol) was added to a flame-dried vial charged with a stir-bar and 500 mg activated 4A molecular sieves. The vial was sealed and backfilled with nitrogen three times and then capped with a nitrogen balloon. A stock solution of Rh2(S-NTTL)4 in DCM (724 pg, 2.00 mL, 0.500 pmol) was then added to the vial, and the reaction solution stirred at 25 °C for at least 10 minutes. A stock solution of 2-diazo-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide (124 mg, 2.00 mL, 0.500 mmol) was then added drop-wise over 10 seconds. After complete addition, thereaction vessel was allowed to stir at 25 °C overnight for 18 hours. The reaction solution was then filtered through a plug of diatomaceous earth, and the filtrate concentrated in vacuum at 65 °C to give the title compound (874.2 mg, 46.7 %).

[0108] 1H NMR (CDCl3) δ7.93 (brd, J = 5.1 Hz, 1H), 7.42 (brd, J = 7.0 Hz, 1H), 6.82 (dd, J = 7.0, 5.1 Hz, 1H), 6.80 (brs, 1H), 4.29 (d, J = 10.5 Hz, 1H), 4.25 (d, J = 10.5 Hz, 1H), 3.77 (d, J = 10.7 Hz, 1H), 3.72 (d, J = 11.1 Hz, 1H), 3.37 (dd, J = 11.1, 3.8 Hz, 1H), 3.30 (dd, J = 10.7, 3.8 Hz, 1H), 2.80 (s, 2H), 2.24 (s, 3H), 1.77 - 1.60 (m, 3H), 1.47 (s, 3H), 1.41 (s, 3H), 1.39 (s, 9H).Preparation 5Base Isomerization of Endo- Amide / -Butyl (lR,5S,6r)-6-((2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3- azabicyclo [3.1.0]hexane-3-carboxylate

[0109] A mixture of tert-butyl (lR,5S,6s)-6-((2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (12 mg, 31 pmol) and sodium tert-pentoxide, 40% in toluene (85 mg, 40% wt, 0.31 mmol) was heated to 55 °C and stirred for 18 hours. The solution was then diluted with saturated bicarbonate solution, extracted with EtOAc three times, dried with MgSO4, filtered through a diatomaceous earth plug, and the filtrate concentrated in vacuum at 55 °C to give the title compound (10.3 mg, 86 %). The epimerization of the endo amide completely converted to the exo amide.

[0110] 1H NMR (CDCl3) δ7.95 (brd, J = 5.2 Hz, 1H), 7.42 (brd, J = 7.1 Hz, 1H), 6.82 (dd, J = 7.0, 5.2 Hz, 1H), 6.51 (s, 1H), 4.33 (d, J = 10.4 Hz, 1H), 4.29 (d, J = 10.4 Hz, 1H), 3.62 (d, J = 11.1 Hz, 1H), 3.53 (d, J = 11.1 Hz, 1H), 3.43 - 3.35 (m, 2H), 2.22 (s, 3H), 2.08 - 2.04 (two brm, total 1H), 2.01 - 1.92 (m, 2H), 1.47 (s, 6H), 1.43 (s, 9H).

[0111] FIG. 3 shows ’H NMR data of an exemplary endo-amide showing isomerization in the presence of a base. The data shown in FIG. 3 illustrates that the base isomerization described above that when the reaction was ran for 18 hours, the reaction proceeded cleanly to the exo-azabicylo[3.1.0]hexanes-6-carboxamide (shown as 1 in FIG. 3) from a pure (to the detection limits of the detection machine) endo-azabicylo[3.1.0]hexanes-6-carboxamide (shownas 2 in FIG. 3). Thus, such isomerization processes may be used for large scale manufacturing processes where either (i) the exo-amide is desired, or (ii) the endo-amide is desired. Thus, the various aspects of the methods described herein can produce higher purity of either the endo-amide or the exo-amide, depending on the desired diastereomer of the biologically active compound. Such methods will also be appreciated by a skilled artisan to be synthetically useful in drug discovery.

[0112] As can be appreciated by a skilled artisan, the above novel compounds and methods are improved synthesis methods of useful compounds (such as SSTR4 inhibitors, antivirals active against the hepatitis B vims (HBV), antibiotics, retinoid-related orphan receptor RORy modulators) that are more suitable for commercial scale up and manufacture. Also, the novel intermediates disclosed herein help to help facilitate new and improved synthesis methods. Such new and improved scalable methods allow for better cost-effective and efficient production of such desirable biologically active compounds.

[0113] Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

[0114] The term “comprising” and variations thereof as used herein is used synonymously with the terms “including” and “containing” and variations thereof, and are open, non-limiting terms. Although the terms “comprising,” “including,” and “containing” have been used herein to describe various aspects, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising,” “including,” or “containing” to provide for more specific aspects and are also disclosed.

[0115] Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood to be construed in light of the number of significant digits and ordinary rounding approaches, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims.

Claims

CLAIMSWhat is claimed is:

1. A method for preparing a compound of the formula:Formula I or a salt thereof, the method comprising:Formula Acombining a compound of the Formula Awith a compound of the Formula Formula BB N2in the presence of from about 0.0001 to about 1 mol% Rh or Ru catalyst, whereinW is C-H, N-A, SO2, O,A is H, or an organic protecting group., or a halogen, each Rxis independently C1-C6alkyl, optionally substituted with from 1 to 6 halogens,Y is covalent bond, O, S, C1to C6ether, or C1to C6thioether,Z is absent, a covalent bond, CH2, or CH2CH2,is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6to C10aryl,(A)is substituted with one or more Rn, andeach Rnis independently OH, F, Cl, Br, I, NH2, CF3, Ci to Ce alkyl, C3 to C7 cycloalkyl, Ci tC1to C7ether, or Ci to C7 thioether.

2. The method of claim 1, wherein the compound of Formula I is:Formula Ia3. The method of claim 2, wherein the compound of Formula I is:Formula lb4. The method of claim 2, wherein the compound of Formula I is:Formulaic5. The method of any one of the proceeding claims, wherein the compound of Formula B e compound of Formula B2:, wherein R is chosen from C1-C12 alkyl and C1-C12 aryl alkyl.

6. The method of any one of the proceeding claims, wherein the compound of Formula B e compound of Formula B4:Formula B4, wherein, the compound of Formula B4 is made by mixing the compoundFormula B57. The method of any one of claims 1 -4, whereinthe compound of Formula I is the compound of Formula II:Formula IIthe compound of Formula B is the compound of Formula B3:Formula B38. The method of claim 7, wherein W is N-A.

9. The method of any one of the proceeding claims, wherein A is chosen from tertbutyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), and fluorenylmethyloxycarbonyl (Fmoc).

10. The method of any one of the proceeding claims, wherein the compound of Formula Ais chosen from11. The method of any one of claims 1 - 5, 8, or 10, wherein X is chosen from:

12. The method of any one of claims 1 - 5, or 8 - 10, wherein X is chosen from:

13. The method of any one of claims 1 - 5, or 8 - 10, wherein X chosen from:

14. The method of any one of claims 1-4, or 8 - 10, wherein X is OH or O-Rx15. The method of any one of claims 1-4, or 8 - 10, wherein X is O-Rxand Rxis C2 alkyl.

16. The method of any one of claims 1-4, or 8 - 10, wherein the compound of Formula B is chosen from:acceptable salts thereof.

17. The method of any one of the proceeding claims, wherein the catalyst is an Rh2catalyst of the formula Rh2(L)2or Rh2(L)4, and L is a ligand.

18. The method of any one of the proceeding claims, wherein the Rh catalyst is of the formula Rh2(L)2or Rh2(L)4, and wherein L is acetate (OAc), pivalate (OPiv), octanoate (Oct), triphenylacetate (TPA), or 3-[3-(2-carboxy-2-methylpropyl)phenyl]-2,2-dimethylpropanoic acid (esp).

19. The method of any one of claims 1 17, wherein the Rh or Ru catalyst is chosen from the group:, and combinations thereof.

20. The method of any one of the proceeding claims, wherein the Rh catalyst is21. The method of any one of the proceeding claims, wherein the Rh or Ru catalyst is present in an amount of from about 0.0001 to about 0.1 mol%.

22. The method of any one of the proceeding claims, wherein the Rh or Ru catalyst is present in an amount of from about 0.001 to about 0.01 mol%.

23. The method of any one of the proceeding claims, wherein the Rh or Ru catalyst is present in an amount of about 0.005 mol%.

24. The method of any one of the proceeding claims, wherein the method further comprises isomerizing the compound of Formula I:Formula I, or a salt thereof, by exposing the compound of Formula I with a base to yield the compound of Formula Ib:Formula Te25. The method of claim 24, wherein W is N-A.

26. The method of claim 24, wherein the base has a pH of about 12 or greater.

27. The method of claim 24 - 26, wherein the comprises sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), triazabicyclodecene (TBD), or 2-terf-Butyl-l,1,3, 3 -tetramethylguanidine (BTMG).

28. The method of claim 24 - 26, wherein the base comprises sodium tert-butoxide.

29. A method for preparing a compound of the Formula III:pharmaceutically acceptable salts thereof,whereinY is covalent bond, O, S, C1to C6ether, or C1to C6thioether,Z is absent, a covalent bond, CH2, or CH2CH2,A )'-' / is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or Ce to C10 aryl,substituted with one or more Rn, andeach Rnis independently OH, F, Cl, Br, I, NH2, CF3, Ci to C6 alkyl, C3 to C7 cycloalkyl, Ci tC1to C7ether, or Ci to C7 thioether,the method comprising:(i) mixing a compound of the formulaa compound of the formulathe presence of from about 0.0001 to about 1 mol% of an Rh or Ru catalyst, whereinAis H or an organic protecting group,Y is covalent bond, O, S, C1to C6ether, or C1to C6thioether, Z is absent, a covalent bond, CH2, or CH2CH2,an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6to C10aryl,substituted with one or more Rn, andeach Rnis independently OH, F, Cl, Br, I, NH2, CF3, Ci to C, alkyl, C3 to C7 cycloalkyl, Ci tC1 tC1to C7ether, or Ci to C7 thioether, andRxis Ci-Ce alkyl, optionally substituted with from 1 to 6 halogens.

30. The method of claim 29, further comprisingisomerizing the compoundsalt thereof, byexposing the compound with a base to yield a compound31. The method of claim 30, wherein Z is absent.

32. The method of claim 31, the compound is chosen from:pharmaceutically acceptable salts thereof.

33. The method of claims 29 - 31, wherein the compound is of the formula:or a pharmaceutically acceptable salt thereof.

35. The method of claims 29 - 31, wherein the compound is of the formula:

36. The method of claims 29 - 31, wherein the compound is of the formula:

37. The method of claim any one of claims 29 - 34, wherein A is tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc).

38. The method of any one of claims 29 - 37, wherein the catalyst is an Rh catalyst of the formula Rh2(L)2 or Rh2(L)4.

39. The method of any one of claims 38, wherein the Rh catalyst is of the formula Rh2(L)2or Rh2(L)4, and wherein L is acetate (OAc), pivalate (OPiv), octanoate (Oct), triphenylacetate (TPA), or 3-[3-(2-carboxy-2-methylpropyl)phenyl]-2,2-dimethylpropanoic acid (esp).

40. The method of any one of claims 39, wherein the Rh catalyst is of the formula:

41. The method of any one of claims 29 - 40, wherein the Rh catalyst is present in an amount of from about 0.0001 to about 0.1 mol%.

42. The method of any one of claims 29 - 41, wherein the Rh catalyst is present in an amount of from about 0.001 to about 0.01 mol%.

43. The method of any one of claims 29 - 42, wherein the Rh catalyst is present in an amount of about 0.005 mol%.

44. The method of claim 43, wherein the base is chose from sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), triazabicyclodecene (TBD), and 2-tert-Butyl-l, 1,3, 3 -tetramethylguanidine (BTMG).

45. The method of claims 43 or 44, wherein the base is sodium / e / 7-butoxide.

46. The method of claims 43 or 44, wherein the base is potassium t -butoxide.

47. A compound of the formula:salt thereof, whereinW is C-H, N-A, SO2, O,A is H, or an organic protecting group,, , or a halogen,each Rxis independently Ci-Ce alkyl, optionally substituted with from 1 to 6 halogens.Y is covalent bond, O, S, C1to C6ether, or C1to C6thioether,Z is absent, a covalent bond, CH2, or CH2CH2,an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6 to C10 aryl,A )—s is substituted with one or more Rn, andeach Rn is independently OH, F, Cl, Br, I, NH2, CF3, Ci to Ce alkyl, C3 to C7 cycloalkyl, C1 tC1to C7ether, or Ci to C7 thioether, andthe compound is prepared by the method of any one of claims 1 to 13.

48. The compound of claim 47, wherein W is N-A49. The compound of claim 48, wherein A is terZ-butyloxycarbonyl (Boc), X is O-Rx, and Rxis C2 alkyl.

50. A compound of the formula:salt thereof, andwherein A is H or an organic protecting group.

51. The compound of claim 48 or 50, wherein A is tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc).

52. The compound of claim 48 or 50, wherein A is tert-butyloxycarbonyl (Boc).

53. A compound of the formula:pharmaceutically acceptable salts thereof,whereinY is covalent bond, O, S, Ci to O> ether, or Ci to C, thioether,Z is absent, a covalent bond, CH2, or CH2CH2,(Ais an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6 to C10 aryl,) is substituted with one or more Rn, andeach Rn is independently OH, F, Cl, Br, I, NH2, CF3, C1to C6alkyl, C3 to C7 cycloalkyl, C1to C7ether, or Ci to C7 thioether,and wherein the compound is prepared with the method of any one of claims 14 to 29.

54. The compound of claim 53, wherein the compound is of the formula:

56. The compound of claim 54, wherein the compound is:

57. The compound of claim 54, wherein the compound is:

58. A compound of the formula:salt thereof, wherein the compound is chosen from the group of:acceptable salts thereof, whereinthe compound is prepared by the method of any one of claims 1, 4, or 8 - 10.

59. The compound of claim 58, wherein the compound is:

60. A compound of the formulaN2 wherein X is chosen from:and pharmaceutically acceptable salts thereof.

61. The compound of claim 60, wherein X is chosen from, and pharmaceutically acceptable salts thereof.

62. The compound of claim 60, wherein X is chosen from:acceptable salts thereof.

63. The compound of claim 60, wherein X is chosen fromand pharmaceutically acceptable salts thereof.

64. The compound of claim 60, wherein X is chosen from chosen from:

65. The compound of claim 60, wherein X is chosen from chosen from:, and pharmaceutically acceptable salts thereof.

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