Patent Grant
11964949
The invention relates generally to compounds with antibacterial activity and, more specifically, with anti-tuberculosis properties. In particular, it relates to substituted phenyloxazolidinone compounds useful for the treatment of tuberculosis in patients in need thereof.
All documents cited to or relied upon below are expressly incorporated herein by reference.
Linezolid is the first-in-class drug and was approved in 2000 for a number of clinical applications including the treatment of nosocomial and community-acquired pneumonia and skin infections caused by Staphylococcus aureus/Methicillin-resistant S. aureus, Vancomycin-resistant Enterococci, and Streptococcus pneumoniae (Pen-S). Linezolid exhibits in vitro bacteriostatic activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) and extensively drug resistant (XDR) strains, with a minimum inhibitory concentration (MIC) of less than 1 ag/ml. However, it has demonstrated only modest activity in murine models of tuberculosis. Nonetheless, Linezolid has been used off-label in combination regimens to treat multidrug-resistant tuberculosis.
Oxazolidinones currently in clinical development show bone marrow toxicity in animals after long term administration (i.e., greater than one month) that is believed to be related to mitochondrial protein synthesis (MPS) inhibition, with very narrow safety margins or no safety margins. Since the antimicrobial mode of action of this class of compounds is inhibition of microbial protein synthesis, the MPS inhibition and consequent bone marrow toxicity exhibited by these compounds is considered mechanism specific. These oxazolidinones generally show high clearance and so require administration of high doses in clinical treatment of TB or the other indications for which they are being developed (e.g., 500 mg to 1600 mg daily) to achieve efficacious exposures. Therefore, it would be highly desirable to identify a new generation of oxazolidinones for TB treatment that would demonstrate improved potency and efficacy against TB, reduced systemic clearance to reduce the daily dose below 500 mg, and diminished MPS inhibition and related bone marrow toxicity, resulting in an improved safety margin for long term administration.
The present invention relates to novel oxazolidinones of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein,
R is independently OR1, OC(O)R2, OC(O)NHR2, OS(O2)R2, NHS(O)2R2, NR3R4, NHC(O)R5;
R′ and R″ are independently H, F, Cl or OMe;
each R1 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C1-C6 alkyl, C1-C6 alkyloxy;
each R2 is independently C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;
each R3 and R4 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, aryl; or R3 and R4 taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, CF3, NO2, CN;
each R5 is independently C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, heteroaryl, aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;
Ring A is selected from:
wherein,
each R6 and R7 is independently H, F, CH3, CH2CH3, CF3, phenyl;
X=O, S, SO, SO2;
Y=O, S, SO, SO2, and NR8;
m is 1, or 2;
n is 1, or 2;
p is 1, or 2;
q is 1, or 2;
R8 in independently H, C1-C4 alkyl, C3-C6 cycloalkyl, COCH3, and p-toluenesulfonyl, wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2.
In a further aspect, the present invention provides pharmaceutical compositions comprising at least one compound of Formula I, or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and/or additives.
In a further aspect, the present invention provides a method for treating microbial infections in humans by administering a therapeutically effective amount of a compound of Formula I, or a salt, hydrate, or solvate thereof to a patient in need thereof.
In a further aspect, the present invention includes pharmaceutical compositions of Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective treatments.
In still a further aspect, the present invention relates to a compound in accordance with Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in a human.
One aspect of the present invention is to provide novel compounds according to Formula I shown and described above. Specifically, the compounds of the invention are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria, Mycobacterium tuberculosis, Mycobacterium avium, and the like. As a result, this invention provides novel compounds according to Formula I, as well as pharmaceutically acceptable salts, hydrates, or solvates thereof. Values for the variables in Formula I are provided in the following paragraphs.
Table 1 below shows some specific examples of the compounds of the invention, by indicating their structures as well as their in vitro activity against Mycobacterium tuberculosis H37Rv strains, and in vitro MPS inhibition activity when tested as described in Example 9 and 10 below, respectively. As shown in Table 1 below, potent anti-tubercular agents demonstrate low MIC values (particular compounds with MIC's below 1 μg/mL). Conversely, high MPS inhibition IC50's indicate diminished mitochondrial protein synthesis activity in vitro, and are indicative of reduced myelosuppression toxicity in vivo. In certain embodiments of the invention, compounds having the best therapeutic index are those demonstrating a relatively lower MIC value combined a relatively higher MPS inhibition IC50. Representative compounds of the invention are provided in Table 1 (wherein the entry “NA” (i.e., “not available”) indicates that a particular value was not measured):
As used herein unless otherwise indicated, “alkyl” includes branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified carbon atom numbers. Commonly used abbreviations for alkyl groups are used throughout the application, e.g. methyl may be represented by conventional abbreviations including “Me” or CH3 or a symbol that is an extended bond without defined terminal group, e.g. “”, ethyl is represented by “Et” or CH2CH3, propyl is represented by “Pr” or CH2CH2CH3, butyl can be represented by “Bu” or CH2CH2CH2CH3, etc. “C1-6 alkyl” (or “C1-C6 alkyl”) means branched or linear chain alkyl groups, including all isomers, having the specified number of carbon atoms. C1-6 alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is provided, 1-10 carbon atoms are intended for linear or branched alkyl groups. C1-6 alkyl may be unsubstituted or substituted with 1-3 fluorine or 1-3 chlorine atoms.
“Cycloalkyl” means C3-10 carbocycles not containing heteroatoms. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, and the like.
“Aryl” means mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, indenyl and so on. Aryl also includes monocyclic rings fused to an aryl group. Examples include tetrahydronaphthyl, indanyl and the like.
“Heterocyclyl,” unless otherwise indicated, means a 4-, 5-, 6-, 7- or 8-membered monocyclic saturated ring containing 1-2 heteroatoms selected from N, O and S, in which the point of attachment may be carbon or nitrogen. Examples of “heterocyclyl” include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, and so on. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1H, 3H)-pyrimidine-2,4-diones (N-substituted uracils). Heterocyclyl may also include such moieties in charged form, e.g., piperidinium.
“Heteroaryl” means a mono- or bicyclic aromatic ring or ring system having 5 to 10 atoms and containing 1-3 heteroatoms selected from N, O, and S. Examples include, but are not limited to, oxadiazolyl, thiadiazolyl, pyrrolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl, isoxazolyl, triazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, pyridinyl, oxazolyl, thiazolyl, tetrazolyl, and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Additional examples of heteroaryls include, but are not limited to, imidazopyridinyl, imidazopyridazinyl, pyrazolopyrazolyl, indazolyl, thienopyrazolyl, pyrazolopyridinyl, and imidazothiazolyl. Heteroaryl also includes such groups in charged form, such as pyridinium. In an embodiment, heteroaryl is triazolyl, imidazolyl, oxadiazolyl, pyrazolyl, oxazolyl, and pyridinyl.
“Heterocyclic alkyl,” unless otherwise indicated, includes both branched- and straight-chain saturated aliphatic hydrocarbon groups which is bonded to a carbon or nitrogen atom of a heterocyclyl, as described above.
“Halogen (or halo)” includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halogen is chlorine or fluorine.
Substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound can be prepared and isolated, and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time that allows use of the compound for the described purposes.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkyl COOR is equivalent to
When a variable (e.g., R2, Rx, etc.) occurs more than once in any constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents and/or variables are allowed only if such combinations lead to stable compounds.
In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, R, etc., are to be chosen in conformity with common principles of chemical structure connectivity and stability.
The term “substituted” is used to include multiple degrees of substitution by a named substituent. Where multiple substituents are claimed, the substituted compound can be independently substituted by one or more of the disclosed substituents. By independently substituted, it is meant that the (two or more) substituents can be the identical or different.
Where a substituent or variable has multiple definitions, the substituent or variable is defined as being selected from the group consisting of the indicated definitions.
Salts:
Compounds of structural Formula I also cover the pharmaceutically acceptable salts. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” means salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases or acids. Pharmaceutically acceptable salts of basic compounds refer to non-toxic salts of the compounds of this invention which are generally prepared by mixing the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, clavulanate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate and the like. Suitable pharmaceutically acceptable salts of acids covered by Formula I include, but are not limited to, salts generated from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and so on.
Solvates and hydrates of the compounds of Formula I are also included in the present invention.
The present invention also discloses processes to synthesize the compounds of Formula I, as described below.
One aspect of the invention that is of interest relates to a compound in accordance with Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in a method of treatment of microbial infections in humans.
Another aspect of the invention that is of interest is a method of treating microbial infections in a human patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof to said patient.
In a further aspect, the present invention provides pharmaceutical compositions of Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents.
In still a further aspect, the present invention relates to a compound in accordance with Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in a human.
While it may be possible for the compounds of the invention to be administered as the raw chemical, it is preferable to present these as a pharmaceutical composition. Thus, according to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. Tablets, capsules, intraocular topical formulations and parenteral solutions are common among aminoglycosides. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Throughout the synthetic schemes and examples below, abbreviations are used with the following meanings unless otherwise indicated:
Synthetic methods for preparing the representative compounds of the present invention are illustrated in the following Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein. The following Examples are intended to help illustrate the invention, and are not intended to, nor should they be constructed to limit its scope.
To a solution of dihydro-2H-thiopyran-4(3H)-one (10 g, 0.086 mol) and hydroxylamine hydrochloride (10.4 g, 0.15 mol) in H2O (100 mL) and ethanol (40 mL) was added sodium acetate (13.1 g, 0.16 mol). The mixture was refluxed for 4 h, the organic solvent was removed in vacuum and the residue was cooled in an ice bath, 8.92 g solid was obtained in 79% yield by filtration. 1H-NMR (400 MHz, CDCl3) δ: 2.88 (m, 2H), 2.80 (m, 2H), 2.74 (m, 2H), 2.57 (m, 2H).
The mixture of dihydro-2H-thiopyran-4(3H)-one oxime (4.01 g, 0.03 mol) in polyphosphoric acid was heated at 115□ for 15 min, and cooled to rt, ice-water was added, then the mixture was extracted with EtOAc 5 times. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to give 2.4 g product as brown solid in 60% yield. 1H-NMR (400 MHz, CDCl3) δ: 6.79 (brs, 1H), 3.63 (m, 2H), 2.94 (m, 2H), 2.74 (m, 4H).
To a solution of 1,4-thiazepan-5-one (2.07 g, 15.7 mmol) in dry THF was added LiAlH4 (0.66 g, 17.3 mmol) at 0□, then the mixture was stirred at rt for 4 h. H2O (0.7 mL), 15% NaOH (0.7 mL) and H2O (2.1 mL) were added to the reaction in successively. The mixture was filtrated to give 1.77 g product in 96% yield. 1H-NMR (400 MHz, CDCl3) δ: 3.07 (m, 2H), 2.98 (m, 2H), 2.75 (m, 4H), 1.93 (m, 2H).
A solution of benzylamine (10.7 g, 0.1 mol) in MeOH (50 mL) was added in dropwise to a solution of methyl acrylate (18.9 g, 0.022 mol) in MeOH (100 mL) at rt. The result mixture was refluxed for 8 h, and evaporated in vacuum to give 27.9 g product in quantitative yield. 1H-NMR (400 MHz, CDCl3) δ: 7.28 (m, 5H), 3.64 (s, 2H), 3.59 (s, 6H), 2.80 (m, 4H), 2.47 (m, 4H).
To a solution of dimethyl 3,3′-(benzylazanediyl)dipropanoate (4.47 g, 16.0 mmol) in dry THF was added LiAlH4 (0.77 g, 20.2 mmol) at 0, then the mixture was stirred at rt for 24 h. MeOH (1.5 mL), 15% NaOH (1.0 mL) and H2O (1.0 mL) were added to the reaction in successively. The mixture was filtrated to give 3.4 g product in 91% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.31 (m, 5H), 3.68 (t, J=5.6 Hz, 5.6 Hz, 4H), 3.57 (s, 2H), 2.63 (t, J=6.4 Hz, 6.0 Hz, 4H), 1.76 (m, 4H).
To a solution of 3,3′-(benzylazanediyl)bis(propan-1-ol) (447 mg, 2.0 mmol) in dry CH2Cl2 was added PBr3 in dropwise at 0□, then the mixture was stirred at rt for 12 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated. The 0.43 g product was obtained as yellow oil in 61% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.27 (m, 5H), 3.56 (s, 2H), 3.44 (t, J=6.8 Hz, 6.4 Hz, 4H), 2.58 (t, J=6.4 Hz, 6.4 Hz, 4H), 2.02 (m, 4H).
To a solution of N-benzyl-3-bromo-N-(3-bromopropyl)propan-1-amine (1.0 g, 2.9 mmol) in ethanol was added Na2S·9H2O (697 mg, 2.9 mmol). The mixture was refluxed for 18 h. The mixture was then cooled to r.t., and the solvent was removed in vacuum. To the residue was added H2O and Et2O. The aqueous layer was extracted with Et2O, and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude product was used without purification.
To a solution of 5-benzyl-1,5-thiazocane (8.6 g, 39 mmol) in CH2Cl2 was added (6.15 g, 43 mmol) at 0. The mixture was stirred at rt for 6 h. the solvent was evaporated in vacuum and the residue was refluxed in MeOH for 3 h. The mixture was concentrated and washed with Et2O. The crude product was used without purification.
To a solution of dihydro-2H-pyran-2,6(3H)-dione (11.4 g, 0.1 mol) and PBr3 (0.1 mL) was added Br2 (32 g, 0.2 mol) dropwise at 100° C., the mixture was stirred at 100° C. for 7 h and cooled to rt. HCl/EtOH (10 mL) was added to the reaction mixture and stirred overnight at rt. After EtOH was evaporated, Et2O was added to the residue and washed with sat. NaHCO3 and brine, dried over Na2SO4, concentrated to give 32 g product was used for next step without purification.
A mixture of (2R,4S)-diethyl 2,4-dibromopentanedioate (54 g, 156 mmol), benzylamine (17 g, 159 mmol) and K2CO3 (25.9 g, 187.2 mmol) in toluene was refluxed for 24 h. the mixture was washed with brine, dried over and concentrated. The crude product was purified by chromatography on silica gel to give 18.39 g product in 41% yield. HRMS (ESI): m/z [M+H]+ calcd for C16H22NO4: 292.1549; found: 292.1542.
To a solution of (2R,4S)-diethyl 1-benzylazetidine-2,4-dicarboxylate (0.8 g, 2.75 mmol) in EtOH/MeOH (9:1; 10 mL) was added CaCl2 (0.92 g, 8.25 mmol) at r.t. To the resulting stirred mixture was then added NaBH4 (0.63 g, 16.5 mmol) in portions. The reaction mixture was stirred for overnight at r.t. Subsequently H2O (5 mL) was added, and the mixture was stirred for 30 min. The mixture was then concentrated in vacuum, and partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give 0.25 g product as yellow oil. This product was used in the next step without further purification. MS (ESI): m/z [M+H]+: 208.1477.
To a solution of ((2R,4S)-1-benzylazetidine-2,4-diyl)dimethanol (0.52 g, 2.9 mmol) in MeOH (10 mL) was added Pd(OH)2 (0.13 g), and the mixture was stirred for 2 h under H2 at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in anhydrous CH2Cl2 (30 mL). To the resulting solution was added DIPEA (0.37 g, 2.9 mmol), and then CbzCl (0.44 g, 2.56 mmol) dropwise. The mixture was stirred for 2 h at r.t., and then quenched with H2O (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography on silica gel (5% MeOH in CH2Cl2) to afford 0.33 g product as a yellow oil in 45% yield.
To a solution of (2R,4S)-benzyl 2,4-bis(hydroxymethyl)azetidine-1-carboxylate (51 mg, 0.2 mmol) in CH2Cl2 (15 mL) was added Et3N (61 mg, 0.6 mmol), and then MsCl (70 mg, 0.6 mmol) dropwise. The mixture was stirred for 5 h at r.t., and the reaction mixture was washed with 1N HCl and brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography on silica gel (5% MeOH in CH2Cl2) to afford 65 mg product as a yellow oil in 80% yield. HRMS (ESI): m/z [M+H]+ calcd for C15H22NO8S2: 408.0787; found: 408.0780.
A mixture of (2R,4S)-benzyl-2,4-bis(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (65 mg, 0.16 mmol) and LiBr (139 mg, 1.6 mmol) in acetone (15 mL) was refluxed for 10 h. The reaction mixture was evaporated, the residue was added H2O (20 mL) and Et2O (20 mL). The aqueous layer was extracted with Et2O (2×20 mL), and the combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum to give 51 mg product as yellow oil in 85% yield. HRMS (ESI): m/z [M+H]+ calcd for C13H15Br2NO2: 375.9548; found: 375.9558.
To a solution of (2R,4S)-benzyl 2,4-bis(bromomethyl)azetidine-1-carboxylate (0.77 g, 2.05 mmol) in DMF (5 mL) was added Na2S·9H2O (0.59 g, 2.46 mmol). The mixture was stirred at rt for 45 min. To the solution was added H2O (20 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20-30% EtOAc in PE) to give 0.15 g product as a colorless oil in 28.7% yield. HRMS (ESI): m/z [M+H]+ calcd for C13H17NO2S: 250.0902; found: 250.0900.
To a solution of (1R, 5S)-benzyl-3-thia-6-azabicyclo[3.1.1]heptane-6-carboxylate (0.19 g, 0.8 mmol) in anhydrous CH2Cl2 (20 mL) was added TMSI (0.39 g, 1.9 mmol) under Ar at 0° C. The resulting mixture was stirred at rt for 2 h, and MeOH (5 mL) was added to the reaction dropwise. The result solution was stirred for additional 0.5 h, and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (2:1) to give 0.24 g crude product as a brown solid and was used without purification.
To a stirred solution of diethyl 2,5-dibromohexanedioate (10.8 g, 30 mmol) and benzylamine (3.2 g, 30 mmol) in toluene (45 mL) and H2O (9 mL) was added K2CO3 (5 g, 36 mmol) at r.t. The mixture was refluxed for 20 h under Ar, and then poured into H2O (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, and purified by chromatography on silica gel (10-20% EtOAc in PE) to afford 6.1 g product as a yellow oil in 67% yield.
1H-NMR (400 MHz, CDCl3) δ: 7.35-7.22 (m, 5H), 4.06-4.00 (m, 4H), 3.97 (s, 2H), 3.46 (brs, 2H), 2.08-2.04 (m, 4H), 1.19 (t, J=7.1 Hz, 6H). HRMS (ESI): m/z [M+H]+ calcd for C17H24NO4: 306.1705; found: 306.1695.
To a solution of cis-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (5.4 g, 17.7 mmol) in MeOH (100 mL) was added 10% Pd/C (0.54 g), and the mixture was shaken in a Parr Shaker for 4 h at 50 psi under H2 at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in anhydrous CH2Cl2 (50 mL), and cooled to 0° C. To the resulting solution was added Et3N (2.2 g, 21.6 mmol), and then CbzCl (3.7 g, 21.6 mmol) dropwise. The mixture was stirred overnight at r.t., and then quenched with H2O (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography on silica gel (5-20% EtOAc in PE) to afford 5.22 g product as a yellow oil in 84% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.33-7.29 (m, 5H), 5.19-5.10 (m, 2H), 4.47 (m, 1H), 4.40 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.09 (q, J=6.8 Hz, 2H), 2.25-2.14 (m, 4H), 1.28 (t, J=6.8 Hz, 3H), 1.17 (t, J=6.8 Hz, 3H). HRMS (ESI): m/z [M+H]-calcd for C18H24NO6: 350.1604; found: 350.1649.
To a solution of cis-1-benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (5.75 g, 16.4 mmol) in EtOH/MeOH (10:1; 300 mL) was added CaCl2 (5.5 g, 49.2 mmol) at r.t. To the resulting stirred mixture was then added NaBH4 (3.75 g, 98.4 mmol) in portions. The reaction mixture was stirred for overnight at r.t. Subsequently H2O (50 mL) was added, and the mixture was stirred for 30 min. The mixture was then concentrated in vacuo, and partitioned between H2O (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×50 mL), and the organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give 4.57 g product as colorless oil. This product was used in the next step without further purification.
1H-NMR (400 MHz, CDCl3) δ: 7.39-7.33 (m, 5H), 5.16 (s, 2H), 4.09-3.82 (m, 4H), 3.56 (d, J=8.1 Hz, 2H), 2.91 (brs, 2H), 2.04-1.97 (m, 4H). HRMS (ESI): m/z [M+Na]+ calcd for C14H19NNaO4: 288.1206; found: 288.1196.
A solution of compound cis-benzyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (4.35 g, 16.4 mmol), Et3N (3.65 g, 36.1 mmol), and DMAP (4.01 g, 32.8 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. To this mixture was added p-toluenesulfonyl chloride (6.88 g, 36.1 mmol) in one portion and the resulting mixture was stirred overnight at r.t. The mixture was then washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (30-40% EtOAc in PE) to give 8.97 g product as a semi-solid in 95% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.73 (brs, 4H), 7.36-7.29 (m, 9H), 5.03-4.96 (m, 2H), 4.15-3.89 (m, 6H), 2.44 (s, 6H), 1.87-1.83 (m, 4H). 13C-NMR (100 MHz, CDCl3) δ (rotamers): 165.30, 154.49, 144.90, 135.88, 132.61, 129.90, 128.55, 128.19, 127.89, 69.16, 68.87, 67.28, 57.30, 56.56, 26.61, 25.44, 21.63. HRMS (ESI): m/z [M+H]+ calcd for C28H32NO8S2: 574.1564; found: 574.1547.
To a solution of cis-benzyl 2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate (4.1 g, 7.1 mmol) in ethanol (25 mL) and H2O (25 mL) was added Na2S·9H2O (5.12 g, 21.3 mmol). The mixture was refluxed for 5 h. The mixture was then cooled to r.t., and the solvent was removed in vacuo. To the residue was added H2O (20 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20-30% EtOAc in PE) to give 1.38 g product as a colorless oil in 73% yield.
1H-NMR (400 MHz, CDCl3) δ: 7.37-7.30 (m, 5H), 5.16 (s, 2H), 4.52-4.47 (m, 2H), 3.22 (d, J=11.6 Hz, 1H), 3.11 (d, J=10.8 Hz, 1H), 2.12 (d, J=12.8 Hz, 2H), 2.06 (d, J=1.2 Hz, 4H). 13C-NMR (100 MHz, CDCl3) δ: 152.95, 136.59, 128.40, 127.93, 127.80, 66.73, 53.94, 32.72, 32.08, 28.82, 27.99. HRMS (ESI): m/z [M+H]+ calcd for C14H18NO2S: 264.1058; found: 264.1113.
To a solution of (1R, 5S)-benzyl-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate (0.24 g, 0.91 mmol) in anhydrous CH2Cl2 (20 mL) was added TMSI (0.44 g, 2.18 mmol) under Ar at 0° C. The resulting mixture was stirred at rt for 0.5 h, and MeOH (0.26 mL) was added to the reaction dropwise. The result solution was stirred for additional 0.5 h, and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (1:2) to give 0.21 g product as a yellow solid in 91% yield. Mp: 208-210□. 1H-NMR (400 MHz, CDCl3) δ: 8.92 (brs, 1H), 8.72 (brs, 1H), 4.38 (s, 2H), 3.78 (d, J=14.0 Hz, 2H), 2.41-2.35 (m, 4H), 2.24-2.22 (d, J=7.6 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ: 55.67, 31.42, 27.23. HRMS (ESI): m/z [M+H]+ calcd for C6H12NS: 130.0685; found: 130.0686.
To a solution of KOH (9.04 μg, 161 mmol) and 3-bromo-2,2-bis(bromomethyl)propan-1-ol (15.3 g, 47.0 mmol) in 500 mL ethanol was added p-tosylamide (17.9 g, 104 mmol) at room temperature and the reaction mixture was refluxed for 20 h. The solvent was removed by evaporation, 100 mL 8% NaOH solution was added and the suspension was stirred for another 2 h. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried to give the title product. Yield: 6.1 g (40.2%). 1H-NMR (400 MHz, CDCl3) δ: 7.71 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 4.59 (s, 4H), 3.91 (s, 4H), 2.46 (s, 3H). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C12H16NO3S: 254.0825; found: 254.0851.
To a suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (1e-1) (9.79 g, 38.7 mmol) in Et2O (200 mL) at 0° C. was added a solution of hydrobromic acid (ca. 33% in AcOH) in dropwise. The resulting solution was stirred at room temperature for 30 min, it was adjusted to pH=8 with 1 mol/L NaOH. The phases were separated and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as a colorless solid. Yield: 10.0 g (77.4%). 1H-NMR (400 MHz, CDCl3) δ: 7.74 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.68 (s, 2H), 3.68 (s, 2H), 3.62 (d, J=8.4 Hz, 2H), 3.55 (d, J=8.4 Hz, 2H), 3.45 (s, 2H), 2.47 (s, 3H).
(3-(Bromomethyl)-1-tosylazetidin-3-yl)methanol (1e-2) (10.0 g, 30.0 mmol) was dissolved in CH2Cl2 and CBr4 (16.4 g, 49.4 mmol) was added. The resulting solution was cooled to 0° C. and PPh3 (17.9 g, 104 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (5-10% EtOAc in PE) to give the pure title compound. Yield: 8.85 g (74.8%). 1H-NMR (400 MHz, CDCl3) δ: 7.73 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.59 (s, 4H), 3.53 (s, 4H), 2.47 (s, 3H).
To a solution of 3,3-bis(bromomethyl)-1-tosylazetidine (1e-3) (8.82 g, 7.9 mmol) in a mixture of CH3CN (90 mL) and H2O (9 mL) was added Na2S·9H2O (10.7 g, 44.7 mmol) and the reaction mixture was stirred at 50° C. for 4 h, then it was concentrated to dryness. EtOAc (100 mL) and NaHCO3 solution (100 mL) were added, and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. Yield: 5.46 g (90.1%). 1H-NMR (400 MHz, CDCl3) δ: 7.71 (d J=8.0 Hz, 2H), 7.37 (d J=8.0 Hz, 2H), 3.78 (s, 4H), 3.14 (s, 4H), 2.46 (s, 3H). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C12H16NO2S2: 270.0622; found: 270.0621.
6-Tosyl-2-thia-6-azaspiro[3.3]heptane (1e-4) (2.0 g, 7.9 mmol) was dissolved in MeOH (40 mL). To the resulting solution was added magnesium powder (1.0 g), and the reaction mixture was sonicated at RT for about 3 hrs. The reaction mixture was concentrated in vacuo, the crude product was used in next step without purification.
This product was synthesized as described in Example 5, Step 1.
6-Tosyl-2-oxa-6-azaspiro[3.3]heptane (6.3 g, 25.0 mmol) was dissolved in MeOH (50 mL). To the resulting solution was added magnesium powder (6.0 g), and the reaction mixture was sonicated at RT for about 3 hrs. The reaction mixture was concentrated in vacuo, the crude product was used in next step without purification.
To a suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (6.25 g, 24.7 mmol) (obtained according to Example 5 step 1) in Et2O (100 mL) at 0° C. was dropwise added over a period of 15 min a solution of hydrobromic acid (ca. 33% in AcOH; 4.1 mL, 24.7 mmol) in Et2O (5 mL). The resulting mixture was warmed to room temperature and stirred for 45 min. The resulting colorless solution was poured into a saturated aqueous solution of NaHCO3 (100 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound 7.74 g as a colorless solid. The crude product was pure enough for further transformations.
The above crude product 1g-1 (7.74 g, 23.1 mmol) was dissolved in CH2Cl2 (100 mL) and CBr4 (13.7 g, 41.2 mmol) was added in one portion. The resulting solution was cooled to 0° C. and PPh3 (26.26 g, 41.2 mmol) was added in one portion. The reaction mixture turned to a dark orange solution, which was stirred at 0° C. for 1.5 h, then warmed to room temperature and stirred for further 8 h. The mixture was concentrated under reduced pressure to afford a dark orange oil, which was purified by chromatography (hexanes:EtOAc 4:1) to give the title compound 7.61 g. 1H-NMR (400 MHz, CDCl3) δ: 7.73 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.6 Hz, 2H), 3.60 (s, 4H), 3.53 (s, 4H), 2.48 (s, 3H).
Dibromide 1g-2 (7.61 g, 19.1 mmol) was dissolved in CH3CN (100 mL). Benzylamine (4.1 g, 38.3 mmol) and DIPEA (12.4 g, 95.5 mmol) were added to the above mixture and the reaction mixture was heated to reflux for 3 d. Then the yellowish solution was cooled to room temperature and concentrated to about ⅙ of the initial volume. The residue was partitioned between CH2Cl2 (100 mL) and 1 mol/L NaOH (100 mL). The organic phase was separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (hexanes:EtOAc:Et3N 1:1:1% to 1:2:1% gradient) to afford the title compound 4.0 g. 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, 0.1=8.2 Hz, 2H), 7.34 (d, 0.1=8.2 Hz, 2H), 7.32-7.11 (m, 5H), 3.82 (s, 4H), 3.47 (s, 2H), 3.13 (s, 4H), 2.44 (s, 3H).
Benzyl azetidine 1g-3 (2.70 g, 7.88 mmol) was dissolved in MeOH (40 mL), and Pd/C (10% on charcoal; 0.54 g) was added to the above mixture. A hydrogen atmosphere (50 PSI) was built up and the mixture was heated to 45° C. and stirred at this temperature for 48 h. Then the reaction mixture was cooled to room temperature and filtered over celite. The filter cake was washed thoroughly with MeOH (2×20 mL). To the above solution of the intermediate Ts-protected azetidine (1g-4) in MeOH (ca. 80 mL) was added Boc2O (1.77 g, 7.88 mmol). The resulting solution was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by chromatography (hexanes:EtOAc 1:1 to 1:2 gradient) to furnish the pure title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.71 (d, J=7.6 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 3.85 (s, 4H), 3.84 (s, 4H), 2.46 (s, 3H), 1.39 (s, 9H).
The above product 1g-5 (3.50 g, 10.0 mmol) was dissolved in MeOH (30 mL). Mg powder (1.92 g, 80.0 mmol) was added, and the mixture was sonicated for 6 h. The reaction mixture was concentrated in vacuo to afford a dark gray solid, which can be used for the further reaction without purification.
wherein,
represents ring A as previously defined in Formula I; X=H, or F. General procedures for the preparation of (S)—N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (OTB-114) and its sulfoxide (OTB-124), are provided below.
A solution of 3,4-difluoronitrobenzene (4.92 μg, 31 mmol) and N,N-diisopropylethylamine (8.81 g, 68 mmol) in CH3CN (30 mL) was treated with 1,5-thiazocane hydrochloride (5.2 g, 31 mol) at ambient temperature and the reaction mixture heated to reflux for 24 h. The reaction mixture was cooled to rt and concentrated. The residue was diluted with H2O and CH2Cl2, aqueous layer was extracted with CH2Cl2 (50 mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (PE/CH2Cl2=10:1) to give 3.36 g (40%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 7.92 (m, 2H), 6.80 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.67 (t, J=6.0 Hz, 5.6 Hz, 4H), 2.72 (t, J=5.6 Hz, 6.0 Hz, 4H), 2.08 (m, 4H).
To a solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (3.0 g, 12.5 mmol) in MeOH/THF was added 10% Pd/C (0.3 g), and the mixture was shaken 4 h under H2 at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in THF/H2O (50 mL). To the resulting solution was added NaHCO3 (2.12 g, 25.2 mmol), and then CbzCl (2.58 g, 15.1 mmol) dropwise. The mixture was stirred overnight at r.t., and concentrated. The residue was added H2O (50 mL) and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography on silica gel (PE/EtOAc=5:1) to afford 4.6 g product as a colorless solid in 98% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.30 (m, 5H), 6.96 (m, 2H), 6.76 (s, 1H), 4.11 (m, 2H), 3.30 (m, 4H), 2.74 (m, 4H), 1.93 (m, 4H).
A solution of benzyl(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)carbamate (2.44 g, 6.5 mmol) in dry THF (20 mL) was cooled to −78° C. (dry ice/acetone bath) under N2. n-Butyllithium (2.5 M solution in hexanes, 2.9 mL, 7.2 mmol) was added to the reaction mixture over 10 min. The resultant light yellow solution was stirred at −78° C. for 50 min and then treated with (R)-(−)-glycidyl butyrate (0.95 mL, 6.9 mmol) dropwise. The reaction mixture was stirred for an additional 30 min at −78° C., and then the cooling bath was removed. The reaction mixture was allowed to warm to ambient temperature overnight. Saturated aqueous NH4Cl (50 mL) was added to the reaction mixture. The reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by by chromatography on silica gel (PE/EtOAc-1:2) to afford 1.33 g product as a colorless solid in 59% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.37 (dd, J=14.8 Hz, 2.4 Hz, 1H), 7.09 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.00 (m, 1H), 4.73 (m, 1H), 3.95 (m, 3H), 3.76 (m, 1H), 3.35 (m, 4H), 2.74 (m, 4H), 1.97 (m, 4H).
A solution of (R)-[3-[3-Fluoro-4-(1,5-thiazocane-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methanol (1.0 g, 2.94 mmol) in dry CH2Cl2 was cooled with an ice bath and treated with Et3N (446 mg, 4.41 mmol) and methanesulfonyl chloride (404 mg, 3.53 mmol). The mixture was stirred for 2 h at rt, and was washed with H2O, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The product was used in next step without purification.
A solution of (R)-[3-[3-Fluoro-4-(1,5-thiazocane-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl methanesulfonate (859 mg, 2.1 mmol) in dry DMF was treated with solid NaN3 (683 mg, 10.5 mmol) at rt. The mixture was then heated to 65° C. for 8 h, after cooling to rt; the reaction mixture was quenched with H2O and was extracted with EtOAc. The combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The product was used in next step without purification.
To a solution of (R)-[3-[3-fluoro-4-(1,5-thiazocane-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl azide (216 mg, 0.59 mmol) in MeOH/THF was added 10% Pd/C (22 mg), and the mixture was shaken 4 h under H2 at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and was treated with Et3N (121 mg, 1.2 mmol) and AcCl (56 mg, 1.2 mmol). The reaction mixture was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH=100:1) to afford 0.1 g product as a colorless solid in 44% yield. mp 78-80° C. [α]D20 −15.4 (c 0.25, CHCl3). 1H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1H), 7.02 (m, 2H), 6.23 (m, 1H), 4.75 (m, 1H), 4.00 (t, J=8.8 Hz, 8.8 Hz, 1H), 3.73 (m, 2H), 3.64 (m, 1H), 3.36 (t, J=6.4 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 2.04 (s, 3H), 1.97 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J=243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J=26.8 Hz), 71.9, 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H25O3N3FS: 382.1595; found: 382.1620.
A solution of sodium metaperiodate (30 mg, 0.14 mmol) in H2O (2 mL) was cooled to 0° C. (S)—N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl) methyl)acetamide (50 mg, 0.13 mmol) was added and then MeOH (3 mL). The reaction mixture was stirred at 0° C. for 2 h, and was concentrated. H2O was added to the residue and then extracted with CH2Cl2 The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (CH2C2/MeOH=100:1) to afford 39 mg product as a colorless solid in 75% yield. mp 69-70° C. 1H-NMR (400 MHz, CDCl3) δ: 7.46 (dd, J=2.8 Hz, 14.8 Hz, 1H), 7.14 (t, J=9.2 Hz, 8.8 Hz, 1H), 7.07 (m, 1H), 6.15 (m, 1H), 4.78 (m, 1H), 4.03 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.74 (m, 3H), 3.31 (m, 1H), 3.18 (m, 4H), 2.98 (m, 2H), 2.17 (m, 4H), 2.03 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J=26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2. HR-MS (ESI): m/z [M+H]+ calcd for C18H25O4N3FS: 398.1544; found: 398.1540.
Antimicrobial susceptibility testing was performed in 96-well microplates. Initial drug dilutions (6.4 mg/ml) were prepared in dimethyl sulfoxide, and subsequent two-fold dilutions were performed in 0.1 ml of 7H9 broth media (BD) in the microplates. The final drug concentrations were about 0.008 ag/ml. Every concentration of test compounds was added to two wells. Control wells consisted of bacteria and positive drug (Linezolid). Plates were incubated at 37° C. The final bacterial titers were 1×106 CFU/ml for H37Rv. Starting at day 7 of incubation, 20 μl of 10× Alamar blue solution (Life Technologies) and 12.5 μl of 20% Tween 80 (Sigma-Aldrich) were added to each well and the plates were reincubated at 37° C. Wells were observed at 24 h and the colors of all were recorded. Visual MICs were defined as the lowest amount of drug that prevented a color change from blue to pink. Fluorescence was measured in a microplate fluorometer in bottom-reading mode with excitation at 530 nm and emission at 590 nm. For fluorometric MICs, the lowest drug concentration effecting an inhibition of >90% was considered the MIC. The MIC results are provided in Table 1 above.
H9C2 cells were incubated in DMEM (Hyclone, GE LifeSciences) with 10% FBS (Gibco, Life Technologies) and 1× Glutamine (Gibco, Life Technologies) and NEAA (Gibco, Life Technologies) at 37° C., 5% CO2 at 1500 cells/well in a 384-well plate. Test compound was added after 18 hr incubation, and then incubated for 5 days. COX-1 protein (cyclooxygenase I) and SDH-A (succinate dehydrogenase-A) formation reduction were measured by ELISA assay (MitoBiogenesis™ In-Cell ELISA Kit (Colorimetric, Abcam). MPS assay results are provided in Table 1 above.
1H-NMR (400 MHz, CDCl3) δ: 7.94 (s, 1H), 7.75 (s, 1H), 7.17 (dd, J=15.2 Hz, 1.2 Hz, 1H), 6.89 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.82 (t, J=9.6 Hz, 8.8 Hz, 1H), 5.03 (m, 1H), 4.78 (s, 2H), 4.10 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.87 (m, 1H), 3.68 (m, 4H), 2.87 (m, 2H), 2.68 (t, J=6.4 Hz, 6.0 Hz, 2H), 2.06 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 153.4, 151.0, 134.3, 124.9, 116.8, 115.1, 108.7 (d, J=27.3 Hz), 70.2, 56.1, 51.9, 51.3, 47.4, 34.0, 31.5, 30.3. HR-MS (ESI): m/z [M+H]+ calcd for C17H21O2N5FS: 378.1395; found: 378.1396.
1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2H), 7.27 (m, 1H), 7.01 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.84 (t, J=9.2 Hz, 9.2 Hz, 1H), 5.11 (m. 1H), 4.85 (dd, J=14 Hz, 4.8 Hz, 1H), 4.74 (dd, J=14 Hz, 6.8 Hz, 1H), 4.05 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.95 (m, 1H), 3.67 (m, 4H), 2.87 (m, 2H), 2.69 (t, J=6.4 Hz, 6.0 Hz, 2H), 2.06 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ: 153.7, 152.4 (d, J=241.8 Hz), 135.0, 134.7, 129.1, 116.9 (d, J=5.1 Hz), 114.7 (d, J=2.9 Hz), 108.4 (d, J=27.4 Hz), 69.9, 56.2, 56.1, 51.4, 48.2, 34.1, 31.6, 30.4. HR-MS (ESI): m/z [M+H]+ calcd for C17H21O2N5FS: 378.1395; found: 378.1403.
1H-NMR (400 MHz, CDCl3) δ: 7.30 (dd, J=15.6 Hz, 2.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.82 (t, J=9.6 Hz, 9.6 Hz, 1H), 4.83 (m, 1H), 4.02 (t, J=8.8 Hz, 8.4 Hz, 1H), 3.79 (t, J=8.0 Hz, 7.2 Hz, 1H), 3.67 (m, 4H), 2.97 (m, 2H), 2.87 (m, 2H), 2.68 (m, 2H), 2.54 (s, 3H), 2.05 (m, 2H). HR-MS (ESI): m/z [M+H]+ calcd for C16H23O2N3FS: 340.1490; found: 340.1484.
1H-NMR (400 MHz, CDCl3) δ: 7.34 (dd, J=15.6 Hz, 2.4 Hz, 1H), 7.05 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.89 (m, 1H), 4.84 (m, 1H), 4.37 (dd, J=16.0 Hz, 4.0 Hz, 1H), 4.31 (dd, J=12.0 Hz, 4.8 Hz, 1H), 4.06 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.76 (m, 1H), 3.68 (m, 4H), 2.89 (m, 2H), 2.70 (t, J=6.4 Hz, 6.0 Hz, 2H), 2.34 (t, J=7.6 Hz, 7.2 Hz, 2H), 2.08 (m, 2H), 1.65 (m, 2H), 0.94 (t, J=7.6 Hz, 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ: 173.3, 154.4, 152.7 (d, J=241.6 Hz), 134.9 (d, J 8.3 Hz), 129.5 (d, J=10.1 Hz), 117.2 (d, J=5.4 Hz), 114.7 (d, J=2.9 Hz), 108.5 (d, J=27.5 Hz), 70.2, 64.1, 56.3, 51.7, 47.5, 36.0, 34.4, 31.9, 30.7, 18.4, 13.7. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C19H26O4N2FS: 397.1592; found: 397.1613.
1H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 7.32 (dd, J=16.0 Hz, 2.0 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H), 7.01 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.87 (m, 1H), 6.81 (m, 1H), 6.52 (s, 1H), 4.82 (m, 1H), 4.04 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.89 (m, 1H), 3.76 (m, 2H), 3.67 (m, 4H), 2.88 (m, 2H), 2.69 (t, J=6.4 Hz, 6.0 Hz, 2H), 2.07 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ: 159.0, 154.4, 152.6 (d, J=241.9 Hz), 147.1, 144.5, 134.5, 129.3, 117.2, 115.1, 114.7, 112.3, 108.5 (d, J=27.4 Hz), 71.9, 56.3, 51.7, 47.9, 41.6, 34.1, 31.7, 30.5. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H23O4N3FS: 420.1388; found: 420.1400.
1H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1H), 7.02 (m, 2H), 6.23 (m, 1H), 4.75 (m, 1H), 4.00 (t, J=8.8 Hz, 8.8 Hz, 1H), 3.73 (m, 2H), 3.64 (m, 1H), 3.36 (t, J=6.4 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 2.04 (s, 3H), 1.97 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J=243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J=26.8 Hz), 71.9, 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H25O3N3FS: 382.1595; found: 382.1620.
1H-NMR (400 MHz, CDCl3) δ: 7.34 (dd, J=15.6 Hz, 2.0 Hz, 1H), 7.01 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.89 (m, 1H), 6.12 (m, 1H), 4.74 (m, 1H), 3.99 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.74 (m, 1H), 3.67 (m, 6H), 2.89 (t, J=5.6 Hz, 5.2 Hz, 2H), 2.70 (t, J=6.4 Hz, 6.4 Hz, 2H), 2.08 (m, 2H), 1.17 (s, 9H). 13C-NMR (125 MHz, CDCl3) δ: 179.7, 154.6, 152.7 (d, J=241.6 Hz), 134.8, 129.5, 117.2 (d, J=5.4 Hz), 114.7 (d, J=2.9 Hz), 108.5 (d, J=27.6 Hz), 72.1, 56.3, 51.7, 48.0, 42.4, 39.0, 34.4, 31.9, 30.7, 27.7. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H29O3N3FS: 410.1908; found: 410.1942.
1H-NMR (300 MHz, CDCl3) δ: 7.42-7.23 (m, 2H), 7.01 (dd, J=8.9, 2.3 Hz, 1H), 6.04 (s, 1H), 4.75 (ddd, J=9.0, 7.9, 4.6 Hz, 1H), 4.00 (t, J=9.0 Hz, 1H), 3.79-3.05 (m, 7H), 2.91 (dd, J=16.2, 10.1 Hz, 2H), 2.70 (t, J=6.3 Hz, 2H), 2.28-2.13 (m, 2H), 2.13-1.97 (m, 2H), 1.82-1.25 (m, 3H), 0.92 (t, J=7.4 Hz, 3H), 0.01 (s, 1H).
LC-MS (ESI): m/z=395.9 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J=15.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.88 (m, 1H), 4.92 (t, J=6.8 Hz, 6.4 Hz, 1H), 4.78 (m, 1H), 4.02 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.90 (m, 1H), 3.69 (m, 4H), 3.54 (m, 1H), 3.43 (m, 1H), 3.07 (m, 2H), 2.94 (m, 2H), 2.69 (m, 2H), 2.08 (m, 2H), 1.79 (m, 2H), 1.46 (m, 2H), 0.95 (t, J=7.2 Hz, 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ: 154.2, 152.5 (d, J=241.8 Hz), 134.8 (d, J=8.3 Hz), 129.2 (d, J=10.5 Hz), 117.2, 115.0, 108.6 (d, J=27.5 Hz), 71.5, 56.3, 53.2, 51.6, 47.5, 45.5, 34.1, 31.7, 30.5, 25.6, 21.5, 13.5. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C19H29O4N3FS2: 446.1578; found: 446.1623.
1H-NMR (400 MHz, CDCl3) δ: 8.24 (s, 1H), 7.96 (s, 1H), 7.22 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 5.02 (m, 1H), 4.54 (d, J=4.8 Hz, 2H), 4.10 (t, J=9.2 Hz, 9.2 Hz, 1H), 3.94 (m, 1H), 3.68 (m, 4H), 2.89 (m, 2H), 2.70 (m, 2H), 2.08 (m, 2H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H21O2N5FS: 378.1395; found: 378.1421.
1H-NMR (400 MHz, CDCl3) δ: 7.29-7.33 (m, 1H), 7.03-7.05 (m, 1H), 6.82 (t, J 8.8 Hz, 1H), 5.10 (m, 1H), 4.73 (m, 1H), 3.99 (t, J=9.9 Hz, 1H), 3.69-3.74 (m, 1H), 3.67 (s, 3H), 3.66-3.67 (m, 4H), 3.61 (m, 1H), 3.50-3.55 (m, 1H), 2.87 (m, 1H), 2.68 (m, 2H), 2.04-2.07 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 71.7, 56.2, 56.2, 51.5, 47.7, 43.7, 34.3, 31.8, 30.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H23O4N3FS: 384.1388; found: 384.1371.
1H-NMR (400 MHz, CDCl3) δ: 7.29-7.33 (m, 1H), 7.03-7.00 (m, 1H), 6.81 (t, J 9.6 Hz, 1H), 6.09 (m, 1H), 4.74 (m, 1H), 3.98 (t, J=8.8 Hz, 1H), 3.73-3.74 (m, 1H), 3.67-3.71 (m, 4H), 3.62-3.66 (m, 1H), 2.87 (t, J=4.8 Hz, 2H), 2.68 (t, J 10.0 Hz, 2H), 2.04-2.07 (m, 2H), 1.36-1.43 (m, 1H), 1.05-1.07 (m, 1H), 0.93-0.97 (m, 2H), 0.77-0.78 (m, 1H). 13C-NMR (150 MHz, CDCl3) δ: 174.5, 154.5, 153.3, 151.7, 134.8, 134.7, 129.2, 129.2, 117.0, 114.7, 108.6, 108.4, 72.0, 56.2, 51.5, 47.8, 42.1, 34.3, 31.8, 30.6, 14.7, 7.7. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C19H25O3N3FS: 394.1595; found: 394.1580.
1H-NMR (400 MHz, CDCl3) (δ: 7.29-7.34 (m, 1H), 7.03-7.00 (m, 1H), 6.82 (t, J 9.6 Hz, 1H), 5.84 (m, 1H), 4.75 (m, 1H), 3.99 (t, J=8.8 Hz, 1H), 3.72-3.76 (m, 1H), 3.67-3.71 (m, 4H), 3.63-3.66 (m, 1H), 3.14-3.23 (m, 2H), 2.68 (m, 1H), 1.89-2.35 (m, 10H). 13C-NMR (150 MHz, CDCl3) δ: 180.2, 176.0, 154.5, 134.8, 134.8, 129.2, 129.1, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 72.0, 56.2, 56.2, 51.5, 51.5, 47.9, 42.0, 39.7, 37.8, 34.3, 31.8, 30.6, 25.2, 18.4. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H27O3N3FS: 408.1752; found: 408.1736.
1H-NMR (400 MHz, CDCl3) c: 7.07 (d, J=10.4 Hz, 2H), 6.08 (m, 1H), 4.76-4.77 (m, 1H), 3.98 (t, J=9.2 Hz, 1H), 3.59-3.70 (m, 3H), 3.45-3.48 (m, 4H), 2.89 (t, J 6.0 Hz, 2H), 2.77-2.80 (m, 2H), 2.02 (s, 3H). 13C-NMR (150 MHz, CDCl3) δ: 171.1, 159.8, 159.7, 158.1, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 71.9, 58.8, 54.1, 47.5, 41.9, 36.1, 31.8, 31.6, 23.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H22O3N3F2S: 386.1344; found: 386.1330.
1H-NMR (500 MHz, CDCl3) δ: 7.09 (d, J=10.0 Hz, 2H), 5.09 (m, 1H), 4.76 (m, 1H), 3.99 (t, J=9.0 Hz, 1H), 3.74-3.76 (m, 1H), 3.73 (s, 3H), 3.61 (m, 1H), 3.52-3.55 (m, 1H), 3.46-3.47 (m, 4H), 2.90 (t, J=6.0 Hz, 1H), 2.78-2.80 (m, 2H), 1.94-1.98 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.4, 108.4, 71.3, 56.2, 56.2, 51.5, 47.8, 43.7, 34.3, 31.8, 30.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H22O4N3F2S: 402.1297; found: 402.1287.
1H-NMR (400 MHz, CDCl3) δ: 7.07 (d, J=10.8 Hz, 2H), 6.06 (m, 1H), 4.76 (m, 1H), 3.96 (t, J=8.8 Hz, 1H), 3.66-3.75 (m, 3H), 3.43-3.47 (m, 3H), 2.89 (t, J=9.2 Hz, 2H), 2.78-2.80 (m, 3H), 1.94-1.97 (m, 2H), 1.37-1.39 (m, 1H), 0.97 (m, 1H), 0.93 (m, 1H), 0.77-0.79 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ: 174.7, 159.8, 159.7, 158.2, 158.1, 154.0, 133.4, 126.0, 102.6, 102.4, 72.0, 58.8, 54.1, 47.5, 42.0, 36.1, 31.8, 31.6, 14.7, 7.8, 7.7. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C19H24O3N3F2S: 412.1501; found: 412.1485.
1H-NMR (400 MHz, CDCl3) δ: 7.07 (d, J=10.8 Hz, 2H), 5.81 (m, 1H), 4.75 (m, 1H), 3.98 (t, J=8.8 Hz, 1H), 3.72-3.76 (m, 1H), 3.64-3.66 (m, 2H), 3.45-3.46 (m, 3H), 3.01 (t, J=8.8 Hz, 1H), 2.90 (t, J=6.4 Hz, 2H), 2.77-2.80 (m, 2H), 2.13-2.26 (m, 4H), 1.92-1.96 (m, 3H). 13C-NMR (150 MHz, CDCl3) δ: 176.0, 159.8, 159.8, 158.2, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 72.0, 58.8, 54.1, 47.5, 41.9, 39.7, 36.1, 31.8, 31.6, 25.4, 25.3, 18.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H26O3N3F2S: 426.1658; found: 426.1643.
1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J=11.2 Hz, 2H), 6.95 (d, J=10.4 Hz, 2H), 5.04-5.07 (m, 1H), 4.78 (d, J=4.0 Hz, 2H), 4.10 (t, J=9.2 Hz, 1H), 3.86-3.90 (m, 1H), 3.44-3.46 (m, 4H), 2.88 (t, J=6.4 Hz, 2H), 2.76-2.79 (m, 2H), 1.91-1.97 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ: 159.8, 159.8, 157.9, 157.8, 153.0, 134.6, 125.1, 102.8, 102.5, 70.3, 58.7, 54.0, 51.9, 47.1, 36.1, 31.8, 31.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H20O2N5F2S: 396.1300; found: 396.1296.
1H-NMR (400 MHz, CDCl3) δ: 7.45 (dd, J=14.8 Hz, 1.6 Hz, 1H), 7.07 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.96 (t, J=9.2 Hz, 9.2 Hz, 1H), 4.85 (m, 1H), 4.37 (dd, J=12.0 Hz, 4.0 Hz, 1H), 4.30 (dd, J=12.4 Hz, 4.8 Hz, 1H), 4.07 (m, 1H), 3.78 (m, 2H), 3.40 (m, 2H), 3.19 (m, 4H), 2.98 (m, 1H), 2.72 (m, 1H), 2.33 (t, J=7.6 Hz, 7.2 Hz, 2H), 2.04 (m, 1H), 1.63 (m, 2H), 0.92 (t, J=7.6 Hz, 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ: 173.2, 154.1, 154.0 (d, J=241.8 Hz), 136.6, 131.4, 118.1 (d, J 4.3 Hz), 114.0, (d, J=2.9 Hz), 107.8 (d, J=26.9 Hz), 70.1, 63.9, 52.8, 49.6, 47.2, 46.4, 43.7, 35.8, 18.3, 16.2, 13.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C19H26O5N2FS: 413.1541; found: 413.1573.
1H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 7.42 (m, 1H), 7.14 (d, J=3.2 Hz, 1H), 7.04 (m, 1H), 6.87 (m, 2H), 6.51 (m, 1H), 4.85 (m, 1H), 4.05 (m, 1H), 3.81 (m, 4H), 3.38 (m, 2H), 3.15 (m, 2H), 3.04 (m, 3H), 2.70 (m, 1H), 2.03 (m, 1H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H23O5N3FS: 436.1337; found: 436.1371.
1H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1H), 7.75 (s, 1H), 7.30-7.25 (m, 1H), 6.91-6.89 (m, 2H), 5.07-5.02 (m, 1H), 4.78 (d, J=4.0 Hz, 2H), 4.11 (t, J=9.2 Hz, 1H), 3.93-3.88 (m, 1H), 3.82-3.76 (m, 1H), 3.43-3.36 (m, 2H), 3.24-2.91 (m, 4H), 2.75-2.69 (m, 1H), 2.04-2.02 (m, 2H). HR-MS (ESI): m/z [M+H]+ calcd for C17H21O3N5FS: 394.1344; found: 394.1328.
1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2H), 7.39 (d, J=14.4 Hz, 1H), 7.04-6.98 (m, 2H), 5.15-5.09 (m, 1H), 4.86 (dd, J=14.0, 4.4 Hz, 1H), 4.75 (dd, J=14.0, 6.8 Hz, 1H), 4.06 (dt, J=9.2, 2.4 Hz, 1H), 4.00-3.96 (m, 1H), 3.86-3.82 (m, 1H), 3.46-3.38 (m, 2H), 3.29-3.08 (m, 3H), 3.02-2.96 (m, 1H), 2.76-2.71 (m, 1H), 2.04-2.02 (m, 2H). HR-MS (ESI): m/z [M+H]+ calcd for C17H21O3N5FS: 394.1344; found: 394.1338.
1H-NMR (400 MHz, CDCl3) δ: 8.24 (s, 1H), 7.94 (s, 1H), 7.35 (d, J=14.4 Hz, 1H), 7.0-6.96 (m, 2H), 5.02-4.99 (m, 1H), 4.55 (d, J=4.4 Hz, 2H), 4.10 (dt, J=8.8, 2.0 Hz, 1H), 3.99-3.95 (m, 1H), 3.86-3.82 (m, 1H), 3.45-3.38 (m, 2H), 3.29-3.09 (m, 3H), 3.00-2.94 (m, 1H), 2.77-2.71 (m, 1H), 2.07-2.03 (m, 2H). HR-MS (ESI): m/z [M+H]+ calcd for C17H21O3N5FS: 394.1344; found: 394.1339.
1H-NMR (300 MHz, CDCl3) δ: 7.52 (d, J=15.0 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 5.99 (s, 1H), 4.78 (s, 1H), 4.02 (t, J=8.8 Hz, 2H), 3.88-3.56 (m, 3H), 3.55-2.92 (m, 7H), 2.77 (s, 1H), 2.20 (t, J=7.1 Hz, 3H), 1.64 (dd, 0.1=14.9, 7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).
LC-MS (ESI): m/z=411.8 [M+H]+.
1H-NMR (300 MHz, CDCl3) δ: 7.51 (d, J=14.7 Hz, 1H), 7.10 (d, J=9.9 Hz, 2H), 5.92 (s, 1H), 4.78 (s, 1H), 4.03 (t, J=9.0 Hz, 1H), 3.87-3.39 (m, 7H), 3.27 (d, J=5.7 Hz, 2H), 2.39 (d, J=6.2 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H), 1.64 (dd, J=14.8, 7.4 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H).
LC-MS (ESI): m/z=427.8 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (dd, J=14.8 Hz, 4.0 Hz, 1H), 7.09 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.04 (t, J=10.4 Hz, 9.2 Hz, 1H), 4.85 (m, 1H), 4.37 (m, 1H), 4.31 (m, 1H), 4.08 (m, 1H), 3.78 (m, 1H), 3.37 (m, 4H), 2.75 (m, 4H), 2.34 (t, J=7.6 Hz, 7.2 Hz, 2H), 1.97 (m, 4H), 1.64 (m, 2H), 0.93 (t, 7.6 Hz, J=7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ: 173.3, 155.4 (d, J=243.5 Hz), 154.3, 134.5 (d, J=8.3 Hz), 131.1 (d, J=10.1 Hz), 128.2, 127.1, 120.0 (d, J=4.9 Hz), 114.3 (d, J=3.0 Hz), 108.4 (d, J=26.8 Hz), 70.2, 64.0, 48.1, 47.4, 36.0, 32.1, 29.8, 18.4, 13.7. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H28O4N2FS: 411.1748; found: 411.1786.
1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2H), 7.30 (d, J=14.8 Hz, 1H), 7.03 (m, 2H), 5.10 (m, 1H), 4.85 (dd, J=14.0 Hz, 4.8 Hz, 1H), 4.74 (dd, J=14.0 Hz, 7.2 Hz, 1H), 4.06 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.97 (m, 1H), 3.37 (t, J=6.0 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 1.97 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 155.2 (d, J 243.5 Hz), 135.2, 134.4 (d, J=8.1 Hz), 130.8 (d, J=10.3 Hz), 119.8 (d, J=4.9 Hz), 114.5 (d, J=3.1 Hz), 108.4 (d, J=26.6 Hz), 70.0, 56.3, 48.3, 47.9, 31.9, 29.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H23O2N5FS: 392.1551; found: 392.1590.
1H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1H), 7.02 (m, 2H), 6.23 (m, 1H), 4.75 (m, 1H), 4.00 (t, J=8.8 Hz, 8.8 Hz, 1H), 3.73 (m, 2H), 3.64 (m, 1H), 3.36 (t, J=6.4 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 2.04 (s, 3H), 1.97 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J=243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J=26.8 Hz), 71.9, 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H25O3N3FS: 382.1595; found: 382.1620.
1H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 7.36 (d, J=14.4 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H), 7.01 (m, 2H), 6.78 (m, 1H), 6.51 (m, 1H), 4.84 (m, 1H), 4.05 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.88 (m, 1H), 3.80 (m, 2H), 3.36 (t, J=6.0 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 1.96 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 159.0, 155.2 (d, J=243.6 Hz), 154.3, 147.1, 144.5, 134.3, 130.9, 119.8, 115.1, 114.3 (d, J=3.0 Hz), 112.3, 108.4 (d, J=26.8 Hz), 71.9, 47.9, 41.5, 31.9, 29.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C21H25O4N3FS: 434.1544; found: 434.1581.
1H-NMR (400 MHz, CDCl3) δ: 7.54 (m, 1H), 7.52 (m, 1H), 7.34 (m, 1H), 7.10 (m, 1H), 7.04 (m, 1H), 7.00 (m, 1H), 6.57 (t, J=6.0 Hz, 6.0 Hz, 1H), 4.86 (m, 1H), 4.07 (t, J=9.2 Hz, 8.8 Hz, 1H), 4.07 (m, 1H), 3.82 (m, 2H), 3.36 (t, J=6.0 Hz, 6.0 Hz, 4H), 2.74 (m, 4H), 1.96 (m, 4H). 13C-NMR (125 MHz, CDCl3) δ: 162.7, 155.2 (d, J=243.5 Hz), 154.5, 137.9, 130.8, 128.7, 127.8, 119.8, 114.5 (d, J=3.0 Hz), 108.5 (d, J=26.8 Hz), 72.1, 48.0, 42.5, 31.9, 29.6. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C21H25O4N4FS2: 450.1316; found: 450.1356.
1H-NMR (400 MHz, CDCl3) δ: 7.42 (d, J=14.4 Hz, 1H), 7.08 (m, 2H), 4.94 (m, 1H), 4.79 (m, 1H), 4.04 (t, J=8.8 Hz, 8.8 Hz, 1H), 3.93 (m, 1H), 3.55 (m, 1H), 3.43 (m, 5H), 3.07 (m, 2H), 2.76 (m, 4H), 2.01 (m, 4H), 1.80 (m, 2H), 1.45 (m, 2H), 0.95 (t, J=7.6 Hz, 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ: 155.2 (d, J 243.6 Hz), 154.2, 134.5, 130.7, 119.8 (d, J=4.9 Hz), 114.5 (d, J=3.0 Hz), 108.5 (d, 0.1=26.8 Hz), 71.5, 53.1, 47.9, 47.4, 45.5, 31.9, 29.6, 25.6, 21.5, 13.5. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H31O4N3FS2: 460.1735; found: 460.1778.
1H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J=14.4 Hz, 1H), 7.04 (m, 2H), 6.11 (m, 1H), 4.74 (m, 1H), 4.00 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.76 (m, 1H), 3.67 (m, 2H), 3.39 (m, 4H), 2.74 (m, 4H), 1.98 (m, 4H), 1.17 (s, 9H). 13C-NMR (125 MHz, CDCl3) δ: 179.6, 155.2 (d, J=243.6 Hz), 154.4, 134.3 (d, J=8.0 Hz), 130.9 (d, J 5.4 Hz), 128.8, 119.8 (d, J=4.9 Hz), 114.2 (d, J=2.9 Hz), 108.2 (d, J=26.9 Hz), 72.0, 47.9, 47.8, 42.2, 38.9, 31.9, 29.6, 27.5. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C21H31O3N3FS: 424.2065; found: 424.2096.
1H-NMR (300 MHz, CDCl3) δ: 7.76 (d, J=17.6 Hz, 2H), 7.41-7.09 (m, 1H), 7.11-6.73 (m, 2H), 5.04 (d, J=3.0 Hz, 1H), 4.78 (d, J=3.4 Hz, 2H), 4.12 (t, J=9.2 Hz, 1H), 3.88 (dd, J=9.2, 6.1 Hz, 1H), 3.36 (t, J=6.0 Hz, 3H), 2.92-2.59 (m, 4H), 2.01 (dd, J=27.9, 7.3 Hz, 4H).
LC-MS (ESI): m/z=391.9 [M+H]+.
1H-NMR (300 MHz, CDCl3) δ: 7.50 (s, 2H), 7.03 (d, J=6.1 Hz, 1H), 5.99 (s, 1H), 4.77 (d, J=5.7 Hz, 1H), 4.02 (t, J=9.0 Hz, 2H), 3.70 (ddd, J=20.7, 15.2, 7.7 Hz, 4H), 3.48 (s, 4H), 2.95-2.68 (m, 4H), 2.20 (t, J=7.2 Hz, 3H), 2.06 (d, J=6.1 Hz, 4H), 1.64 (dd, J=14.8, 7.4 Hz, 4H), 0.91 (t, J=7.4 Hz, 4H).
LC-MS (ESI): m/z=409.9 [M+H]+.
1H-NMR (300 MHz, CDCl3) δ: 8.24 (s, 1H), 7.97 (s, 1H), 7.00 (s, 2H), 5.12-4.91 (m, 1H), 4.56 (d, J=4.7 Hz, 2H), 4.24-3.83 (m, 2H), 3.38 (t, J=6.0 Hz, 4H), 2.95-2.59 (m, 4H), 1.98 (s, 5H).
LC-MS (ESI): m/z=391.9 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.46 (dd, J=2.8 Hz, 14.8 Hz, 1H), 7.14 (t, J=9.2 Hz, 8.8 Hz, 1H), 7.07 (m, 1H), 6.15 (m, 1H), 4.78 (m, 1H), 4.03 (t, J=9.2 Hz, 8.8 Hz, 1H), 3.74 (m, 3H), 3.31 (m, 1H), 3.18 (m, 4H), 2.98 (m, 2H), 2.17 (m, 4H), 2.03 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J=26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2. HR-MS (ESI): m/z [M+H]+ calcd for C18H25O4N3FS: 398.1544; found: 398.1540.
1H-NMR (300 MHz, CDCl3) δ: 7.92-7.67 (m, 2H), 7.32 (d, J=16.8 Hz, 1H), 7.12 (t, J=9.0 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 5.07 (s, 1H), 4.81 (d, J=4.0 Hz, 2H), 4.15 (t, J=9.0 Hz, 1H), 4.01-3.83 (m, 1H), 3.32 (d, J=14.2 Hz, 5H), 3.11-2.87 (m, 2H), 2.59 (s, 2H), 2.19 (s, 4H).
LC-MS (ESI): m/z=407.8 [M+H]+.
1H-NMR (300 MHz, CDCl3) δ: 7.44 (dd, J=14.7, 2.4 Hz, 1H), 7.19-6.99 (m, 2H), 6.44 (s, 1H), 4.84-4.71 (m, 1H), 4.02 (t, J=8.9 Hz, 1H), 3.78 (dd, J=9.0, 6.6 Hz, 1H), 3.66 (t, J=4.6 Hz, 2H), 3.38-3.09 (m, 6H), 2.99 (dd, J=12.6, 6.3 Hz, 2H), 2.20 (dd, J=9.4, 5.3 Hz, 6H), 1.71-1.56 (m, 2H), 0.91 (dd, J=9.6, 5.1 Hz, 3H).
LC-MS (ESI): m/z=425.8 [M+H]+.
1H-NMR (300 MHz, CDCl3) δ: 8.24 (s, 1H), 7.93 (s, 1H), 7.41-7.20 (m, 1H), 7.19-6.92 (m, 2H), 5.10-4.92 (m, 1H), 4.56 (d, J=4.7 Hz, 2H), 4.12 (t, J=9.0 Hz, 1H), 3.97 (dd, J=9.2, 6.2 Hz, 1H), 3.28 (dd, J=13.0, 6.9 Hz, 2H), 3.12 (dd, J=12.5, 5.9 Hz, 4H), 3.02-2.83 (m, 2H), 2.22-1.99 (m, 5H), 1.26 (d, J=9.4 Hz, 4H).
LC-MS (ESI): m/z=407.8 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J=14.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (t, J=9.2 Hz, 1H), 6.35 (brs, 1H), 4.76-4.74 (m, 1H), 4.56-4.54 (m, 2H), 4.00 (t, J=9.2 Hz, 1H), 3.76-3.65 (m, 2H), 3.62-3.57 (m, 1H), 3.43 (d, J=12.0 Hz, 2H), 2.93-2.87 (m, 1H), 2.74 (d, J=12.0 Hz, 2H), 2.09 (s, 1H), 2.03 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.1, 154.5, 151.8 (d, J=238.5 Hz), 131.9 (d, J=11.8 Hz), 129.2 (d, J=9.5 Hz), 115.2 (d, J=6.2 Hz), 114.7 (d, J=2.8 Hz), 108.0 (d, 0.1=24.9 Hz), 71.9, 60.8, 47.8, 41.9, 29.4, 25.3, 23.2. HRMS (ESI-TOF+): m/z [M+H]+ calcd for C17H21FN3O3S: 366.1288; found: 366.1277.
1H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J=12.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 6.90 (t, J=9.2 Hz, 1H), 4.74 (m, 1H), 4.43 (s, 2H), 3.99-3.96 (m, 3H), 3.79-3.75 (m, 1H), 3.48 (d, J=13.2 Hz, 2H), 2.21-2.10 (m, 6H). HRMS (ESI): m/z [M+H]+ calcd for C16H20N2O3FS: 339.1179; found: 339.1169.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (dd, J=15.2, 2.4 Hz, 1H), 7.06 (dd, J=8.8, 1.8 Hz, 1H), 6.83 (t, J=9.2 Hz, 1H), 6.18 (s, 1H), 4.77-4.75 (m, 1H), 4.40 (s, 2H), 4.00 (t, J=8.8 Hz, 1H), 3.76-3.72 (m, 2H), 3.68-3.62 (m, 1H), 3.37 (d, J=12.8 Hz, 2H), 2.26-2.04 (m, 6H), 2.02 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.1, 154.5, 152.8 (d, J=241.7 Hz), 132.2 (d, J=8.6 Hz), 130.2 (d, J=10.4 Hz), 118.1 (d, J=5.0 Hz), 114.7, 108.4 (d, J=27.2 Hz), 71.9, 57.4, 47.8, 42.0, 30.2, 28.4, 23.1. HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H23N3O3FS: 380.1444; found: 380.1435.
1H-NMR (400 MHz, CDCl3) δ: 7.80 (s, 1H), 7.76 (s, 1H), 7.24 (m, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.83 (t, J=8.8 Hz, 1H), 5.07-5.04 (m, 1H), 4.79 (s, 2H), 4.40 (s, 2H), 4.11 (t, J=8.0 Hz, 1H), 3.90-3.87 (m, 1H), 3.42 (d, J=12.8 Hz, 2H), 2.20-2.07 (m, 6H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H21N5O2FS: 390.1400; found: 390.1385.
1H-NMR (400 MHz, CDCl3) δ: 7.47-7.41 (m, 1H), 7.13 (d, J=9.6 Hz, 1H), 7.02 (t, J=9.6 Hz, 1H), 4.76-4.70 (m, 1H), 4.34 (s, 2H), 4.08 (t, J=9.2 Hz, 1H), 3.76 (t, J=8.8 Hz, 1H), 3.29-3.26 (m, 2H), 3.11 (d, J=12.8 Hz, 2H), 2.93 (s, 3H), 2.11 (d, J=12.4 Hz, 2H), 2.02 (s, 4H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C17H23N3O4FS2: 416.1114; found: 416.1097.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J=15.2 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.81 (t, J=9.2 Hz, 1H), 5.18 (brs, 1H), 4.74 (brs, 1H), 4.39 (s, 2H), 4.01 (t, J=8.8 Hz, 1H), 3.76 (t, J=7.6 Hz, 1H), 3.69 (s, 3H), 3.56-3.51 (m, 1H), 3.33 (d, J=12.8 Hz, 2H), 2.18-2.07 (m, 6H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H23N3O4FS: 396.1393; found: 396.1388.
1H-NMR (300 MHz, DMSO-d6) δ: 8.18 (s, 1H), 7.42 (d, J=16.0 Hz, 1H), 7.35-6.88 (m, 2H), 4.71 (s, 1H), 4.35 (s, 2H), 4.07 (t, J=8.7 Hz, 1H), 3.77-3.57 (m, 1H), 3.51-3.27 (m, 2H), 3.12 (d, J=12.4 Hz, 2H), 2.09 (dd, J=20.9, 12.2 Hz, 8H), 1.47 (dd, J=14.0, 7.1 Hz, 2H), 0.80 (dd, J=8.0, 6.7 Hz, 3H).
LC-MS (ESI): m/z=407.9 [M+H]+.
1H-NMR (300 MHz, DMSO-d6) δ: 8.57 (s, 1H), 8.01 (s, 1H), 7.36 (dd, J=15.8, 2.1 Hz, 1H), 7.18-6.92 (m, 2H), 5.06 (dd, 0.1=8.9, 4.8 Hz, 1H), 4.72-4.52 (m, 2H), 4.36 (s, 2H), 4.17 (t, J=9.1 Hz, 1H), 3.84 (dt, J=49.3, 24.7 Hz, 1H), 3.12 (d, J=12.8 Hz, 2H), 2.16 (s, 1H), 2.11 (s, 1H), 2.04 (s, 4H).
LC-MS (ESI): m/z=389.9 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.37 (d, J=13.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.85 (brs, 1H), 6.22 (t, J=6.0 Hz, 1H), 4.79-4.73 (m, 1H), 4.41 (brs, 2H), 3.99 (t, J=7.2 Hz, 1H), 3.77-3.64 (m, 3H), 3.39 (d, J=12.8 Hz, 2H), 2.20-2.09 (m, 6H), 1.43-1.37 (m, 1H), 0.98-0.90 (m, 2H), 0.82-0.75 (m, 2H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C20H25N3O3FS: 406.1595; found: 406.1527.
1H-NMR (400 MHz, CDCl3) δ: 7.45 (d, J=12.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H) 5.95 (m, 1H), 4.78 (m, 1H), 4.51 (brs, 2H), 4.00 (t, J=9.2 Hz, 1H), 3.84-3.74 (m, 3H), 3.66 (m, 2H), 3.02 (m, 1H), 2.28-2.15 (m, 10H), 1.95 (m, 1H), 1.85 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 175.9, 154.3, 153.0 (d, J=242.9 Hz), 131.2, 127.0, 118.6 (d, 0.1=4.4 Hz), 114.5 (d, J=2.9 Hz), 108.3 (d, 0.1=27.1 Hz), 71.9, 58.2, 47.7, 41.9, 39.6, 30.3, 28.3, 25.4, 25.3, 18.1. HRMS (ESI): m/z [M+H]+ calcd for C21H27N3O3SF: 420.1757; found: 420.1736.
1H-NMR (400 MHz, CDCl3) δ: 7.08 (m, 2H), 6.00 (m, 1H), 4.76 (m, 1H), 4.24 (brs, 2H), 3.97 (t, J=8.8 Hz, 1H), 3.75-3.60 (m, 3H), 3.38 (m, 2H), 2.21 (m, 2H), 2.14 (s, 4H), 2.03 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.2, 155.3 (dd, J=241.5, 9.5 Hz), 154.1, 130.6 (t, J=13.6 Hz), 122.9 (t, J=12.4 Hz), 102.9 (dd, J=20.7, 11.3 Hz), 71.9, 60.4, 47.4, 41.9, 33.7, 29.2, 23.1. HRMS (ESI): m/z [M+H]+ calcd for C18H22N3O3SF2: 398.1350; found: 398.1329.
1H-NMR (400 MHz, CDCl3) δ: 7.09 (m, 2H), 5.08 (m, 1H), 4.76 (m, 1H), 4.24 (brs, 2H), 3.98 (t, J=8.8 Hz, 1H), 3.75-3.50 (m, 6H), 3.38 (m, 2H), 2.20 (m, 2H), 2.14 (s, 4H). 13C-NMR (100 MHz, CDCl3) δ: 157.5, 155.3 (dd, J=241.6, 9.4 Hz), 153.9, 130.7 (t, J=13.6 Hz), 122.9 (t, J=12.3 Hz), 102.9 (dd, J=20.7, 11.3 Hz), 71.8, 60.4, 52.6, 47.3, 43.6, 33.7, 29.2. HRMS (ESI): m/z [M+H]+ calcd for C18H22N3O4SF2: 414.1294; found: 414.1278.
1H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.76 (s, 1H), 6.94 (d, J=11.6 Hz, 2H), 5.07-5.04 (m, 1H), 4.79 (d, J=3.6 Hz, 2H), 4.20 (brs, 2H), 4.09 (t, J=8.8 Hz, 1H), 3.88-3.83 (m, 1H), 3.32 (d, J=12.8 Hz, 2H), 2.19-2.11 (m, 6H). 13C-NMR (100 MHz, CDCl3) δ: 155.3 (d, J=242.1 Hz), 155.2 (d, J=242.1 Hz), 153.1, 134.5, 129.9 (t, J=13.6 Hz), 125.1, 123.3 (t, J=12.3 Hz), 103.3 (dd, J=20.7, 11.2 Hz), 70.3, 60.4, 52.0, 47.2, 33.8, 29.2. HRMS (ESI): m/z [M+H]+ calcd for C18H20N5O2SF2: 408.1300; found: 408.1295.
1H-NMR (400 MHz, CDCl3) δ: 7.05 (m, 2H), 6.12 (m, 1H), 4.76 (m, 1H), 4.21 (brs, 2H), 3.95 (t, J=9.2 Hz, 1H), 3.72-3.65 (m, 3H), 3.34 (m, 2H), 2.21-2.12 (m, 6H), 1.37 (m, 1H), 0.99-0.75 (m, 4H). 13C-NMR (100 MHz, CDCl3) δ: 174.8, 155.3 (dd, J=241.7, 9.5 Hz), 154.2, 130.5 (t, J=13.6 Hz), 123.0 (t, J=12.5 Hz), 103.0 (dd, J=20.8, 11.4 Hz), 72.1, 60.4, 47.5, 41.9, 33.8, 29.2, 14.6, 7.8, 7.7. HRMS (ESI): m/z [M+H]+ calcd for C20H24N3O3SF2: 420.1506; found: 424.1484.
1H-NMR (400 MHz, CDCl3) δ: 7.09 (m, 2H), 5.78 (m, 1H), 4.75 (m, 1H), 4.23 (brs, 2H), 3.97 (t, J=8.8 Hz, 1H), 3.73 (m, 1H), 3.65 (m, 2H), 3.36 (m, 2H), 2.99 (m, 1H), 2.27-2.14 (m, 9H), 1.97 (m, 1H), 1.85 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 176.0, 155.3 (dd, J=243.4, 9.5 Hz), 154.1, 130.6 (t, J=13.5 Hz), 122.9 (t, J=12.2 Hz), 102.9 (dd, J=20.7, 11.4 Hz), 72.0, 60.4, 47.5, 41.8, 33.7, 29.2, 25.4, 25.3, 18.1. HRMS (ESI): m/z [M+H]+ calcd for C21H26N3O3SF2: 438.1663; found: 438.1642.
1H-NMR (400 MHz, CDCl3) δ: 7.45 (dd, J=16.0, 2.8 Hz, 1H), 7.12 (dd, J=8.8, 2.0 Hz, 1H), 6.83 (t, J=9.2 Hz, 1H), 6.14 (s, 1H), 4.78-4.77 (m, 1H), 4.61 (s, 2H), 4.00 (t, J=8.8 Hz, 1H), 3.77-3.64 (m, 3H), 3.45 (d, J=9.6 Hz, 2H), 2.85 (d, J=12.4 Hz, 2H), 2.22-2.20 (m, 2H), 2.03 (s, 3H), 1.92-1.88 (m, 2H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H23N3O4FS: 396.1388; found: 396.1379.
1H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1H), 7.75 (s, 1H), 7.30 (dd, J=15.2, 2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.79 (t, J=9.2 Hz, 1H), 5.07-5.05 (m, 1H), 4.79 (s, 2H), 4.58 (s, 2H), 4.12 (t, J=9.2 Hz, 1H), 3.91-3.89 (m, 1H), 3.43 (d, J=11.6 Hz, 2H), 2.88-2.81 (m, 2H), 2.21-2.18 (m, 2H), 1.89-1.87 (m, 2H). HR-MS (ESI-TOF): m/z [M+H]+ calcd for C18H21N5O3FS: 406.1349; found: 406.1339.
1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=12.0 Hz, 2H), 5.97 (brs, 1H), 4.77-4.75 (m, 1H), 4.45 (s, 2H), 3.97 (t, J=8.8 Hz, 1H), 3.74 (t, J=8.4 Hz, 1H), 3.66 (t, J=5.2 Hz, 2H), 3.54 (d, 0.1=9.2 Hz, 2H), 3.02 (m, 1H), 2.91 (d, 0.1=12.0 Hz, 2H), 2.26-2.11 (m, 6H), 1.99-1.92 (m, 1H), 1.87-1.85 (m, 3H). HRMS (ESI): m/z [M+H]+ calcd for C21H26N3O4SF2: 454.1606; found: 454.1588.
1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=12.0 Hz, 2H), 6.15 (brs, 1H), 4.81-4.75 (m, 1H), 4.45 (s, 2H), 3.98 (t, J=8.8 Hz, 1H), 3.74-3.63 (m, 3H), 3.56 (d, J=9.2 Hz, 2H), 2.92 (d, J=12.4 Hz, 2H), 2.20-2.17 (m, 2H), 2.03 (s, 3H), 1.89-1.83 (m, 2H). HRMS (ESI): m/z [M+H]+ calcd for C18H22N3O4SF2: 414.1293; found: 414.1275.
1H-NMR (300 MHz, CDCl3) δ: 7.39 (dd, J=15.8, 2.3 Hz, 1H), 7.03 (d, J=6.1 Hz, 2H), 6.78 (t, J=9.3 Hz, 1H), 4.72 (s, 1H), 4.55 (s, 2H), 3.94 (t, J=8.9 Hz, 1H), 3.81-3.66 (m, 1H), 3.58 (s, 2H), 3.42 (d, J=10.3 Hz, 2H), 2.77 (d, J=11.9 Hz, 2H), 2.17 (dd, J=25.1, 17.8 Hz, 4H), 1.84 (d, J=7.9 Hz, 2H), 1.56 (dd, J=14.5, 7.2 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H).
LC-MS (ESI): m/z=423.8 [M+H]+.
1H-NMR (300 MHz, DMSO-d6) δ: 12.17 (s, 1H), 8.69 (d, J=2.9 Hz, 1H), 8.20-8.03 (m, 1H), 7.44 (d, J=16.2 Hz, 1H), 7.28-7.02 (m, 2H), 5.08 (dd, J=8.5, 5.1 Hz, 1H), 4.68-4.52 (m, 4H), 4.20 (t, J=9.1 Hz, 1H), 3.91 (dd, J=8.7, 6.0 Hz, 1H), 3.56 (d, J=11.1 Hz, 2H), 2.48 (d, J=12.3 Hz, 2H), 2.06 (d, J=5.1 Hz, 2H), 1.79 (d, J=7.6 Hz, 2H).
LC-MS (ESI): m/z=405.8 [M+H]+.
1H-NMR (400 MHz, CDCl3) δ: 7.38 (d, J=14.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.55 (t, J=8.8 Hz, 1H), 4.72 (brs, 1H), 4.02 (s, 4H), 3.99-3.89 (m, 3H), 3.76-3.73 (m, 1H), 3.42 (s, 4H). 13C-NMR (100 MHz, CDCl3) δ: 154.8, 152.2 (d, J=240.8 Hz), 135.9 (d, J=11.7 Hz), 130.2 (d, J=9.3 Hz), 114.6 (d, J=5.2 Hz), 114.5 (d, J=3.1 Hz), 107.6 (d, J=23.8 Hz), 72.8, 66.8, 62.8, 46.7, 44.3, 36.8. HRMS (ESI): m/z [M+H]+ calcd for C15H18FN2O3S: 325.1022; found: 325.1010.
1H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J=14.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.48 (t, J=8.8 Hz, 1H), 6.20 (brs, 1H), 4.75-4.73 (m, 1H), 3.98-3.96 (m, 5H), 3.73-3.66 (m, 2H), 3.62-3.57 (m, 1H), 3.41 (s, 4H), 2.01 (s, 3H). HRMS (ESI): m/z [M+H]+ calcd for C17H21FN3O3S: 366.1288; found: 366.1274.
1H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1H), 7.75 (s, 1H), 7.22 (dd, J=13.6, 2.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.51 (t, J=9.2 Hz, 1H), 5.06-5.00 (m, 1H), 4.78-4.77 (m, 2H), 4.08 (t, J=9.2 Hz, 1H), 4.01 (s, 4H), 3.89-3.85 (m, 1H), 3.40 (s, 4H). 13C-NMR (100 MHz, CDCl3) δ: 153.6, 152.0 (d, J=243.1 Hz), 136.3 (d, J=11.1 Hz), 134.5, 129.1 (d, J=9.0 Hz), 125.1, 115.0 (d, J=3.2 Hz), 114.5 (d, J=5.2 Hz), 108.1 (d, J=23.6 Hz), 70.4, 66.7, 52.1, 47.7, 44.3, 36.8. HRMS (ESI): m/z [M+H]+ calcd for C17H19FN5O2S: 376.1244; found: 376.1231.
1H-NMR (400 MHz, CDCl3) δ: 7.03 (d, J=12.0 Hz, 2H), 4.74-4.70 (m, 1H), 4.18 (s, 4H), 3.98 (dd, J=12.8, 3.2 Hz, 1H), 3.93-3.85 (m, 2H), 3.75 (dd, J=12.4, 4.0 Hz, 1H), 3.41 (s, 4H). HRMS (ESI): m/z [M+H]+ calcd for C15H17N2O3SF2: 343.0922; found: 343.0912.
1H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J=11.6 Hz, 2H), 5.99 (brs, 1H), 4.74-4.72 (m, 1H), 4.16 (s, 4H), 3.94 (t, 0.1=8.8 Hz, 1H), 3.71-3.65 (m, 2H), 3.61-3.55 (m, 1H), 3.40 (s, 4H), 2.01 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.1, 154.2, 152.6 (dd, J=240.6, 11.1 Hz), 153.1, 134.5, 128.5 (t, J=12.6 Hz), 124.7 (t, J=13.3 Hz), 102.8 (dd, J=18.2, 10.7 Hz), 71.9, 68.7, 47.6, 45.2, 42.0, 36.5, 23.1. HRMS (ESI): m/z [M+H]+ calcd for C17H20N3O3SF2: 384.1188; found: 384.1168.
1H NMR (400 MHz, CDCl3) δ: 7.00 (d, J=11.6 Hz, 2H), 5.16 (brs, 1H), 4.81-4.67 (m, 1H), 4.16 (s, 4H), 3.94 (t, J=8.8 Hz, 1H), 3.68 (s, 3H), 3.56-3.50 (m, 3H), 3.40 (s, 4H). HRMS (ESI): m/z [M+H]+ calcd for C17H20F2N3O4S: 400.1143; found: 400.1125.
1H NMR (400 MHz, CDCl3) δ: 7.77 (s, 1H), 7.74 (s, 1H), 6.87 (d, J=11.6 Hz, 2H), 5.03-5.01 (m, 1H), 4.77-4.76 (m, 2H), 4.15 (s, 4H), 4.06 (t, J=9.2 Hz, 1H), 3.86-3.82 (m, 1H), 3.41 (s, 4H). HRMS (ESI): m/z [M+H]+ calcd for C17H8F2N5O2S: 394.1149; found: 394.1129.
1H NMR (400 MHz, CDCl3) δ: 6.98 (d, J=11.6 Hz, 2H), 6.25-6.24 (m, 1H), 4.77-4.71 (m, 1H), 4.16 (s, 4H), 3.92 (t, J=8.8 Hz, 1H), 3.71-3.56 (m, 3H), 3.40 (s, 4H), 1.40-1.38 (m, 1H), 1.04-0.87 (m, 2H), 0.82-0.73 (m, 2H). HRMS (ESI): m/z [M+H]+ calcd for C19H22F2N3O3S: 410.1350; found: 410.1331.
1H NMR (400 MHz, CDCl3) δ: 6.99 (d, J=11.6 Hz, 2H), 5.83 (brs, 1H), 4.82-4.68 (m, 1H), 4.17 (s, 4H), 3.93 (t, J=8.8 Hz, 1H), 3.72-3.64 (m, 3H), 3.40 (s, 4H), 3.03-2.96 (m, 1H), 2.26-1.85 (m, 6H). HRMS (ESI): m/z [M+H]+ calcd for C20H24F2N3O3S: 424.1506; found: 424.1483.
1H-NMR (400 MHz, CDCl3) δ: 7.42 (dd, J=14.0, 2.0 Hz, 1H), 7.03 (dd, J=8.8, 2.0 Hz, 1H), 6.62 (t, J=8.8 Hz, 1H), 4.85 (s, 4H), 4.73 (m, 1H), 4.17 (s, 4H), 4.00-3.95 (m, 2H), 3.93-3.89 (m, 1H), 3.77-3.74 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 155.2, 152.3 (d, J=240.7 Hz), 135.9 (d, J=11.3 Hz), 130.4 (d, J=8.9 Hz), 114.7 (d, J=3.0 Hz), 114.6 (d, J=5.6 Hz), 107.8 (d, J=23.8 Hz), 81.3, 73.2, 63.1, 62.9, 46.9, 40.1. HRMS (ESI): m/z [M+H]+ calcd for C15H18FN2O4: 309.1251; found: 309.1269.
1H-NMR (300 MHz, CDCl3) δ: 7.35 (d, J=14.1 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.51 (t, J=9.0 Hz, 1H), 6.03 (s, 1H), 4.84 (s, 4H), 4.74 (m, 1H), 4.12 (s, 4H), 3.99 (t, J=8.7 Hz, 1H), 3.73-3.69 (m, 2H), 3.61 (m, 1H), 2.02 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.4, 154.8, 152.4 (d, J=240.8 Hz), 136.1 (d, J=11.9 Hz), 130.1 (d, J=9.2 Hz), 114.7 (d, J=3.1 Hz), 114.6 (d, J=5.0 Hz), 107.9 (d, J=23.6 Hz), 81.2, 72.1, 63.1, 48.1, 42.2, 40.1, 23.4. HRMS (ESI): m/z [M+H]+ calcd for C17H21FN3O4: 350.1516; found: 350.1497.
1H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.75 (s, 1H), 7.18 (d, J=13.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.46 (t, J=9.2 Hz, 1H), 5.03 (m, 1H), 4.83 (s, 4H), 4.78 (m, 2H), 4.10-4.07 (m, 5H), 3.91-3.85 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 153.6, 152.1 (d, J=241.4 Hz), 136.1 (d, J=10.6 Hz), 134.5, 129.2 (d, J=9.3 Hz), 125.1, 115.0 (d, J=2.9 Hz), 114.5 (d, J=4.7 Hz), 108.1 (d, J=23.7 Hz), 81.0, 70.4, 62.9, 52.1, 47.7, 39.8. HRMS (ESI): m/z [M+H]+ calcd for C17H19FN5O3: 360.1472; found: 360.1451.
1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2H), 7.31 (d, J=14.4, 2.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.59 (t, J=9.2 Hz, 1H), 5.14-5.07 (m, 1H), 4.88-4.83 (m, 5H), 4.77-4.71 (m, 1H), 4.16 (s, 4H), 4.07-4.02 (m, 1H), 3.98-3.92 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 158.99, 154.38, 147.08, 144.53, 135.18, 115.11, 114.43, 112.30, 107.91, 107.87, 81.04, 71.85, 70.04, 62.91, 48.38, 48.02, 41.57, 39.85. HRMS (ESI): m/z [M+H]+ calcd for C17H19FN5O3: 360.1472; found: 360.1451.
1H-NMR (400 MHz, CDCl3) δ: 7.46 (s, 1H), 7.32 (dd, J=14.0, 2.4 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.81 (t, J=6.4 Hz, 1H), 6.51 (d, J=3.2 Hz, 1H), 6.45 (t, J=9.2 Hz, 1H), 4.83 (brs, 5H), 4.08 (s, 4H), 4.03 (t, J=8.8 Hz, 1H), 3.92-3.85 (m, 1H), 3.79-3.73 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 159.2, 154.6, 152.4 (d, J=240.8 Hz), 147.3, 144.7, 136.5, 130.5 (d, J=9.4 Hz), 115.3, 114.7 (d, J=3.1 Hz), 112.5, 109.9, 107.9 (d, J=23.9 Hz), 81.2, 72.1, 63.1, 48.2, 41.8, 40.1. HRMS (ESI): m/z [M+H]+ calcd for C20H21FN3O5: 402.1465; found: 402.1561.
1H-NMR (400 MHz, CDCl3) δ: 7.53 (d, J=3.2 Hz, 1H), 7.50 (d, 0.1=4.8 Hz, 1H), 7.32 (d, J=14.0 Hz, 1H), 7.09-6.96 (m, 2H), 6.66 (m, 1H), 6.45 (t, J=9.2 Hz, 1H), 4.82 (s, 4H), 4.09-4.01 (m, 6H), 3.81-3.79 (m, 1H), 3.78-3.73 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 162.9, 154.7, 152.5 (d, J=241.1 Hz), 150.1, 140.8, 138.1, 130.9, 128.9, 128.0, 114.9 (d, J=2.8 Hz), 114.2 (d, J=3.2 Hz), 108.1 (d, J=23.9 Hz), 81.20 72.2, 63.2, 48.3, 42.7, 40.0. HRMS (ESI): m/z [M+H]+ calcd for C20H21FN3O4S: 418.1237; found: 418.1331.
1H-NMR (400 MHz, CDCl3) δ: 7.44-7.35 (m, 1H), 7.07-6.97 (m, 1H), 6.69-6.59 (m, 1H), 4.98-4.91 (m, 1H), 4.85 (s, 4H), 4.81-4.75 (m, 1H), 4.24-4.14 (m, 4H), 4.13-4.09 (m, 1H), 4.06-3.98 (m, 1H), 3.92-3.86 (m, 1H), 3.63-3.53 (m, 1H), 3.47-3.36 (m, 1H), 3.03 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ: 154.5, 151.7 (d, J=237.7 Hz), 135.9 (d, J=11.0 Hz), 130.5 (d, J=9.4 Hz), 115.2 (d, J=5.4 Hz), 115.1 (d, J=2.8 Hz), 107.3 (d, J=23.8 Hz), 80.2, 71.7, 62.7, 47.6, 45.5. HRMS (ESI): m/z [M+H]+ calcd for C16H21FN3O5S: 386.1186; found: 386.1185.
1H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J=14.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.61 (t, 0.1=9.2 Hz, 1H), 5.11 (brs, 1H), 4.84 (s, 4H), 4.73 (brs, 1H), 4.16 (s, 4H), 3.99 (t, J=8.8 Hz, 1H), 3.77-3.75 (m, 1H), 3.68 (s, 3H), 3.64-3.60 (m, 1H), 3.55-3.50 (m, 1H). HRMS (ESI): m/z [M+H]+ calcd for C17H21FN3O5: 366.1465; found: 366.1466.
1H-NMR (400 MHz, CDCl3) δ: 7.35 (dd, J=14.0, 2.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.51 (t, J=9.2 Hz, 1H), 6.13 (brs, 1H), 4.84 (s, 4H), 4.75-4.73 (m, 1H), 4.12 (s, 4H), 3.97 (t, J=8.8 Hz, 1H), 3.75-3.65 (m, 3H), 1.39-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.79-0.75 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 174.8, 154.6, 151.6 (d, J=240.8 Hz), 136.0 (d, J=11.3 Hz), 129.8 (d, J=9.2 Hz), 114.5 (d, J=3.1 Hz), 114.6 (d, J=3.1 Hz), 114.3 (d, J=5.2 Hz), 107.8 (d, J=23.8 Hz), 81.1, 72.1, 62.9, 47.9, 42.0, 39.9, 14.6, 7.7. HRMS (ESI): m/z [M+H]+ calcd for C19H23FN3O4: 376.1673; found: 376.1652.
1H-NMR (400 MHz, CDCl3) δ: 7.49 (d, J=14.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.85 (t, J=9.2 Hz, 1H), 5.82 (brs, 1H), 4.86 (s, 4H), 4.76 (brs, 1H), 4.27 (s, 4H), 4.00 (t, J=9.2 Hz, 1H), 3.78-3.65 (m, 3H), 3.03-2.99 (m, 1H), 2.26-2.13 (m, 4H), 1.99-1.85 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 176.0, 154.5, 152.1 (d, J=240.9 Hz), 136.0 (d, J=11.2 Hz), 129.8 (d, J=9.2 Hz), 114.4 (d, J=3.1 Hz), 114.3 (d, J=5.2 Hz), 107.7 (d, J=23.9 Hz), 81.1, 71.9, 62.8, 47.9, 41.9, 39.7, 25.4, 25.3, 18.2. HRMS (ESI): m/z [M+H]+ calcd for C20H25FN3O4: 390.1829; found: 390.1808.
1H-NMR (400 MHz, CDCl3) δ: 7.03 (d, J=10.8 Hz, 2H), 4.82 (s, 4H), 4.72 (brs, 1H), 4.28 (s, 4H), 3.99-3.85 (m, 3H), 3.75-3.72 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 154.6, 152.6 (dd, J=240.2, 10.8 Hz), 128.9 (t, J=12.8 Hz), 124.3 (t, J=13.3 Hz), 102.8 (dd, J=18.2, 10.7 Hz), 81.0, 72.9, 64.9, 62.6, 46.3, 40.8. HRMS (ESI): m/z [M+H]+ calcd for C15H17F2N2O4: 327.1156; found: 327.1135.
1H-NMR (400 MHz, CDCl3) δ: 6.97 (d, J=10.0 Hz, 2H), 6.49 (brs, 1H), 4.81 (s, 4H), 4.75 (brs, 1H), 4.27 (s, 4H), 3.94 (t, J=8.8 Hz, 1H), 3.70-3.63 (m, 3H), 2.02 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 171.2, 154.2, 152.5 (dd, J=240.5, 10.9 Hz), 128.6 (t, J=12.6 Hz), 124.5 (t, J=13.4 Hz), 102.8 (dd, J=18.2, 10.6 Hz), 80.9, 71.9, 64.9, 47.5, 41.9, 40.8, 23.1. HRMS (ESI): m/z [M+H]+ calcd for C17H20F2N3O4: 368.1422; found: 368.1418.
1H-NMR (400 MHz, CDCl3) δ: 7.04 (d, J=10.8 Hz, 2H), 5.08 (brs, 1H), 4.83 (s, 4H), 4.74 (brs, 1H), 4.34 (s, 4H), 3.96 (t, J=9.2 Hz, 1H), 3.72-3.51 (m, 6H). 13C-NMR (100 MHz, CDCl3) δ: 157.5, 154.0, 152.6 (dd, J=240.4, 10.9 Hz), 128.7 (t, J=12.8 Hz), 124.5 (t, J=13.5 Hz), 102.8 (dd, J=23.3, 15.7 Hz), 80.9, 71.7, 64.8, 52.6, 47.4, 43.6, 40.8. HRMS (ESI): m/z [M+H]+ calcd for C17H20F2N3O5: 384.1371; found: 384.1367.
1H-NMR (400 MHz, DMSO-d6) δ: 7.8 (d, J=12.4 Hz, 2H), 4.74-4.69 (m, 5H), 4.23 (s, 4H), 4.06 (t, J=8.8 Hz, 1H), 3.74-3.70 (m, 1H), 3.31-3.27 (m, 2H), 2.94 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ: 154.3, 152.2 (dd, J=237.8, 11.3 Hz), 129.5 (t, J=13.0 Hz), 124.4 (t, J=13.6 Hz), 102.9 (dd, J=18.2, 10.5 Hz), 80.0, 71.8, 64.7, 47.4, 45.5, 40.7. HRMS (ESI): m/z [M+H]+ calcd for C16H20F2N3O5S: 404.1092; found: 404.1087.
1H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J=10.0 Hz, 2H), 6.36 (brs, 1H), 4.82 (s, 4H), 4.75 (brs, 1H), 4.28 (s, 4H), 3.93 (t, J=8.8 Hz, 1H), 3.72-3.65 (m, 3H), 1.42-1.40 (m, 1H), 0.96-0.88 (m, 2H), 0.77-0.75 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 174.9, 154.4, 152.5 (dd, J=240.4, 10.3 Hz), 128.6 (t, J=12.7 Hz), 124.4 (t, J=13.4 Hz), 102.8 (dd, J=18.2, 10.6 Hz), 80.9, 72.2, 64.8, 47.6, 41.9, 40.8, 14.5, 7.7. HRMS (ESI): m/z [M+H]+ calcd for C19H22F2N3O4: 394.1578; found: 394.1575.
1H-NMR (400 MHz, CDCl3) δ: 7.77 (s, 1H), 7.75 (s, 1H), 6.86 (d, J=11.6 Hz, 2H), 5.03-5.02 (m, 1H), 4.81 (s, 4H), 4.77-4.76 (m, 2H), 4.27 (s, 4H), 4.06 (t, J=9.2 Hz, 1H), 3.86-3.82 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 153.2, 152.4 (dd, J=240.7, 11.0 Hz), 134.5, 127.8 (t, J=12.8 Hz), 125.1, 124.8 (t, J=13.3 Hz), 103.1 (dd, J=18.1, 10.7 Hz), 80.9, 70.4, 64.8, 52.0, 47.3, 40.8. HRMS (ESI): m/z [M+H]+ calcd for C17H18F2N5O3: 378.1378; found: 378.1365.
1H-NMR (400 MHz, CDCl3) δ: 7.00 (d, J=12.0 Hz, 2H), 5.87 (t, J=6.0 Hz, 1H), 4.82 (s, 4H), 4.77-4.71 (m, 1H), 4.28 (s, 4H), 3.94 (t, J=8.8 Hz, 1H), 3.72-3.64 (m, 3H), 3.03-2.99 (m, 1H), 2.26-2.13 (m, 4H), 1.99-1.82 (m, 2H). HRMS (ESI): m/z [M+H]+ calcd for C20H24F2N3O4: 408.1735; found: 408.1716.
1H-NMR (400 MHz, CDCl3) δ: 7.38 (d, J=14.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.58 (t, J=9.2 Hz, 1H), 4.76 (m, 2H), 4.30 (s, 4H), 4.10 (s, 4H), 3.76 (m, 1H), 3.54 (m, 2H), 1.96 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 172.6, 155.4, 153.2, 150.8, 135.6, 130.5, 114.4, 107.3, 72.0, 62.2, 55.0, 48.0, 41.7, 37.2, 21.0. HRMS (ESI): m/z [M+H]+ calcd for C17H22FN4O3: 349.1671; found: 349.1662.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J=14.4 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.57 (t, J=9.2 Hz, 1H), 4.75 (m, 1H), 4.10 (t, J=9.2 Hz, 1H), 4.01 (s, 4H), 3.74 (m, 1H), 3.73 (s, 4H), 3.53 (m, 2H), 2.52 (s, 3H), 1.96 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.6, 155.4, 153.2, 150.8, 136.1, 130.3, 114.4, 107.3, 72.0, 64.9, 62.6, 48.0, 43.0, 41.7, 34.8, 21.0. HRMS (ESI): m/z [M+H]+ calcd for C18H24FN4O3: 363.1827, found: 363.1819.
1H-NMR (400 MHz, CD3OD) δ: 7.12 (d, J=9.6 Hz, 2H), 4.76, (m, 1H), 4.30 (s, 4H), 4.24 (s, 4H), 4.06 (m, 1H), 3.73 (m, 1H), 3.53 (m, 2H), 1.96 (s, 3H). 13C NMR (100 MHz, CD3OD) δ: 172.6, 155.0, 153.7, 151.3, 129.6, 129.4, 102.7, 102.5, 72.0, 64.3, 55.0, 48.0, 41.6, 38.3, 21.0. HRMS (ESI): m/z [M+H]+ calcd for C17H21F2N4O3: 367.1583, found: 367.1576.
1H-NMR (400 MHz, CD3OD) δ: 7.12 (d, J=10.0 Hz, 2H), 4.75 (m, 1H), 4.22 (s, 4H), 4.05 (m, 1H), 3.78 (s, 4H), 3.73 (m, 1H), 3.53 (m, 2H), 2.55 (s, 3H), 1.96 (s, 3H). 13C-NMR (100 MHz, CD3OD) δ: 172.6, 155.0, 153.7, 151.3, 129.4, 102.8, 72.0, 64.7, 64.6, 48.0, 42.7, 41.7, 22.4, 21.0. HRMS (ESI): m/z [M+H]+ calcd for C18H23F2N4O3: 381.1733, found: 381.1725.
To a solution of tetrahydrothiopyran-4-one (100 g, 862 mmol) in Et2O (150 mL) was added BF3-Et2O (120 mL, 948 mmol) at −30° C., then the reaction mixture was stirred at −30° C. for 2 h under a nitrogen gas atmosphere, after that the solution of ethyl 2-diazoacetate (147 g, 1293 mmol) in Et2O (100 mL) was added to the mixture at −30° C., then the mixture was warmed to room temperature and stirred for overnight. Quenched with K2CO3, the solvent was concentrated and dried to give ethyl 5-oxothiepane-4-carboxylate (2) (80 g, 46%) as brown oil.
A mixture of ethyl 5-oxothiepane-4-carboxylate (2) (80 g, 396 mmol) and lithium chloride (16.6 g, 396 mmol) in DMSO (100 mL) and H2O (5 drop) was stirred at 180° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, extracted with EA, the organic layer was concentrated under reduced pressure to afford thiepan-4-one (3) (15.9 g crude, 31%) as brown solid.
To a solution of thiepan-4-one (3) (15.9 g, 122 mmol) in EtOH (150 mL) and H2O (50 mL) was added with NH2OH—HCl (8.47 g, 122 mmol), then the reaction mixture was stirred at 75° C. for 4 h under a nitrogen gas atmosphere, then mixture was concentrated and dried to give (Z)-thiepan-4-one oxime (4) (9.97 g, 56%) as brown solid.
A mixture of (Z)-thiepan-4-one oxime (4) (9.97 g, 68.7 mmol) and polyphosphoric acid (50 g) was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, adjusted pH=8 using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to afford 1,5-thiazocan-4-one (5) (3 g crude, 30%) as brown solid.
To a solution of 1,5-thiazocan-4-one (5) (3 g, 20.7 mmol) in THF (100 mL) was added BH3 (31 mL, 31.1 mmol) in THF at 0° C., followed by refluxing for 12 h. The reaction was quenched with CH3OH (50 mL). The solvent was evaporated to afford 1,5-thiazocane (6) as a white oil (1.7 g, 63%), and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=132 [M+H]+.
To a solution of 1,5-thiazocane (6) (1 g, 7.6 mmol) and 1,2-difluoro-4-nitrobenzene (1.2 g, 7.6 mmol) in DMF (10 mL) was added K2CO3 (1.05 g, 7.6 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.5 g, 74%) as a yellow solid. LC-MS (ESI) m z=271 [M+H]+.
To a solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.5 g, 5.7 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3-fluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.2 g, 91%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=241 [M+H]+.
Benzyl carbonochloridate (1.76 g, 10.4 mmol) was added to a suspension of 3-fluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.2 g, 5.2 mmol) and triethylamine (1.05 g, 10.4 mmol) in DCM (200 mL) at −20° C. under a nitrogen gas atmosphere, then reaction mixture was stirred at 0° C. for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (740 mg, 38%) as a white solid.
LC-MS (ESI) m/z=375 [M+H]+.
To a solution of benzyl 3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (740 mg, 1.97 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (1.3 ml, 2.96 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (427 mg, 2.96 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford
(11) (382 mg, 57%) as a white solid.
LC-MS (ESI) m/z=341 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (418 mg, 2.2 mmol) was added to a suspension of (R)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (11) (382 mg, 1.1 mmol) and Et3N (222 mg, 2.2 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (407 mg, 75%) as a white solid.
LC-MS (ESI) m/z=495 [M+H]+.
To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,3-triazole (56 mg, 0.8 mmol) in DMF (5 mL) was added K2CO3 (110 mg, 0.8 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=2:1) to afford (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (OBD-001) (70 mg, 45%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.76 (d, J=17.6 Hz, 2H), 7.41-7.09 (m, 1H), 7.11-6.73 (m, 2H), 5.04 (d, J=3.0 Hz, 1H), 4.78 (d, J=3.4 Hz, 2H), 4.12 (t, J=9.2 Hz, 1H), 3.88 (dd, J=9.2, 6.1 Hz, 1H), 3.36 (t, J=6.0 Hz, 3H), 2.92-2.59 (m, 4H), 2.01 (dd, J=27.9, 7.3 Hz, 4H).
LC-MS (ESI) m/z=391.9 [M+H]+.
To a solution of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (OBD-001) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (80 mg, 0.13 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-002) (22 mg, 41%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.92-7.67 (m, 2H), 7.32 (d, J=16.8 Hz, 1H), 7.12 (t, J=9.0 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 5.07 (s, 1H), 4.81 (d, J=4.0 Hz, 2H), 4.15 (t, J=9.0 Hz, 1H), 4.01-3.83 (m, 1H), 3.32 (d, J=14.2 Hz, 5H), 3.11-2.87 (m, 2H), 2.59 (s, 2H), 2.19 (s, 4H).
LC-MS (ESI) m/z=407.8 [M+H]+.
To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,4-triazole (56 mg, 0.8 mmol) in DMF (5 mL) was added K2CO3 (110 mg, 0.8 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=2:1) to afford (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (OBD-008) (84 mg, 54%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 8.24 (s, 1H), 7.97 (s, 1H), 7.00 (s, 2H), 5.12-4.91 (m, 1H), 4.56 (d, J=4.7 Hz, 2H), 4.24-3.83 (m, 2H), 3.38 (t, J=6.0 Hz, 4H), 2.95-2.59 (m, 4H), 1.98 (s, 5H).
LC-MS (ESI) m/z=391.9 [M+H]+.
To a solution of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (OBD-008) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (80 mg, 0.13 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-009) (22 mg, 41%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 8.24 (s, 1H), 7.93 (s, 1H), 7.41-7.20 (m, 1H), 7.19-6.92 (m, 2H), 5.10-4.92 (m, 1H), 4.56 (d, J=4.7 Hz, 2H), 4.12 (t, J=9.0 Hz, 1H), 3.97 (dd, J=9.2, 6.2 Hz, 1H), 3.28 (dd, J=13.0, 6.9 Hz, 2H), 3.12 (dd, J=12.5, 5.9 Hz, 4H), 3.02-2.83 (m, 2H), 2.22-1.99 (m, 5H), 1.26 (d, J=9.4 Hz, 4H).
LC-MS (ESI) m z=407.8 [M+H]+.
To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (800 mg, 1.62 mmol) and sodium azide (105 mg, 1.62 mmol) in DMF (10 mL) was added K2CO3 (447 g, 3.24 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13) (470 mg, 80%) as a white solid.
LC-MS (ESI) m/z=366 [M+H]+.
To a solution of (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13) (470 mg, 1.3 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14) (374 mg, 85%) as a white solid.
LC-MS (EST) m/z=340 [M+H]+.
To a solution of (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14) (374 mg, 1.1 mmol) and butyric acid (97 mg, 1.1 mmol) in DCM (10 mL) were added HOBt (223 mg, 1.65 mmol), EDCI (420 mg, 2.2 mmol) and DIPEA (284 mg, 2.2 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (S)—N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)buty ramide (OBD-003) (252 mg, 56%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 7.50 (s, 2H), 7.03 (d, J=6.1 Hz, 1H), 5.99 (s, 1H), 4.77 (d, J=5.7 Hz, 1H), 4.02 (t, J=9.0 Hz, 2H), 3.70 (ddd, J=20.7, 15.2, 7.7 Hz, 4H), 3.48 (s, 4H), 2.95-2.68 (m, 4H), 2.20 (t, J=7.2 Hz, 3H), 2.06 (d, J=6.1 Hz, 4H), 1.64 (dd, J=14.8, 7.4 Hz, 4H), 0.91 (t, J=7.4 Hz, 4H). LC-MS (ESI) m/z=409.9 [M+H]+.
To a solution of (S)—N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)buty ramide (OBD-003) (150 mg, 0.37 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (225 mg, 0.37 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-004) (48 mg, 31%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.44 (dd, J=14.7, 2.4 Hz, 1H), 7.19-6.99 (m, 2H), 6.44 (s, 1H), 4.84-4.71 (m, 1H), 4.02 (t, J=8.9 Hz, 1H), 3.78 (dd, J=9.0, 6.6 Hz, 1H), 3.66 (t, J=4.6 Hz, 2H), 3.38-3.09 (m, 6H), 2.99 (dd, J=12.6, 6.3 Hz, 2H), 2.20 (dd, J=9.4, 5.3 Hz, 6H), 1.71-1.56 (m, 2H), 0.91 (dd, J=9.6, 5.1 Hz, 3H).
LC-MS (ESI) m z=425.8 [M+H]+.
To a solution of 1,5-thiazocane (6) (1 μg, 7.6 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1.35 g, 7.6 mmol) in DMF (10 mL) was added K2CO3 (2.1 g, 15.2 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.64 g, 75%) as a yellow solid.
LC-MS (ESI) m/z=289 [M+H].
To a solution of 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.64 g, 5.7 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.4 g, 94%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=259 [M+H]+.
Benzyl carbonochloridate (1.87 g, 10.6 mmol) was added to a suspension of 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.4 μg, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in DCM (200 mL) at −20° C. under a nitrogen gas atmosphere, then reaction mixture was stirred at 0° C. for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 3,5-difluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (872 mg, 42%) as a white solid.
LC-MS (ESI) m/z=393 [M+H].
To a solution of benzyl 3,5-difluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (872 mg, 2.23 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (1.4 ml, 3.34 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (480 mg, 3.34 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (11) (519 mg, 65%) as a white solid.
LC-MS (ESI) m/z=359 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (550 mg, 2.9 mmol) was added to a suspension of (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (11) (519 mg, 1.45 mmol) and Et3N (292 mg, 2.9 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (594 mg, 80%) as a white solid.
LC-MS (ESI) m/z=513 [M+H]+.
To a solution of (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (594 g, 1.2 mmol) and sodium azide (75 mg, 1.2 mmol) in DMF (10 mL) was added K2CO3 (160 mg, 2.4 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13) (400 mg, 87%) as a white solid.
LC-MS (ESI) m/z=384 [M+H]+.
To a solution of (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13) (400 g, 1.04 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14) (331 g, 89%) as a white solid.
LC-MS (ESI) m/z=358 [M+H].
To a solution of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol) and DIPEA (118 mg, 0.92 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (S)—N-((3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl) butyramide (OBD-026) (82 mg, 42%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.14 (d, J=11.1 Hz, 1H), 5.93 (s, 1H), 4.81 (s, 1H), 4.02 (t, J=8.9 Hz, 1H), 3.70 (s, 2H), 3.31 (s, 3H), 2.87 (s, 2H), 2.22 (s, 2H), 1.90 (s, 5H), 1.66 (d, J=7.3 Hz, 2H), 0.93 (t, J=7.4 Hz, 2H).
LC-MS (ESI) m/z=428 [M+H]+.
To a solution of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol) and DIPEA (118 mg, 0.92 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford N—(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-027) (82 mg, 45%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.23-6.85 (m, 2H), 6.00 (s, 1H), 4.90-4.66 (m, 1H), 4.17-3.86 (m, 1H), 3.71 (s, 2H), 3.28 (s, 2H), 2.84 (s, 3H), 2.04 (s, 3H), 1.88 (s, 5H).
LC-MS (ESI) m/z=400 [M+H]+.
The synthesis route:
To a solution of tetrahydrothiopyran-4-one (20 g, 172 mmol) in EtOH (150 mL) and H2O (50 mL) was added with NH2OH—HCl (11.9 g, 172 mmol), then the reaction mixture was stirred at 75° C. for 4 h under a nitrogen gas atmosphere, then mixture was concentrated and dried to give tetrahydrothiopyran-4-one oxime (2) (14.7 g, 66%) as brown solid.
A mixture of tetrahydrothiopyran-4-one oxime (2) (14.7 g, 112 mmol) and polyphosphoric acid (50 g) was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, adjusted pH=8 using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to afford 1,4-thiazepan-5-one (3) (11.9 g crude, 81%) as brown solid.
To a solution of 1,4-thiazepan-5-one (3) (11.9 g, 105 mmol) in THF (100 mL) was added BH3 (158 mL, 158 mol) in THF at 0° C., followed by refluxing for 12 h. The reaction was quenched with CH3OH (50 mL). The solvent was evaporated to afford 1,4-thiazepane (4) as a white oil (10.7 g, 87%), and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=118 [M+H]+.
To a solution of 1,4-thiazepane (4) (7 g, 59.8 mmol) and 1,2-difluoro-4-nitrobenzene (10.4 g, 65.8 mmol) in DMF (10 mL) was added K2CO3 (16.5 g, 119.6 mmol) at 25° C. and then reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6) (10 g, 65%) as a yellow solid.
LC-MS (ESI) m/z=257 [M+H]+.
To a solution of 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6) (8 g, 31.2 mmol) and Palladium carbon (500 mg) in MeOH (15 mL), then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3-fluoro-4-(1,4-thiazepan-4-yl)benzenamine (7) (6.4 g, 93%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=227 [M+H]+.
Benzyl carbonochloridate (9.6 g, 56.6 mmol) was added to a suspension of 3-fluoro-4-(1,4-thiazepan-4-yl)benzenamine (7) (6.4 μg, 28.3 mmol) and triethylamine (5.7 g, 56.6 mmol) in DCM (200 mL) at −20° C. under a nitrogen gas atmosphere, then reaction mixture was stirred at 0° C. for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate (8) (2.34 g, 23%) as a white oil.
LC-MS (ESI) m/z=361 [M+H]+.
To a solution of benzyl 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate (8) (2.34 g, 6.5 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (4 ml, 9.7 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1.4 g, 9.7 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (9) (1.16 g, 55%) as a white solid.
LC-MS (ESI) m/z=327 [M+H]+.
4-Methylbenzene-1-sulfonyl chloride (1.4 g, 7.2 mmol) was added to a suspension of (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (9) (1.16 g, 3.6 mmol) and Et3N (727 mg, 7.2 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (10) (1.41 g, 41%) as a white solid.
LC-MS (ESI) m/z=481 [M+H]+.
To a solution of (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (10) (1.41 g, 2.95 mmol) and sodium azide (190 mg, 2.95 mmol) in DMF (10 mL) was added K2CO3 (814 g, 5.9 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (11) (830 mg, 80%) as a white solid.
LC-MS (ESI) m/z=352 [M+H]+.
To a solution of (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (11) (830 mg, 2.4 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (12) (654 mg, 85%) as a white solid.
LC-MS (ESI) m/z=326 [M+H]+.
To a solution of (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (12) (654 mg, 2 mmol) and butyric acid (177 mg, 2 mmol) in DCM (10 mL) were added HOBt (405 mg, 3 mmol), EDCI (764 mg, 4 mmol) and DIPEA (516 mg, 4 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (S)—N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)buty ramide (OBD-005) (286 mg, 34%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 7.42-7.23 (m, 2H), 7.01 (dd, J=8.9, 2.3 Hz, 1H), 6.04 (s, 1H), 4.75 (ddd, J=9.0, 7.9, 4.6 Hz, 1H), 4.00 (t, J=9.0 Hz, 1H), 3.79-3.05 (m, 7H), 2.91 (dd, J=16.2, 10.1 Hz, 2H), 2.70 (t, J=6.3 Hz, 2H), 2.28-2.13 (m, 2H), 2.13-1.97 (m, 2H), 1.82-1.25 (m, 3H), 0.92 (t, J=7.4 Hz, 3H), 0.01 (s, 1H).
LC-MS (ESI) m/z=395.9 [M+H]+.
To a solution of (S)—N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)buty ramide (OBD-005) (150 mg, 0.38 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (233 mg, 0.38 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-006) (50 mg, 32%) as a white solid and (OBD-007) (24 mg, 15%) as a white solid.
(OBD-006)
1H NMR (301 MHz, CDCl3) δ 7.52 (d, J=15.0 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 5.99 (s, 1H), 4.78 (s, 1H), 4.02 (t, J=8.8 Hz, 2H), 3.88-3.56 (m, 3H), 3.55-2.92 (m, 7H), 2.77 (s, 1H), 2.20 (t, J=7.1 Hz, 3H), 1.64 (dd, J=14.9, 7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).
LC-MS (ESI) m/z=411.8 [M+H]+.
(OBD-007)
1H NMR (301 MHz, CDCl3) δ 7.51 (d, J=14.7 Hz, 1H), 7.10 (d, J=9.9 Hz, 2H), 5.92 (s, 1H), 4.78 (s, 1H), 4.03 (t, J=9.0 Hz, 1H), 3.87-3.39 (m, 7H), 3.27 (d, J=5.7 Hz, 2H), 2.39 (d, J=6.2 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H), 1.64 (dd, J=14.8, 7.4 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H).
LC-MS (ESI) m/z=427.8 [M+H]+.
The mixture of (2R,5S)-diethyl 2,5-dibromohexanedioate (1) (100 g, 278 mmol), BnNH2 (44.6 g, 416 mmol) and K2CO3 (76.84 g, 556 mmol) in toluene/H2O was stirred at 110° C. for overnight, monitored by TLC. The mixture was extracted with EtOAc, washed with water and brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 75%) as a white oil.
LC-MS (ESI) m/z=306 [M+H]+.
To a solution of (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 209 mmol) and Palladium carbon (2 g) in MeOH (15 mL) was added CH3COOH (5 mL), then the reaction mixture was stirred at 50° C. under a hydrogen gas atmosphere, 4 atm for 5 h, monitored by TLC. The filter was concentrated under reduced pressure, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=216 [M+H]+.
To a solution of (2S,5R)-diethyl pyrrolidine-2,5-dicarboxylate (3) (62 g, 288 mmol) and Et3N (58 g, 577 mmol) in DCM (100 mL) was added benzyl carbonochloridate (98 g, 577 mmol) at −20° C. under a nitrogen gas atmosphere, then the reaction mixture was stirred at rt for 5 h, monitored by TLC. The mixture was extracted with DCM, washed with water and brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-1-benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (4) (80 g, 80%) as a white oil.
LC-MS (ESI) m/z=350 [M+H]+.
CaCl2 (76 g, 688 mmol) and NaBH4 (43 g, 1146 mmol) were added to a stirred solution of (2S,5R)-1-benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (4) (80 g, 229 mmol) in EtOH-MeOH (9:1; 200 mL) at rt under a nitrogen gas atmosphere, then the reaction mixture was stirred for 5 h, monitored by TLC. H2O (5 mL) was added, and the mixture was stirred for a further 15 min. The mixture was then concentrated in vacuo. The mixture was extracted with EtOAc, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-benzyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (5) (32 g, 52%) as a white oil.
LC-MS (ESI) m/z=266 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (92 g, 483 mmol) was added to a stirred solution of (2S,5R)-benzyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (5) (32 g, 121 mmol) and Et3N in DCM (200 mL) at 0° C. under a nitrogen gas atmosphere, then the reaction mixture was allowed to warm to room temperature and stirred for 5 h, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=2:1) to afford (2S,5R)-benzyl 2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate (6) (30 g, 43%) as a white solid.
LC-MS (ESI) m/z=574 [M+H]+.
Sodium sulfide hydrate (38 g, 157 mmol) was added to a stirred solution of (2S,5R)-benzyl 2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate (6) (30 g, 50 mmol) in EtOH (50 mL) and water (50 mL) at room temperature, then the reaction mixture was stirred at 90° C. for 2 h, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford 8-benzyl-3-thia-8-aza-bicyclo[3.2.1]octane-1-carboxylate (7) (10 g, 73%) as a white solid.
LC-MS (ESI) m/z=264 [M+H]+.
Iodotrimethylsilane (15 g, 75 mmol) was added to a stirred solution of 8-benzyl-3-thia-8-aza-bicyclo[3.2.1]octane-1-carboxylate (7) (10 g, 38 mmol) in DCM (200 mL) at 0° C. under a nitrogen gas atmosphere, then the reaction mixture was allowed to warm to room temperature and stirred for 30 min, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=15:1) to afford 3-thia-8-aza-bicyclo[3.2.1]octane hydrogen iodide (8) (8.13 g, 84%) as a brown solid.
LC-MS (ESI) m/z=130 [M+H]+
To a solution of 3-thia-8-aza-bicyclo[3.2.1]octane hydrogen iodide (8) (5.58 g, 21.7 mmol) and 1,2-difluoro-4-nitrobenzene (3.8 g, 23.8 mmol) in DMF (10 mL) was added K2CO3 (6 g, 43.4 mmol) at 25° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 80° C. for 2 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 8-(2-fluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3.2.1]octane (10) (4.89 g, 84%) as a yellow solid.
LC-MS (ESI) m/z=269 [M+H]+.
To a solution of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3.2.1]octane (10) (4.89 g, 18.2 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorobenzenamine (11) (4.08 g, 94%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=239 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (6.38 g, 25.6 mmol) was added to a suspension of 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorobenzenamine (11) (4.08 g, 17.1 mmol) in THF (30 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate (12) (4.34 μg, 68%) as a white solid.
LC-MS (ESI) m/z=373 [M+H]+.
To a solution of benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate (12) (4.34 g, 11.6 mmol) in THF (10 mL) at 78° C. under a nitrogen gas atmosphere was added n-BuLi (7.3 ml, 17.5 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (2.5 g, 17.4 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]Octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (3.03 g, 77%) as a white solid.
LC-MS (ESI) m/z=339 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (3.41 g, 17.9 mmol) was added to a suspension of (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl oxazolidin-2-one (13) (3.03 g, 8.9 mmol) and Et3N (1.8 g, 17.9 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (14) (3.74 g, 85%) as a white solid.
LC-MS (ESI) m z=493 [M+H]+.
To a solution of ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (14) (500 mg, 1 mmol) and 1H-1,2,4-triazole (140 mg, 2 mmol) in DMF (10 mL) was added K2CO3 (280 mg, 2 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=2:1) to afford (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidin-2-one (OBD-021) (177 mg, 45%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.01 (s, 1H), 7.36 (dd, J=15.8, 2.1 Hz, 1H), 7.18-6.92 (m, 2H), 5.06 (dd, J=8.9, 4.8 Hz, 1H), 4.72-4.52 (m, 2H), 4.36 (s, 2H), 4.17 (t, J=9.1 Hz, 1H), 3.84 (dt, J=49.3, 24.7 Hz, 1H), 3.12 (d, J=12.8 Hz, 2H), 2.16 (s, 1H), 2.11 (s, 1H), 2.04 (s, 4H).
LC-MS (ESI) m/z=390 [M+H]+.
To a solution of (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidin-2-one (OBD-021) (100 mg, 0.26 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (157 mg, 0.26 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-018) (52 mg, 50%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.69 (d, J=2.9 Hz, 1H), 8.20-8.03 (m, 1H), 7.44 (d, J=16.2 Hz, 1H), 7.28-7.02 (m, 2H), 5.08 (dd, J=8.5, 5.1 Hz, 1H), 4.68-4.52 (m, 4H), 4.20 (t, J=9.1 Hz, 1H), 3.91 (dd, J=8.7, 6.0 Hz, 1H), 3.56 (d, J=11.1 Hz, 2H), 2.48 (d, J=12.3 Hz, 2H), 2.06 (d, J=5.1 Hz, 2H), 1.79 (d, J=7.6 Hz, 2H).
LC-MS (ESI) m z=405.8 [M+H]+.
To a solution of ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (14) (2 g, 4 mmol) and sodium azide (265 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (1.1 g, 8 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one (15) (1.01 g, 70%) as a white solid.
LC-MS (ESI) m/z=364 [M+H]+.
To a solution of (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one (15) (1.01 g, 2.8 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-081) (800 mg, 85%) as a white solid.
LC-MS (ESI) m/z=338 [M+H]+.
To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-081) (200 mg, 0.59 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol) and DIPEA (115 mg, 0.88 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford N—(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-016) (156 mg, 65%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.42 (d, J=16.0 Hz, 1H), 7.35-6.88 (m, 2H), 4.71 (s, 1H), 4.35 (s, 2H), 4.07 (t, J=8.7 Hz, 1H), 3.77-3.57 (m, 1H), 3.51-3.27 (m, 2H), 3.12 (d, J=12.4 Hz, 2H), 2.09 (dd, J=20.9, 12.2 Hz, 8H), 1.47 (dd, J=14.0, 7.1 Hz, 2H), 0.80 (dd, J=8.0, 6.7 Hz, 3H).
LC-MS (ESI) m/z=407.9 [M+H]+.
To a solution of N—(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-016) (100 mg, 0.25 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (157 mg, 0.26 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-017) (16 mg, 15%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.39 (dd, J=15.8, 2.3 Hz, 1H), 7.03 (d, J=6.1 Hz, 2H), 6.78 (t, J=9.3 Hz, 1H), 4.72 (s, 1H), 4.55 (s, 2H), 3.94 (t, J=8.9 Hz, 1H), 3.81-3.66 (m, 1H), 3.58 (s, 2H), 3.42 (d, J=10.3 Hz, 2H), 2.77 (d, J=11.9 Hz, 2H), 2.17 (dd, J=25.1, 17.8 Hz, 4H), 1.84 (d, J=7.9 Hz, 2H), 1.56 (dq, J=14.5, 7.2 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H).
LC-MS (ESI) m/z=423.8 [M+H]+.
To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-081) (100 mg, 0.29 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (182 mg, 0.29 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-085) (28 mg, 28%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=16.4, 2.2 Hz, 1H), 7.24 (dd, J=8.9, 2.0 Hz, 1H), 7.13 (t, J=9.6 Hz, 1H), 4.58 (dd, J=14.1, 4.9 Hz, 3H), 4.04 (t, J=8.9 Hz, 1H), 3.84 (dd, J=8.7, 6.5 Hz, 1H), 3.56 (d, J=10.0 Hz, 2H), 2.81 (dd, J=9.3, 4.9 Hz, 2H), 2.46 (s, 2H), 2.17-1.99 (m, 2H), 1.79 (dd, J=17.3, 9.5 Hz, 4H).
LC-MS (ESI) m/z=354 [M+H]+.
To a solution of 3-thia-8-aza-bicyclo[3.2.1]octane hydrogen iodide (8) (5.0 g, 19.4 mmol) and 1,2,3-trifluoro-5-nitrobenzene (4.13 g, 23.3 mmol) in DMF (10 mL) was added K2CO3 (5.35 g, 38.8 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 8-(2,6-difluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3.2.1]octane (10) (3.6 g, 65%) as a yellow solid.
LC-MS (ESI) m/z=287 [M+H]+.
To a solution of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3.2.1]octane (10) (3.6 g, 12.5 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzenamine (11) (2.9 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=257 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (5.57 g, 22.4 mmol) was added to a suspension of 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzenamine (11) (2.9 g, 11.2 mmol) in THF (30 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate (12) (3.0 g, 68%) as a white solid.
LC-MS (ESI) m/z=391 [M+H]+.
To a solution of benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate (12) (3.0 g, 7.7 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (4.8 ml, 11.5 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1.66 g, 11.5 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (2.3 g, 84%) as a white solid.
LC-MS (ESI) m/z=357 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (2.45 g, 13 mmol) was added to a suspension of (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (2.3 g, 6.5 mmol) and Et3N (1.3 g, 13 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (14) (2.81 g, 85%) as a white solid.
LC-MS (ESI) m/z=511 [M+H]+.
To a solution of ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (14) (2.81 g, 5.52 mmol) and sodium azide (360 mg, 5.52 mmol) in DMF (10 mL) was added K2CO3 (1.52 mg, 11.04 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (15) (1.85 g, 88%) as a white solid.
LC-MS (ESI) m/z=382 [M+H]+.
To a solution of (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (15) (1.85 g, 4.87 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-083) (1.6 g, 90%) as a white solid.
1H NMR (400 MHz, DMSO) δ 7.34-7.15 (m, 2H), 4.59 (td, J=11.0, 5.0 Hz, 1H), 4.10 (s, 2H), 3.99 (t, J=8.9 Hz, 1H), 3.79 (dd, J=8.9, 6.4 Hz, 1H), 3.11 (dd, J=12.6, 1.6 Hz, 2H), 2.79 (qd, J=13.7, 4.9 Hz, 2H), 2.26 (dd, J=12.4, 3.3 Hz, 2H), 2.01 (s, 4H), 1.72 (d, J=59.8 Hz, 2H).
LC-MS (ESI) m/z=356 [M+H]+.
To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-083) (100 mg, 0.28 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (173 mg, 0.28 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-087) (31 mg, 30%) as a white solid.
1H NMR (400 MHz, DMSO) δ 7.32 (t, J=9.4 Hz, 2H), 4.61 (dd, J=8.8, 6.0 Hz, 0H), 4.34 (s, 1H), 4.02 (t, J=8.9 Hz, 1H), 3.82 (dd, J=8.9, 6.4 Hz, 1H), 3.68 (dd, J=12.4, 3.7 Hz, 1H), 2.81 (qd, J=13.7, 4.9 Hz, 1H), 2.58 (d, J=11.6 Hz, 1H), 2.12-1.98 (m, 1H), 1.78 (q, J=6.9 Hz, 2H).
LC-MS (ESI) m/z=372 [M+H]+.
To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-083) (200 mg, 0.56 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol) and DIPEA (115 mg, 0.88 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford N—(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-029) (119 mg, 50%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.22 (d, J=12.2 Hz, 2H), 4.73 (d, J=3.6 Hz, 1H), 4.07 (dd, J=19.1, 10.0 Hz, 3H), 3.68 (dd, J=9.1, 6.2 Hz, 1H), 3.41 (s, 2H), 3.12 (d, J=11.3 Hz, 2H), 2.26 (dd, J=12.4, 3.0 Hz, 2H), 2.05 (dd, J=16.8, 9.5 Hz, 6H), 1.47 (dd, J=14.7, 7.3 Hz, 2H), 0.79 (t, J=7.4 Hz, 3H).
LC-MS (ESI) m/z=426 [M+H]+.
To a solution of N—(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-029) (100 mg, 0.23 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (144 mg, 0.23 mmol) at 0° C., then the reaction mixture was stirred at 0° C. for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-242) (30 mg, 15%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=5.6 Hz, 1H), 7.28 (d, J=12.7 Hz, 3H), 4.77-4.69 (m, 1H), 4.34 (s, 2H), 4.07 (t, J=9.0 Hz, 1H), 3.67 (d, J=9.0 Hz, 3H), 3.40 (dd, J=11.0, 5.5 Hz, 1H), 2.56 (d, J=11.9 Hz, 1H), 2.06 (t, J=7.3 Hz, 4H), 1.82-1.72 (m, 2H), 1.51-1.40 (m, 2H), 0.78 (t, J=7.4 Hz, 3H).
LC-MS (ESI) m/z=442 [M+H]+.
To a solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 μg, 890 mmol) in ethanol (1000 mL) was added 3-bromo-2,2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) at 25° C. then the reaction mixture was stirred at 100° C. for 48 h. The mixture was concentrated under reduced pressure, and the crude material was poured into solution of potassium hydroxide (75 mL) and stirred for 2 h, to afford filter cake (3) (10 g, 59%) as a white solid.
LC-MS (ESI) m/z=254 [M+H]+.
A mixture of (3) (10 g, 39.5 mmol) and magnesium (6.7 g) in methanol (15 mL) was sonicated for 1 h at 40° C., after that the solvent was removed under reduced pressure to afford a viscous grey residue, Et2O and sodium sulfate were added and the resulting grey mixture was stirred vigorously for 30 min before filtration. A solution of oxalic acid in ethanol was added to the filtrate. A think white precipitate formed instantly, which was target product (4) (3.7 g, 50%), and the crude material was used for next reaction without further purification.
To a solution of (4) (3.7 g, 19.5 mmol) and 1,2,3-trifluoro-5-nitrobenzene (3.81 g, 21.5 mmol) in DMF (10 mL) was added K2CO3 (5.38 g, 39 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford (5) (1.9 g, 38%) as a yellow solid.
LC-MS (ESI) m/z=257 [M+H]+.
To a solution of (5) (1.9 g, 7.4 mmol) and Palladium carbon (200 mg) in methanol (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford (6) (1.5 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=227 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (3.3 g, 13.3 mmol) was added to a suspension of (6) (1.5 g, 6.7 mmol) in THF (30 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford (7) (1.6 g, 68%) as a white solid.
LC-MS (ESI) m/z=361 [M+H]+.
To a solution of (7) (1.6 g, 4.6 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (2.8 ml, 6.8 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (980 mg, 6.8 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (8) (1.2 g, 84%) as a white solid.
LC-MS (ESI) m/z=327 [M+H]+.
(E)-N1,N1,N2-trimethyldiazene-1,2-dicarboxamide (443 mg, 2.6 mmol) was added to a suspension of (8) (560 mg, 1.7 mmol), tert-butyl isoxazol-3-ylcarbamate (380 mg, 2.1 mmol) and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 mL) at 0° C. under a nitrogen gas atmosphere and then the reaction mixture was stirred at 60° C. for overnight, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford (9) (309 mg, 37%) as a white solid.
LC-MS (ESI) nm/z=493 [M+H]+.
To a solution of (9) (309 g, 0.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added trifluoroacetic acid (1 ml), then the mixture was stirred at 0° C. for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with CH2Cl2, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (OBD-061) (93 mg, 38%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.01 (d, J=12.1 Hz, 2H), 5.85 (d, J=1.7 Hz, 1H), 4.92 (s, 1H), 4.82 (s, 4H), 4.29 (s, 4H), 3.99 (s, 2H), 3.75 (s, 2H), 3.60 (s, 2H)
LC-MS (ESI) m/z=392.9 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (2.45 g, 13 mmol) was added to a suspension of (8) (2.3 g, 6.5 mmol) and Et3N (1.3 g, 13 mmol) in DCM (10 mL) at 0° C. and then the reaction mixture was stirred at room temperature for overnight under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (9) (2.65 g, 85%) as a white solid.
LC-MS (ESI) m/z=481 [M+H]+.
To a solution of (9) (2.65 g, 5.52 mmol) and sodium azide (360 mg, 5.52 mmol) in DMF (10 mL) was added K2CO3 (1.52 mg, 11.04 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (10) (1.7 g, 88%) as a white solid.
LC-MS (ESI) m/z=352 [M+H]+.
To a solution of (10) (1.7 g, 4.86 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (OBD-062) (1.3 g, 85%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 7.34-6.98 (m, 2H), 4.70 (s, 4H), 4.59 (dt, J=11.3, 5.1 Hz, 1H), 4.23 (d, J=2.2 Hz, 4H), 3.99 (dd, J=20.9, 12.0 Hz, 1H), 3.78 (dd, J=8.9, 6.4 Hz, 1H), 2.80 (ddd, J=24.5, 13.6, 4.9 Hz, 2H), 1.99 (s, 2H).
LC-MS (ESI) m/z=326.1 [M+H]+.
To a solution of (1) (3.7 g, 19.5 mmol) and 1,2-difluoro-4-nitrobenzene (3.41 g, 21.5 mmol) in DMF (10 mL) was added K2CO3 (5.38 g, 39 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford (3) (1.7 g, 38%) as a yellow solid.
LC-MS (ESI) m/z=239 [M+H]+.
To a solution of (3) (1.7 g, 7.4 mmol) and Palladium carbon (200 mg) in methanol (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford (4) (1.4 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=209 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (3.3 g, 13.3 mmol) was added to a suspension of (6) (1.4 g, 6.7 mmol) in THF (30 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford (7) (1.6 g, 70%) as a white solid.
LC-MS (ESI) m/z=343 [M+H]+.
To a solution of (7) (1.6 g, 4.7 mmol) in THF (10 mL) at 78° C. under a nitrogen gas atmosphere was added n-BuLi (2.9 ml, 7.0 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1 g, 7.0 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (8) (1.2 g, 84%) as a white solid.
LC-MS (ESI) m/z=309 [M+H]+.
LC-MS (ESI) m/z=475 [M+H]+.
To a solution of (9) (298 mg, 0.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added trifluoroacetic acid (1 ml), then the mixture was stirred at 0° C. for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with CH2Cl2, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (OBD-056) (84 mg, 38%) as a white solid. 1H NMR (301 MHz, CDCl3) δ 7.39 (d, J=14.4 Hz, 1H), 7.25 (s, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.83 (t, J=8.9 Hz, 1H), 5.14 (s, 1H), 4.73 (s, 1H), 4.39 (s, 2H), 4.00 (t, J=8.8 Hz, 1H), 3.84-3.42 (m, 8H), 3.05 (dd, J=23.2, 11.2 Hz, 5H), 2.13-1.88 (m, 5H).
LC-MS (ESI) m/z=375 [M+H]+.
To a solution of 8-oxa-3-aza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoro-5-nitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL) was added K2CO3 (12.2 g, 88.4 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) (9.3 g, 78%) as a yellow solid.
LC-MS (ESI) m/z=271 [M+H]+.
To a solution of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) (9.3 g, 34.4 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzenamine (4) (7.8 g, 95%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=241 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (12 g, 48.7 mmol) was added to a suspension of 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzenamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=10:1) to afford benzyl 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid.
LC-MS (ESI) m/z=375 [M+H]+.
To a solution of benzyl 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (13.8 ml, 33.1 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (4.7 g, 33.1 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (OBD-114) (4.5 g, 60%) as a white solid.
LC-MS (ESI) m/z=341 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (OBD-114) (4.5 g, 13.3 mmol) and Et3N (2.7 g, 26.6 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (5.58 g, 85%) as a white solid. LC-MS (ESI) m/z=495 [M+H]+.
To a solution of (3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (300 mg, 0.6 mmol) and 1H-1,2,3-triazole (42 mg, 0.6 mmol) in DMF (10 mL) was added K2CO3 (166 mg, 1.2 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-di fluorophenyl)oxazolidin-2-one (OBD-054) (82 mg, 35%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=1.0 Hz, 1H), 7.73 (d, J=1.0 Hz, 1H), 7.17 (d, J=11.7 Hz, 2H), 5.11 (d, J=3.5 Hz, 1H), 4.79 (d, J=5.0 Hz, 2H), 4.18 (dd, J=23.1, 13.7 Hz, 3H), 3.91-3.70 (m, 1H), 3.23 (d, J=10.9 Hz, 3H), 2.72 (d, J=10.7 Hz, 3H), 2.07-1.61 (m, 7H).
LC-MS (ESI) m/z=392 [M+H]+.
To a solution of (3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 mL) was added K2CO3 (2.2 mg, 16 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.57 g, 88%) as a white solid.
LC-MS (ESI) m/z=366 [M+H]+.
To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.57 g, 7 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-115) (2.1 g, 85%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.40-7.20 (m, 2H), 4.62 (td, J=10.9, 4.9 Hz, 1H), 4.28 (s, 2H), 4.02 (t, J=8.9 Hz, 1H), 3.81 (dd, J=8.9, 6.3 Hz, 1H), 3.27 (d, J=10.4 Hz, 2H), 2.81 (ddd, J=28.3, 18.6, 7.7 Hz, 4H), 2.21 (s, 2H), 2.04-1.94 (m, 2H), 1.88-1.71 (m, 2H).
LC-MS (ESI) m/z=340 [M+H]+.
To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-115) (200 mg, 0.59 mmol) and R—OH (0.59 mmol) in DCM (10 mL) were added HOBt (119 mg, 0.88 mmol), EDCI (225 mg, 1.18 mmol) and DIPEA (152 mg, 1.18 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-048, 049, 252, 253, 254) as a white solid.
1H NMR (300 MHz, CDCl3) δ 7.06 (d, J=10.9 Hz, 2H), 5.98 (s, 1H), 4.75 (s, 1H), 4.33 (s, 2H), 3.98 (t, J=8.8 Hz, 1H), 3.68 (dd, J=19.8, 11.0 Hz, 3H), 3.45 (d, J=10.9 Hz, 3H), 2.78 (d, J=11.1 Hz, 2H), 2.11 (d, J=6.6 Hz, 3H), 1.98 (d, J=24.1 Hz, 6H).
LC-MS (ESI) m/z=426 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.06 (d, J=11.0 Hz, 2H), 5.15 (s, 1H), 4.75 (s, 1H), 4.32 (s, 2H), 3.97 (t, J=9.0 Hz, 2H), 3.80-3.70 (m, 4H), 3.56 (d, J=5.9 Hz, 2H), 3.42 (s, 2H), 2.77 (d, J=11.1 Hz, 2H), 2.10 (d, J=6.4 Hz, 2H), 1.92 (d, J=5.0 Hz, 2H).
LC-MS (ESI) m/z=397.7 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.07 (d, J=11.0 Hz, 2H), 6.19 (s, 1H), 4.77 (s, 1H), 4.35 (s, 2H), 3.97 (t, J=8.9 Hz, 1H), 3.78-3.62 (m, 3H), 3.46 (d, J=10.1 Hz, 2H), 2.79 (d, J=11.1 Hz, 2H), 2.12 (d, J=6.5 Hz, 2H), 1.94 (d, J=4.5 Hz, 2H), 1.43-1.33 (m, 1H), 0.95 (dd, J=9.5, 4.4 Hz, 2H), 0.78 (d, J=6.4 Hz, 2H).
LC-MS (ESI) m/z=408.1 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.07 (d, J=11.0 Hz, 2H), 5.88 (s, 1H), 4.76 (s, 1H), 4.34 (s, 2H), 3.98 (t, J=9.0 Hz, 1H), 3.79-3.59 (m, 3H), 3.45 (d, J=10.8 Hz, 2H), 3.12-2.97 (m, 1H), 2.79 (d, J=11.3 Hz, 2H), 2.38-2.10 (m, 6H), 2.00-1.79 (m, 4H).
LC-MS (ESI) m/z=422.1 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.17-6.96 (m, 2H), 6.07 (s, 1H), 4.78 (s, 1H), 4.34 (s, 2H), 3.98 (t, J=8.9 Hz, 1H), 3.82-3.64 (m, 3H), 3.45 (d, J=10.0 Hz, 2H), 2.79 (d, J=11.2 Hz, 2H), 2.38-2.06 (m, 4H), 1.98-1.78 (m, 2H), 1.63 (dq, J=14.7, 7.3 Hz, 2H), 1.26 (s, 1H), 0.90 (t, J=7.4 Hz, 3H).
LC-MS (ESI) m/z=410.1 [M+H]+.
To a solution of 8-oxa-3-aza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2-difluoro-4-nitrobenzene (7.7 g, 48.6 mmol) in DMF (10 mL) was added K2CO3 (12.2 g, 88.4 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=5:1) to afford 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) (9.1 g, 82%) as a yellow solid.
LC-MS (ESI) m/z=253 [M+H]+.
To a solution of 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) (3) (9.1 g, 36.2 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorobenzenamine (4) (7.3 g, 91%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=223 [M+H]-.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (16.4 g, 65.88 mmol) was added to a suspension of 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorobenzenamine (4) (7.3 g, 32.9 mmol) in THF (100 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=10:1) to afford benzyl 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenylcarbamate (5) (7.1 g, 61%) as a white solid.
LC-MS (ESI) m/z=357 [M+H]-.
To a solution of benzyl 4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenylcarbamate (5) (7.1 g, 20.1 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (12.5 ml, 30.1 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (4.3 g, 30.1 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (OBD-112) (3.9 g, 60%) as a white solid.
1H NMR (301 MHz, DMSO-d6) δ 7.46 (dd, J=15.4, 2.5 Hz, 1H), 7.14 (d, J=6.5 Hz, 1H), 7.03-6.84 (m, 1H), 5.18 (s, 1H), 4.64 (d, J=3.3 Hz, 1H), 4.31 (s, 2H), 4.00 (t, J=9.0 Hz, 1H), 3.81-3.72 (m, 1H), 3.57 (d, J=24.9 Hz, 2H), 3.00 (d, J=11.2 Hz, 3H), 2.85 (d, J=10.9 Hz, 2H), 2.08-1.63 (m, 5H).
LC-MS (ESI) m/z=323 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (2.3 g, 24 mmol) was added to a suspension of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (OBD-112) (3.9 g, 12 mmol) and Et3N (1.2 g, 24 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl 4-methylbenzenesulfonate (7) (4.86 g, 85%) as a white solid.
LC-MS (ESI) m/z=477 [M+H]+.
To a solution of (3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl 4-methylbenzenesulfonate (7) (4.86 g, 10.2 mmol) and sodium azide (663 mg, 10.2 mmol) in DMF (10 mL) was added K2CO3 (1.4 g, 20.4 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.97 g, 84%) as a white solid.
LC-MS (ESI) m/z=348 [M+H]+.
To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.97 g, 8.5 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-113) (2.2 g, 81%) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.53-7.35 (m, 1H), 7.09 (d, J=8.9 Hz, 1H), 6.96-6.73 (m, 1H), 4.66 (s, 1H), 4.40 (s, 1H), 4.00 (t, J=8.7 Hz, 1H), 3.89-3.74 (m, 1H), 3.06 (dd, J=21.9, 11.0 Hz, 6H), 2.27-1.85 (m, 4H).
LC-MS (ESI) m/z=322 [M+H]+.
To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-113) (200 mg, 0.62 mmol) and R—OH (0.62 mmol) in DCM (10 mL) were added HOBt (126 mg, 0.96 mmol), EDCI (237 mg, 1.24 mmol) and DIPEA (160 mg, 1.24 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-110, 111) as a white solid.
1H NMR (301 MHz, CDCl3) δ 7.51-7.32 (m, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.83 (t, J=9.1 Hz, 1H), 6.07 (s, 1H), 4.74 (s, 1H), 4.39 (s, 2H), 4.00 (t, J=8.9 Hz, 1H), 3.85-3.49 (m, 3H), 3.05 (dd, J=23.2, 10.6 Hz, 4H), 2.32-1.67 (m, 8H).
LC-MS (ESI) m/z=426 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.41 (s, 1H), 7.03 (s, 1H), 6.17 (s, 0H), 5.20-5.02 (m, 1H), 4.85-4.62 (m, 1H), 4.41 (s, 1H), 4.01 (s, 1H), 3.68 (s, 3H), 3.09 (d, J=7.9 Hz, 2H), 2.05 (d, J=42.7 Hz, 3H), 1.83-1.35 (m, 3H).
LC-MS (ESI) m/z=397.7 [M+H]+.
To a solution of 3-oxa-8-aza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoro-5-nitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL) was added K2CO3 (12.2 g, 88.4 mmol) at 25° C. then the reaction mixture was stirred at 80° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA:PE=3:1) to afford 8-(2,6-difluoro-4-nitrophenyl)-3-oxa-8-aza-bicyclo[3.2.1]octane (3) (9.3 g, 78%) as a yellow solid.
LC-MS (ESI) m/z=271 [M+H]+.
To a solution of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) (9.3 g, 34.4 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzenamine (4) (7.8 g, 95%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z=241 [M+H]+.
Carbonic acid, 2,5-dioxo-1-pyrrolidinyl phenylmethyl ester (12 g, 48.7 mmol) was added to a suspension of 4-(3-oxa-8-aza-bicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzenamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at 50° C. for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=10:1) to afford benzyl 4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid.
LC-MS (ESI) m/z=375 [M+H]+.
To a solution of benzyl 4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF (10 mL) at −78° C. under a nitrogen gas atmosphere was added n-BuLi (13.8 ml, 33.1 mmol), then the mixture was stirred at −78° C. for 30 min, after that the solution of (R)-oxiran-2-ylmethyl butyrate (4.7 g, 33.1 mmol) in THF was added to the mixture at −78° C., then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=70:1) to afford (5R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (6) (4.5 g, 60%) as a white solid.
LC-MS (ESI) m/z=341 [M+H]+.
4-methylbenzene-1-sulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of (5R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (6) (4.5 g, 13.3 mmol) and Et3N (2.7 g, 26.6 mmol) in DCM (10 mL) at 0° C. under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford ((R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (5.58 g, 85%) as a white solid.
LC-MS (ESI) m/z=495 [M+H]+.
To a solution of ((R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (300 mg, 0.6 mmol) and 1H-1,2,3-triazole (42 mg, 0.6 mmol) in DMF (10 mL) was added K2CO3 (166 mg, 1.2 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)oxazolidin-2-one (OBD-055) (82 mg, 35%) as a white solid. 1H NMR (301 MHz, CDCl3) δ 7.76 (d, J=5.7 Hz, 2H), 6.94 (d, J=12.1 Hz, 2H), 5.06 (s, 1H), 4.78 (d, J=4.1 Hz, 1H), 4.08 (t, J=9.0 Hz, 1H), 3.90 (t, J=8.9 Hz, 4H), 3.58 (d, J=10.4 Hz, 2H), 2.04 (t, J=8.0 Hz, 4H), 1.76 (s, 2H). LC-MS (ESI) m/z=391.8 [M+H]+.
To a solution of ((R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (7) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 mL) was added K2CO3 (2.2 g, 16 mmol) at 25° C., then the reaction mixture was stirred at 80° C. for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE:EA=2:1) to afford (5R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.4 g, 82%) as a white solid.
LC-MS (ESI) m/z=366 [M+H]+.
To a solution of (5R)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (8) (2.4 g, 6.5 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25° C., then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to afford (5S)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (9) (1.9 g, 86%) as a white solid.
LC-MS (ESI) m/z=340 [M+H]+.
To a solution of (5S)-3-(4-(3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidin-2-one (9) (200 mg, 0.59 mmol) and R—OH (0.59 mmol) in DCM (10 mL) were added HOBt (119 mg, 0.88 mmol), EDCI (224 mg, 1.18 mmol) and DIPEA (152 mg, 1.18 mmol) at 25° C., then the reaction mixture was stirred at 25° C. for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to afford (OBD-051, 052) as a white solid.
1H NMR (301 MHz, CDCl3) δ 6.99 (t, J=9.3 Hz, 2H), 5.38 (s, 1H), 4.84-4.69 (m, 1H), 3.98-3.86 (m, 4H), 3.75-3.60 (m, 4H), 2.24-1.97 (m, 8H).
LC-MS (ESI) m/z=381.9 [M+H]+.
1H NMR (301 MHz, CDCl3) δ 7.06 (d, J=12.4 Hz, 2H), 5.10 (s, 1H), 4.75 (s, 1H), 4.02-3.86 (m, 4H), 3.68 (s, 2H), 3.58 (d, J=9.6 Hz, 2H), 2.02 (d, J=7.7 Hz, 2H), 1.80 (s, 4H), 0.98 (d, J=6.7 Hz, 3H).
LC-MS (ESI) m/z=398.0 [M+H]+.
In a manner similar to those disclosed in Examples 8 and 12 above, the following compounds were made:
1H-NMR (400 MHz, CDCl3) δ: 7.45 (d, J=16.4 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.83 (t, J=9.2 Hz, 1H), 5.17-5.12 (m, 1H), 4.80-4.74 (m, 1H), 4.62 (brs, 2H), 4.02 (t, J=8.4 Hz, 1H), 3.77 (t, J=8.0 Hz, 1H), 3.69-3.53 (m, 4H), 3.45 (d, J=10.4 Hz, 2H), 2.86 (d, J=12.0 Hz, 2H), 2.22 (m, 2H), 1.90-1.88 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C18H23FN3O5S: 412.1344; found: 412.1359.
1H-NMR (400 MHz, CDCl3) δ: 7.13 (d, J=12.4 Hz, 2H), 5.10 (m, 1H), 4.80-4.74 (m, 1H), 4.46 (brs, 2H), 3.98 (1, J=8.8 Hz, 1H), 3.76-3.69 (m, 4H), 3.60-3.49 (m, 3H), 2.94 (d, J=12.0 Hz, 2H), 2.20-2.18 (m, 2H), 1.87-1.85 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C18H22F2N3O5S: 430.1248; found: 430.1259.
1H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1H), 7.77 (s, 1H), 6.98 (d, J=12.0 Hz, 2H), 5.10-5.04 (m, 1H), 4.79 (d, J=4.0 Hz, 2H), 4.43 (brs, 2H), 4.10 (t, J=9.2 Hz, 1H), 3.91-3.87 (m, 1H), 3.55 (d, J=12.4 Hz, 2H), 2.92 (d, J=10.4 Hz, 2H), 2.19-2.16 (m, 2H), 1.88-1.83 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C18H20F22N5O3S: 424.1249; found: 424.1271.
1H-NMR (400 MHz, CDCl3) δ: 7.34 (d, J=14.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.41 (t, J=8.8 Hz, 1H), 6.12 (t, J=6.0 Hz, 1H), 4.76-4.73 (m, 1H), 4.01-3.90 (m, 7H), 3.74-3.66 (m, 2H), 3.62-3.56 (m, 1H), 3.45-3.40 (m, 2H), 2.02 (s, 3H).
HRMS (ESI): m/z [M+H]+ calcd for C17H21FN3O4S: 382.1237; found: 382.1217.
HNMR (400 MHz, CDCl3) δ: 7.03-6.94 (m, 2H), 6.09 (t, J=5.6 Hz, 1H), 4.75 (q, J=3.2 Hz, J=2.8 Hz, 1H), 4.16 (s, 4H), 3.95 (t, J=8.8 Hz, 1H), 3.72-3.61 (m, 3H), 3.40 (s, 4H), 2.03 (s, 3H).
m/z [M+Na]+ calcd for C17H19F2N3O3S: 383.1115; found: 384.0.
HNMR (400 MHz, CDCl3) δ: 7.33 (q, J=2.0 Hz, J=11.6 Hz, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.44 (t, J=9.2 Hz, 1H), 5.15 (bs, 1H), 4.77-4.73 (m, 1H), 4.01-3.97 (m, 4H), 3.76-3.52 (m, 6H), 3.42 (s, 4H).
m/z [M+Na]+ calcd for C17H20FN3O4S: 381.1159; found: 404.1.
1H-NMR (400 MHz, CDCl3) δ: 7.51 (d, J=14.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 5.09 (brs, 1H), 4.76 (brs, 1H), 4.16 (d, J=13.2 Hz, 4H), 4.01-3.98 (m, 3H), 3.77-3.75 (m, 1H), 3.69 (s, 3H), 3.61-3.55 (m, 2H), 3.46-3.44 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C17H21FN3O5S: 398.1186; found: 398.1166.
HNMR (400 MHz, CDCl3) δ: 7.78 (d, J=0.8 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.18 (dd, J=13.6, 2.4 Hz, 1H), 6.87 (dd, J=8.8, 1.6 Hz, 1H), 6.37 (t, J=9.2 Hz, 1H), 5.04-5.00 (m, 1H), 4.77 (d, J=3.6 Hz, 2H), 4.08 (t, J=9.2 Hz, 1H), 3.96 (dd, J=10.4, 1.6 Hz, 4H), 3.92-3.89 (m, 3H), 3.42-3.39 (m, 2H).
m/z [M+H]+ calcd for C17H18FN5O3S: 391.1114; found: 392.0.
1H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J=14.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.47 (t, J=9.2 Hz, 1H), 6.13 (brs, 1H), 4.73 (m, 1H), 3.98-3.95 (m, 5H), 3.73-3.66 (m, 3H), 3.42 (s, 4H), 1.39-1.37 (m, 1H), 0.97-0.91 (m, 2H), 0.78-0.76 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C19H23FN3O3S: 392.1444; found: 392.1426.
1H-NMR (400 MHz, CDCl3) δ: 7.35 (d, J=14.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.44 (t, J=9.2 Hz, 1H), 6.13 (brs, 1H), 4.74 (m, 1H), 4.00-3.91 (m, 7H), 3.75-3.62 (m, 3H), 3.47-3.41 (m, 2H), 1.38-1.37 (m, 1H), 0.97-0.92 (m, 2H), 0.78-0.76 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C19H23FN3O4S: 408.1393; found: 408.1378.
HNMR (400 MHz, CDCl3) δ: 7.76 (d, J=8.8 Hz, 2H), 6.92-6.83 (m, 2H), 5.04 (m, 1H), 4.78 (q, J=0.8 Hz, J=3.2 Hz 2H), 4.15 (t, J=2.4 Hz, 4H), 3.85 (t, J=6.0 Hz, 1H), 3.72-3.63 (m, 3H), 3.40 (s, 4H), 3.05-2.99 (m, 1H), 2.24-2.13 (m, 4H), 1.97-1.60 (m, 2H).
m/z [M+Na]+ calcd for C20H24FN3O3S: 405.1522; found: 428.2.
1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J=14.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.47 (t, J=9.2 Hz, 1H), 5.80 (brs, 1H), 4.73 (brs, 1H), 4.00 (d, J=12.0 Hz, 4H), 3.95-3.92 (m, 3H), 3.76-3.72 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.41 (m, 2H), 3.02-2.96 (m, 1H), 2.26-2.13 (m, 4H), 1.98-1.84 (m, 2H).
HRMS (ESI): m/z [M+H]+ calcd for C20H25FN3O4S: 422.1549; found: 422.1531.
HNMR (400 MHz, CDCl3) δ: 7.04-6.95 (m, 2H), 5.05 (s, 1H), 4.80-4.77 (m, 1H), 4.15 (t, J=2.4 Hz, 4H), 3.97 (t, J=8.8 Hz, 1H), 3.86 (dd, J=6.4, 8.8 Hz, 1H), 3.56 (dd, J=3.6, 14.4 Hz, 1H), 3.43-3.39 (m, 5H), 3.01 (s, 3H).
m/z [M+H]+ calcd for C16H20FN3O4S2: 401.0879; found: 402.1.
HNMR (400 MHz, CDCl3) δ: 7.32 (dd, J=14.0, 2.4 Hz, 1H), 7.04-7.02 (m, 1H), 6.41 (t, J=9.6 Hz, 1H), 4.86-4.77 (m, 2H), 4.04-3.95 (m, 8H), 3.93 (dd, J=9.6, 3.2 Hz, 1H), 3.43-3.40 (m, 3H), 3.02 (s, 3H).
m/z [M+H]+ calcd for C16H20FN3O5S2: 417.0828; found: 418.0.
HNMR (400 MHz, CDCl3) δ: 7.64 (s, 2H), 7.24-7.21 (m, 1H), 6.99 (dd, J=8.8, 1.6 Hz, 1H), 6.41 (t, J=9.6 Hz, 1H), 5.12-5.06 (m, 1H), 4.87-4.82 (m, 1H), 4.75-4.72 (m, 1H), 4.05-4.01 (m, 1H), 3.96-3.93 (m, 5H), 3.40 (s, 4H).
m/z [M+H]+ calcd for C17H18FN5O2S: 375.1165; found: 376.1.
HNMR (400 MHz, CDCl3) δ: 7.64 (s, 2H), 7.27-7.23 (m, 1H), 6.99 (dd, J=8.8, 2.0 Hz, 1H), 6.39 (t, J=9.2 Hz, 1H), 5.11-5.06 (m, 1H), 4.87-4.82 (m, 1H), 4.76-4.70 (m, 1H), 4.06-4.03 (m, 1H), 3.98-3.90 (m, 7H), 3.43-3.40 (m, 2H).
m/z [M+H]+ calcd for C17H18FN5O3S: 391.1114; found: 392.1.
HNMR (400 MHz, CDCl3) δ: 7.33 (dd, J=2.4, 13.6 Hz, 1H), 7.04 (dd, J=1.6, 8.4 Hz, 1H), 6.44 (t, J=9.2 Hz, 1H), 4.88-4.72 (m, 2H), 4.33 (t, J=4.0 Hz, 2H), 4.02 (t, J=9.2 Hz, 1H), 3.97 (d, J=1.6 Hz, 4H), 3.77 (dd, J=6.4, 8.8 Hz, 1H), 3.42 (s, 4H), 2.80 (d, J=4.8 Hz, 3H).
m/z [M+H]+ calcd for C17H20FN3O4S: 381.1159; found: 382.0.
HNMR (400 MHz, CDCl3) δ: 7.35 (dd, J=2.0, 11.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.42 (1, J=9.2 Hz, 1H), 4.89-4.70 (m, 2H), 4.42-4.26 (m, 2H), 4.08-3.88 (m, 7H), 3.84-3.71 (m, 1H), 3.47-3.37 (m, 2H), 2.81 (m, 3H).
m/z [M+H]+ calcd for C17H20FN3O5S: 397.1108; found: 398.0.
1H-NMR (400 MHz, CDCl3) δ: 7.02 (d, J=12.0 Hz, 2H), 5.92 (brs, 1H), 4.75-4.74 (m, 1H), 4.16 (d, J=12.0 Hz, 4H), 3.97-3.90 (m, 2H), 3.72-3.65 (m, 4H), 3.41-3.37 (m, 2H), 2.02 (s, 3H).
HRMS (ESI): m/z [M+H]+ calcd for C17H20F2N3O4S: 400.1143; found: 400.1158.
1H-NMR (400 MHz, CDCl3) δ: 7.00 (d, J=10.8 Hz, 2H), 5.36 (m, 1H), 4.72 (m, 1H), 4.14 (d, J=12.0 Hz, 4H), 3.92 (m, 3H), 3.69 (m, 1H), 3.67 (s, 3H), 3.52 (m, 2H), 3.39 (d, J=12.4 Hz, 2H).
HRMS (ESI) calcd for C17H20F2N3O5S [M+H]+ 416.1086, found: 416.1073.
HNMR (400 MHz, CDCl3) δ: 7.75 (d, J=8.0 Hz, 2H), 6.92-6.83 (m, 2H), 5.05-5.01 (m, 1H), 4.77 (d, J=4.0 Hz, 2H), 4.15 (dt, J=11.6, 2.4 Hz, 4H), 4.05 (t, J=9.2 Hz, 1H), 3.92-3.89 (m, 3H), 3.40-3.37 (m, 2H).
m/z [M+H]+ calcd for C17H17F2N5O3S: 409.1020; found: 410.1.
1H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J=11.6 Hz, 2H), 6.60 (m, 1H), 4.73 (m, 1H), 4.13 (d, J=12.4 Hz, 4H), 3.91 (m, 3H), 3.70 (m, 1H), 3.64 (m, 2H), 3.79 (d, J=10.4 Hz, 2H), 1.41 (m, 1H), 0.94 (m, 1H), 0.87 (m, 1H), 0.74 (m, 2H)
HRMS (ESI) calcd for C19H22F2N3O4S [M+H]+ 426.1294, found: 426.1278.
1H-NMR (400 MHz, CDCl3) δ: 6.99 (d, J=10.4 Hz, 2H), 6.06 (m, 1H), 4.74 (m, 1H), 4.14 (d, J=12.4 Hz, 4H), 3.93 (m, 3H), 3.70 (m, 1H), 3.62 (m, 2H), 3.38 (d, J=12.4 Hz, 2H), 3.00 (m, 1H), 2.21 (m, 1H), 2.11 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H)
HRMS (ESI) calcd for C20H24F2N3O4S [M+H]+ 440.1450, found: 440.1441.
HNMR (400 MHz, CDCl3) δ: 7.04-6.95 (m, 2H), 5.05 (s, 1H), 4.80-4.77 (m, 1H), 4.15 (t, J=2.4 Hz, 4H), 3.97 (t, J=8.8 Hz, 1H), 3.86 (dd, J=6.4, 8.8 Hz, 1H), 3.56 (dd, J=3.6, 14.4 Hz, 1H), 3.43-3.39 (m, 5H), 3.01 (s, 3H).
m/z [M+H]+ calcd for C16H19F2N3O4S2: 419.0785; found: 420.1.
HNMR (400 MHz, CDCl3) δ: 7.03-7.00 (m, 2H), 4.81-4.78 (m, 2H), 4.18-4.14 (m, 4H), 3.98-3.93 (m, 1H), 3.91-3.85 (m, 3H), 3.60-3.41 (m, 4H), 3.40-3.37 (m, 3H), 3.02 (s, 3H).
m/z [M+H]+ calcd for C16H19F2N3O5S2: 435.0734; found: 436.0.
HNMR (400 MHz, CDCl3) δ: 7.08-6.91 (m, 2H), 4.91-4.70 (m, 2H), 4.38-4.28 (m, 2H), 4.16 (t, J=2.4 Hz, 4H), 3.98 (t, J=9.2 Hz, 1H), 3.74 (dd, J=6.4, 8.8 Hz, 1H), 3.43-3.37 (m, 4H), 2.81 (d, J=4.8 Hz, 3H).
m/z [M+H]+ calcd for C17H19F2N3O4S: 399.1064; found: 400.1.
HNMR (400 MHz, CDCl3) δ: 7.10-6.95 (m, 2H), 4.89-4.69 (m, 2H), 4.30-4.36 (m, 2H), 4.17 (d, J=11.6 Hz, 4H), 4.02-3.89 (m, 3H), 3.74 (dd, J=6.4, 8.6 Hz, 1H), 3.44-3.33 (m, 2H), 2.81 (d, J=4.8 Hz, 3H).
m/z [M+H]+ calcd for C17HF2N3O5S: 415.1013; found: 416.0.
1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2H), 7.31 (d, J=14.4, 2.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.59 (t, J=9.2 Hz, 1H), 5.14-5.07 (m, 1H), 4.88-4.83 (m, 5H), 4.77-4.71 (m, 1H), 4.16 (s, 4H), 4.07-4.02 (m, 1H), 3.98-3.92 (m, 1H)
HRMS (ESI): m/z [M+H]+ calcd for C17H19FN5O3: 360.1472; found: 360.1451.
The invention will be further described, without limitation, by the following numbered paragraphs:
1. A compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate of:
wherein:
R is independently OR1, OC(O)R2, OC(O)NHR2, OS(O2)R2, NHS(O)2R2, NR3R4, NHC(O)R5;
R′ and R″ are independently H, F, Cl or OMe;
each R1 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C1-C6 alkyl, C1-C6 alkyloxy;
each R2 is independently C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;
each R3 and R4 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, aryl; or R3 and R4 taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, CF3, NO2, CN;
each R5 is independently C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, heteroaryl, aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2; Ring A is selected from:
wherein,
each R6 and R7 is independently H, F, CH3, CH2CH3, CF3, phenyl;
X=O, S, SO, SO2;
Y=O, S, SO, SO2, and NR8;
m is 1, or 2;
n is 1, or 2;
p is 1, or 2;
q is 1, or 2;
R8 in independently H, C1-C4 alkyl, C3-C6 cycloalkyl, COCH3, and p-toluenesulfonyl, wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2.
2. The compound of paragraph 1, wherein the compound is represented by Formula II:
R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;
R′ and R″ are independently H, or F;
R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;
R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;
R3 and R4 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached to form morpholine, thiamorpholine, piperazine and triazole;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl;
R6 and R7 is independently H, F, CH3, CH2CH3, CF3;
X=O, S, SO, SO2; when X=S, SO, SO2, R′=H, R″=F, R5 can not be CH3;
3. The compound of paragraph 1, wherein the compound is represented by Formula III:
R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;
R′ and R″ are independently H, or F;
R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;
R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;
R3 and R4 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl; or R3 and R4 taken together with the nitrogen to which they are attached to form morpholine, thiamorpholine, piperazine and triazole;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl;
R6 and R7 is independently H, F, CH3, CH2CH3, CF3;
X=O, S, SO, SO2;
4. The compound of paragraph 1, wherein the compound is represented by Formula IV:
R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;
R′ and R″ are independently H, or F;
R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;
R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;
R3 and R4 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R3 and R4 taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl; and
X=O, S, SO, SO2.
5. The compound of paragraph 1, wherein the compound is represented by Formula V:
R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;
R′ and R″ are independently H, or F;
R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;
R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;
R3 and R4 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R3 and R4 taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl; and
X=O, S, SO, SO2.
6. The compound of paragraph 1, wherein the compound is represented by Formula VI:
7. The compound of paragraph 6, wherein the compound is represented by Formula VII, Formula VIII, or Formula IX:
wherein
R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;
R′ and R″ are independently H, or F;
R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;
R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;
R3 and R4 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R3 and R4 taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl; and
X=O, S, SO, SO2.
8. The compound of paragraph 1, the compound is represented by Formula IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa, or IXb:
wherein,
R is independently OH, OCH3, OCH2CH3, OC(O)CH3, NH2, NHCH3, NHC6H5, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, NHS(O)2R2, NHC(O)R5;
R2 is independently C1-C6 alkyl;
R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, furan, thiophene or phenyl; in Formula IIa, R5 can not be CH3; and
X=O, S, SO, SO2.
9. The compound of paragraph 1, wherein the compound is:
10. A pharmaceutical composition comprising at least one compound of Formula I, or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and/or additives.
11. The pharmaceutical compositions Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective treatments.
12. A method of preventing and treating microbial infections in humans by administering a therapeutically effective amount of a compound of Formula I, or a salt, hydrate, or solvate thereof to a patient in need thereof.
13. The method of paragraph 12, wherein the microbial infection is caused by Mycobacterium tuberculosis.
It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.
This application is a Divisional of application Ser. No. 15/738,503, filed Dec. 20, 2017, issued as U.S. Pat. No. 10,550,092, which in turn is a National Stage Application of PCT/US2016/042486, filed Jul. 15, 2016, which claims priority from U.S. Provisional Patent Application No. 62/193,963, filed on Jul. 17, 2015. Each of the prior mentioned applications is hereby incorporated by reference herein in its entirety.
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| Number | Date | Country | |
|---|---|---|---|
| 20200148651 A1 | May 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62193963 | Jul 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15738503 | US | |
| Child | 16740660 | US |
