ES2536001T3 - Procedure for the synthesis of biaryloxazolidinones - Google Patents

Abstract

Process for preparing a compound having the formula:**Formula**, the process comprising the steps of: combining a compound (I) of the formula:**Formula** with a compound (II) of the formula:**Formula* * in a solvent comprising a mixture of water, toluene, and ethanol, in the presence of a potassium carbonate and a palladium catalyst, wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium(0) and the equivalent ratio of tetrakis(triphenylphosphine)palladium (0) with respect to the equivalents of compound (I) is 1:20; wherein further R3 is -NHC(O)R4 and R4 is -CH3; ML is M-CH2-X-CH2, where X is NR4 and R4 is H or an amine protecting group selected from the group consisting of: a) benzyl, b) t-butyldimethylsilyl, c) t-butyldiphenylsilyl, d ) t-butyloxycarbonyl, e) p-methoxybenzyl, f) methoxymethyl, g) tosyl, h) trifluoroacetyl; i) trimethylsilyl, j) fluorenylmethyloxycarbonyl, k) 2-trimethylsilylethoxycarbonyl, l) 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, m) allyloxycarbonyl and n) benzyloxycarbonyl; M is triazole, tetrazole, oxazole, isoxazole; Z is I; and Q is -B(OH)2.

Description

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DESCRIPTION

Procedure for the synthesis of biaryloxazolidinones

Field of the Invention

The present invention generally relates to a method for synthesizing anti-infective, anti-proliferative, anti-inflammatory and prokinetic agents. More particularly, the invention relates to a process for synthesizing biaryloxazolidinone compounds that are useful as therapeutic agents.

Background

Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many new compounds have been specifically discovered or designed for use as antibiotic agents. Once it was believed that infectious diseases could be completely controlled or eradicated with the use of such therapeutic agents. However, such beliefs have been shaken by the fact that strains of cells or microorganisms resistant to currently effective therapeutic agents continue to evolve. In fact, virtually every antibiotic agent developed for clinical use has ultimately encountered problems with the emergence of resistant bacteria. For example, resistant strains of Gram positive bacteria such as methicillin-resistant staphylococci, penicillin-resistant streptococci and vancomycin-resistant enterococci have emerged, which can cause serious and even fatal outcomes for patients infected with such resistant bacteria. Bacteria have emerged that are resistant to macrolide antibiotics, that is, antibiotics based on a lactone ring of 14 to 16 members. In addition, resistant strains of Gram negative bacteria such as H. influenzae and M. catarrhalis have been identified. See, for example, F.D. Lowry, "Antimicrobial Resistance: The Example of Staphylococcus aureus," J. Clin. Invest., 2003, 111 (9), 1265-1273; and Gold,

H.S. and Moellering, R.C., Jr., "Antimicrobial-Drug Resistance", N. Engl. J. Med., 1996, 335, 1445-53.

The problem of resistance is not limited to the area of anti-infective agents, because resistance has also been found with the antiproliferative agents used in cancer chemotherapy. Therefore, there is a need for new anti-infective and anti-proliferative agents that are effective against both resistant bacteria and resistant strains of cancer cells.

In the area of antibiotics, despite the problem of increasing antibiotic resistance, no major new class of antibiotics has been developed for clinical use since the 2000 authorization of the ring-containing antibiotic in the United States in 2000 oxazolidinone, N - [[(5S) -3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo5-oxazolidinyl] methylacetamide, which is known as linezolid and is sold under the trade name Zyvox® ( see compound A). See R.C. Moellering, Jr., "Linezolid: The First Oxazolidinone Antimicrobial," Annals of Internal Medicine, 2003, 138 (2), 135-142.

image 1

Linezolid was authorized for use as an active antibacterial agent against Gram positive organisms. Unfortunately, strains of organisms resistant to linezolid have already been reported. See, Tsiodras et al., Lancet, 2001, 358, 207; Gonzales et al., Lancet, 2001, 357, 1179; Zurenko et al., Proceedings Of The 39th Annual Interscience Conference On Antibacterial Agents And Chemotherapy (ICAAC); San Francisco, CA, USA, (September 26-29, 1999). Because linezolid is both a clinically effective and commercially significant antimicrobial agent, researchers have been working to develop other effective linezolid derivatives.

Despite the above, there is a continuing need for new anti-infective and anti-proliferative agents. In addition, because many anti-infective and anti-proliferative agents have utility as anti-inflammatory agents and prokinetic agents, there is also a continuing need for new compounds useful as anti-inflammatory and prokinetic agents, as well as methods for making such compounds.

Summary of the invention

The present invention provides methods for preparing biaryloxazolidinone compounds as defined in the claims.

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The procedures generally provide the desired biaryloxazolidinone compound at or near the end of the overall process, and additional synthetic manipulation of the biaryl system or its substituents is generally not necessary.

The foregoing and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims.

Detailed description of the invention

The present invention relates to processes for preparing biaryloxazolidinone compounds useful as antiproliferative agents and / or anti-infective agents. The compounds can be used without limitation, for example, as anticancer, antimicrobial, antibacterial, antifungal, antiparasitic and / or antiviral agents. In addition, the compounds produced by the methods of the invention can be used without limitation as anti-inflammatory agents, for example, for use in the treatment of chronic inflammatory diseases of the airways and / or as prokinetic agents, for example, for use in the treatment of disorders in gastrointestinal motility such as gastroesophageal reflux disease, gastroparesis (diabetic and post-surgical), irritable bowel syndrome and constipation.

Compounds synthesized according to the methods of the invention can be used to treat a disorder in a mammal by administering to the mammal an effective amount of one or more compounds of the invention to thereby improve a symptom of a particular disorder. Such a disorder can be selected from the group consisting of a skin infection, nosocomial pneumonia, postviral pneumonia, an abdominal infection, a urinary tract infection, bacteraemia, septicemia, endocarditis, an infection of the atrioventricular shunts, an infection of the vascular access, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant enterococcal infection, an infection by organisms resistant to linezolid and tuberculosis.

1. Definitions

The term "substituted" as used herein means that any of one or more hydrogens in the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. When the substituent is keto (i.e., = O), then 2 hydrogens in the atom are replaced. Keto substituents are not present in aromatic moieties. Double ring bonds, as used herein, are double bonds that form between two adjacent ring atoms (for example, C = C, C = N or N = N).

The present invention is intended to include all isotopes of the atoms that appear in the present compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of a general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include C-13 and C-14.

The compounds described herein may have asymmetric centers. The compounds of the present invention that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All geometric, racemic, diastereomeric, and chiral isomeric forms of a structure are intended, unless the specific isomeric or stereochemical form is specifically indicated. It is also considered that all tautomers of the compounds shown or described are part of the present invention.

When any variable (for example, R1) occurs more than once in any constituent or formula for a compound, its definition in each case is independent of its definition in all other cases. Thus, for example, if it is shown that a group is substituted with 0-2 residues R1, then the group may optionally be substituted with up to two residues R1 and in each case R1 is independently selected from the definition of R1. In addition, combinations of substituents and / or variables are acceptable, but only if such combinations result in stable compounds.

When it is shown that a bond to a substituent crosses a bond that connects two atoms in a ring, then such a substituent can be linked to any atom in the ring. When a substituent is included without indicating the atom by which such substituent is linked to the rest of the compound of a given formula, then such substituent can be linked by any atom in such substituent. Combinations of substituents and / or variables are acceptable, but only if such combinations result in stable compounds.

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The compounds of the present invention that contain nitrogen can be converted into N-oxides by treatment with an oxidizing agent (eg, 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxides) to provide other compounds of the present invention. Therefore, when valence and structure permit, all nitrogen-containing compounds shown and claimed are considered to include both the compound as shown and its N-oxide derivative (which can be designated as N → Oo N + -O -). In addition, in other cases, the nitrogens in the compounds of the present invention can be converted into N-hydroxyl or N-alkoxy compounds. For example, N-hydroxyl compounds can be prepared by oxidation of the original amine by an oxidizing agent such as m-CPBA. When valence and structure permit, it is also considered that all the nitrogen-containing compounds shown and claimed cover both the compound as shown and its N-hydroxyl (i.e., N-OH) and N-alkoxy derivatives ( that is, N-OR, wherein R is a C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C3-14 carbocycle or 3-14 membered heterocycle, substituted or unsubstituted).

When a chemical atom or residue is followed by a numerical interval in subscript (for example, C1-6), the invention is intended to encompass each number within the range as well as all intermediate intervals. For example, "C1-6 alkyl" is intended to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5 and 5-6 carbons.

As used herein, "alkyl" is intended to include saturated aliphatic hydrocarbon groups of both branched and linear chains having the specified number of carbon atoms. For example, C1-6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

As used herein, "alkenyl" is intended to include hydrocarbon chains of either linear or branched configuration having one or more carbon-carbon double bonds that appear at any stable point along the chain. For example, C2-6 alkenyl is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

As used herein, "alkynyl" is intended to include hydrocarbon chains of either linear or branched configuration having one or more triple carbon-carbon bonds that appear at any stable point along the chain. For example, C2-6 alkynyl is intended to include C2, C3, C4, C5 and C6 alkynyl groups. Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. "Counterion" is used to represent a negatively charged small species such as chloride, bromide, hydroxide, acetate and sulfate.

As used herein, "carbocycle" or "carbocyclic ring" is intended to mean any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated or aromatic. For example, a C3-14 carbocycle is intended to mean a mono, bi or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl. Bridge rings are also included in the definition of carbocycle, including, for example, [3.3.0] bicyclooctane, [4.3.0] biciclononano, [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring appears when one or more carbon atoms join two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring has a bridge, the substituents cited for the ring may also be present on the bridge. Condensed rings (for example, naphthyl and tetrahydronaphthyl) and spiro are also included.

As used herein, the term "heterocycle" or "heterocyclic" is intended to mean any stable monocyclic, bicyclic or tricyclic ring that is saturated, unsaturated or aromatic and comprising carbon atoms and one or more ring heteroatoms, by example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. A bicyclic or tricyclic heterocycle may have one or more heteroatoms located in a ring, or the heteroatoms may be located in more than one ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (ie, N → O and S (O) p, where p = 1 or 2). When a nitrogen atom is included in the ring it is either N or NH, depending on whether it is attached to a double bond in the ring or not (that is, a hydrogen is present if it is necessary to maintain the trivalence of the nitrogen atom ). The nitrogen atom may be substituted or unsubstituted (ie, N or NR in which R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally quaternize. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Bridge rings are also included in the definition of heterocycle. A bridged ring appears when one or more atoms (i.e., C, O, N or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridges include,

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but they are not limited to a carbon atom, two carbon atoms, a nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring has a bridge, the substituents cited for the ring may also be present on the bridge. Spiral and condensate rings are also included.

As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6 or 7 membered monocyclic or bicyclic aromatic heterocyclic ring or a 7, 8, 9, 10 bicyclic aromatic heterocyclic ring , 11 or 12 members consisting of carbon atoms and one or more heteroatoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. In the case of bicyclic heterocyclic aromatic rings, it is only necessary that one of the two rings be aromatic (for example, 2,3-dihydroindole), although both may be (for example, quinoline). The second ring may also be condensed or have a bridge as defined above for the heterocycles. The nitrogen atom may be substituted or unsubstituted (ie, N or NR in which R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can be optionally oxidized (ie, N → O and S (O) p, where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not greater than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzothoxazolyl, benzyl-nazolyl, benzyl-nazolyl, benzyl-nazolyl, benzyl-ozolyl, benzyl-ozolyl, benzyl-ozolyl, benzyl-azamzolyl, benzyl-ozolyl, benzyl-ozolyl, benzyl-thiazolyl, benzyl-thiazolyl group, Chromenyl, cinolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolizinyl 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadyl-oxoyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadyl-oxoyl, 1,2,3-oxadiazolyl 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenazinyl, phenothiazinyl, f enoxatinilo, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, tiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 5-triazolyl, 1,3,4-triazolyl and xanthenyl.

As used herein, the term "amine protecting group" is intended to mean a functional group that converts an amine, amide or other nitrogen-containing moiety into a different chemical group that is substantially inert to the conditions of a chemical reaction. particular. The amine protecting groups are preferably removed easily and selectively with good performance under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl, p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl, fluorenylmethyloxycarbonyl, 2- (trimethyl) carbonyl, 2- (trimethyl) 1-methyl-1- (4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl and benzyloxycarbonyl. Those skilled in the art directly identify other suitable amine protecting groups, for example, referring to Green and Wuts, Protective Groups in Organic Synthesis, 3rd Ed. (1999, John Wiley & Sons, Inc.).

"Stable compound" and "stable structure" are intended to indicate a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture and formulation in an effective therapeutic agent.

Unless otherwise indicated, all percentages and ratios used herein are by weight.

Throughout the description, when it is described that the compositions have, include or comprise specific components, it is contemplated that the compositions also consist essentially of, or consist of, the cited components. Similarly, when it is described that the procedures have, include or comprise specific process steps, the procedures also essentially consist of, or consist of, the mentioned processing steps. In addition, it should be understood that the order of the stages or the order to perform certain actions are irrelevant as long as the invention remains feasible. In addition, two or more stages or actions can be carried out simultaneously.

2. Procedures of the invention

The methods of the invention involve a Suzuki-type coupling reaction between an arylborane compound (for example, an arylboronic acid, arylboronic ester, arylboronic or organoborane halide) and an aryl compound having an electronegative substituent (for example, a halide of aryl or aryl sulfonate) in a solvent in the presence of a base and a palladium catalyst. See, for example, Miyaura et al., Tetrahedron Letters, 3437 (1979) and Miyaura and Suzuki, Chem. Comm., 866 (1979).

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Procedures for synthesizing compounds having the formula are disclosed herein:

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In one approach, the process includes the step of combining a compound of formula (I):

with a compound of formula (II):

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in a solvent in the presence of a base and a palladium catalyst, in which 15 A is selected from the group consisting of: phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; B is selected from the group consisting of:

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phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; Het-CH2-R3 is selected from the group consisting of:

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M-L is selected from the group consisting of:

a) MX, b) M-L1, c) M-L1-X, d) MX-L2, e) M-L1-X-L2, f) MX-L1-X-L2, g) M-L1- X-L2-X, h) MXX-, i) M-L1-XX-, 30 j) MXX-L2 and k) M-L1-XX-L2, in which

in each case, X is independently selected from the group consisting of:

a) -O-, b) -NR4-, c) -N (O) -, d) N (OR4) -, e) -S (O) p-, f) -SO2NR4-, g) -NR4SO2- , h) -NR4-N =, i) = N-NR4-, j) -O35 N =, k) = NO-, l) -N =, m) = N-, n) -NR4-NR4-, o) -NR4C (O) O-, p) -OC (O) NR4-, q) -NR4C (O) NR4-, r) NR4C (NR4) NR4-y s)

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40 L1 is selected from the group consisting of:

a) C1-6 alkyl, b) C2-6 alkenyl and c) C2-6 alkynyl,

wherein any of a) -c) is optionally substituted with one or more R5 groups; Y

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L2 is selected from the group consisting of: a) C1-6 alkyl, b) C2-6 alkenyl and c) C2-6 alkynyl, wherein any of a) -c) is optionally substituted with one or more R5 groups;

alternatively, L in M-L is a link; M is selected from the group consisting of: a) saturated, unsaturated or aromatic C3-14 carbocycle, b) saturated, unsaturated or aromatic heterocycle of 3-14

members containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl and f) -CN, in which any of a ) -e) is optionally substituted with one or more R5 groups;

Q is a borane having the formula -BY2, in which in each case, Y is independently selected from the group consisting of: a) -OH, b) -O-C1-6 alkyl, c) -O-C2 alkenyl -6, d) -O-C2-6 alkynyl, e) -O-saturated, unsaturated or carbo-cycle

C1-14 aromatic, f) C1-6 alkyl, g) C2-6 alkenyl, h) C2-6 alkynyl ei) saturated, unsaturated or C1-14 aromatic carbocycle, in which any of b) -i) is optionally substituted with one or more halogens;

alternatively, two Y groups taken together comprise a chemical moiety selected from the group consisting of: a) -OC (R4) (R4) C (R4) (R4) O and b) -OC (R4) (R4) CH2C (R4 ) (R4) O-; alternatively, Q is an alkali metal salt of BF3 or 9-borabcycle [3.3.1] nonane; Z is selected from the group consisting of: a) I, b) Br, c) Cl and d) R9OSO3-;

in each case, R1 is independently selected from the group consisting of: a) F, b) Cl, c) Br, d) I, e) -CF3, f) -OR4, g) -CN, h) -NO2, i) -NR4R4, j) -C (O) R4, k) -C (O) OR4, l) -OC (O) R4, m) -C (O) NR4R4, n) -NR4C (O) R4, o) -OC (O) NR4R4, p) NR4C (O) OR4, q) NR4C (O) NR4R4, r) -C (S) R4, s) -C (S) OR4, t) -OC (S) R4, u) -C (S) NR4R4, v) -NR4C (S) R4, w) -OC (S) NR4R4, x) NR4C (S) OR4, y) -NR4C (S) NR4R4, z) -C (NR4) R4, aa) -C (NR4) OR4, bb) -OC (NR4) R4, cc) -C (NR4) NR4R4, dd) -NR4C (NR4) R4, ee) -OC (NR4) NR4R4, ff) -NR4C (NR4) OR4, gg) -NR4C (NR4) NR4R4, hh) -S (O) pR4, ii) -SO2NR4R4 and jj) R4;

in each case, R2 is independently selected from the group consisting of: a) F, b) Cl, c) Br, d) I, e) -CF3, f) -OR4, g) -CN, h) -NO2, i) -NR4R4, j) -C (O) R4, k) -C (O) OR4, l) -OC (O) R4, m) -C (O) NR4R4, n) -NR4C (O) R4, o) -OC (O) NR4R4, p) NR4C (O) OR4, q) NR4C (O) NR4R4, r) -C (S) R4, s) -C (S) OR4, t) -OC (S) R4, u) -C (S) NR4R4, v) -NR4C (S) R4, w) -OC (S) NR4R4, x) NR4C (S) OR4, y) -NR4C (S) NR4R4, z) -C (NR4) R4, aa) -C (NR4) OR4, bb) -OC (NR4) R4, cc) -C (NR4) NR4R4, dd) -NR4C (NR4) R4, ee) -OC (NR4) NR4R4, ff) -NR4C (NR4) OR4, gg) -NR4C (NR4) NR4R4, hh) -S (O) pR4, ii) -SO2NR4R4 and jj) R4; R3 is selected from the group consisting of: a) -OR4, b) NR4R4, c) -C (O) R4, d) -C (O) OR4, e) -OC (O) R4, f) -C ( O) NR4R4, g) NR4C (O) R4, h) -OC (O) NR4R4, i) NR4C (O) OR4, j) NR4C (O) NR4R4, k) -C (S) R4, l) -C (S) OR4, m) -OC (S) R4, n) -C (S) NR4R4, or) -NR4C (S) R4, p) -OC (S) NR4R4, q) NR4C (S) OR4, r ) NR4C (S) NR4R4, s) -C (NR4) R4, t) -C (NR4) OR4, u) -OC (NR4) R4, v) -C (NR4) NR4R4, w) -NR4C (NR4) R4, x) -OC (NR4) NR4R4, y) -NR4C (NR4) OR4, z) -NR4C (NR4) NR4R4, aa) -S (O) pR4, bb) -SO2NR4R4 and cc) R4; in each case, R4 is independently selected from the group consisting of: a) H, b) -OR6, c) an amine protecting group, d) C1-6 alkyl, e) C2-6 alkenyl, f) C2- alkynyl 6, g) C3-14 saturated, unsaturated or aromatic carbocycle, h) 3-14 saturated, unsaturated or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and

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sulfur, i) -C (O) -C1-6 alkyl, j) -C (O) -C2-6 alkenyl, k) -C (O) -C2-6 alkynyl, l) -C (O) -carbocycle saturated, unsaturated or aromatic C3-14, m) -C (O) - saturated, unsaturated or aromatic heterocycle of 3-14 members comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, n) -C (O) O-C1-6 alkyl, o) -C (O) O-C2-6 alkenyl, p) -C (O) O-C2-6 alkynyl, q) -C (O) saturated O-carbocycle, unsaturated or aromatic C3-14 and r) -C (O) O-saturated, unsaturated or aromatic 3-14-membered heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,

wherein any of d) -r) is optionally substituted with one or more R5 groups;

In each case, R5 is independently selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) = O, f) = S, g) NR6, h) NOR6, i) = N-NR6R6, j) -CF3, k) -OR6 , l) -CN, m) -NO2, n) NR6R6, o) -C (O) R6, p) -C (O) OR6, q) -OC (O) R6, r) -C (O) NR6R6 , s) NR6C (O) R6, t) -OC (O) NR6R6, u) -NR6C (O) OR6, v) -NR6C (O) NR6R6, w) -C (S) R6, x) -C ( S) OR6, y) -OC (S) R6, z) -C (S) NR6R6, aa) -NR6C (S) R6, bb) -OC (S) NR6R6, cc) -NR6C (S) OR6, dd ) NR6C (S) NR6R6, ee) -C (NR6) R6, ff) -C (NR6) OR6, gg) -OC (NR6) R6, hh) -C (NR6) NR6R6, ii) -NR6C (NR6) R6, jj) -OC (NR6) NR6R6, kk) -NR6C (NR6) OR6, ll) -NR6C (NR6) NR6R6, mm) -S (O) pR6, nn) -SO2NR6R6 and oo) R6;

in each case R6 is independently selected from the group consisting of:

a) H, b) -OR8, c) an amine protecting group, d) C1-6 alkyl, e) C2-6 alkenyl, f) C2-6 alkynyl, g) saturated, unsaturated or C3-14 aromatic carbocycle, h) 3-14 membered saturated, unsaturated or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, i) -C (O) -C 1-6 alkyl, j) -C (O ) -C2-6 alkenyl, k) -C (O) -C2-6 alkynyl, l) -C (O) -C3-14 saturated, unsaturated or aromatic carboxy, m) -C (O) -unsaturated, unsaturated heterocycle or 3-14-aromatic aromatic comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, n) -C (O) O-C1-6 alkyl, or) -C (O) O-C2-alkenyl -6, p) -C (O) C2-6 O-alkynyl, q) -C (O) C3-14 saturated, unsaturated or aromatic O-carbocycle and r) -C (O) saturated, unsaturated or aromatic O-heterocycle 3-14 members comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,

wherein any of d) -r) is optionally substituted with one or more R7 groups;

In each case, R7 is independently selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) = O, f) = S, g) = NR8, h) NOR8, i) N-NR8R8, j) -CF3, k) -OR8 , l) -CN, m) -NO2, n) NR8R8, o) -C (O) R8, p) -C (O) OR8, q) -OC (O) R8, r) -C (O) NR8R8 , s) -NR8C (O) R8, t) -OC (O) NR8R8, u) -NR8C (O) OR8, v) -NR8C (O) NR8R8, w) -C (S) R8, x) -C (S) OR8, y) -OC (S) R8, z) -C (S) NR8R8, aa) -NR8C (S) R8, bb) -OC (S) NR8R8, cc) -NR8C (S) OR8, dd) -NR8C (S) NR8R8, ee) -C (NR8) R8, ff) -C (NR8) OR8, gg) -OC (NR8) R8, hh) -C (NR8) NR8R8, ii) NR8C (NR8 ) R8, jj) -OC (NR8) NR8R8, kk) NR8C (NR8) OR8, ll) -NR8C (NR8) NR8R8, mm) -S (O) pR8, nn) -SO2NR8R8, oo) C1-6 alkyl, pp) C2-6 alkenyl, qq) C2-6 alkynyl, rr) saturated C3-14 unsaturated or aromatic carbocycle and ss) 3-14 membered saturated, unsaturated or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting in nitrogen, oxygen and sulfur,

wherein any of oo) -ss) is optionally substituted with one or more moieties selected from the group consisting of R8, F, Cl, Br, I, -CF3, -OR8, -SR8, -CN, -NO2, - NR8R8, -C (O) R8, -C (O) OR8, -OC (O) R8, -C (O) NR8R8, -NR8C (O) R8, -OC (O) NR8R8, NR8C (O) OR8, -NR8C (O) NR8R8, -C (S) R8, -C (S) OR8, -OC (S) R8, -C (S) NR8R8, -NR8C (S) R8, -OC (S) NR8R8, - NR8C (S) OR8, NR8C (S) NR8R8, -C (NR8) R8, -C (NR8) OR8, -OC (NR8) R8, -C (NR8) NR8R8, -NR8C (NR8) R8, -OC ( NR8) NR8R8, NR8C (NR8) OR8, -NR8C (NR8) NR8R8, -SO2NR8R8 and -S (O) pR8;

In each case, R8 is independently selected from the group consisting of:

a) H, b) an amine protecting group, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, f) saturated, unsaturated or aromatic C3-14 carbocycle, g) saturated heterocycle, unsaturated or aromatic 3-14 membered comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, h) -C (O) -C 1-6 alkyl, i) -C (O) -C 2 -alkenyl 6, j) -C (O) -C2-6 alkynyl, k) -C (O) -C3-14 saturated, unsaturated or aromatic carbocycle, l) -C (O) -3-saturated, unsaturated or aromatic heterocycle 3- 14 members comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, m) -C (O) O-C1-6 alkyl, n) -C (O) O-C2-6 alkenyl, or) -C (O) C2-6 O-alkynyl, p) -C (O) C3-14 saturated, unsaturated or aromatic O-carbocycle and q) -C (O) 3-14 membered saturated, unsaturated or aromatic O-heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,

wherein any of c) -q) is optionally substituted with one or more moieties selected from the group E04779405

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consisting of F, Cl, Br, I, -CF3, -OH, -O-C1-6 alkyl, -SH, -S-C1-6 alkyl, -CN, NO2, NH2, -NH-C1-6 alkyl , -N (C1-6 alkyl) 2, -C (O) C1-6 alkyl, -C (O) O-C1-6 alkyl, -C (O) NH2, -C (O) NH-C1-alkyl 6, -C (O) N (C1-6 alkyl) 2, -NHC (O) C1-6 alkyl, -SO2NH2-, -SO2NH-C1-6 alkyl, -SO2N (C1-6 alkyl) 2 and -S (O) p-C1-6 alkyl;

R9 is selected from the group consisting of: a) C1-6 alkyl, b) phenyl and c) toluyl; wherein any of a) -c) is optionally substituted with one or more moieties selected from the group

10 consisting of F, Cl, Br and I; m is 0.1, 2.3 or 4; n is 0, 1,2, 3 or 4; Y

In each case, p is independently 0, 1 or 2. In an alternative approach, the method includes the step of combining a compound of formula (III):

with a compound of formula (IV):

image6

in a solvent in the presence of a base and a palladium catalyst, in which A, B, Het, L, M, R1, R2, R3, R4, Q, Z, m and n are defined as described above.

In another aspect, the invention provides methods for preparing a compound having the formula:

image7

In one approach, the process includes the step of combining a compound of formula (V):

with a compound of formula (VI):

image8

in a solvent in the presence of a base and a palladium catalyst. In an alternative approach, the method includes

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the step of combining a compound of formula (VII):

with a compound of formula (VIII):

image9

image10

in a solvent in the presence of a base and a palladium catalyst. In any of the approaches, A, B, L, M, 10 R1, R2, R3, Q, Z, m and n are defined as described above.

In yet another aspect, the disclosure provides methods for preparing a compound having the formula:

image11

In one approach, the process includes the step of combining a compound of formula (IX):

image12

20 with a compound of formula (X):

image13

in a solvent in the presence of a base and a palladium catalyst. Alternatively, the compound can be prepared by combining a compound of formula (XI):

image14

with a compound of formula (XII):

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image15

in a solvent in the presence of a base and a palladium catalyst. In any of the approaches, A, B, L, M, R1, R2, R3, Q, Z, m and n are defined as described above. 5 The embodiments of any of the above procedures may include the following:

In the preferred compounds, A and B are independently selected from the group consisting of phenyl and pyridyl, and myn are independently 0, 1 or 2. R3 can be triazole, tetrazole, oxazole or isoxazole, and particularly 10 [1,2,3] triazol-1-yl. Alternatively, R3 may be NHC (O) R4 and particularly -NHC (O) CH3.

In various embodiments, the compounds (II), (VI) or (X) may have a formula selected from:

image16

In which R2, R3, Z and n are defined as described above. In addition, the compounds (I), (V) or (IX) may have a formula selected from:

image17

in which L, M, Q, R1 and m are defined as described above. In other embodiments, the compounds (IV), (VIII) or (XII) may have a formula selected from:

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image18

in which R2, R3, Q and n are defined as described above. Additionally, the compounds (III), (VII) or (XI) may have one of the following formulas:

image19

in which L, M, R1, Z and m are defined as described above.

In any of these embodiments, M-L may be M-CH2-X-CH2-. In some embodiments, X is -NR4-, in which R4 can be, for example, H or an amine protecting group. Examples of suitable amine protecting groups include benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl, p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl, fluorenylmethyloxycarbonyl, 2-trimethylsilyl-1-ethyloxy-1- 4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl and benzyloxycarbonyl. In embodiments where R4 is an amine protecting group,

The procedures may include the step of removing the amine protecting group.

In alternative embodiments, M-L is M-S-L1-NR4-L2, wherein L1 and L2 are C1-6 alkyl. Particularly, M-L can be M-S-CH2CH2-NH-CH2-. In still other embodiments, L is C1-6 alkyl and particularly -CH2-.

In the above embodiments, M may be a 5-6 membered saturated, unsaturated or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of suitable heterocycles include triazole, tetrazole, oxazol and isoxazole, and particularly isoxazol-4-yl, [1,2,3] triazol-1-yl and [1,2,3] triazol-4-yl.

Alternatively, M-L can be M-X-CH2-. In some embodiments, X is -NR4-, in which R4 can be, for example, H or an amine protecting group, as described above. In embodiments where R4 is an amine protecting group, the procedures may include the step of removing the amine protecting group. In other embodiments, M-L is

image20

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or, more particularly,

image21

In the above embodiments, M may be a C1-6 alkyl, C2-6 alkenyl or halogenated C2-6 alkynyl group, optionally substituted with one or more R5 groups, as defined above. Alternatively, M can be a -CN group. In particular embodiments, M is a C1-6 alkyl substituted with one or more atoms selected from the group consisting of F, Cl, Br and I, for example, -CH2CH2CH2F. M may also be a C1-6 alkyl substituted with one or more -CN groups, for example, -CH2CH2CN. Other examples of suitable M groups include, but are not

10 limit to, -CH2CH (OH) CH2F and -CH2C (O) NH2.

In alternative embodiments, M is a C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, in which one or more carbons are replaced by S (O) p and one or more of the remaining carbons are optionally substituted with one or more R5 groups.

Other embodiments include compounds in which M has the formula:

image22

Wherein V is H, -NR4R4, -OR4 or C1-6 alkyl optionally substituted with one or more R5 groups; W is O or S; and L1 and L2 are defined as described above.

The Z group can be a halogen or a sulphonate. Examples of suitable sulfonates include, but are not limited to, methanesulfonate ("mesylate"), trifluoromethanesulfonate ("triflate") and p-toluenesulfonate ("tosylate"). In preferred embodiments, the Z group is I. Preferred Q groups include -B (OH) 2, -BF2 · KF and

image23

In any of the above procedures, the base can be selected from the group consisting of hydroxides

30 alkali metals, alkali metal carbonates, alkali metal fluorides, trialkylamines and mixtures thereof. Examples of suitable bases include potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium fluoride, triethylamine, diisopropylethylamine and mixtures thereof. In certain embodiments, the ratio of the equivalents of the bases with respect to the equivalents of the compound (I), (IV), (V), (VIII), (IX) or (XII) is approximately 3: 1.

The catalyst can be a palladium catalyst, for example, a palladium (0) catalyst coordinated to a ligand (for example, a tetrakis (trialkylphosphine) palladium (0) or tetrakis (triarylphosphine) palladium (0)) catalyst. or a palladium (II) catalyst coordinated to a ligand. Suitable catalysts include, for example, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1’-bis (diphenylphosphino) ferrocene] palladium (II), dichlorobis (triphenylphosphine) palladium (II),

40 palladium (II) acetate and palladium (II) chloride. In particular embodiments, the catalyst is tetrakis (triphenylphosphine) palladium (0), and the ratio of the equivalents of the catalyst with respect to the equivalents of the compound (I), (IV), (V), (VIII), (IX) or (XII) is about 1:20.

The solvent may be an aqueous solvent, or a mixture of water and an organic solvent, in which the

The organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, benzene, toluene, tetrahydrofuran, dimethylformamide, 1,2-diethyl ether, dimethoxyethane, diisopropyl ether, methyl tert-butyl ether, methoxymethyl ether, 2-methoxyethyl ether, 1,4-dioxane, 1,3-dioxolane, and mixtures thereof. In particular embodiments, the solvent is a mixture of water, toluene and ethanol, for example, in a ratio of about 1: 3: 1 by volume.

The process can be carried out at a temperature of about 20 ° C to about 100 ° C. In some embodiments, the process is carried out at the reflux temperature of the solvent.

Those skilled in the art directly identify other reaction conditions for the reactions of

55 Suzuki type coupling described herein, for example, referring to Suzuki and Brown, Organic Synthesis Via Boranes Volume 3: Suzuki Coupling, (Aldrich, 2003).

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Table 1 includes exemplary compounds that can be synthesized according to the procedures described herein.

Table 1

Compound number

Structure

one

image24

(5S) N- [3- (2-fluoro-4 ’- {[(quinolin-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2-oxo-oxazolidin-5-methyl] -acetamide

2

(5S) N- [3- (2-fluoro-4 '- {[([1,2,3] thiadiazol-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2-oxo- oxazolidin-5-methyl] -acetamide

3

image25

(5S) N- {3- [3-Fluoro-4- (6-tetrazol-1-ylmethyl-pyridin-3-yl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

4

image26

(5S) N- [3- (2-fluoro-4 ’- [1,2,3] triazol-1-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

5

image27

(5S) N- [3- (2-fluoro-4 ’- {[(isoxazol-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2-oxo-oxazolidin-5-methyl] -acetamide

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6

image28

(5S) N- [3- (2-fluoro-4 '- {[(3H- [1,2,3] triazol-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2- oxo-oxazolidin5-ylmethyl] -acetamide

7

image29

(5R) 3- (2-Fluoro-4 '- {[(3H- [1,2,3] triazol-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -5- [1, 2,3] triazol-1-methyl-oxazolidin-2-one

8

image30

(5S) N- [3- (2-fluoro-4 '- {[methyl- (3H- [1,2,3] triazol-4-ylmethyl) -amino] -methyl} -biphenyl-4-yl) - 2-oxooxazolidin-5-ylmethyl] -acetamide

9

image31

(5S) N- [3- (2-Fluoro-4’-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

10

image32

(5S) N- [3- (2-Fluoro-4’-piperidin-1-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

eleven

image33

(5S) N- [3- {2-fluoro-4 ’- [(3-fluoro-propylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl] acetamide

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12

image34

(5S) N- (3- {4 ’- [(2-cyano-ethylamino) -methyl] -2-fluoro-biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) acetamide

13

image35

(5S) N- {3- [4- (4-N- (N-methyl-N’-cyano) guanylaminomethyl-phenyl-4-yl) -3-fluorophenyl] -2-oxooxazolidin-5-ylmethyl} -acetamide

14

image36

(5R) 2 - {[2'-fluoro-4 '- (2-oxo-5- [1,2,3] triazol-1-ylmethyl-oxazolidin-3-yl) -biphenyl-4-ylmethyl] -amino } acetamide

fifteen

image37

(5S) N- (3- {2-fluoro-4 ’- [(3-fluoro-2-hydroxy-propylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

16

image38

(5R) 3- {2-fluoro-4 ’- [(3-fluoro-propylamino) -methyl] -biphenyl-4-yl} -5- [1,2,3] triazol-1-ylmethyloxazolidin-2-one

17

image39

(5S) N- {3- [4 ’- (ethanesulfonylamino-methyl) -2-fluoro-biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

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18

image40

(5S) N- [3- (2-Fluoro-4’-methylsulfamoylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

19

image41

(5S) N- (3- {2-fluoro-4 '- [3- (3-imidazol-1-yl-propyl) -ureido] -biphenyl-4-yl} -2-oxo-oxazolidin-5-methyl) - acetamide

twenty

image42

(5S) N- [3- (2-fluoro-4 '- {[2- (3H- [1,2,3] triazol-4-ylsulfanyl) -ethylamino] -methyl} -biphenyl-4-yl) - 2oxo-oxazolidin-5-ylmethyl] -acetamide

twenty-one

image43

(5S) N- {3- [2-fluoro-4 ’- (pyridin-4-ylmethanesulfonyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

22

image44

(5S) N- (3- {2-fluoro-4 ’- [(pyridin-2-ylmethyl) -sulfamoyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) acetamide

2. 3

(5S) N- (3- {2-fluoro-4 '- [(1-methyl-1H-imidazol-4-sulfonylamino) -methyl] -biphenyl-4-yl} -2-oxooxazolidin-5-ylmethyl) - acetamide

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24

image45

(5S) N- {3- [2-fluoro-4 ’- ([1,2,4] triazol-4-ylaminomethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5ylmethyl} -acetamide

25

image46

(5S) N- {3- [2-fluoro-4 ’- (3H- [1,2,3] triazol-4-sulfonylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5ylmethyl} -acetamide

26

(5S) 2 - ({4 ’- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2’-fluoro-biphenyl-4-ylmethyl} -amino) acetamide

27

image47

(5S) N- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2’-fluoro-biphenyl-4-ylmethyl} -2-amino-acetamide

28

image48

(5S) N- {3- [2-fluoro-4 ’- (methanesulfonylamino-methyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5ylmethyl} -acetamide

29

image49

(5S) N- {3- [2,3’-difluoro-4 ’- (methanesulfonylamino-methyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

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30

image50

(5S) N- [3- (2-Fluoro-4’-tetrazol-2-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

31

image51

(5S) N- {3- [2-fluoro-4 ’- (pyridin-4-ylmethanesulfinylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5ylmethyl} -acetamide

32

image52

(5S) N- {3- [3-Fluoro-4- (6-tetrazol-1-ylmethyl-pyridin-3-yl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

33

image53

(5S) N- {3- [3-fluoro-4- (6- [1,2,3] triazol-1-ylmethyl-pyridin-3-yl) -phenyl] -2-oxo-oxazolidin-5-methyl] - acetamide

3. 4

image54

(5S) N- {3- [2-fluoro-4 ’([1,3,4] thiadiazol-2-sulfinylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethylacetamide

35

image55

(5S) N- [3- (2-fluoro-4 ’- [1,2,4] triazol-1-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

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36

image56

(5S) N- {3- [2-fluoro-4 ’- (5-methyl-tetrazol-1-ylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

37

image57

(5S) N- {3- [2-fluoro-4 ’- (5-methyl-tetrazol-2-ylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

38

image58

(S, S) N- {3- [2-fluoro-4 '- (1-hydroxy-2- [1,2,3] triazol-1-yl-ethyl) -biphenyl-4-yl] -2- oxo-oxazolidin-5ylmethyl} -acetamide

39

image59

(5S) N- (3- {2-fluoro-4 ’- [(2-methylsulfanyl-ethylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

40

image60

(5S) N- {3- [3-fluoro-4- (6- [1,2,4] triazol-1-ylmethyl-pyridin-3-yl) -phenyl] -2-oxo-oxazolidin-5ylmethyl} - acetamide

41

image61

(5S) N- (3- {4 ’- [(acetyl-cyanomethyl-amino) -methyl] -2-fluoro-biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

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42

image62

(5S) N- {3- [3-fluoro-4- (6-pyrazol-1-ylmethyl-pyridin-3-yl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

43

image63

(5S) N- {3- [4 ’- (5-chloro-tetrazol-1-ylmethyl) -2-fluoro-biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

44

image64

(5R) 3- (2-Fluoro-4’-imidazol-1-ylmethyl-biphenyl-4-yl) -5- [1,2,3] triazol-1-ylmethyl-oxazolidin-2-one

Four. Five

image65

(5S) N- [3- (2-Fluoro-4’-prop-2-inylaminomethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

46

image66

(5S) N- [3- (4’-allylaminomethyl-2-fluoro-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide

47

image67

(5S) N- [3- (4’-but-3-enylaminomethyl-2-fluoro-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

48

image68

(5S) N- [3- (4’-but-3-inylaminomethyl-2-fluoro-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

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49

image69

(5S) N- [3- (2-Fluoro-4’-pent-4-inylaminomethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

fifty

image70

(5S) N- [3- (4’-but-2-inylaminomethyl-2-fluoro-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

51

image71

(5S) N- {3- [2-fluoro-4 ’- (3-fluoro-piperidin-1-ylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

52

image72

(5S) N- [3- (2-fluoro-4 '- {[3- (3H- [1,2,3] triazol-4-yl) -propylamino] -methyl} -biphenyl-4-yl) - 2-oxooxazolidin-5-ylmethyl] -acetamide

53

image73

(5S) N- (3- {4 ’- [(2,2-difluoro-ethylamino) -methyl] -2-fluoro-biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

54

image74

(5R) 3- (2-Fluoro-4’-prop-2-inylaminomethyl-biphenyl-4-yl) -5- [1,2,3] triazol-1-ylmethyl-oxazolidin-2one

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55

image75

(5S) N- [3- (2-Fluoro-4’-isoxazolidin-2-ylmethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-ylmethyl] acetamide

56

image76

(5S) N- {3- [4- (6-Cyano-pyridin-3-yl) -3-fluoro-phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide

57

image77

(5S) N- (3- {2-fluoro-4 ’- [(1-methyl-prop-2-inylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

58

image78

(5S) N- {3- [3-fluoro-4- (6 - {[(3H- [1,2,3] triazol-4-ylmethyl) -amino] -methyl} -pyridin-3-yl) - phenyl] -2oxo-oxazolidin-5-ylmethyl} -acetamide

59

image79

(5S) N- [3- (2-fluoro-4 '- {[(1-methyl-1H-tetrazol-5-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2-oxooxazolidin-5 -ylmethyl] -acetamide

60

(5S) N- [3- (2-fluoro-4 '- {[(2-methyl-2H-tetrazol-5-ylmethyl) -amino] -methyl} -biphenyl-4-yl) -2-oxooxazolidin-5 -ylmethyl] -acetamide

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61

image80

(5S) N- (3- {2-fluoro-4 ’- [(2-fluoro-allylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) acetamide

62

image81

(5S) N- (3- {4 ’- [(2,3-difluoropropylamino) -methyl] -2-fluoro-biphenyl-4-yl} -2-oxo-oxazolidin-5ylmethyl) -acetamide

63

image82

5- {4- [5- (Acetylamino-methyl) -2-oxooxazolidin-3-yl] -2-fluorophenyl} - (2- (3H-imidazol-4-yl) -ethyl] -amide pyridine-2-carboxylic

64

image83

4 ’- [5- (Acetylamino-methyl) -2-oxooxazolidin-3-yl] -2’-fluorobiphenyl-4-carboxylic acid ([1,2,4] oxadiazol-3-ylmethyl) -amide

65

image84

(5S) 4 ’- [5- (Acetylamino-methyl) -2-oxooxazolidin-3-yl] -2’-fluorobiphenyl-4-carboxylic acid ([1,2,4] thiadiazol-3-ylmethyl) -amide

66

image85

(5S) N- (1- {4 ’- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2’-fluoro-biphenyl-4-yl} -ethyl) -2amino-acetamide

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67

image86

(5S) 2- (1- {4 ’- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2’-fluorobiphenyl-4-yl} -ethylamino) acetamide

68

image87

(5S) N- {3- [2-fluoro-4 ’- (pyridin-4-ylmethylsulfanyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide

69

image88

(5S) N- (3- {2-fluoro-4 ’- [(pyridin-4-ylmethyl) -sulfamoyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) acetamide

70

image89

(S, S) N- (3- {2-fluoro-4 '- [2- (3-fluoro-propylamino) -1-hydroxy-ethyl] -biphenyl-4-yl} -2-oxooxazolidin-5-ylmethyl ) -acetamide

71

image90

(5S) N- {3- [2-fluoro-4 '- (5-oxo-2,5-dihydro- [1,2,4] oxadiazol-3-ylmethyl) -biphenyl-4-yl] -2- oxooxazolidin-5-ylmethyl} -acetamide

72

image91

(5S) N- {3- [2-fluoro-4 '- (5-methyl- [1,2,4] oxadiazol-3-ylmethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-methyl] -acetamide

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73

(5S) N- [3- (2-fluoro-4 '- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -thiazol-4-ylmethyl} -biphenyl-4-yl) -2oxo-oxazolidin -5-ylmethyl] -acetamide

74

image92

(5S) N- (3- {2-fluoro-4 '- [2- (3-methoxy-benzylamino) -thiazol-4-ylmethyl] -biphenyl-4-yl} -2-oxooxazolidin-5-ylmethyl) - acetamide

75

image93

(S, S) N- {3- [4 '- (1-amino-2-imidazol-1-yl-ethyl) -2-fluoro-biphenyl-4-yl] -2-oxo-oxazolidin-5-methyl] - acetamide

76

image94

(5S) 5-aminomethyl-3- (2-fluoro-4’-tetrazol-1-ylmethyl-biphenyl-4-yl) -oxazolidin-2-one

77

image95

(S, S) N- (3- {2-fluoro-4 '- [2- (4-formyl-piperazin-1-yl) -1-hydroxy-ethyl] -biphenyl-4-yl} -2-oxooxazolidin -5-ylmethyl) -acetamide

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image96

(R, S) N- (3- {2-fluoro-4 '- [1- (4-formyl-piperazin-1-yl) -2-hydroxy-ethyl] -biphenyl-4-yl} -2-oxooxazolidin -5-ylmethyl) -acetamide

79

image97

(S, S) N- {3- [2-fluoro-4 '- (1-hydroxy-2-imidazol-1-yl-ethyl) -biphenyl-4-yl] -2-oxo-oxazolidin-5-methyl] - acetamide

80

image98

(5S) 2,2-Difluoro-N- (3- {2-fluoro-4 '- [(3-fluoro-propylamino) -methyl] -biphenyl-4-yl} -2-oxooxazolidin-5-ylmethyl) - acetamide

81

image99

(5S) 2,2-Difluoro-N- [3- (2-fluoro-4’-prop-2-inylaminomethyl-biphenyl-4-yl) -2-oxo-oxazolidin-5-methyl] -acetamide

The exemplary compounds in Table 1 can be synthesized by the procedure depicted in Scheme A using, for example, the arylboronic acids and aryl iodides listed in Table 2, below.

image100

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Table 2

M

L Y Q Z R3 Product

 image101

-CH2NHCH2- * CH B (OH) 2 I -NHAc one

 image102

-CH2NHCH2- * CH B (OH) 2 I -NHAc 2

 image102

-CH2- CH B (OH) 2 I -NHAc 3

 image102

-CH2- CH B (OH) 2 I -NHAc 4

 image102

-CH2NHCH2- * CH B (OH) 2 I -NHAc 5

 image102

-CH2NHCH2- * CH B (OH) 2 I -NHAc 6

-CH2NHCH2- *

CH B (OH) 2 I image102 7

 image102

-CH2N (CH3) CH2- CH B (OH) 2 I -NHAc 8

 image102

-CH2- CH B (OH) 2 I -NHAc 9

 image102

-CH2- CH B (OH) 2 I -NHAc 10

FCH2CH2CH2

-NHCH2- * CH B (OH) 2 I -NHAc eleven

NCCH2CH2

-NHCH2- * CH B (OH) 2 I -NHAc 12

 image103

-CH2- CH B (OH) 2 I -NHAc 13

H2NC (O) CH2

-NHCH2 * CH B (OH) 2 I image102 14

FCH2CH (OH) CH2

-NHCH2 * CH B (OH) 2 I -NHAc fifteen

FCH2CH2CH2

-NHCH2 * CH B (OH) 2 I image102 16

CH3CH2

-SO2NHCH2 * CH B (OH) 2 I -NHAc 17

CH3

-NHSO2CH2 * CH B (OH) 2 I -NHAc 18

 image102

- (CH2) 3NHC (O) NH- * CH B (OH) 2 I -NHAc 19

 image102

-SCH2CH2NHCH2- * CH B (OH) 2 I -NHAc twenty

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 image102

-CH2SO2- CH B (OH) 2 I -NHAc twenty-one

 image102

-CH2NHSO2 * CH B (OH) 2 I -NHAc 22

 image102

-SO2NHCH2 * CH B (OH) 2 I -NHAc 2. 3

 image102

-NHCH2 * CH B (OH) 2 I -NHAc 24

 image102

-S (O) CH2- CH B (OH) 2 I -NHAc 25

H2NC (O) CH2

-NHCH2 * CH B (OH) 2 I -NHAc 26

H2NCH2C (O)

-NHCH2 * CH B (OH) 2 I -NHAc 27

CH3

-SO2N-HCH2 * CH B (OH) 2 I -NHAc 28

CH3

-SO2NHCH2 * CF B (OH) 2 I -NHAc 29

 image102

-CH2- CH B (OH) 2 I -NHAc 30

 image102

-CH2S (O) CH2- CH B (OH) 2 I -NHAc 31

 image102

-CH2- N B (OH) 2 I -NHAc 32

 image102

-CH2- N B (OH) 2 I -NHAc 33

 image102

-S (O) CH2- CH B (OH) 2 I -NHAc 3. 4

 image102

-CH2- CH B (OH) 2 I -NHAc 35

 image104

-CH2- CH B (OH) 2 I -NHAc 36

 image102

-CH2- CH B (OH) 2 I -NHAc 37

 image102

-CH2CH (OH) - CH B (OH) 2 I -NHAc 38

CH3

-SCH2CH2NHCH2- * CH B (OH) 2 I -NHAc 39

 image102

-CH2- N B (OH) 2 I -NHAc 40

NCCH2-

CH B (OH) 2 I -NHAc 41

 image102

-CH2- N B (OH) 2 I NHAc 42

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 image105

-CH2- CH B (OH) 2 I -NHAc 43

 image102

-CH2- CH B (OH) 2 I   image102 44

HC≡CCH2-

NHCH2 * CH B (OH) 2 I -NHAc Four. Five

H2C = CHCH2

-NHCH2 * CH B (OH) 2 I -NHAc 46

H2C = CHCH2CH2

-NHCH2 * CH B (OH) 2 I -NHAc 47

HC≡CCH2CH2

-NHCH2 * CH B (OH) 2 I -NHAc 48

HC≡C (CH2) 3

-NHCH2 * CH B (OH) 2 I -NHAc 49

CH3C≡CCH2

-NHCH2 * CH B (OH) 2 I -NHAc fifty

 image106

-CH2- CH B (OH) 2 I -NHAc 51

 image102

- (CH2) 3NHCH2 * CH B (OH) 2 I -NHAc 52

F2HCCH2

-NHCH2 * CH B (OH) 2 I -NHAc 53

HC≡CCH2

-NHCH2 * CH B (OH) 2 I image102 54

 image102

-CH2- CH B (OH) 2 I -NHAc 55

NC

(link) N B (OH) 2 I -NHAc 56

 image107

-NHCH2 * CH B (OH) 2 I -NHAc 57

 image102

-CH2NHCH2 * N B (OH) 2 I -NHAc 58

 image108

-CH2NHCH2 * CH B (OH) 2 I -NHAc 59

 image102

-CH2NHCH2 * CH B (OH) 2 I -NHAc 60

HC = CFCH2

-NHCH2 * CH B (OH) 2 I -NHAc 61

FH2CCHFCH2

-NHCH2 * CH B (OH) 2 I NHAc 62

 image102

-CH2CH2NHC (O) - * N B (OH) 2 I NHAc 63

 image102

-CH2NHC (O) * CH B (OH) 2 I -NHAc 64

 image102

-CH2NHC (O) * CH B (OH) 2 I -NHAc 65

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H2NCH2C (O) -

image109 CH B (OH) 2 I -NHAc 66

H2NC (O) CH2-

image110 CH B (OH) 2 I -NHAc 67

 image102

-CH2S- CH B (OH) 2 I -NHAc 68

 image102

-CH2NHSO2 * CH B (OH) 2 I -NHAc 69

FCH2CH2CH2

-NHCH2CH (OH) - * CH B (OH) 2 I -NHAc 70

 image111

-CH2- CH B (OH) 2 I -NHAc 71

 image102

-CH2- CH B (OH) 2 I -NHAc 72

 image112

-CH2- CH B (OH) 2 I -NHAc 73

 image113

-CH2- CH B (OH) 2 I -NHAc 74

 image102

image114 CH B (OH) 2 I -NHAc 75

 image102

-CH2- CH B (OH) 2 I -NH2 76

 image115

-CH2CH (OH) - CH B (OH) 2 I -NHAc 77

 image116

image102 CH B (OH) 2 I -NHAc 78

 image102

-CH2CH (OH) - CH B (OH) 2 I -NHAc 79

FCH2CH2CH2

-NHCH2 * CH B (OH) 2 I -NHC (O) CHF2 80

HC≡CCH2

-NHCH2 * CH B (OH) 2 I -NHC (O) CHF2 81

Compounds containing L groups that have free amines (for example, compounds derived from reagents that have L groups marked with * in Table 2) can alternatively be synthesized from the corresponding protected amines (eg, -CH2N (BOC) CH2-or -N (BOC) CH2-) followed by deprotection of the amine.

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Alternatively, the exemplary compounds in Table 1 can be synthesized by the procedure described in Scheme B using, for example, the arylboronic acids and aryl iodides listed in Table 3, below.

image117

Table 3

M

L Y Z Q R3 Product

 image118

-CH2NHCH2 * CH I B (OH) 2 -NHAc one

 image102

-CH2NHCH2 * CH I B (OH) 2 -NHAc 2

 image102

-CH2- CH I B (OH) 2 -NHAc 3

 image102

-CH2- CH I B (OH) 2 -NHAc 4

 image102

-CH2NHCH2 * CH I B (OH) 2 -NHAc 5

 image102

-CH2NHCH2 * CH I B (OH) 2 -NHAc 6

 image102

-CH2NHCH2 * CH I B (OH) 2   image102 7

 image102

-CH2N (CH3) CH2- CH I B (OH) 2 -NHAc 8

 image102

-CH2- CH I B (OH) 2 -NHAc 9

 image102

-CH2- CH I B (OH) 2 -NHAc 10

FCH2CH2CH2

-NHCH2 * CH I B (OH) 2 -NHAc eleven

NCCH2CH2

-NHCH2 * CH I B (OH) 2 -NHAc 12

 image119

-CH2- CH I B (OH) 2 -NHAc 13

H2NC (O) CH2

-NHCH2 * CH IB (OH) 2 image102 14

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FCH2CH (OH) CH2

-NHCH2 * CH I B (OH) 2 -NHAc fifteen

FCH2CH2CH2

-NHCH2 * CH IB (OH) 2 image102 16

CH3CH2

-SO2NHCH2 * CH I B (OH) 2 -NHAc 17

CH3

-NHSO2CH2- CH I B (OH) 2 -NHAc 18

 image102

- (CH2) 3NHC (O) NH- * CH I B (OH) 2 -NHAc 19

 image102

-SCH2CH2NHCH2- * CH I B (OH) 2 -NHAc twenty

 image102

-CH2SO2- CH I B (OH) 2 -NHAc twenty-one

 image102

CH2NHSO2 * CH I B (OH) 2 -NHAc 22

 image102

-SO2NHCH2 * CH I B (OH) 2 -NHAc 2. 3

 image102

-NHCH2 * CH I B (OH) 2 -NHAc 24

 image102

-S (O) CH2- CH I B (OH) 2 -NHAc 25

H2 NC (O) CH2

-NHCH2 - * CH I B (OH) 2 -NHAc 26

H2NCH2C (O)

-NHCH2 * CH I B (OH) 2 -NHAc 27

CH3

-SO2NHCH2 * CH I B (OH) 2 -NHAc 28

CH3

-SO2NHCH2 * CF I B (OH) 2 -NHAc 29

 image102

-CH2- CH I B (OH) 2 NHAc 30

 image102

-CH2S (O) CH2- CH I B (OH) 2 -NHAc 31

 image102

-CH2- N I B (OH) 2 -NHAc 32

 image102

-CH2- N I B (OH) 2 -NHAc 33

 image102

-S (O) CH2- CH I B (OH) 2 -NHAc 3. 4

 image102

-CH2- CH I B (OH) 2 -NHAc 35

 image120

-CH2- CH I B (OH) 2 -NHAc 36

 image102

-CH2- CH I B (OH) 2 -NHAc 37

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 image102

-CH2CH (OH) - CH I B (OH) 2 -NHAc 38

CH3

-SCH2CH2NHCH2- * CH I B (OH) 2 -NHAc 39

 image102

-CH2- N I B (OH) 2 -NHAc 40

NCCH2-

CH I B (OH) 2 -NHAc 41

 image102

-CH2- N I B (OH) 2 -NHAc 42

 image121

-CH2- CH I B (OH) 2 -NHAc 43

 image102

-CH2- CH I B (OH) 2   image102 44

HC≡CCH2

-NHCH2 * CH I B (OH) 2 -NHAc Four. Five

H2C = CHCH2

-NHCH2 * CH I B (OH) 2 -NHAc 46

H2C = CHCH2CH2

-NHCH2 * CH I B (OH) 2 -NHAc 47

HC≡-CCH2CH2

-NHCH2 * CH I B (OH) 2 -NHAc 48

HC≡C (CH2) 3

-NHCH2 * CH I B (OH) 2 -NHAc 49

CH3C≡CCH2

-NHCH2 * CH I B (OH) 2 -NHAc fifty

 image122

-CH2- CH I B (OH) 2 -NHAc 51

 image102

- (CH2) 3NHCH2 * CH I B (OH) 2 -NHAc 52

F2HCCH2

-NHCH2 * CH I B (OH) 2 -NHAc 53

HC≡CCH2

-NHCH2 * CH IB (OH) 2 image102 54

 image102

-CH2- CH I B (OH) 2 -NHAc 55

NC

(link) N I B (OH) 2 -NHAc 56

 image123

-NHCH2 * CH I B (OH) 2 -NHAc 57

 image102

-CH2NHCH2 * N I B (OH) 2 -NHAc 58

 image124

-CH2NHCH2 * CH I B (OH) 2 -NHAc 59

 image102

-CH2NHCH2 * CH I B (OH) 2 -NHAc 60

HC = CFCH2

-NHCH2 * CH I B (OH) 2 -NHAc 61

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FH2CCHFCH2

-NHCH2 * CH I B (OH) 2 -NHAc 62

 image102

-CH2CH2NHC (O) - * N I B (OH) 2 NHAc 63

 image102

-CH2NHC (O) * CH I B (OH) 2 -NHAc 64

 image102

-CH2NHC (O) * CH I B (OH) 2 -NHAc 65

H2NCH2C (O) -

image125 CH IB (OH) 2 -NHAc 66

H2NC (O) CH2-

image125 CH IB (OH) 2 -NHAc 67

 image102

-CH2S- CH I B (OH) 2 -NHAc 68

 image102

-CH2NHSO2 * CH I B (OH) 2 -NHAc 69

FCH2CH2CH2

-NHCH2CH (OH) - * CH I B (OH) 2 -NHAc 70

 image126

-CH2- CH I B (OH) 2 -NHAc 71

 image102

-CH2- CH I B (OH) 2 -NHAc 72

 image127

-CH2- CH I B (OH) 2 -NHAc 73

 image128

-CH2- CH I B (OH) 2 -NHAc 74

 image102

image129 CH IB (OH) 2 -NHAc 75

 image102

-CH2- CH I B (OH) 2 -NH2 76

 image130

-CH2CH (OH) - CH I B (OH) 2 -NHAc 77

 image131

image102 CH IB (OH) 2 -NHAc 78

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 image102

-CH2CH (OH) - CH I B (OH) 2 -NHAc 79

FCH2CH2CH2

-NHCH2 * CH I B (OH) 2 -NHC (O) CHF2 80

HC≡CCH2

-NHCH2 * CH I B (OH) 2 -NHC (O) CHF2 81

As previously mentioned, compounds containing L groups that have free amines (for example, compounds derived from reagents that have L groups marked * in Table 3) can alternatively be synthesized from the corresponding protected amines (by example, -CH2N (BOC) CH2-or -N (BOC) CH2-) followed by deprotection of the amine.

In addition to the reagents listed in Tables 2 and 3, reagents containing other Q groups (for example, boronic esters, boronic halides or organoborane) and / or reagents containing other Z groups (for example

For example, other halogens or sulphonates) to synthesize the compounds by way of example in Table 1 according to the methods of the invention.

3. Examples

15 The embodiments of the present disclosure are described in the following examples.

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer. The common reaction solvents were either quality for high performance liquid chromatography (HPLC). or quality for the American Chemical Society

20 (ACS), and anhydrous as obtained from the manufacturer unless otherwise indicated. "Chromatography" or "purified by silica gel" refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise indicated.

Example 1

Scheme 1 represents the synthesis of compound 11 from aryl iodide 108 and arylboronic acid 120.

Scheme 1

image132

30 a. Synthesis of aryl iodide 108-Method A Scheme 2 represents the synthesis of aryl iodide 108 from 3-fluoroaniline 101.

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image133

A solution of 3-fluoroaniline 101 (18.7 g, 168.3 mmol) in tetrahydrofuran (THF, 150 ml) was treated with potassium carbonate (K2CO3, 46.45 g, 336.6 mmol, 2.0 eq) and H2O (150 ml) before a solution of benzyl chloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 ml, 1.1 eq) in THF (50 ml) is added dropwise to the mixture reaction temperature at room temperature under N2. The resulting reaction mixture was stirred at room temperature for 2 h. When the CCF demonstrated that the reaction was complete, the reaction mixture was treated with H2O (100 ml) and ethyl acetate (EtOAc, 100 ml). The two phases were separated and the aqueous phase was extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with H2O (2 x 100 ml) and saturated aqueous sodium chloride (NaCl, 100 ml), dried over magnesium sulfate (MgSO4) and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (3-fluorophenyl) -carbamic acid 102 (39.2 g, 95% yield) benzyl ester as a pale yellow oil. This product was used directly in subsequent reactions without further purification. 1H-NMR (300 MHz, CDCl3) δ 5.23 (s, 2H, OCH2Ph), 6.75-6.82 (m, 2H), 7.05 (dd, 1H, J = 1.4, 8, 2 Hz), 7,227.45 (m, 6H). C14H12FNO2, LC-MS (EI) m / e 246 (M + + H).

A solution of amine 102 (39.2 g, 160.0 mmol) in anhydrous THF (300 ml) was cooled to -78 ° C in a dry ice / acetone bath before a n-butyllithium solution was added dropwise (n-BuLi, 2.5 M solution in hexane, 70.4 ml, 176 mmol, 1.1 eq) under N2. The resulting reaction mixture was subsequently stirred at -78 ° C for 1 h before a solution of (R) - (-) - glycidyl butyrate (25.37 g, 24.6 ml, 176 mmol, 1, was added dropwise). 1 eq) in anhydrous THF (100 ml) to the reaction mixture at -78 ° C under N2. The resulting reaction mixture was stirred at -78 ° C for 30 min before gradually warming to room temperature for 12 h under N2. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was quenched with H2O (200 ml) and the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 ml) was added. The two phases were separated and the aqueous phase was extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with H2O (2 x 100 ml) and saturated aqueous NaCl (100 ml), dried over MgSO4 and concentrated in vacuo. When most of the solvent was evaporated, white crystals precipitated from the concentrated solution. The residue was then treated with 20% EtOAc / hexane (100 ml) and the resulting thick suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with 20% EtOAc / hexane (2 x 50 mL) to provide the desired (5R) - (3- (3-fluoro-phenyl) -5-hydroxymethyloxazolidin-2-one 103 ( 24.4 g, 72.3% yield) as white crystals This product was used directly in subsequent reactions without further purification 1 H-NMR (300 MHz, DMSO-d6) δ 3.34-3.72 (m , 2H), 3.83 (dd, 1H, J = 6.2, 9.0 Hz), 4.09 (t, 1H, J = 12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J = 5.6 Hz, OH), 6.96 (m, 1H), 7.32-7.56 (m, 3H). C10H10FNO3, LC-MS (EI) ) m / e 212 (M + + H).

A solution of alcohol 103 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 ml) was treated with N

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iodosuccinimide (12.03 g, 53.45 mmol, 1.05 eq) at 25 ° C and stirred for 2 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 ml) and 20% EtOAc / hexane (100 ml) at 25 ° C and the resulting mixture was stirred at 25 ° C for 30 min before cooling to 0-5 ° C for 2 h. The white solids were collected by filtration, washed with H2O (2 x 25 ml) and 20% EtOAc / hexane (2 x 25 ml) and dried under vacuum to provide the (5R) -3- (3-fluoro- Desired 4-iodo-phenyl) -5-hydroxymethyl-oxazolidin-2-one 104 (15.1 g, 88% yield) as a bone-colored powder. This product was used directly in subsequent reactions without further purification. 1H-NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J = 4.2, 12.6 Hz), 3.67 (dd, 1H, J = 3.0, 12.6 Hz ), 3.67 (dd, 1H, J = 6.3, 9.0 Hz), 4.07 (t, 1H, J = 9.0 Hz), 4.72 (m, 1H), 5.21 (sa, 1H, OH), 7.22 (dd, 1H, J = 2.4, 8.4 Hz), 7.58 (dd, 1H, J = 2.4, 11.1 Hz), 7, 81 (dd, 1H, J = 7.8, 8.7 Hz). C10H9FINO3, LC-MS (EI) m / e 338 (M + + H).

A solution of iodine-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 ml) was treated with triethylamine (TEA, 15.15 g, 20.9 ml, 150 mmol, 2, 0 eq) at 25 ° C and the resulting mixture was cooled to 0-5 ° C before methane sulfonyl chloride (MsCl, 10.28 g, 6.95 ml, 89.7 mmol, 1.2 eq) was introduced dropwise reaction at 0-5 ° C under N2. The resulting reaction mixture was subsequently stirred at 0-5 ° C for 1 h under N2. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was quenched with H2O (100 ml) and CH2Cl2 (100 ml). The two phases were separated and the aqueous phase was extracted with CH2Cl2 (100 ml). The combined organic extracts were washed with H2O (2 x 100 ml) and saturated aqueous NaCl (100 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5R) -ester 3- (3fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl of the desired methanesulfonic acid 105 (30.71 g, 98 yield) , 9%) as a bone-colored powder. This product was used directly in subsequent reactions without further purification. C11H11FINO5S, LC-MS (EI) m / e 416 (M + + H).

A solution of mesylate 105 (26.38 g, 63.57 mmol) in anhydrous N, N-dimethylformamide (DMF, 120 ml) was treated with solid potassium phthalimide (12.95 g, 70.0 mmol, 1.1 eq) at 25 ° C and the resulting reaction mixture was heated to 70 ° C for 2 h. When TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature before quenching with H2O (400 ml). The resulting mixture was stirred at room temperature for 10 min before cooling to 0-5 ° C for 1 h. The white precipitate was collected by filtration, washed with water (3 x 100 ml) and dried in vacuo to provide (5R) -2- [3- (3-fluoro-4-iodo-phenyl) -2-oxooxazolidin -5-ylmethyl] -iso-indole-1,3-dione 106 desired (27.85 g, 94%) as a bone-colored powder. This product was used directly in subsequent reactions without further purification. C18H12FIN2O4, LC-MS (EI) m / e 467 (M + + H).

A solution of phthalimide 106 (23.3 g, 50.0 mmol) in ethanol (EtOH, 150 ml) was treated with hydrazine monohydrate (12.52 g, 12.1 ml, 250 mmol, 5.0 eq) at 25 ° C and the resulting reaction mixture was heated to reflux for 2 h. A white precipitate formed as the reaction mixture was refluxed. When the CCF and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature before quenching with H2O (100 ml). The aqueous solution was then extracted with CH2Cl2 (3 x 200 ml), and the combined organic extracts were washed with H2O (2 x 100 ml) and saturated aqueous NaCl (100 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5S) -5-aminomethyl-3- (3fluoro-4-iodo-phenyl) -oxazolidin-2-one 107 (16.0 g, 95.2% yield) Like a white powder This product was used directly in subsequent reactions without further purification. C10H10FIN2O2, LC-MS (EI) m / e 337 (M ++ H).

A suspension of amine 107 (16.0 g, 47.6 mmol) in CH2Cl2 (150 ml) was treated with TEA (9.62 g, 13.2 ml, 95.2 mmol, 2.0 eq) at 25 ° C and cooled the resulting reaction mixture to 0-5 ° C before being treated with acetic anhydride (AC2O, 7.29 g, 6.75 ml, 71.4 mmol, 1.5 eq) and 4-N, N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 eq) at 0-5 ° C under N2. The resulting reaction mixture was subsequently stirred at 0-5 ° C for 2 h. When TLC and HPLC showed that the reaction was completed, the reaction mixture was quenched with H2O (100 ml). The two phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 50 ml). The combined organic extracts were washed with H2O (2 x 100 ml) and saturated aqueous NaCl (100 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5S) -N- [3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] acetamide 108 (17.36 g, 96.5% yield) as a white powder. This product was used directly in subsequent reactions without further purification. 1H-NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J = 5.4 Hz), 3.56 (dd, 1H, J = 6 , 4, 9.2 Hz), 3.95 (t, 1H, J = 9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J = 5.7 Hz, OH ), 7.02 (dd, 1H, J = 2.4, 8.2 Hz), 7.38 (dd, 1H, J = 2.4, 10.8 Hz), 7.66 (t, 1H, J = 7.5, 8.4 Hz), 8.08 (t, 1H, J = 5.8 Hz, NHCOCH3). C12H12FIN2O3, LC-MS (EI) m / e 379 (M + + H).

b. Synthesis of aryl iodide 108 - Method B

Scheme 3 represents an alternative synthesis of aryl iodide 108 from alcohol 103.

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image134

A solution of alcohol 103 (6.33 g, 30.0 mmol) in CH2Cl2 (60 ml) was treated with TEA (6.07 g, 8.36 ml, 60 mmol, 2.0 eq) at 25 ° C and cooled the resulting mixture to 0-5 ° C before introducing MsCl (3.78 g, 2.55 ml, 33.0 mmol, 1.1 eq) dropwise into the reaction mixture at 0-5 ° C under N2. The resulting reaction mixture was subsequently stirred at 0-5 ° C for 1 h under N2. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was quenched with H2O (40 ml) and CH2Cl2 (40 ml). The two phases were separated and the aqueous phase was extracted with CH2Cl2 (40 ml). The combined organic extracts were washed with H2O (2 x 40 ml) and saturated aqueous NaCl (40 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5R) -ester 3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester of the desired methanesulfonic acid 109 (7.69 g, 88.7 yield %) as a bone-colored powder. This product was used directly in subsequent reactions without further purification. C11H12FNO5S, LC-MS (EI) m / e 290 (M + + H).

A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 ml) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 eq) at 25 ° C and was heated the resulting reaction mixture to 70 ° C for 4 h. When the CCF and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature before quenching with H2O (60 ml). The resulting mixture was stirred at room temperature for 10 min before cooling to 0-5 ° C for 1 h. The white precipitate was collected by filtration, washed with water (2 x 40 ml) and dried in vacuo to give the (6R) -2- [3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5 -methyl] -isoindol-1,3-dione 110 desired (3.12 g, 91.8% yield) as a bone-colored powder. This product was used directly in subsequent reactions without further purification. C18H13FN2O4, LC-MS (EI) m / e 341 (M + + H).

A solution of phthalimide 110 (3.0 g, 8.82 mmol) in ethanol (EtOH, 30 ml) was treated with hydrazine monohydrate (2.20 g, 2.2 ml, 44.12 mmol, 5.0 eq) at 25 ° C and the resulting reaction mixture was heated to reflux for 2 h. White precipitates formed as the reaction mixture was refluxed. When the CCF and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature before quenching with H2O (20 ml). The aqueous solution was then extracted with CH2Cl2 (3 x 40 ml), and the combined organic extracts were washed with H2O (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5S) -5-aminomethyl-3- (3-fluorophenyl) -oxazolidin-2-one 111 (1.79 g, 96.6% yield) as a white powder . This product was used directly in subsequent reactions without further purification. C10H11FN2O2, LC-MS (EI) m / e 211 (M + + H).

A suspension of amine 111 (2.60 g, 12.38 mmol) in CH2Cl2 (40 ml) was treated with TEA (2.50 g, 3.4 ml, 24.76 mmol, 2.0 eq) at 25 ° C and The resulting reaction mixture was cooled to 0-5 ° C before being treated with acetic anhydride (AC2O, 1.90 g, 1.75 ml, 18.75 mmol, 1.5 eq) and DMAP (15 mg, 0.12 mmol , 0.01 eq) at 0-5 ° C under N2. The resulting reaction mixture was subsequently stirred at 0-5 ° C for 2 h. When the CCF and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (20 ml). The two phases were separated and then the aqueous phase was extracted with CH2Cl2 (2 x 20 ml). The combined organic extracts were washed with H2O (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (5S) -N- [3- (3-fluoro-4-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide 112 (2.93 g, yield 94%) as a white powder. This product was used directly in subsequent reactions without further purification. C12H13FN2O3, LC-MS (EI) m / e 253 (M + + H).

A solution of acetamide 112 (2.3 g, 9.1 mmol) in TFA (20 ml) was treated with N-iodosuccinimide (2.3 g, 10.0 mmol, 1.1 eq) at 25 ° C and the mixture was stirred resulting reaction mixture at 25 ° C for 2 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was treated with H2O (20 ml) and 20% EtOAc / hexane (20 ml) at 25 ° C and the resulting mixture was stirred at 25 ° C for 30 min before

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to cool to 0-5 ° C for 2 h. The white solids were collected by filtration, washed with H2O (2 x 20 ml) and 20% EtOAc / hexane (2 x 20 ml) and dried in vacuo to provide the (5S) -N- [3- (3 -fluoro-4-iodo-phenyl) 2-oxo-oxazolidin-5-ylmethyl] -acetamide 108 (3.34 g, 96.8% yield) as a bone-colored powder. This product was found to be identical to the material obtained from method A and was used directly in the

5 subsequent reactions without further purification.

C. Synthesis of arylboronic acid 120

Scheme 4 describes three synthetic routes to obtain arylboronic acid 115. 10

image135

i. Synthesis of amine 113

A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 ml of CH2Cl2 was treated with methanesulfonyl chloride (55 g, 38 ml, 480 mmol, 1.2 eq) at 0 ° C . The resulting reaction mixture was gradually heated to room temperature and stirred for 1-2 hours. When 1 H-NMR showed that the reaction was complete, the reaction mixture was treated with H2O (100 ml) and the two phases were separated. The aqueous phase was extracted with CH2Cl2 (2 x 100 ml). The combined organic phases were washed with H2O (3 x 100 ml) and dried over MgSO4. Be

20 removed the solvent in vacuo to provide the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g, 91% yield) as a yellow oil.

A solution of the 3-fluoro-propyl ester of methanesulfonic acid (34.5 g, 221 mmol) in 250 ml of anhydrous DMF was treated with solid potassium phthalimide (49 g, 265 mmol, 1.2 eq) at 25 ° C. The resulting suspension was heated to

25 70-80 ° C for 2 hours. When 1 H-NMR showed that the reaction was complete, the reaction mixture was treated with H2O (200 ml). The aqueous solution was extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with H2O (3 x 100 ml) and dried over MgSO4. The solvent was removed in vacuo to provide the desired 2- (3-fluoropropyl) -isoindole-1,3-dione (45.4 g, theoretical 45.5 g, 99.7% yield) as a white powder.

A suspension of 2- (3-fluoro-propyl) -isoindole-1,3-dione (45.4 g, 221 mmol) in 400 ml of 95% aqueous ethanol was treated with hydrazine monohydrate (11.3 g, 11.1 ml, 223 mmol, 1.0 eq). The solution was refluxed for three hours. When 1 H-NMR showed that the reaction was complete, the reaction mixture was cooled to temperature

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Ambient before being treated with concentrated aqueous HCl (250 ml) at pH 1-2. The white phthahydrazide precipitate was collected by filtration and washed with 95% aqueous ethanol (4 x 100 ml). The combined filtrates were then concentrated to approximately 100 ml before adding 250 ml of H2O. The insoluble material was removed by filtration and the filtrates were concentrated to dryness in vacuo. The filtrates were recrystallized from ethanol / diethyl ether and dried in vacuo to provide the desired 3-fluoropropylamine 113 hydrochloride salt (20.83 g, 83.8% yield) as white crystals. This product was used directly in subsequent reactions without further purification. 1H-NMR (DMSO-d6, 300 MHz) δ 1.89-2.07 (m, 2H), 2.52-2.90 (m, 2H), 4.47 (t, 1H, J = 5, 8 Hz), 4.63 (t, 1H, J = 5.8 Hz), 8.19 (s, 3H).

ii. Synthesis of bromide 115

Method A

To a solution of amine 113 (6.0 g, 52.8 mmol, 1.16 eq) in DMF (200 ml) was added 4-bromobenzalaldehyde 114 (8.50 g, 45.5 mmol) at room temperature. The resulting reaction mixture was then treated with sodium triacetoxyborohydride (NaB (OAc) 3H, 16.10 g, 72.0 mmol, 1.6 eq) at room temperature and stirred for 2 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was quenched with water (100 ml). The resulting aqueous mixture was treated with solid sodium carbonate (Na2CO3, 99.64 g, 91.0 mmol, 2.0 eq) and di-tert-butyl dicarbonate (BOC2O, 12.9 g, 59.1 mmol, 1.3 eq) at room temperature. The mixture was then stirred at room temperature for 1.5 h before being quenched with water (100 ml). The reaction mixture was then extracted with EtOAc (3 x 60 ml). The combined organic extracts were washed with 0.5 M aqueous HCl (100 ml) and water (3 x 100 ml), dried over anhydrous sodium sulfate (Na2SO4) and concentrated in vacuo. The residue was then purified by flash column chromatography (3-4% EtOAc / hexane) to provide the desired (4-bromo-benzyl) - (3-fluoro-propyl) -carbamic acid tert-butyl ester 115 (11.38 g, 72% yield) as a colorless oil. C15H21BrFNO2, HPLC / MS (ESI) m / e 347 (N ++ H).

Method B

A solution of 4-bromobenzylamine hydrochloride 116 (2,225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 eq) in THF (20 ml) and water (5) were treated ml) with BOC2O (2.40 g, 11.0 mmol, 1.1 eq) at room temperature and stirred for 12 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was treated with water (10 ml) and EtOAc (40 ml). The two phases were separated and the aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with water (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired (4-bromo-benzyl) -carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil.

To a solution of 117 (286 mg, 1.0 mmol) in anhydrous DMF (3.0 ml) was added sodium hydride (NaH, 60% oil dispersion, 48.0 mg, 1.2 mmol, 1 , 2 eq) at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 min before adding 1-bromo-3-fluoropropane 118 (170 mg, 1.2 mmol, 1.2 eq). Subsequently, the reaction mixture was heated to 50-60 ° C and stirred for 24 hours. The reaction mixture was then quenched with water (10 ml) and the resulting aqueous solution was extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with water (10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (gradient elution of 10-15% EtOAc / hexane) to provide the desired (4-bromo-benzyl) - (3-fluoro-propyl) -carbamic acid tert-butyl ester 115 (158 mg, 46% yield) as a colorless oil.

Method C

A solution of 4-bromobenzylbromide 119 (0.30 g, 1.20 mmol) and amine 113 (0.272 g, 2.40 mmol, 2.0 eq) in anhydrous DMF (8.0 ml) was treated with diisopropylethylamine (2 ml of Hünig base) at room temperature. The resulting reaction mixture was heated to 60 ° C for 24 h. When TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled to 25 ° C before being treated with water (8.0 ml). The resulting aqueous solution was then treated with solid sodium bicarbonate (NaHCO3, 0.30 g, 3.60 mmol, 3.0 eq) and BOC2O (0.524 g, 2.40 mmol, 2.0 eq) at 25 ° C and was stirred for 24 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was treated with water (20 ml) and EtOAc, 20 ml. The two phases were separated and the aqueous phase was extracted with EtOAc (2 x 30 ml). The combined organic extracts were washed with H2O (4 x 10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (3% EtOAc / hexanes) to provide the desired (4-bromo-benzyl) tert-butyl ester (3-fluoro-propyl) -carbamic acid 115 (0.24 g, yield 57.8%) as a colorless oil.

iii. Synthesis of Boronic Acid 120

To a solution of bromide 115 (3.0 g, 8.7 mmol) in anhydrous THF (30 ml) was added at -78 ° C a 2.5 M solution of n-BuLi in hexane (3.64 ml, 9, 1 mmol, 1.05 eq). The resulting reaction mixture was stirred at -78 ° C for 1 h before trimethyl borate (B (OMe) 3, 1.2 ml, 10.4 mmol, 1.2 eq) was added dropwise. The mixture was stirred

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resulting reaction at -78 ° C for 0.5 h before gradually heating to room temperature overnight. The reaction mixture was poured into water (60 ml) and the aqueous solution was treated with 1.0 N aqueous HCl until pH 4.0. The aqueous mixture was then extracted with EtOAc (4 x 30 ml). The combined organic extracts were washed with saturated aqueous NaCl (30 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the desired 4- (N-tert-butylcarbonyl-3-fluoropropylaminomethyl) -phenyl boronic acid 120 (2 , 5 g). This product was used directly in subsequent reactions without further purification. C15H23BFNO4, HPLC / MS (ESI) m / e 312 (M + + H).

d. Synthesis of compound 11

Scheme 5 represents the synthesis of compound 11 from aryl iodide 108 and arylboronic acid 120.

image136

A suspension of arylboronic acid 120 (2.50 g, 8.03 mmol) in a mixture of toluene (24 ml), EtOH (8 ml) and water (8 ml) was treated with aryl iodide 108 (2.53 g , 6.7 mmol, 0.83 eq) and solid K2CO3 (2.80 g, 20.1 mmol, 3.0 eq) at room temperature. The resulting reaction mixture was degassed three times under a constant stream of argon before tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4, 387 mg, 0.335 mmol, 0.05 eq) was added. The resulting reaction mixture was degassed three times under a constant stream of argon before heating to reflux for 8 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before pouring into water (60 ml) and EtOAc (60 ml). The two phases were separated and the organic phase was washed with water (30 ml) and saturated aqueous NaCl (2 x 30 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The product was then recrystallized from EtOAc / hexanes and dried in vacuo to provide the (5S) tert-butyl ester of {4 '- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] - Desired 2'-fluoro-biphenyl-4-ylmethyl} - (3-fluoro-propyl) 121 (1.3 g, 30%) as a bone-colored powder.

A solution of BOC-amine 121 (15.65 g, 30.3 mmol) in CH2Cl2 (30 ml) was treated with a solution of 4N hydrogen chloride in 1,4-dioxane (37.5 ml, 150.0 mmol, 5.0 eq) at room temperature and stirred for 12 h. When TLC and HPLC / MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was suspended in a mixture of acetonitrile (CH3CN, 200 ml) and methanol (MeOH, 50 ml) and the resulting thick suspension was stirred at room temperature for 1 h. The solids were collected by filtration, washed with 20% MeOH / CH3CN (2 x 50 ml) and dried in vacuo to provide the salt of (5S) -N- (3- {2-fluoro4 '- [) monohydrochloride. (3-Fluoro-propylamino) -methyl] -biphenyl-4-yl} -2-oxo-oxazolidin-5-yl-methyl) -acetamide 11 (13.0 g, 95.3% yield) as white crystals . 1H-NMR (300 MHz, DMSO-d6) δ 1.90 (s, 3H, COCH3), 2.11-2.20 (m, 2H), 3.10 (m, 2H), 3.50 (t , 2H, J = 5.4 Hz), 3.87 (dd, 1H, J = 6.4, 9.2 Hz), 4.24 (t, 1H, J = 9.1 Hz), 4.27 (s, 2H, ArCH2), 4.54 (t, 1H, J =

5.8 Hz), 4.70 (t, 1H, J = 5.8 Hz), 4.83 (m, 1H), 7.50 (dd, 1H, J = 2.2, 8.6 Hz), 7.65 -7.74 (m, 6H, aromatic H), 8.37 (t, 1H, J = 5.8 Hz, NHCOCH3), 9.43 (sa, 2H, RArN + H2). C22H25F2N3O3 HCl, LC-MS (EI) m / e 418 (M + + H).

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Example 2

Scheme 6 represents an alternative synthesis of arylboronic acid 120, which is coupled to aryl iodide 108 to produce compound 11.

image137

A solution of 4-formylphenylboronic acid 122 (10.0 g, 66.69 mmol) in anhydrous DMF (150 ml) was treated with 3-fluoropropylamine hydrochloride salt 113 (8.70 g, 76.70 mmol, 1, 15 eq, prepared as described above in example 1) at room temperature. The resulting mixture was treated with 3B NaB (OAc) (28.30 g, 133.39 mmol, 2.0 eq) at room temperature and stirred for 3 h. When TLC and HPLC / MS showed that the reaction was completed, the reaction mixture was treated with water (150 ml), solid Na2CO3 (14.14 g, 133.39 mmol, 2.0 eq) and BOC2O (22 , 05 g, 100.04 mmol, 1.5 eq). The resulting reaction mixture was stirred at room temperature for 3 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was poured into water (500 ml) and EtOAc (500 ml). The two phases were separated and the aqueous phase was treated with 2N aqueous HCl (130 ml) at pH

4. The aqueous phase was then extracted with EtOAc (160 ml) and the combined organic phases were washed with water (2 x 100 ml) and saturated aqueous NaCl (2 x 100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was further dried under vacuum to provide the desired 4- (N-tert-butylcarbonyl-3-fluoropropylaminomethyl) phenylboronic acid (25.0 g) as a pale yellow oil. This product was found to be identical to the material obtained from example 1 above and was used directly in subsequent reactions without further purification.

A suspension of arylboronic acid 120 (25.0 g, 64.30 mmol, 1.45 eq) in a mixture of toluene (120 ml), EtOH (40 ml) and water (40 ml) was treated with (5S) - N- [3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide 108 (16.80 g, 44.44 mmol, prepared as described above in the example 1) and solid K2CO3 (18.40 g, 133.4 mmol, 3.0 eq) at room temperature. The resulting reaction mixture was degassed three times under a constant argon current before being treated with Pd (PPh3) 4 (2.57 g, 2.23 mmol, 0.05 eq). The resulting reaction mixture was degassed three times under a constant stream of argon before heating to reflux for 8 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being poured into water (300 ml) and ethyl acetate (EtOAc, 300 ml). The two phases were separated, and the organic phase was washed with water (60 ml) and saturated aqueous NaCl (2 x 50 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The product was recrystallized from EtOAc / hexanes and dried in vacuo to provide {4 '- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] - (5S) tert-butyl ester Desired 2'-fluoro-biphenyl-4-ylmethyl} - (3-fluoropropyl) -carbamic 121 (21.2 g, 61.5% yield over three steps) as a bone-colored powder.

The BOC 121 protected amine was subsequently treated with 4 N hydrogen chloride in 1,4-dioxane as in Example 1 to provide compound 11. The product obtained from this procedure was identical by

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NMR and LC-MS to the material obtained in example 1.

Example 3

Scheme 7 represents the synthesis of compound 11 from aryl bromide 115 and arylboronic ester 123.

image138

Synthesis of boronic ester 123

A suspension of (5S) -N- [3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide 108 (20.0 g, 52.8 mmol,) was treated. prepared as described above in example 1) in anhydrous 1,4-dioxane (130 ml) with 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (10.2 g, 11.6 ml, 80.0 mmol, 1.5 eq) and triethylamine (16.0 g, 22.4 ml, 158.4 mmol, 3.0 eq) at room temperature. The resulting reaction mixture was degassed three times under a constant argon current before being treated with dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) 2Cl2, 1.32 g, 1, 6 mmol, 0.03 eq) at room temperature. The resulting reaction mixture was degassed three times under a constant stream of argon before being heated to reflux for 7 h. When HPLC / MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 ml) and ethyl acetate (100 ml). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (2 x 50 ml) and saturated aqueous NaCl (50 ml), dried over MgSO4 and concentrated in vacuo. The residual brown oil was further dried under vacuum to provide the (5S) -N- {3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2- il) -phenyl] -2-oxo-oxazolidin-5-methylmethyl} acetamide 123 (18.8 g, 94%) as brown solids. This product was used directly in subsequent reactions without further purification. C18H24BFN2O5, HPLC / MS (ESI) m / e 379 (M + + H).

Synthesis of compound 11

A solution of boronic ester 123 (1.40 g, 3.7 mmol, 1.3 eq) and tert-butyl ester of (4-bromobenzyl) - (3-fluoro-propyl) -carbamic acid 115 (1, 0 g, 2.89 mmol, prepared as described above in example 1) in a mixture of 1,4-dioxane (21 ml), EtOH (7.0 ml) and H2O (7.0 ml) with carbonate of solid potassium (1.2 g, 8.7 mmol, 3.0 eq) at room temperature. The resulting reaction mixture was degassed three times under a constant argon stream before being treated with Pd (dppf) 2Cl2 (118 mg, 0.144 mmol, 0.05 eq) at room temperature. The reaction mixture was degassed three times under a constant stream of argon before heating to reflux for 2 h. When TLC and HPLC / MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (60 ml). The aqueous solution was then extracted with CH2Cl2 (3 x 20 ml), and the combined organic extracts were washed with water (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution from 0-5% MeOH -CH2Cl2) to provide the (5S) tert-butyl ester of {4 '- [5- (acetylamino-methyl) -2 -oxo-oxazolidin-3-yl] -2'-fluoro-biphenyl-4-ylmethyl} - (3-fluoro-propyl) -carbamic 121 (1.36 g, 91% yield) as a colorless oil, which is solidified after leaving at room temperature under vacuum.

The BOC 121 protected amine was subsequently treated with 4 N hydrogen chloride in 1,4-dioxane as in the

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Example 1 to provide compound 11. The product obtained from this procedure was identical by NMR and LC-MS to the material obtained in Example 1.

Example 4 - Synthesis of compound 63

Scheme 8 illustrates the synthesis of amide 63. 2,5-Dibromopyridine 124 is converted to activated pyridyl ester 125 which is then treated with histamine 126 to provide amide 127. Suzuki type coupling of 127 and boronate 123 gave the final objective amide 63.

image139

Under argon, triethylamine (0.31 ml, 2.25 mmol) was added to a mixture of 2,5-dibromopyridine 124 (355 mg, 1.5 mmol), palladium acetate (16.8 mg, 0.075 mmol ), Xantphos (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, (43.4 mg, 0.075 mmol) and N-hydroxysuccinimide (241.5 mg, 2.1 mmol) in DMSO (2 ml). The solution was purged with

15 carbon monoxide for 15 min and stirred on a balloon with carbon monoxide at 80 ° C for 16 h. The reaction mixture was then cooled to room temperature, diluted with 20 ml of ethyl acetate and washed with a solution of saturated sodium bicarbonate and water. The organic phase was dried over sodium sulfate and evaporated to give a crude product. Chromatography on silica gel using hexane: acetone (3: 1) provided ester 125 (75 mg; 17%). 1H-NMR (300 MHz, CDCl3) δ 8.85 (m, 1H), 8.06 (m, 2H), 2.90 (s, 4H).

A mixture of active ester 125 (350 mg, 1.17 mmol), histamine 126 hydrochloride (216 mg, 1.17 mmol) and triethylamine (Et3N, 0.33 ml, 2.34 mmol) in CH2Cl2 (20) was stirred. 5 ml) at room temperature for 1 h. The reaction was washed with brine and dried in vacuo. The crude product was purified by chromatography (CH2Cl2: MeOH: NH3.H2O / 15: 1: 0.05) to provide 127 (280 mg; 81%). LC-MS (ESI) m / z 295 (M + H) +.

Under an argon atmosphere, a mixture of amide 127 (230 mg, 0.78 mmol), boronate 123 (295 mg, 0.78 mmol), PdCl2 (dppf) 2 (19 mg, 0.023 mmol) and K2CO3 was heated (323 mg, 2.34 mmol) in 5 ml of a mixture of dioxane: EtOH: H2O (3: 1: 1) at 100 ° C for 12 h. The reaction was concentrated and the residue was dissolved in MeOH (2 ml) and CH2Cl2 (10 ml). Organic salts were removed by filtration. The filtrate was concentrated and purified by

Chromatography (CH2Cl2: MeOH: NH3.H2O / 15: 1: 0.05) to provide amide 63 (106 mg; 29%). LC-MS (ESI) m / z 467 (M + H) +.

Example 5 - Synthesis of compounds 64 and 65

35 Scheme 9 illustrates the synthesis of amides 64 and 65. Aryl bromides 128 and 129 were coupled to boronate 123 to provide respectively 64 and 65.

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Synthesis of compound 64

A mixture of 4-bromobenzoyl chloride (110 mg, 0.5 mmol), 1,2,4-oxadiazol-3-ylmethylamine hydrochloride (68 mg, 0.5 mmol), DMF (1 drop) and Et3N was stirred. (0.33 ml, 2.34 mmol) in CH2Cl2 (5 ml) at room temperature for 4 h. The reaction was washed with brine and dried under vacuum to provide crude amide 128. The resulting amide 128 was added to a mixture of boronate 123 (189 mg, 0.5 mmol), Pd (dppf) 2Cl2 (20 mg, 0.025 mmol) and K2CO3 (207 mg, 1.5 mmol) in 5 ml of dioxane : EtOH: H2O (3: 1: 1) under an argon atmosphere. After heating at 100 ° C for 12 h, the reaction was diluted with water and MeOH and then filtered through Celite. The filtrate was concentrated to remove the organic solvent. The crude product was collected by filtration and further purified by chromatography (CH2Cl2: MeOH: NH3.H2O / 25: 1: 0.05) to provide compound 246 (45 mg; 32% (2 steps)). LC-MS (ESI) m / z 452 (M-H) +.

Synthesis of compound 65

A mixture of 4-bromobenzoyl chloride (29 mg, 0.132 mmol), 1,2,4-thiadiazol-3-ylmethylamine hydrochloride (20 mg, 0.132 mmol), DMF (1 drop) and Et3N (27 mg, was stirred. 0.264 mmol) in THF (4 ml) at room temperature for 2 h. The reaction was concentrated, dissolved in CH2Cl2, washed with brine and dried in vacuo to provide crude amide 129. The resulting amide 129 was added to a mixture of boronate 123 (50 mg, 0.132 mmol), PdCl2 (dppf) 2 (6 mg, 0.0066 mmol) and K2CO3 (55 mg, 0.396 mmol) in 2 ml of dioxane: EtOH : H2O (3: 1: 1) under an argon atmosphere. After heating at 100 ° C for 12 h, the reaction was concentrated, dissolved in EtOAc, washed with brine and dried in vacuo. The crude product was purified by silica gel chromatography (CH2Cl2: MeOH: NH3.H2O / 25: 1: 0.05) to provide compound 65 (30 mg; 48% (2 steps)). LC-MS (ESI) m / z 470 (M + H) +.

Example 6 - Synthesis of compound 66

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To a solution of Boc-glycine 130 (1.04 g, 5.88 mmol) and 4-bromobenzylethylamine 131 (1.00 g, 4.90 mmol) in CH2Cl2 (25 ml) at room temperature was added Hünig base (1.30 ml, 7.35 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured into water (40 ml) and saturated NaHCO3 (3 ml), then extracted with CH2Cl2 (60 ml), washed with water (100 ml) and dried with Na2SO4. The residue was isolated by column chromatography (50/50 / 0.1 EtOAc / Hexane / NH4OH), to give 1.30 g of amide 132 as a white crystalline solid in 69% yield. 1H-NMR (300 MHz, CDCl3, ppm): δ: 7.37 (d, J = 7 Hz, 2H), 7.09 (d, J = 7 Hz, 1H), 6.50 (sa, 1H) , 5.15 (sa, 1H), 5.01-4.95 (m, 1H), 3.69 (d, J = 6 Hz, 2H), 1.39 (d, J = 7 Hz, 3H) , 1.37 (s, 9H).

A mixture of amide 132 (143 mg, 0.40 mmol) and boronic ester 123 (168 mg, 0.4 mmol), Pd (dppf) 2Cl2 (16 mg, 0.02 mmol) and K2CO3 (221 mg, was degassed 1.60 mmol) in dioxane (3 ml), EtOH (1 ml) and H2O (1 ml) with argon. The mixture was stirred at 90-95 ° C for 3 h, then water (10 ml) was added. The mixture was extracted with CH2Cl2 (4 x 30 ml) and dried over Na2SO4. The residue was purified by column chromatography (MeOH / CH2Cl2 / NH4OH 5: 100: 0.1) to yield 200 mg of Boc protected product in 100% yield. The product protected with Boc (200 mg) was stirred, taken to 2 ml of CH2Cl2 and 2 ml of TFA and the mixture at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (MeOH / CH2Cl2 / NH4OH

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15: 85: 0.1) to give 168 mg of compound 66 in 99% yield. 1H-NMR (300 MHz, CDCl3, ppm, partial): δ: 7.64-7.33 (m, 7H), 5.13-5.07 (m, 1H), 4.19 (ddd, J = 9.3, 3 Hz, 1H), 3.87 (ddd, J = 9.7, 3 Hz, 1H), 3.77-3.50 (m, 5H), 1.99 (s, 3H), 1.54 (d, J = 7 Hz, 3H). LC-MS (ESI) m / e 429 (M + H) +.

Example 7 - Synthesis of compound 67 Scheme 11 illustrates the synthesis of compound 67.

image142

At a solution of 2-bromoacetamide 133 (827 mg, 5.88 mmol) and 4-bromobenzylethylamine 131 (1.00 g, 4.90 mmol) in MeOH (5 ml) and CH2Cl2 (5 ml) at room temperature is Hünig base (5 ml) was added. The mixture was stirred at 5060 ° C for 16 h, then water (30 ml) was added. The mixture was extracted with CH2Cl2 (4 x 30 mL), dried over Na2SO4 and the solvent removed in vacuo to provide 1.27 g of amide 134 as a white crystalline solid.

15 with a 100% yield. 1H-NMR (300 MHz, CDCl3, ppm): δ: 7.38 (d, J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, 1H), 6.77 (sa, 1H) , 5.69 (sa, 1H), 3.67 (q, J = 7 Hz, 1H), 3.07 (s, 2H), 1.29 (d, J = 7 Hz, 3H).

A mixture of amide 34 (103 mg, 0.40 mmol) and boronic ester 123 (168 mg, 0.4 mmol), Pd (dppf) 2Cl2 (16 mg, 0.02 mmol) and K2CO3 (221 mg, was degassed 1.60 mmol) in dioxane (3 ml), EtOH (1 ml) and H2O (1 ml) with argon. He stirred the

20 mixture at 90-95 ° C for 3 h, then water (10 ml) was added. The mixture was extracted with CH2Cl2 (4 x 30 mL), dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography (MeOH / CH2Cl2 / NH4OH 7: 100: 0.1) to yield 85 mg of compound 67 in 50% yield. 1H-NMR (300 MHz, CDCl3, ppm, partial): δ: 7.70-7.30 (m, 7H), 7.09 (sa, 1H), 6.31 (sa, 1H), 5.63 (sa, 1H), 4.96-4.92 (m, 1H), 4.22 (t, J = 9 Hz, 1H), 3.33 (s, 2H), 2.13 (s, 3H) , 1.55 (d, J = 7 Hz, 3H). LC-MS (ESI) m / e 451.2 (M + Na) +.

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Example 8 - Synthesis of Compound 68

Scheme 12 illustrates the synthesis of compound 68.

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Synthesis of bromide 135

A suspension of 4-bromomethylpyridine hydrochloride (1.59 g, 6.3 mmol) in THF (10 ml) was treated dropwise with a solution of potassium carbonate (3.33 g, 24.0 mmol) in H2O (6 ml) at 0-5 ° C and the resulting mixture was stirred at 0-5 ° C for 10 min before being treated dropwise with a solution of 4-bromo-benzenethiol (1.14 g, 6.0 mmol) in THF ( 5.0 ml) at 0-5 ° C under N2. The resulting reaction mixture was subsequently stirred at 0-5 ° C for an additional 20 min. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was treated with water (15 ml) and ethyl acetate (25 ml). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water (2 x 15 ml) and saturated aqueous NaCl solution (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-25% EtOAc elution gradient -hexane) to provide the desired 4- (4-bromophenylsulfanylmethyl) pyridine (1.374 g; 82%) as a pale yellow solid, which It was used directly in subsequent reactions.

Synthesis of compound 68

A solution of boronate 123 (200 mg, 0.53 mmol) and bromide 135 (150 mg, 0.53 mmol) in toluene (9 ml) was treated with solid potassium carbonate (220 mg, 1.6 mmol), ethanol (3.0 ml) and H2O (3.0 ml) at room temperature and the resulting reaction mixture was degassed three times under a constant stream of argon before being treated with Pd (dppf) 2Cl2 (16 mg, 0.013 mmol) at room temperature. The reaction mixture was then degassed three times again under a constant stream of argon before being heated to reflux for 2 h. When LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (10 ml) and ethyl acetate (20 ml). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were washed with water (2 x 10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column chromatography (gradient elution 0-5% MeOH -CH2Cl2) to provide compound 68 (177 mg; 74%) as a yellow oil, which solidified after leaving at room temperature under vacuum . LC-MS (ESI) m / z 452 (M + H) +.

Example 9 - Synthesis of Compound 69

Scheme 13 illustrates the synthesis of compound 69.

Scheme 13

image144

4-Bromobenzenesulfonyl chloride 136 (2.56 g, 10 mmol) was added to a solution of 4-aminomethylpyridine 137 (1.08 g, 10 mmol) and triethylamine (2 ml, 14.3 mmol) in THF (20 ml ) at 0 ° C. After stirring at 0 ° C for 1 h, 50 ml of water was added. A white solid was collected by filtration, washing with EtOAc and dried in vacuo to give 3.10 g of bromide 138 in 95% yield.

Bromide 138 (327 mg, 1 mmol), boronate 123 (378 mg, 1 mmol), Pd (dppf) 2Cl2 (40 mg, 0.05 mmol) were dissolved and

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K2CO3 (414 mg, 3 mmol) in 8 ml of a mixture of dioxane: EtOH: H2O (3: 1: 1) under argon. After heating at 100 ° C for 12 hours, the reaction mixture was added to 20 ml of cold water. The organic solvent was removed in vacuo and the crude product was collected by filtration. The crude product was treated with activated carbon and recrystallized from a mixed solvent system (MeOH / CH2Cl2 / acetone 1: 2: 2) to give 155 mg of compound 69 with

5 a yield of 31%. MS (ESI): 499.1 (100%, (M + H) +).

Example 10 - Synthesis of Compound 70

Scheme 14 represents the synthesis of compound 70. 10

Scheme 14

image145

15 Epoxy Synthesis 139

To a solution of 4-bromo styrene (5.00 g, 26.8 mmol) in CH2Cl2 (130 mL) was added anhydrous 4-methylmorpholine N-oxide (NMO, 12.90 g, 107.1 mmol) and ( 1S, 2S) - (+) - [1,2- (cyclohexanediamino-N, N'-bis (3,5-di-t-butyl-salicylicidene)] manganese (III) chloride (Jacobsen catalyst, 850 mg , 1.34 mmol.) The solution was cooled to

20-78 ° C, then 3-chloroperoxybenzoic acid (m-CPBA, 7.40 g, 42.8 mmol) was added in four portions every 10 min. The mixture was stirred at -78 ° C for 2 h. The reaction was quenched by the addition of aqueous Na2S2O3 (10.0 g in 30 ml of water), then the cooling bath was removed, and water (70 ml) and 1 N NaOH (60 ml) was added. The aqueous phase was extracted with CH2Cl2 (3 x 30 mL), dried with Na2SO4 and evaporated. The residue was purified by flash chromatography (Et2O / hexane 4: 100) to yield 5.20 g of epoxide 139 (98% yield).

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Synthesis of compound 70

To a suspension of epoxide 139 (1 mmol) in acetonitrile (3.0 ml) at room temperature was added lithium perchlorate (LiClO4, 1.05 mmol). After the formation of a clear solution, benzylamine 140 (1.5 mmol) was added.

The mixture was stirred at 80 ° C for 4.5 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (MeOH / CH2Cl2 3.5: 100), to provide 141 (460 mg; 50% yield). LC-MS (ESI) m / z 307 (M + H) +.

A suspension of 141 (1 eq), boronate ester 123 (1 eq), Pd (dppf) 2Cl2 (0.05 eq) and K2CO3 (4 eq) was degassed in

A 3: 1: 1 mixture of dioxane / EtOH / H2O by passing a constant stream of argon through the mixture. The mixture was stirred at 80 ° C for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (MeOH / CH2Cl2 3: 100), to yield amine 142 (690 mg; 96% yield). LC-MS (ESI) m / z 439 (M + H) +.

A mixture of amine 142 (80 mg, 0.168 mmol), 3-fluoro-1-bromopropane (47 mg, 0.335 mmol) and Hünig base (117 µL, 0.670 mmol) in DMF (1.5 mL) was stirred at DMF (1.5 mL) at 55-60 ° C for 15 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (MeOH / CH2Cl2 2: 100), to give 87 mg of the alkylation product (96% yield). LC-MS (ESI) m / z 538 (M + H) +.

To a solution of the alkylation product (80 mg, 0.149 mmol), 3N aqueous HCl (120 µl, 0.360 mmol) was added in EtOH (1.5 mL) at room temperature, followed by 10% Pd-C (15 mg) The mixture was stirred under the atmosphere of H2 (1 atm.) For 18 h. The mixture was passed through a bed of Celite and the cake was washed with MeOH (3 x 10 ml). The filtrate was evaporated to give the HCl salt of compound 70 (57 mg; 79% yield). LC-MS (ESI) m / z 448 (M + H) +.

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Example 11 - Synthesis of compounds 71 and 72

Scheme 15 illustrates the synthesis of compounds 71 and 72. Hydroxyamidine 143 was converted to bromide 144, which was subsequently coupled to boronate 123 to provide compound 71. Hydroxyamidine 143 was transformed into oxadiazole 145, which was coupled to boronate 123 to provide compound 72.

Scheme 15

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Synthesis of hydroxyamidine 143

A solution of 4-bromophenylacetonitrile (10 g, 54 mmol) in methanol (100 ml) was treated with sodium bicarbonate (2.2 g, 57 mmol) and hydroxylamine hydrochloride (4.0 g, 57 mmol) and subjected at reflux for 1.5 h. They were added

Sodium bicarbonate (0.21 g, 5.4 mmol) and additional hydroxylamine hydrochloride (0.38 g, 5.4 mmol) and the reaction mixture was refluxed for 12 h. The reaction mixture was cooled to 23 ° C and the solvent was removed in vacuo to provide hydroxyamidine 143 as a blue powder (4.0 g; 34%).

Synthesis of compound 71

A solution of hydroxyamidine 143 (0.20 g, 0.91 mmol) in 1,4-dioxane (1 ml) was treated with 1,1'-carbonidyldiimidazole (0.18 g, 1.1 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.15 ml, 0.97 mmol) and stirred at 105 ° C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The water phase was treated with 1.0 M HCl (aqueous) until the pH was 2 and then extracted with ethyl acetate. The organic phase was dried (Na2SO4) and

25 removed the solvent in vacuo to provide bromide 144 as a yellow powder (0.11 g; 49%).

A solution of boronate ester 123 (0.085 g, 0.220 mmol), bromide 144 (0.055 g, 0.220 mmol) and potassium carbonate (0.12 g, 0.90 mmol) in dioxane (1.4 ml), ethanol ( 0.46 ml) and water (0.46 ml) and treated with Pd (dppf) Cl2 (6.0 mg, 6.7 µmol), degassed again and heated at 80 ° C for 1.5 h. The mixture was diluted

Reaction with CH2Cl2 and water and the precipitate was recovered in the water phase by vacuum filtration to provide compound 71 as a gray powder (0.034 g; 36%). LC-MS (ESI) m / z 427 (M + H) +.

Synthesis of compound 71

A solution of hydroxyamidine 143 (0.25 g, 1.1 mmol) in pyridine (5 ml) was cooled to 0 ° C and treated with a solution of acetic anhydride (0.11 ml, 1.1 mmol) in pyridine ( 5 ml) and then stirred at 120 ° C for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed with 1M aqueous HCl and saturated aqueous sodium bicarbonate, dried over Na2SO4 and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography to provide bromide 145 as a clear film (0.10 g; 36%).

A solution of boronate ester 123 (0.15 g, 0.40 mmol), bromide 145 (0.10 g, 0.40 mmol) and potassium carbonate (0.22 g, 1.6 mmol) were degassed in dioxane (2.5 ml), ethanol (0.83 ml) and water (0.83 ml) and treated with Pd (dppf) Cl2 (10.0 mg, 0.012 mmol), degassed again and stirred at 80 ° C for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water. The water phase was extracted with 2 x CH2Cl2, dried (Na2SO4) and evaporated

The solvent in vacuo. The crude product was purified by flash chromatography and preparative TLC to provide compound 72 as a white powder (0.054 g; 32%). LC-MS (ESI) m / z 425 (M + H) +.

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Scheme 16 illustrates the synthesis of compounds 73 and 74. Bromoketone 146 was subjected to alkylation with thioureas 147 and 148 to respectively provide thiazoles 149 and 150. Coupling of 149 and 150 with boronate 123 produced thiazoles 73 and 74.

image147

Synthesis of compound 73

Bromoketone 146 (0.29 g, 1.0 mmol) was dissolved in dioxane (10 ml). Thiourea 147 (0.19 g, 1.2 mmol) and potassium carbonate (0.28 g, 2 mmol) were added sequentially and the resulting thick suspension was stirred at 50 ° C for 4 h. The mixture was cooled to room temperature, diluted with 100 ml of CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The aqueous washings were re-extracted with CH2Cl2 (2 x 50 ml). Be

The combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo to provide bromide 149 as a yellow solid (0.32 g) which was used without further purification. LC-MS (ESI) m / z 353 (M + H) +.

Crude 149 bromide (0.20 g, 0.56 mmol), boronate ester 123 (0.25 g, 0.66 mmol) and K2CO3 (0.14 g, 1.0 mmol) were combined with a mixture 1: 1: 1 toluene, ethanol and water (2 ml each). The thick suspension 20 was degassed by alternatively applying high vacuum to the reaction mixture and washing with dry argon. The reaction vessel was then sealed and heated in an oil bath at 80 ° C for 14 h. The reaction mixture was cooled to room temperature, diluted with 100 ml of CH2Cl2 / MeOH 9: 1 and washed with water and brine (50 ml each). The aqueous washings were back-extracted once with 50 ml of CH2Cl2 / MeOH 9: 1. The combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo to provide 0.48 g of a

25 solid brown. The solid was purified by flash column chromatography (acetone / hexane 7: 3) to yield compound 73 as a bone-colored solid (0.17 g, 0.32 mmol). LC-MS (ESI) m / z 525 (M + H) +.

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Synthesis of compound 74

Compound 74 was synthesized according to the procedure described above for compound 73, using thiourea 148 instead of 147. The coupling reaction of bromide 150 and boronate 123 produced compound 74 as a white solid (0.12 g, 0.21 mmol). LC-MS (ESI) m / z 561 (M + H) +.

Scheme 17 represents the synthesis of compound 75. Dp-hydroxyphenyl glycine 151 was converted to triflate 154, which was subsequently coupled to boronate 123 to provide alcohol 155. Mesylation of 155, followed by imidazole anion displacement and deprotection of the BOC group produced compound 75.

image148

A solution of Dp-hydroxyphenylglycine 151 (23.8 g, 142.3 mmol) and potassium carbonate (39.3 g, 284.6 mmol) in THF (200 ml) and H2O (200 ml) was treated with BOC2O ( 34.14 g, 156.6 mmol) at 25 ° C and the resulting reaction mixture was stirred at 25 ° C for 2 h. When the CCF and LC-MS showed that the reaction was complete, the reaction mixture was treated with ethyl acetate (200 ml) and H2O (200 ml). The two phases were separated and the aqueous solution was extracted with ethyl acetate (200 ml). The aqueous phase was then acidified with 2 N aqueous HCl at pH 4 before being extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were then washed with water (2 x 100 ml) and saturated aqueous NaCl (100 ml), dried over MgSO4 and concentrated in vacuo. The residual white solids were further dried under vacuum to provide the desired crude acid 152 (36.5 g; 96%), which was of purity suitable for use in subsequent reactions.

A solution of acid 152 (4.005 g, 15 mmol) in anhydrous THF (20 ml) was treated dropwise with a 1 M solution of BH3-THF in THF (30 ml, 30 mmol) at 0-5 ° C and the mixture was stirred resulting reaction mixture at 0-5 ° C for an additional 2 h. When TLC and LC-MS showed that the reduction reaction was completed, the reaction mixture was treated with water (50 ml) and ethyl acetate (50 ml). The mixture was then stirred at 25 ° C for 30 min before separating and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were then washed with water (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was then directly purified by flash column chromatography (gradient elution 0-5% MeOH -CH2Cl2) to provide the desired alcohol 153 (2.50 g; 66%) as a white powder that was of adequate purity for use in subsequent reactions.

A suspension of alcohol 153 (670 mg, 2.65 mmol) in CH2Cl2 (10 ml) was treated with N-phenyltrifluoromethanesulfonamide (947 mg, 2.65 mmol) and triethylamine (535.3 mg, 0.74 ml, 5.3 mmol ) at 25 ° C and the resulting reaction mixture was stirred at 25 ° C for an additional 2 h. When the CCF and LC-MS showed that the reaction was complete, the reaction mixture was quenched with water (10 ml) and CH2Cl2 (20 ml). The two phases were then separated and the aqueous phase was extracted with CH2Cl2 (2 x 20 ml). The combined organic extracts were then washed with water (2 x 10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was then directly purified by flash column chromatography (gradient elution MeOH 05% -CH2Cl2) to provide triflate 154 (945 mg; 93%) as a white powder that was of adequate purity for use in subsequent reactions .

A solution of boronate 123 (2.162 g, 5.72 mmol) and triflate 154 (1.70 g, 4.4 mmol) in toluene (24 ml) was treated with solid potassium carbonate (1.82 g, 13.2 mmol), ethanol (8.0 ml) and H2O (8.0 ml) at room temperature, and

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Degassed the resulting reaction mixture three times under a constant argon current before being treated with Pd (dppf) 2Cl2 (184 mg, 0.22 mmol) at room temperature. The reaction mixture was then degassed three times again under a constant stream of argon before being heated to reflux for 2 h. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (20 ml) and ethyl acetate (20 ml). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column chromatography (gradient elution 0-5% MeOH -CH2Cl2) to provide the tert-butyl ester of the acid (1- {4 '- [5- (acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2'-fluoro-biphenyl-4-yl} -2-hydroxyethyl) -carbamic 155 (1,543 g; 72%) as a yellow oil, which solidified after being left at room temperature under vacuum.

A suspension of alcohol 155 (694 mg, 1.43 mmol) in anhydrous CH2Cl2 (10 ml) was treated with diisopropylethylamine (388 mg, 0.522 ml, 2.85 mmol) and methanesulfonyl chloride (196 mg, 0.132 ml, 1, 71 mmol) at 0-5 ° C and the resulting reaction mixture was stirred at 0-5 ° C for an additional 2 h. When TLC and LC-MS showed that the reaction was completed, the reaction mixture was quenched with water (10 ml). The two phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 10 ml). The combined organic extracts were washed with water (2 x 10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column chromatography (gradient elution 0-5% MeOH -CH2Cl2) to provide mesylate 156 (647 mg; 80%) as a pale yellow solid, which was of adequate purity for use in subsequent reactions.

A solution of imidazole (41 mg, 0.6 mmol) in anhydrous THF (3 ml) was treated with sodium hydride (NaH, 60% oil dispersion, 29 mg, 0.72 mmol) at 0 ° C and the mixture was stirred resulting mixture at 0-5 ° C for 30 min before adding a solution of mesylate 156 (170 mg, 0.3 mmol) in anhydrous DMF (3.0 ml). The resulting reaction mixture was then stirred at 0-5 ° C for 30 min before gradually heating to room temperature for 12 h. When TLC and LC-MS showed that the reaction was complete, the solvents were removed in vacuo and the residue was directly purified by flash column chromatography (gradient elution MeOH 05% -CH2Cl2) to provide imidazole 157 (46 mg; 29%) as a yellow solid.

A solution of imidazole 157 (23 mg, 0.043 mmol) in MeOH (1.0 ml) was treated with 4 N HCl in 1,4-dioxane (3.0 ml) and the resulting reaction mixture was stirred at room temperature for 30 min. When TLC and LC-MS showed that the reaction was complete, the solvents were removed in vacuo and N- {3- [4 '(1-amino-2-imidazol-1-yl-ethyl) hydrochloride was obtained. Desired -2-fluoro-biphenyl-4-yl] -2-oxo-oxazolidin-5-ylmethyl} acetamide (18.8 mg; 100%) as a yellow solid. LC-MS (ESI) m / z 438 (M + H) +.

Example 14 - Synthesis of compound 76

Scheme 18 represents the synthesis of compound 76. Iodide 158 was converted to boronate 159, which was coupled to bromide 160 to provide tetrazol 161. Deprotection of 161 provided compound 76.

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10

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twenty

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Scheme 18

A solution of a known 5-aminomethyl-3- (3-fluoro-4-iodo-phenyl) -oxazolidin-2-one (2.02 g, 6.0 mmol) was treated; see U.S. Patent Nos. 5,523. 403 and 5,565,571) and potassium carbonate (1.66 g, 12.0 mmol) in THF (20 ml) and H2O (20 ml) with BOC2O (1.334 g, 6.12 mmol) at 25 ° C and the mixture was stirred resulting reaction mixture at 25 ° C for 2 h. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was treated with ethyl acetate (20 ml) and H2O (20 ml). The two phases were separated and the aqueous solution was extracted with ethyl acetate (20 ml), and then the combined organic extracts were washed with water (2 x 10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and They were concentrated in vacuo. The residual white solids were further dried under vacuum to provide the desired crude iodide 158 (2.40 g; 92%), which was of adequate purity for use in subsequent reactions.

A solution of iodide 158 (1.11 g, 2.55 mmol) in 1,4-dioxane (25 ml) was treated with 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane 159 (489 mg, 0.56 ml, 3.82 mmol) and triethylamine (772 mg, 1.07 ml, 7.65 mmol) at room temperature, and the resulting reaction mixture was degassed three times under a constant stream of argon before treated with Pd (dppf) 2Cl2 (107 mg, 0.13 mmol) at room temperature. The reaction mixture was then degassed three times again under a constant stream of argon before being heated to reflux for 6 h. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (20 ml) and ethyl acetate (20 ml). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water (2 x 20 ml) and saturated aqueous NaCl (20 ml), dried over MgSO4 and concentrated in vacuo. The residual brown oil was then purified by flash column chromatography (elution gradient 10-30% EtOAc -hexanes) to provide boronate 160 (646 mg; 58%) as a brown oil that solidified after leaving at room temperature at empty. The product was of adequate purity for use in subsequent reactions.

Synthesis of bromide 161

A solution of 4-bromobenzylamine hydrochloride (2.22 g, 10.0 mmol) in acetic acid (30 ml) was treated with triethyl orthoformate (2,964 g, 3.29 ml, 20.0 mmol) and sodium azide (NaN3, 2.30 g, 20.0 mmol) at room temperature and the resulting reaction mixture was subsequently stirred at reflux for 12 h. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature and the cooled reaction mixture was poured into ice water (100 ml). The precipitate was then collected by filtration, washed with water (2 x 20 ml) and dried in vacuo to provide bromide 161 (460 mg; 19%) as a white solid that was of purity suitable for use in the reactions. later.

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Synthesis of compound 76

A solution of boronate 160 (658 mg, 1.5 mmol) and bromide 161 (300 mg, 1.25 mmol) in toluene (9.0 ml) was treated with solid potassium carbonate (621 mg, 4.5 mmol) , ethanol (3.0 ml) and H2O (3.0 ml) at room temperature, and the resulting reaction mixture was degassed three times under a constant stream of argon before being treated with Pd (dppf) 2Cl2 (52.3 mg, 0.063 mmol) at room temperature. The reaction mixture was then degassed again three times under a constant stream of argon before heating to reflux for 3 h. When TLC and LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (10 ml) and ethyl acetate (20 ml). The two phases were separated and the aqueous phase was extracted with

10 ethyl acetate (2 x 10 ml). The combined organic extracts were washed with water (2 x 5 ml) and saturated aqueous NaCl (5 ml), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column chromatography (gradient elution 0-5% MeOH -CH2Cl2) to provide tetrazole 162 (357 mg; 61%) as a yellow oil, which solidified after leaving at room temperature under vacuum .

A solution of tetrazole 162 (350 mg, 0.748 mmol) in EtOAc (5.0 ml) was treated with 4 N HCl in 1,4-dioxane (5.0 ml) and the resulting reaction mixture was stirred at room temperature for 30 min. When TLC and LC-MS showed that the reaction was complete, the solvents were removed in vacuo and the residue was treated with aqueous sodium bicarbonate (10 ml) and EtOAc (15 ml). The mixture was stirred at room temperature for 30 min before separating the two phases. The aqueous phase was extracted with EtOAc (10 ml) and the organic extracts were washed

20 combined with H2O (10 ml) and saturated aqueous NaCl (10 ml), dried over MgSO4 and concentrated in vacuo to provide compound 76 (266 mg; 97%) as a pale yellow solid. LC-MS (ESI) m / z 369 (M

+ H) +.

Example 15 - Synthesis of Compounds 77-79

Scheme 19 represents the synthesis of aryl bromides 163-165 required for the synthesis of compounds 77-79. Epoxide 139 was treated with 1-formylpiperazine to provide a mixture of bromides 163 and 164. Opening of the epoxide ring 139 with imidazole provided bromide 165. These bromides were coupled with boronate 123 to provide target compounds 77- 79.

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Scheme 19

image150

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Synthesis of bromides 163 and 164

To a suspension of epoxide 139 (1 mmol, 1 eq) in acetonitrile (3.0 ml) at room temperature was added LiClO4 (1.05 mmol, 1.05 eq). After the formation of a clear solution, 1-formylpiperazine (1.5 mmol,

40 1.5 eq). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH / CH2Cl2 3: 100) to yield 132 mg of bromide 163 and 42 mg of bromide 164.

Synthesis of compound 77

A suspension of bromide 163 (1 eq), boronate 123 (1 eq), PdCl2 (dppf) 2 (0.05 eq) and K2CO3 (4 eq) was degassed in a 3: 1: 1 mixture of dioxane / EtOH / H2O through a stream of argon. The mixture was stirred at 80 ° C for 3.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH / CH2Cl2 4: 100) to provide 150 mg of compound 77. LC-MS (ESI) m / z 485 (M + H) +.

fifty

Synthesis of compound 78

A suspension of bromide 164 (1 eq), boronate 123 (1 eq), PdCl2 (dppf) 2 (0.05 eq) and K2CO3 (4 eq) was degassed in a 3: 1: 1 mixture of dioxane / EtOH / H2O by a stream of argon. The mixture was stirred at 80 ° C for 3.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH / CH2Cl2 5: 100)

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to provide 52 mg of compound 78. LC-MS (ESI) m / z 485 (M + H) +.

Synthesis of bromide 165

To a suspension of epoxide 139 (1 mmol, 1 eq) in acetonitrile (3.0 ml) at room temperature was added LiClO4 (1.05 mmol, 1.05 eq). After the formation of a clear solution, imidazole (1.5 mmol, 1.5 eq) was added. The mixture was stirred at 60 ° C for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH / CH2Cl2 3: 100) to yield 103 mg of bromide 165.

10 Synthesis of compound 79

A suspension of bromide 165 (1 eq), boronate 123 (1 eq), PdCl2 (dppf) 2 (0.05 eq) and K2CO3 (4 eq) was degassed in a 3: 1: 1 mixture of dioxane / EtOH / H2O by a stream of argon. The mixture was stirred at 80 ° C for 2.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (10: 100 MeOH / CH2Cl2)

15 to provide 155 mg of compound 79. LC-MS (ESI) m / z 439 (M + H) +.

Claims (8)

1. Procedure for preparing a compound having the formula: image 1 5 the process comprising the steps of: combining a compound (I) of the formula: 10 image2 with a compound (II) of the formula: image3 fifteen in a solvent comprising a mixture of water, toluene and ethanol, in the presence of a potassium carbonate and a palladium catalyst, In which the palladium catalyst is tetrakis (triphenylphosphine) palladium (0) and the ratio of the equivalents of tetrakis (triphenylphosphine) palladium (0) with respect to the equivalents of the compound (I) is 1:20; in which in addition, R3 is -NHC (O) R4 and R4 is -CH3; M-L is M-CH2-X-CH2, in which X is NR4 and R4 is H or an amine protecting group selected from the group consisting of: A) benzyl, b) t-butyldimethylsilyl, c) t-butyldiphenylsilyl, d) t-butyloxycarbonyl, e) p-methoxybenzyl, f) methoxymethyl, g) tosyl, h) trifluoroacetyl; i) trimethylsilyl, j) fluorenylmethyloxycarbonyl, k) 2-trimethylsilylethoxycarbonyl, l) 1-methyl-1- (4-biphenylyl) ethoxycarbonyl, m) allyloxycarbonyl and n) benzyloxycarbonyl; 35 M is triazole, tetrazole, oxazole, isoxazole; Z is I; Y Q is -B (OH) 2. 40

2.

Method according to claim 1, wherein X is -NR4 and R4 is H.

3.

Process according to claim 1, wherein X is -NR4 and R4 is an amine protecting group.

Method according to claim 3, further comprising the step of removing the amine protecting group.

5. The method according to claim 1, wherein M is isoxazol-4-yl.

Method according to claim 1, wherein M is [1,2,3] triazol-1-yl.

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7.

Process according to claim 1, wherein M is [1,2,3] triazol-4-yl.

8.

Method according to any one of claims 1-7, wherein the ratio of the equivalents of

the base with respect to the equivalents of the compound (I) is 3: 1. 5 9. Process according to any one of claims 1-8, wherein the mixture of water, toluene and ethanol is in a ratio of 1: 3: 1 by volume. 10. Process according to any one of claims 1-9, wherein the process is carried out at the reflux temperature of the solvent. 58