EA043707B1 - SUBSTITUTED PHENYLOXAZOLIDINONES FOR ANTIMICROBIAL THERAPY - Google Patents

Description

Field of technology

The invention generally relates to compounds with antibacterial activity, and more particularly to compounds having anti-tuberculosis properties. In particular, the present invention relates to substituted phenyloxazolidinone compounds suitable for the treatment of tuberculosis in patients in need thereof.

All documents cited or referred to below are expressly incorporated herein by reference.

State of the art

Linezolid is a first-in-class drug and was approved in 2000 for a number of clinical uses, including the treatment of nosocomial and community-acquired pneumonia and skin infections caused by Staphylococcus aureus/methicillin-resistant S. aureus, vancomycin-resistant Enterococcus and Streptococcus pneumoniae ( Pen-S). Linezolid exhibits bacteriostatic activity in vitro against Mycobacterium tuberculosis, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, with a minimum inhibitory concentration (MIC) of less than 1 µg/ml. However, linezolid showed very little activity in mouse models of tuberculosis. However, it is used off-label in combination regimens for the treatment of multidrug-resistant tuberculosis.

Oxazolidinones currently in clinical trials demonstrate bone marrow toxicity in animals after long-term administration (i.e., more than one month), which is believed to be due to inhibition of mitochondrial protein synthesis (MPS), and have very narrow safety margins or are not safe. Since the antimicrobial activity of this class of compounds consists of inhibition of microbial protein synthesis, such inhibition and the corresponding bone marrow toxicity exhibited by these compounds is considered to be specific to this mechanism. Such oxazolidinones typically exhibit high clearance and thus require high doses to be administered for the clinical treatment of tuberculosis or other conditions for which they are developed (eg, 500 mg to 1600 mg per day) to be effective. Thus, there is an urgent need to find a new generation of oxazolidinones for the treatment of tuberculosis that demonstrate improved activity and efficacy against tuberculosis, reduced systemic clearance to reduce the daily dose to values below 500 mg and reduced inhibition of BMS and reduced corresponding toxicity to bone marrow, which has led to would lead to the expansion of safety boundaries with long-term introduction.

Brief description of the invention

The present invention relates to new oxazolidinones of formula I or their pharmaceutically acceptable salts, hydrates or solvates:

(O where R independently represents OR1, OC(O)R ₂ , OC(O)NHR ₂ , OS(O ₂ )R ₂ , NHS(O) ₂ R ₂ , NR3R4, NHC(O)R5;

R' and R are independently H, F, Cl or OMe;

each R1 independently represents H, _CrC6alkyl , C3-C8cycloalkyl _, wherein said alkyl, cycloalkyl is optionally substituted with 1-4 groups selected from halogen, hydroxy, _C1 - _C6alkyl , _C1C6alkyloxy ;

each R2 is independently C1-C6 alkyl, _C3 - _C8 cycloalkyl, heterocyclyl, heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1-4 groups selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;

each R3 and R4 independently represents H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, aryl; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or heteroaryl with 1-3 additional heteroatoms selected from O, S or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted -4 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CF ₃ , NO2, CN;

each R ₅ independently represents C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, heteroaryl, aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1-4 groups selected from halogen, hydroxyl, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;

ring A selected from:

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where each R6 and _R7 independently represents H, F, _CH3 , _{CH2CH3 , CF3} , phenyl;

X=O, S, SO, SO2; Y=O, S, SO, SO2 and NR ₈ ;

m is equal to 1 or 2;

n is 1 or 2;

p is 1 or 2;

q is equal to 1 or 2;

R ₈ independently represents H, C ₁ -C ₄ alkyl, C ₃ -C6 cycloalkyl, COCH ₃ and p-toluenesulfonyl, wherein said alkyl, cycloalkyl are optionally substituted with 1-4 groups selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C ₆ acyloxy, CF ₃ , NO2, CN and NH2.

In another aspect of the present invention, pharmaceutical compositions are provided containing 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 another aspect of the present invention, there is provided a method of treating a microbial infection in a human 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 another aspect, the present invention includes pharmaceutical compositions of a compound of formula I or a salt, hydrate or solvate thereof, further comprising one or more additional anti-infective treatments.

In yet another aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof for use as an agent against tuberculosis (TB) in humans.

Detailed Description of the Invention

One aspect of the present invention is to provide new compounds in accordance with Formula I presented and described above. In particular, the compounds of the present invention are suitable for use as antimicrobial agents effective against a number of animal and human pathogens, including Gram-positive aerobic bacteria, Mycobacterium tuberculosis, Mycobacterium avium and the like. Thus, the present invention provides new compounds in accordance with Formula I, as well as their pharmaceutically acceptable salts, hydrates or solvates. The values of the variables used in Formula I are presented in the following paragraphs.

In the table below. 1 provides some specific examples of the compounds of the present invention by indicating their structures, as well as their in vitro activity against Mycobacterium tuberculosis strain H37Rv and in vitro MPS inhibitory activity when tested in Examples 9 and 10 below, respectively. As shown in the table below. 1, potent antituberculosis agents exhibit low MIC values (particularly compounds with MICs less than 1 μg/ml). In contrast, high IC ₅₀ values upon inhibition of MPS demonstrate reduced activity against mitochondrial protein synthesis in vitro and characterize reduced myelosuppressive toxicity in vivo. In some embodiments of the present invention, compounds having the best therapeutic index are those exhibiting a relatively lower MIC value in combination with the highest IC50 values for inhibiting MPS. Exemplary compounds according to the present invention are presented in table. 1 (indication n/a (that is, no data) means that the specific value has not been determined):

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Table 1

Compound Structure MSNR [M+N] ⁺ MIC (µg/ml) in rel. H ₃₇ Rv ICso (μM) for MBP inhibition OTV-107 O /=\ n= ⁿ . 1 N—G />—NI 1 L y '/ F 378.1396 0.03 84.85 OTV-106 S ^Z ^A /=4 N^\ 1 N—(\ />—NI 1 L F 378.1403 2 > 100 OTV-109 O z^L 7=\Ko 1 N—(\ /)—N 1 N /- ¹ 'OH, F 340.1484 32 N/A OTV-108 s-Λ /=\ to . 1 N—<\ /)—N I ---/ y V F O 397.1613 0.125 > 100 otv-sh O 5 ^x \ / ⁼ \ O-L 1 N—//—NI Η 1 \k / VV wk/N^A/ ^F O 420.1400 0.125 60.32 OTV-112 O k (G b 382.1620 0.5 > 100 OTV-115 o /=\ ^0 1 O ^{N F} o 410.1942 3.733 > 100 OBD-005 s-Λ /=\k 1 N—G /)—N I N / ___/ y // F O 395.1679 0.055 15.63

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OTB-116 O sA /=\ K 1 N—G />—NI N O U—' X/ ' _s ^ \ ' ^{11 F} O 446.1623 3,812 > 100 OTV-119 o S ^X \ /=4. r^ ^N . 1 N—(χ L—NI 1 \ X..UA F 378.1421 0.456 > 100 OTV-412 O S ^Z \ / ⁼ \ 1 N—(\ />—NI N <7 VA O / p ^F o 384.1371 0.199 10 OTV-413 o s' \ / ⁼ \ <^O _l ^F o 394.1580 0.108 9.13 OTV-414 o ^f s 408.1736 0.171 N/A 0 TV-407 IZ A A. 0 386.1330 0.097 3,079 0 TV-410 / o IZ oZ^ A 0 402.1287 0.125 > 100 0 TV-408 )=\ _l A ^F o 412.1485 0.342 3,608 0 TV-409 TZ A 0 426.1643 0.477 8.51 OTV-411 ^F °\ s ^z ^A Xo n=\ I ⁿ A\ /A ⁿ i ¹ A ___/ A 7 F 396.1296 0.124 8.73

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OTV-126 /=\ / 1 N—G /)—N 1 ,--/ F O 413.1573 0.847 35.60 OTV-127 i ^=s \ Ko °Ά ^F o 436.1371 1.234 10.15 OTV-137 A Z-Z A 0 // O 394.1328 0.277 7.64 About TV-138 °*s ^z \ /=4 Ko ^N ^\ O У-Γ F 394.1338 7,565 > 100 OTV-140 O ./ / 0 // o 394.1339 3.695 > 100 OBD-006 /=\ Vo 1 N—(χ />—N I H y-S Q___/ U // F O 411.1628 0.49 7,485 OBD-007 /=\ Co / F O 427.1577 0.46 19.81 otv-by O o /=\ Co . S N—(χ /)—N I ---/ /F O 411.1786 0.125 > 100 otv-pz LA /=\to №\ S N—(x //—N I 1 λ F 392.1590 2 > 100 OTV-114 o /=\ Ko ^s N—(\ />—NI N / ___/ y / F 0 382.1620 0.05-0.11 28-29

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OTV-124 A to O II o 398.1540 0.26-1.4 94->100 OTV-117 /=\ k O _L SN—G /)—N 1 n 1 A y___/ k^NA/ ^F O 434.1581 0.665 56.32 OTV-118 o LA /=\ K SN—G /)—N 1 Η 1 v ^F O 450.1356 1,548 n/a OTV-120 0 /A/. s N—G /)—NIH 0 \ / VV /—'' _s ' \ ^F 0 460.1778 3.877 7.27 OTV-121 O 7 = V to . o yA ^Υν ^F o 424.2096 2.785 17.63 OBD-001 ΛΆ / ⁼ \ n = ⁿ . SN—G /)—NI 1 Λ \ / y // νΑ ^Ν Λ F 391.1478 o, s 12 OBD-002 ABOUT AA /=\Uo No.\ O=S N—G /)—N I 1 L \___y // F 407.1427 1.6 29 OBD-003 ABOUT /=\ Co . s N—G /)—N I N ---/ ___у у // F O 409.1835 0.33 > 100 OBD-004 LA /=\k/ O = S N—G /)—N I N F 0 425.1785 3.338 15.76 OBD-008 O AA /=4 ^ ^N . SN—G //—NI / λ VA F 391.1478 3,513 29.89

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OBD-009 o 0 to 0 407.1427 21,052 > 100 OBD-027 S N—ά λ—N I H / F O 0.3 n/a OBD-240 O II 0 to ΖΙ 0^===^ N/A n/a OBD-026 o Co. ^s N—4 ^N IH /—/ ΐ o 0.4 N/A OBD-241 occ . 0=S N—4 /)—N I H / \J U / / 0 N/A N/A OTB-227 V /=\ K _o X^N —/)—NIH / F O 366.1277 0.889 15.22 OTB-501 ABOUT <\ /=\ K /On—G /)—N 1 >> K // .OH sCy /— F 339.1169 4.5 N/A OBD-081 ω 'K F z T IS) 407.9 0.47 77 OBD-085 0 /=\ Xo o-s>/ yj F 1.1 >100 OTB-502 O A^N—<\ /)—NIH / ^s '4 /— w F O 380.1435 0.246 13.55

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0 TV-503 O II ω K g ΖΙ 396.1379 0.2-1.3 78->100 0 TV-504 0 CV / ⁼ \ ^ν ' ^ν \ (\ /)— NI 1 L U/ V '/ /K# sCy /—' F 390.1385 0.5-0.7 17->100 0 TV-505 0 F 406.1339 1.8-3.5 57->100 0 TV-23 6 <4 /=\ Ko X>N —G //—N I Η O si/ /s 416.1097 14,256 N/A 0 TV-23 7 <\ /=\ to YyN—G /)—N I H V/ V V .N-~_Z siy /—' F O 396.1388 0.03-0.11 15-23 OTV-518 O Ko X>N—(\ /)—Ν 1 N o=s</ )—' d F O 3.5 73 OBD-016 F O 407.1679 0.486 13 OBD-017 O F O 423.8 5.8-6.3 41 OBD-021 0 <\ / ⁼ \f^ ^N \ S</ / ^N F 389.1322 27,456 N/A OBD-018 ABOUT /Λ. YAn—g Λ—n I 1 λ O=si7 AND ''Ά-Ύ' F 405.1271 >32 N/A

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0 TV-506 A (\ />— N I n f— F O 406.1527 1 8 0 TV-507 <A _/=\_ ^-o p F O 420.1736 0.7 10 0 TV-510 to A>N—( _h /)—N 1 N Y spy /— F O 398.1329 0.03-0.22 3-7 OTV-514 F O °- _s Jk abc., F P O 414.1275 0.5 25 OTV-512 F O 414.1278 0.063 42.47 OTV-519 F.0 F O 0.9 51 OTV-511 F 0 Ck ? ⁼ \n= ⁿ . A^N—G />—NI 1 λ spy /—' F 408.1295 0.06-0.2 9->100 OTV-517 F 0 Ck /=4 /^0 No. ⁿ . A^N—/)-N 1 / 4 O=spy /--' F 1.3-2 30-55 0 TV-508 F 0 F 0 424.1484 0.2 8 0 TV-509 F 0 F 0 438.1642 0.04 5

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OTB-513 O 454.1588 1.664 12.96 OBD-083 F O F 0.05 20 OBD-087 eo ^E-v^oa— n 1 o=s</ ² F 0.86 >100 OBD-029 F 0 F 0 oh and >100 OBD-242 E O F 0 0.61 >100 OTB-260 ^s OC ^N -^- ^N b<,OH F 325.1010 1.49 30.03 OTB-261 0 ^F o 366.1274 0.12 2 OTB-523 o ^F o 0.5 4 OTB-515 ^F o n/a 0.03-0.06 23-71

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0 TV-256 0 ^F o 4 46 0 TV-241 F 376.1231 0.116 19.81 0 TV-247 0 F 392.0 1.2-1.4 10 0 TV-249 ^F o 392.1426 0.06-0.15 7->100 0 TV-255 o °<>C“-P-£V1 _Y A ^F o 408.1378 1.9 10 0 TV-250 o ^s OC ^N -^3-vQ,ByC7 ^F o 428.2 0.06 10->100 0 TV-254 o ³ 0Ο^3 ^- 'νΟγ/7 ^F o 422.1531 1.8 23 OTV-260-2A ABOUT 402.1 0.82 >100 OTV-260-2V o “Ooch^chLzΐ O' *0 418.0 0.49 >100 OTV-260-5A 0 F 376.1 0.44 >100

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OTB-260-5B O F 392.1 >32 >100 OTB-260-4A O ^F O 382.0 0.39 >100 OTB-260-4B O °-OO-p-CU IL ^F O 398.0 20 >100 OTB-516 F 343.0912 0.465 15.33 OTV-515 Go ^F 0 384.1168 0.03-0.57 14-21 0 TV-520 F 0 ^F o 400.1158 0.4 17 0 TV-242 llХ Go s X N—G /)—N I H / U 400.1125 0.02-0.06 23-71 0 TV-253 ^F 0 416.1073 0.7 10 0 TV-245 F 0 F 394.1129 0.03-0.5 25-35 0 TV-522 F 410.1 1 38

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0 TV-243 A^ Vo ^F o 410.1331 0.03 14 0 TV-252 Co. O=S^X^N—< th L ^F O 426.1278 0.7 52 0 TV-244 ^KxKo ^s A ^N -yAA,BA7 ^F o 424.1483 0.02-0.6 6->22 0 TV-251 °=\ XN—4 A ^N I N /7 VV Ά_/ ^F o 440.1441 0.9 24 OTV-516-2A to K s. XN—4 A ^N I H v V A / / F O O 420.1 0.05 >100 OTV-516-2V Xr Co. °=\ X M\ U-N 1 N \/\/ A_/ V^A,N^ / F O O 436.0 3 >100 OTV-516-4A vAL sf X nA An IH _F / I ^F o 400.1 0.03 >100 OTV-516-4V av χκ °=S. X n—4 An i h r^Y' 416.0 4.7 >100 0 TV-201 _V /=\ Ko ° X ^N— (\ An I \z\z A // ^A^oh F 309.1269 16 N/A OBD-057 О /=\ Xo ci X n—4 An IAA _/ \A^.nh ₂ f ^z 0.4 67

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0 TV-202 o ^F o 350.1497 0.6-1.2 17-29 0 TV-203 ABOUT F 360.1451 >32 N/A 0 TV-204 ABOUT F 360.1451 3.2-3.7 > 100 0 TV-205 ^F o 402.1561 3.9 N/A 0 TV-206 ^F o 418.1331 2.8 N/A OBD-056 0 1.9 17 0 TV-222 0 ^ο Χ ^Ν ^Ζ) ^Μ νθΝ ^F 0 386.1185 7.4 N/A 0 TV-223 °X ^N ^p^ ^N b<s _Y o^ ^F o 366.1466 0.8-2.6 38->100 0 TV-23 8 o ^F o 376.1652 2-4 20 0 TV-23 9 o ^F o 390.1808 2.1-3.8 19-67

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0 TV-229 F O X/ X/ A // F 327.1135 1.9-7.4 > 100 OBD-062 E O F 0.1-0.25 21->100 0 TV-230 J=v K ⁰ XN—<\ /)—NI N X/ X/ A // ^F O 368.1418 0.2 13 0 TV-231 F O N—2 N^? N x/ X/ y y ^F o 384.1367 0.24-0.7 37-63 0 TV-232 o r ΖΣ ο=ω=ο \ 404.1087 1.5-4 > 100 0 TV-233 F O ^f J 394.1575 0.36-1 8.4-50 0 TV-234 F O F 378.1365 0.39-4 43->100 OBD-061 F 0 0.8 29 0 TV-240 F O °X ^m -0 ^m bc _y T7 ^F o 408.1716 0.24-0.6 19-67 OBD-051 F O F O 381.9 0.6 6

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OBD-052 F.θ Ik ΎΑν—< λ—N I n ^4 F O 398.0 0.95 13 OBD-055 F O <k / \ Ν^ ^Ν . VAN—< λ—Ν 1 / \ y-/ F 391.8 1.3 15 OBD-112 Ο 3.5 >100 OBD-113 ο 0.39 >100 OBD-110 0 /=4 Χο 0.45 7 OBD-111 . /-ν k /An—/ Λ—n I h 0.49 7 OBD-114 F O 4^ 1.7 >100 OBD-115 0.2=0.3 87->100 OBD-048 . kvk 4 v- 0.39 5 OBD-049 0.25-1 6->100 OBD-252 F O 0.47 32.3 OBD-253 /^3=4 k 4 ta 0.53 65 OBD-054 0.5 6-31 OBD-254 0.73 36

Definitions.

As used herein, unless otherwise indicated, the term alkyl includes branched and straight chain saturated aliphatic hydrocarbon groups containing the specified number of carbon atoms. The present invention uses commonly used abbreviations for alkyl groups, for example, methyl may be represented by the traditional abbreviation including

Me or _CH3 or a symbol that represents an extended bond without a specific terminal c_____ group, for example *, ethyl is represented by the abbreviation Et or _CH3CH3 , propyl is represented by the abbreviation Pr or _CH2CH2CH3 , butyl can be represented by the abbreviation Bu or CH2CH2CH2CH3, etc. . C1.6 alkyl (or C1-C6 alkyl) means branched or straight chain alkyl groups, including all isomers having the indicated pure carbon atoms. C1.6 alkyl includes all alkyl isomers of hexyl and pentyl, as well as n-, iso-, sec- and m-butyl, n- and isopropyl, ethyl and methyl.

If the number of atoms is not specified, 1-10 carbon atoms are assumed for linear or branched alkyl groups. C1-6 alkyl may be unsubstituted or substituted with 1-3 fluorine atoms or 1-3 chlorine atoms.

The term cycloalkyl means C ₃ . ₁₀ carbocycles that do not contain heteroatoms. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl and the like.

The term aryl refers to mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryls 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.

The term heterocyclyl, unless otherwise specified, 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 a carbon atom 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 non-aromatic, such as 2- or 4-pyridones attached via a nitrogen atom or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). Heterocyclyl may also include such moieties in a charged form, such as piperidinium.

The term heteroaryl means a mono- or bicyclic aromatic ring or ring system containing from 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. Heteroaryls also include 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. Heteroaryls also include such groups in a charged form, an example being pyridinium. In one embodiment, heteroaryl is triazolyl, imidazolyl, oxadiazolyl, pyrazolyl, oxazolyl, and pyridinyl.

The term heterocyclic alkyl, unless otherwise specified, includes saturated aliphatic hydrocarbon groups, both branched and straight chain, which are bonded to the carbon or nitrogen atom of the heterocyclyl group described above.

Halogen (or halo) includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). In one embodiment, the halogen is chlorine or fluorine.

Substitution with said substituent may be on any ring atom (eg, an aryl ring, a heteroaryl ring, or a saturated heterocyclic ring), provided that such ring substitution is chemically feasible and results in a stable compound. A stable compound can be prepared and isolated and its structure and properties remain substantially unchanged or can be made to remain substantially unchanged for a period of time during which the compound can be used for the purposes described.

According to the standard nomenclature used herein, the terminal portion of the specified side chain is described first, and then the adjacent functional groups are described relative to the point of attachment. For example, C1.5 alkyl COOR is the equivalent

O II StbElkil-C-OR

When a variable (such as R, Rx, etc.) appears more than once in any construct or formula, it is defined in each instance independently of its definition in each other occurrence. In addition, combinations of substituents and/or variables are possible only if such combinations result in stable compounds.

When selecting compounds according to the present disclosure, one skilled in the art will be able to determine that the various substituents, i.e., R ¹ , R ² , R , etc., must be selected in accordance with the general principles of stability and addition to obtain chemical structures.

The term substituted is used to include multiple degrees of substitution with a specified substituent. If multiple substituents are claimed, the substituted compound may be independently substituted with one or more of the disclosed substituents. The term independently substituted means that said substituents (two or more) may be the same or different.

If a proxy or variable has multiple values, such proxy or variable is defined as being selected from the group consisting of the specified values.

Salt.

Compounds of structural formula I also include 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 derived from pharmaceutically acceptable bases or acids, including inorganic or organic bases or acids. Pharmaceutically acceptable salts of the basic compounds refer to non-toxic salts of the compounds of the present invention, which are typically prepared by mixing the free base with a suitable organic or inorganic acid. Exemplary salts of the base compounds of the present invention include, but are not limited to, the following salts: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, clavulanate, citrate, edetate, edisylate , estolate, esilate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate , subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, valerate and the like. Suitable pharmaceutically acceptable salts of acids covered by Formula I include, but are not limited to, salts formed from inorganic bases, including aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese ( III), manganese (II), 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, dicyclohexylamines 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 provides methods for the synthesis of compounds of formula I, described below.

One aspect of interest of the present invention relates to a compound according to Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in a method of treating a microbial infection in a human.

Another aspect of interest of the present invention is a method of treating a microbial infection 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 another aspect of the present invention, pharmaceutical compositions of a compound of formula I or a salt, hydrate or solvate thereof are provided, further comprising one or more additional anti-infective agents.

In yet another aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof for use as an agent against tuberculosis (TB) in humans.

Although the compounds of the present invention can be administered as a parent chemical, it is preferable that it be presented in the form of a pharmaceutical composition. Thus, according to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutical carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be acceptable in terms of compatibility with the other ingredients of the formulation and not harmful to the recipient thereof.

These 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 appropriate route of administration may depend on the condition and disorder of the recipient. Tablets, capsules, intraocular topical formulations, and parenteral solutions are common for aminoglycosides. The compositions may be presented in a convenient unit dosage form and may be prepared by any of the methods well known in the pharmaceutical field. All methods include the step of combining a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (the active

- 18 043707 ingredient) with a carrier that contains one or more additional ingredients. In general, formulations are prepared by uniformly and thoroughly combining the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then molding the product, if necessary, to obtain the desired composition.

The compositions of the present invention suitable for oral administration may be presented in the form of individual units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of 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 prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable device the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. Molded tablets can be prepared by molding in a suitable device a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide delayed, delayed or controlled release of the active ingredient.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatics and solutes that make the composition isotonic with the blood of the desired 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 single-dose or multi-dose containers, such as sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g., saline, phosphate-buffered saline (PBS). ) or the like, immediately before use. Injectable solutions or suspensions prepared for immediate administration can be prepared from sterile powders, granules or tablets such as those described previously.

Preferred unit dose formulations are those containing an effective dose of the active ingredient set forth below, or a suitable portion thereof.

It should be understood that in addition to the ingredients specifically mentioned above, the compositions of the present invention may contain other agents conventional in the art relevant to the type of solution in question, for example, compositions suitable for oral administration may contain flavoring agents.

Abbreviations

The following schemes and synthesis examples use abbreviations and, unless otherwise noted, have the following meanings:

Ac - acetate or acetyl;

aq. - water;

Ar - aryl;

Bn - benzyl;

BnNH2 - benzylamine;

Boc - tert-butylcarbamoyl;

wide - broadening;

Bu - butyl;

'Bu - tert-butyl;

n-BuLi - n-butyllithium;

CbzCl - benzyl chloroformate;

CFU - colony forming units;

CO ₂ - carbon dioxide;

COX-1 - cyclooxygenase I;

^c Pr - cyclopropyl;

DCM - dichloromethane;

DIPEA - N,N-diisopropylethylamine;

DMAP - 4-dimethylaminopyridine;

DMEM - Dulbecco's medium, modified needle medium;

DMF - N-dimethylformamide;

DMSO - dimethyl sulfoxide;

ELISA - enzyme-linked immunosorbent assay;

ESI - electrospray ionization;

- 19 043707

Et - ethyl;

Et ₃ N - triethylamine;

Et2O - diethyl ether;

EtOH - ethanol;

EtOAc - ethyl acetate;

FBS - fetal bovine serum;

halogen - halogen (for example, fluorine or chlorine);

'H-NMR - proton nuclear magnetic resonance;

¹³ C-NMR - nuclear magnetic resonance on carbon nuclei;

H9C2 - rat cardiac myoblast cell line;

HPLC - high performance liquid chromatography;

MSHR - high resolution mass spectrometry;

Hz - Hertz;

i - iso;

IC ₅₀ - concentration of half-maximal inhibition;

kg - kilogram;

M - molar;

Me - methyl;

mcg - microgram;

MeCN - acetonitrile;

MeOH - methanol;

MsCl - methanesulfonyl chloride;

MHz - megahertz;

mm - millimeter;

µl - microliter;

mM - millimolar;

µM - micromolar;

mmol - millimoles;

MAVA - study in microplates with alamar blue;

MIC - minimum inhibitory concentration;

SMB - synthesis of mitochondrial proteins;

m/z is the ratio of mass to charge;

n - normal;

ZAK - nonessential amino acids;

nm - nanometer;

uPr - n-propyl;

p- - para-;

PE - petroleum ether;

Ph - phenyl;

Pr - cut;

room temperature;

second- - secondary;

SDH-A - succinate dehydrogenase-A;

tert- - tertiary;

TFA - trifluoroacetic acid;

TsCl - p-toluenesulfonyl chloride;

TMSI - trimethylsilyl iodide;

TPP - triphenylphosphine;

TsNH ₂ - p-toluenesulfonamide;

tosyl - p-toluenesulfonyl;

THF - tetrahydrofuran;

TLC - thin layer chromatography.

Examples

Synthetic methods for preparing some of the compounds of the present invention are illustrated by the following examples. The starting materials are commercially available or can be prepared according to procedures known in the art or illustrated herein. The following examples are intended to illustrate the present invention and are not intended and should not be construed as limiting its scope.

- 20 043707

Example 1.

Preparation of [1,4]thiazepane (1a)

EYUN/NgO, arr. HOL.

HO-NH ₂ HCI

115 degrees polyphosphoric acid

Step 1. Synthesis of dihydro-2H-thiopyran-4(3H)-onoxime (1a-1)

Sodium acetate was added 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). (13.1 g, 0.16 mol). The resulting mixture was refluxed for 4 hours, the organic solvent was removed in vacuo and the residue was cooled in an ice bath to obtain 8.92 g of a solid in 79% yield by filtration. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.88 (m, 2H), 2.80 (m, 2H), 2.74 (m, 2H), 2.57 (m, 2H).

Step 2. Synthesis of 1,4-thiazepan-5-one (1a-2)

A mixture of dihydro-2H-thiopyran-4(3H)-one oxime (4.01 g, 0.03 mol) in polyphosphoric acid was heated at 115°C for 15 min and cooled to room temperature, ice water was added, then the resulting mixture 5 extracted with EtOAc times. The combined organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 2.4 g of product as a brown solid in 60% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.79 (broad s, 1H), 3.63 (m, 2H), 2.94 (m, 2H), 2.74 (m, 4H) .

Step 3. Synthesis of 1,4-thiazepane (1a)

LiAlH ₄ (0.66 g, 17.3 mmol) was added to a solution of 1,4-thiazepan-5-one (2.07 g, 15.7 mmol) in dry THF at 0°C, then the resulting mixture was stirred at room temperature for 4 hours. H2O (0.7 ml), 15% NaOH (0.7 ml) and H2O (2.1 ml) were sequentially added to the resulting reaction mixture. The mixture was filtered to obtain 1.77 g of product with a yield of 96%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.07 (m, 2H), 2.98 (m, 2H), 2.75 (m, 4H), 1.93 (m, 2H).

Example 2.

Preparation of 1,5-thiazocane hydrochloride (1b)

Bn

N 3-chlorobutanoyl chloride MeOH

CH ₂ C1 _2.0 degrees arr. cold

- 21 043707

Step 1: Synthesis of dimethyl-3,3'-(benzylazanediyl)dipropanoate (1b-1)

Bn / ⁰ y ⁴ -/ N O \

Oh Oh

A solution of benzylamine (10.7 g, 0.1 mol) in MeOH (50 ml) was added dropwise to a solution of methyl acrylate (18.9 g, .022 mol) in MeOH (100 ml) at room temperature. The resulting mixture was refluxed for 8 hours and evaporated in vacuo to give 27.9 g of product in quantitative yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.28 (m., 5H), 3.64 (s, 2H), 3.59 (s, 6H), 2.80 (m, 4H), 2.47 (m, 4H).

Step 2. Synthesis of 3,3'-(benzylazanediyl)bis(propan-1-ol) (1b-2)

Bn

ΗΟχ^Ν^ζ^ΟΗ

LiAlH ₄ (0.77 g, 20.2 mmol) was added to a solution of dimethyl 3,3'-(benzylazandiyl)dipropanoate (4.47 g, 16.0 mmol) in dry THF at 0°C, then the resulting mixture was stirred at room temperature for 24 hours. MeOH (1.5 ml), 15% NaOH (1.0 ml) and H2O (1.0 ml) were sequentially added to the resulting reaction mixture. The mixture was filtered to obtain 3.4 g of product with a yield of 91%.

¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Step 3. Synthesis of N-benzyl-3-bromo-N-(3-bromopropyl)propan-1-amine (1b-3)

Bn

NBr

PBr 3 _was added dropwise to a solution of 3,3'-(benzylazandiyl)bis(propan-1-ol) (447 mg, 2.0 mmol) in dry CH ₂ Cl ₂ at 0°C, then the resulting mixture was stirred at room temperature for 12 hours. The resulting reaction mixture was diluted with water and extraction was carried out with CH ₂ Cl ₂ . The combined organic layer washed us. NaHCO ₃ and saline, dried over Na ₂ SO ₄ and concentrated. 0.43 g of product was obtained as a yellow oil with a yield of 61%. 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).

Step 4. Synthesis of 5-benzyl-1,5-thiazocane (1b-4)

Bn O s—

Na ₂ SH 2 O (697 mg, 2.9 mmol ₎ was added to a solution of N-benzyl-3-bromo-N-(3-bromopropyl)propan-1-amine (1.0 g, 2.9 mmol) in ethanol. . The resulting mixture was refluxed for 18 hours. The mixture was then cooled to room temperature and the solvent was removed under vacuum. H2O and Et ₂ O were added to the residue. The aqueous layer was extracted with Et ₂ O and the combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was used without purification.

Step 5. Synthesis of 1,5-thiazocane hydrochloride (1b)

To a solution of 5-benzyl-1,5-thiazocane (8.6 g, 39 mmol) in CH ₂ Cl ₂ was added (6.15 g, 43 mmol) at 0°C. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated in vacuo and the residue was refluxed in MeOH for 3 hours. The mixture was concentrated and washed with Et2O. The crude product was used without purification.

- 22 043707

Example 3.

Preparation of (^^)-3-thia-6-azabicyclo[3,1,1]heptane (1c)

Step 1. Synthesis of diethyl 2,4-dibromopentanedioate (1c-1)

Br ₂ (32 g, 0.2 mol) was added dropwise to a solution of dihydro-2H-pyran-2,6(3H)-dione (11.4 g, 0.1 mol) and PBr ₃ (0.1 ml) at 100°C, the resulting mixture was stirred at 100°C for 7 hours and cooled to room temperature. HCl/EtOH (10 ml) was added to the resulting reaction mixture and stirred overnight at room temperature. EtOH was evaporated, after which Et2O was added to the residue and we were washed. NaHCO ₃ and saline, dried over Na ₂ SO ₄ , concentrated, obtaining 32 g of product, which was used in the next step without purification.

Step 2. Synthesis of (2R,4S)-diethyl-1-benzylazetidine-2,4-dicarboxylate (1c-2)

IEtOOC-^>—COOEt

N

Bn

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 at for 24 hours. The resulting mixture was washed with brine, dried and concentrated. The crude product was purified by silica gel chromatography to give 18.39 g of product in 41% yield. MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₆ H ₂₂ NO ₄ : 292.1549; experimental value: 292.1542.

Step 3. Synthesis of ((2R,4S)-1-benzylazetidin-2,4-diyl)dimethanol (1с-3)

HE

VP

CaCl ₂ (0.92 g , 8.25 mmol) at room temperature. Next, NaBH4 (0.63 g, 16.5 mmol) was added to the resulting stirred mixture in portions. The reaction mixture was stirred overnight at room temperature. H2O (5 ml) was then added and the resulting mixture was stirred for 30 min. The mixture was then concentrated in vacuo and partitioned between H ₂ O (10 ml) and CH ₂ Cl ₂ (10 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (2x10 ml) and the organic layers were combined, washed with brine (10 ml), dried over Na2SO4 and concentrated in vacuo to give 0.25 g of product as a yellow oil. This product was used in the next step without further purification. MS (IER): m/z [M+H] ⁺ : 208.1477.

Step 4. Synthesis of (2R,4S)-benzyl-2,4-bis(hydroxymethyl)azetidine-1-carboxylate (1c-4)

I Cbz

To a solution of ((2R,4S)-1-benzylazetidin-2,4-diyl)dimethanol (0.52 g, 2.9 mmol) in MeOH (10 ml) was added Pd(OH) ₂ (0.13 g) and the resulting mixture was stirred for 2 hours under H ₂ at room temperature. The suspension was filtered through a small pad of celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in anhydrous CH ₂ Cl ₂ (30 ml). DIPEA (0.37 g, 2.9 mmol) and then CbzCl (0.44 g, 2.56 mmol) were added dropwise to the resulting solution. The mixture was stirred for 2 hours at room temperature and then quenched with H2O (50 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (5% MeOH in CH ₂ Cl ₂ ) to give 0.33 g of product as a yellow oil in 45% yield.

- 23 043707

Step 5. Synthesis of (R,4S)-benzyl-2,4-bis(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (1 c-5)

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 hours at room temperature, and the reaction mixture was washed with 1 N. HCl and saline, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (5% MeOH in CH ₂ Cl ₂ ) to give 65 mg of product as a yellow oil in 80% yield.

MSHR (ESI): m/z [M+H]+ calculated value for C ₁₅ H ₂₂ NO ₈ S ₂ : 408.0787; experimental value: 408.0780.

Step 6. Synthesis of (2R,4S)-benzyl-2,4-bis(bromomethyl)azetidine-1-carboxylate (1c-6)

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 hours. The reaction mixture was evaporated, the residue was added with H ₂ O (20 ml) and Et ₂ O (20 ml). The aqueous layer was extracted with Et ₂ O (2x20 ml) and the combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give 51 mg of product as a yellow oil in 85% yield. MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₃ H ₁₅ Br ₂ NO ₂ : 375.9548; experimental value: 375.9558.

Step 7. Synthesis of (1R,5S)-benzyl-3-thia-6-azabicyclo[3,1,1]heptane-6-carboxylate (1c-7)

Na ₂ S-9H ₂ O (0 .59 g, 2.46 mmol). The resulting mixture was stirred at room temperature for 45 minutes. H2O (20 ml) and EtOAc (25 ml) were added to the solution. The aqueous layer was extracted with EtOAc (2x20 ml) and the combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-30% EtOAc in \PE) to give 0.15 g of product as a colorless oil in 28.7% yield. MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₃ H ₁₇ NO ₂ S: 250.0902; experimental value: 250.0900.

Step 8. Synthesis of (1R,5S)-3-thia-6-azabicyclo[3,1,1]heptane iodate (1c)

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 CH ₂ Cl ₂ (20 ml) TMSI (0.39 g, 1.9 mmol) was added under argon at 0°C. The mixture was stirred at room temperature for 2 hours, and MeOH (5 ml) was added dropwise to the resulting reaction mixture. The resulting solution was stirred for another 0.5 h and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (2:1) to give 0.24 g of crude product as a brown solid and used without purification.

Example 4.

Preparation of (1R,5S)-3-thia-8-azabicyclo[3,2,1]octane iodate (1d)

- 24 043707

Br

OOOEt ^COOEt Br

BnNH ₂ to ₂ co.

Toluene

GL (1)H ₂ 10%Pd/C /—y

EtOOC^N^COOEt ----------► EtOOC^M^COOEt

Bn (2) CbzCI Et ₃ N g _bz

NaBH.

---------* ^NazS ' ^9Нго s-__Λ

CaCL Ν * 'Ο'^Ν

Cbz DMAP cbz cbz

TMSI d

-----------* ^|H NH

Step 1. Synthesis of cis-diethyl-1-benzylpyrrolidine-2,5-dicarboxylate (1d-1)

EtOOC^N^COOEt

Bn

K ₂ CO _{3 (} 5 g, 36 mmol) at room temperature. The mixture was refluxed for 20 hours under argon and then poured into H ₂ O (30 ml). The aqueous layer was extracted with EtOAc (2x20 ml), the combined organic layers were washed with brine (20 ml), dried over Na2SO4, and purified by silica gel chromatography (1020% EtOAc in PE) to give 6.1 g of yellow product oils with a yield of 67%.

¹ H-NMR (400 MHz, CDCl3) δ: 7.35-7.22 (m, 5H), 4.06-4.00 (m, 4H), 3.97 (s, 2H), 3.46 (broad s, 2H), 2.08-2.04 (m, 4H), 1.19 (t, J = 7.1 Hz, 6H). MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₂₄ NO ₄ : 306.1705; experimental value: 306.1695.

Step 2. Synthesis of cis-1-benzyl-2,5-diethylpyrrolidine-1,2,5-tricarboxylate (1d-2)

EtOOC^N^COOEt

Cbz

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 resulting mixture was shaken. Parr for 4 hours at approximately 345 kPa (50 psi) H ₂ pressure and RT. The resulting suspension was filtered through a small pad of celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in anhydrous CH ₂ Cl ₂ (50 ml) and cooled to 0°C. Et ₃ N (2.2 g, 21.6 mmol) and then CbzCl (3.7 g, 21.6 mmol) were added dropwise to the resulting solution. The mixture was stirred overnight at room temperature and then quenched with H ₂ O (50 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (5-20% EtOAc in PE) to give 5.22 g of product as a yellow oil in 84% yield. ¹ H-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). MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₈ H ₂₄ NO ₆ : 350.1604; experimental value: 350.1649.

Step 3. Synthesis of cis-benzyl-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1d-3)

CaCl ₂ (5, 5 g, 49.2 mmol) at room temperature. NaBH ₄ (3.75 g, 98.4 mmol) was then added to the resulting stirred mixture in portions. The reaction mixture was stirred overnight at room temperature. H ₂ O (50 ml) was then added and the resulting mixture was stirred for 30 minutes. The mixture was then concentrated in vacuo and partitioned between H ₂ O (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (2x50 ml) and the organic layers were combined, washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give 4.57 g of product as a colorless oil. This product was used in the next step without further purification.

1H-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 2H), 2.04-1.97 (m, 4H). MSHR (ESI): m/z [M+Na] ⁺ calculated value for C ₁₄ H ₁₉ NNaO ₄ : 288.1206; experimental value: 288.1196.

Step 4. Synthesis of cis-benzyl-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate (1d-4)

TsO,

OTs

At Cbz

Solution of the compound cis-benzyl-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (4.35 g, 16.4

- 25043707 mmol), Et ₃ N (3.65 g, 36.1 mmol), and DMAP (4.01 g, 32.8 mmol) in CH ₂ Cl ₂ (50 ml) were 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 RT. The mixture was then washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo . The residue was purified by flash column chromatography (30-40% EtOAc in PE) to give 8.97 g of product as a semi-solid in 95% yield. 1H-NMR (400 MHz, CDCl ₃ ) δ: 7.73 (broad s, 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. MSVR (IER): m/z [M+H]+calculated value for C ₂₈ H ₃₂ NO ₈ S ₂ : 574.1564; experimental value: 574.1547.

Step 5. Synthesis of (1R,5S)-benzyl-3-thia-8-azabicyclo[3,2,1]octane-8-carboxylate (1d-5)

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 Na ₂ S-9H ₂ O (5.12 g, 21.3 mmol). The resulting mixture was refluxed for 5 hours. The mixture was then cooled to room temperature and the solvent was removed in vacuo. H2O (20 ml) and EtOAc (25 ml) were added to the residue. The aqueous layer was extracted with EtOAc (2x20 ml) and the combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-30% EtOAc in PE) to give 1.38 g of 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). ¹³ C-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. MSVR (IER): m/z [M+H] ⁺ calculated value for C14H ₁₈ NO ₂ S: 264.1058; experimental value: 264.1113.

Step 6. Synthesis of (1R,5S)-3-thia-8-azabicyclo[3,2,1]octane iodate (1d) S-D |H

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 CH ₂ Cl ₂ (20 ml) TMSI (0.44 g, 2.18 mmol) was added under argon at 0°C. The resulting mixture was stirred at room temperature for 0.5 h, and MeOH (0.26 ml) was added dropwise to the resulting reaction mixture. The resulting solution was stirred for another 0.5 h and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (1:2) to give 0.21 g of product as a yellow solid in 91% yield. Melt: 208-210°C. 1H-NMR (400 MHz, CDCl ₃ ) δ: 8.92 (sb, 1H), 8.72 (sb, 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, CDCl ₃ ) δ: 55.67, 31.42, 27.23. MSVR (IER): m/z [M+H] ⁺ calculated value for C6H12NS: 130.0685; experimental value: 130.0686.

Example 5.

Preparation of 2-thia-6-aza-spiro[3,3]heptane (1e)

Na ₂ S-9H ₂ O O /=\ _Md

--------* ^S \X/ ^N- u “A # ^CH z ------* s X NH

CH3CN/H2O, 50 °C x/ XX II MeOH xx X/

Step 1. Synthesis of 6-tosyl-2-oxa-6-azaspiro[3,3]heptane (1e-1)

p-Tosylamide ( 17.9 g, 104 mmol) at room temperature and the resulting

- 26 043707 the reaction mixture was heated at reflux for 20 hours. The solvent was removed by evaporation, 100 ml of 8% NaOH solution was added and the resulting suspension was stirred for another 2 hours. The mixture was filtered and the resulting white precipitate on the filter was washed with water until the washing the water did not become 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). MSHR (ESI-TOF ⁺ ): m/z [M+H] ⁺ calculated value for C ₁₂ H ₁₆ NO ₃ S: 254.0825; experimental value: 254.0851.

Step 2. Synthesis of (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (1e-2)

To a suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3,3]heptane (1e-1) (9.79 g, 38.7 mmol) in Et ₂ O (200 ml) at 0° A solution of hydrobromic acid (approximately 33% in AcOH) was added dropwise. The resulting solution was stirred at room temperature for 30 minutes, and its pH was adjusted to pH=8 using 1 mol/L NaOH. The phases were separated and the aqueous phase was subjected to extraction with Et ₂ O (3x100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as a colorless solid. Yield: 10.0 g (77.4%). ¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Step 3. Synthesis of 3,3-bis(bromomethyl)-1-tosylazetidine (1e-3)

(3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (1e-2) (10.0 g, 30.0 mmol) was dissolved in CH ₂ Cl ₂ and CBr ₄ (16.4 g, 49.0 mmol) was added 4 mmol). The resulting solution was cooled to 0°C and PPh ₃ (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 silica gel chromatography (510% EtOAc in PE) to give the pure title compound. Yield: 8.85 g (74.8%). 1H-NMR (400 MHz, CDCl ₃ ) 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).

Step 4. Synthesis of 6-tosyl-2-thia-6-azaspiro[3,3]heptane (1e-4) o _/= .

NS—S e— sn, X/\/ nA# ³ O —'

_{Na 2} S- 9H ₂ O (10.7 g, 44.7 mmol) and the resulting reaction mixture was stirred at 50°C for 4 hours, then it was concentrated to dryness. A solution (100 ml) of EtOAc (100 ml) and NaHCO ₃ was added and the phases were separated. The aqueous phase was subjected to extraction with EtOAc (2x100 ml). The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound. Yield: 5.46 g (90.1%). 1H-NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₂ H ₁₆ NO ₂ S ₂ : 270.0622; experimental value: 270.0621.

Step 5. Synthesis of 2-thia-6-azaspiro[3,3]heptane (1e)

6-Tosyl-2-thia-6-azaspiro[3,3]heptane (1e-4) (2.0 g, 7.9 mmol) was dissolved in MeOH (40 ml). Magnesium powder (1.0 g) was added to the resulting solution, and the reaction mixture was sonicated at room temperature for about 3 hours. The reaction mixture was concentrated in vacuo, and the crude product was used in the next step without purification.

Example 6.

Preparation of 2-oxa-6-aza-spiro[3,3]heptane (1f)

Step 1: Synthesis of 6-tosyl-2-oxa-6-azaspiro[3,3]heptane

- 27 043707

The specified product was synthesized as described in example 5, stage 1.

Step 2. Synthesis of 2-oxa-6-azaspiro[3,3]heptane (1f)

6-Tosyl-2-oxa-6-azaspiro[3,3]heptane (6.3 g, 25.0 mmol) was dissolved in MeOH (50 ml). Magnesium powder (6.0 g) was added to the resulting solution and the reaction mixture was sonicated at room temperature for about 3 hours. The reaction mixture was concentrated in vacuo, and the resulting crude product was used in the next step without purification.

Example 7.

Preparation of N-Boc-protected 2,6-diaza-spiro[3,3]heptane (1g)

Step 1. Synthesis of (3-(bromomethyl)-1-(p-toluenesulfonyl)azetidin-3-yl)-methanol (1g-1)

To a suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3,3]heptane (6.25 g, 24.7 mmol) (prepared according to example 5, step 1) in Et ₂ O (100 ml ) at 0°C, a solution of hydrobromic acid (approximately 33% in AcOH; 4.1 ml, 24.7 mmol) in Et ₂ O (5 ml) was added dropwise over 15 min. The resulting mixture was warmed to room temperature and stirred for 45 minutes. 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 (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound 7.74 g as a colorless solid. The resulting crude product was pure enough for further transformations.

Step 2. Synthesis of 3,3-bis(bromomethyl)-1-(p-toluenesulfonyl)azetidine (1g-2)

The above crude product 1g-1 (7.74 g, 23.1 mmol) was dissolved in CH2Cl2 (100 ml) and CBr ₄ (13.7 g, 41.2 mmol) was added in one portion. The resulting solution was cooled to 0°C and PPh ₃ (26.26 g, 41.2 mmol) was added in one portion. The resulting reaction mixture turned into a dark orange solution, which was stirred at 0°C for 1.5 hours, then warmed to room temperature and stirred for another 8 hours. The resulting mixture was concentrated under reduced pressure to give a dark orange oil, which was purified with chromatography (hexane:EtOAc 4:1) to give the title compound, 7.61 g. ¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Step 3. Synthesis of 2-benzyl-6-(p-toluenesulfonyl)-2,6-diazaspiro[3,3]heptane (1g-3)

Ts—N

N—Bz

Dibromide 1g-2 (7.61 g, 19.1 mmol) was dissolved in CH ₃ CN (100 ml). Benzylamine (4.1 g, 38.3 mmol) and DIPEA (12.4 g, 95.5 mmol) were added to this mixture and the resulting reaction mixture was refluxed for 3 days. Next, the resulting yellowish solution was cooled to room temperature and concentrated to approximately 1/6 of the original volume. The residue was partitioned between CH ₂ Cl ₂ (100 ml) and 1 mol/l NaOH (100 ml). The organic phase was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (50 ml). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography (hexane:EtOAc: _Et3N gradient 1:1:1% to 1:2:1%) to give the title compound 4.0 g. 1H-NMR (400 MHz, _CDCl3 ) δ: 7.69 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 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).

- 28 043707

Step 4. Synthesis of tert-butyl-6-(p-toluenesulfonyl)-2,6diazaspiro[3,3]heptane-2-carboxylate (1 g-5) Ts—N^<^N—Boc

Benzylazetidine 1g-3 (2.70 g, 7.88 mmol) was dissolved in MeOH (40 ml), and Pd/C (10% on carbon; 0.54 g) was added to the above mixture. A hydrogen atmosphere was created (approximately 345 kPa (50 psi)) and the resulting mixture was heated to 45 °C and stirred at this temperature for 48 hours. The reaction mixture was then cooled to room temperature and filtered through celite. The filter cake was thoroughly washed with MeOH (2x20 ml). To the above solution of the Ts-protected azetidine intermediate (1g-4) in MeOH (ca. 80 mL) was added Boc ₂ O (1.77 g, 7.88 mmol). The resulting solution was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by chromatography (1:1 to 1:2 hexane:EtOAc gradient) to give 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).

Step 5. Synthesis of tert-butyl-2,6-diazaspiro[3,3]heptane-2-carboxylate (1g)

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 resulting mixture was sonicated for 6 hours. The reaction mixture was concentrated in vacuo to give a dark gray solid that could be used for the subsequent reaction without purification.

Example 8.

General synthesis methods: preparation of oxazolidinone compounds

where, ^R1 'N' ^R2 n represents ring A, previously defined in formula I; X = H or F.

General methods for the preparation of (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)-phenyl)-2-oxooxazolidin-5yl)methyl)acetamide (OTB-114) and its sulfoxide (OTV-124) are presented below. oh oh

OTV-114 OTV-124

Step A. 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane

F

A solution of 3,4-difluoronitrobenzene (4.92 g, 31 mmol) and 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 resulting reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with H ₂ O and CH ₂ Cl ₂ , and the aqueous layer was extracted with CH ₂ Cl ₂ (50 ml*3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The resulting crude product was purified by silica gel chromatography (PE/CH2-SiA) to obtain 3.36 g (40%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl ₃ ) 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).

Step B. benzyl-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)carbamate

To a solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (3.0 g, 12.5 mmol) in MeOH/THF, 10% Pd/C (0.3 g) was added and the resulting mixture was shaken 4 h under H ₂ at room temperature. The suspension was filtered through a small pad of celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in THF/H ₂ O (50 ml). NaHCO ₃ (2.12 g, 25.2 mmol) and then CbzCl (2.58 g, 15.1 mmol) were added dropwise to the resulting solution. The mixture was stirred overnight at room temperature and concentrated. H ₂ O (50 ml) was added to the residue and extraction was carried out with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (PE/EtOAc=5:1) to give 4.6 g of product as a colorless solid in 98% yield. 1H-NMR (400 MHz, CDCl ₃ ) 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).

Step C. (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxαzolidinyl]methanol o

F

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 (bath with dry ice/acetone) in an N ₂ atmosphere. n-Butyllithium (2.5 M solution in hexane, 2.9 ml, 7.2 mmol) was added to the resulting reaction mixture over 10 minutes. The resulting light yellow solution was stirred at -78°C for 50 min and then treated dropwise with (R)-(-)glycidyl butyrate (0.95 ml, 6.9 mmol). The reaction mixture was stirred for another 30 minutes at 78°C and then the cooling bath was removed. The reaction mixture was allowed to warm to ambient temperature overnight. A saturated aqueous solution of NH ₄ Cl (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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=1:2) to give 1.33 g of product as a colorless solid in 59% yield. 1H-NMR (400 MHz, CDCl ₃ ) 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).

Step D. (K)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5oxazolidinyl]methylmethanesulfonate

A solution of (K)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methanol (1.0 g, 2.94 mmol) in dry CH2Cl2 was cooled in 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 hours at room temperature and washed with H ₂ O, saturated aqueous NaHCO ₃ and brine. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated. The resulting product was used in the next step without purification.

Step E. (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]-methylazide

A solution of (K)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methylmethanesulfonate (859 mg, 2.1 mmol) in dry DMF treated with solid NaN ₃ (683 mg, 10.5 mmol) at room temperature. Next, the resulting mixture was heated to 65 °C for 8 hours, cooled to room temperature; the reaction mixture was then quenched with H ₂ O and extracted with EtOAc. The combined organic layer was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting product was used in the next step without purification.

Step F. (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxαzolidin-5-yl)methyl)acetamide

To a solution of (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl azide (216 mg,

- 30 043707

0.59 mmol) in MeOH/THF was added 10% Pd/C (22 mg) and the resulting mixture was shaken for 4 hours in an atmosphere of H ₂ at room temperature. The resulting suspension was filtered through a small pad of celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in CH ₂ Cl ₂ and treated with Et ₃ N (121 mg, 1.2 mmol) and AcCl (56 mg, 1.2 mmol). The reaction mixture was quenched with H2O and extraction was carried out with CH ₂ Cl ₂ . The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ /MeOH=100:1) to give 0.1 g of product as a colorless solid in 44% yield. Tpl. 78-80°C. [a] ²⁰ ,D -15.4 (with 0.25, CHCl3). ¹ H-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, CDCl ₃ ) 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] ⁺ calculated value for C ₁₈ H ₂₅ O ₃ N ₃ FS: 382.1595; experimental value: 382.1620.

Step G. (S)-N-[[3-(3-fluoro-4-(1-oxido-1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]acetamide

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 resulting reaction mixture was stirred at 0°C for 2 hours and concentrated. H2O was added to the resulting residue, followed by extraction with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ /MeOH=100:1) to give 39 mg of product as a colorless solid in 75% yield. Tpl. 69-70°C. ¹ H-NMR (400 MHz, CDC/) 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] ⁺ calculated value for C18H ₂₅ O ₄ N ₃ FS: 398.1544; experimental value: 398.1540.

Example 9.

In vitro antimicrobial susceptibility testing Antimicrobial susceptibility testing was performed in 96-well microplates. Initial dilutions of drugs (6.4 mg/ml) were prepared in dimethyl sulfoxide and then subsequent twofold dilutions were prepared in 0.1 ml of 7H9 medium (BD) in microplates. The final drug concentrations were approximately 0.008 μg/mL. Each concentration of test compounds was added to two wells. Control wells contained bacteria and a positive control drug (linezolid). The plates were incubated at 37°C. The final bacterial titers were 1 χ 10 ⁶ CFU/ml for H ₃₇ Rv. Beginning on day 7 of incubation, 20 μl of 10χ Alamar Blue (Life Technologies) and 12.5 μl of 20% Tween 80 (Sigma-Aldrich) were added to each well and the plates were re-incubated at 37°C. The wells were monitored after 24 h and the color of each well was recorded. The MIC was visually determined as the minimum amount of drug that prevented the development of color from blue to pink. Fluorescence was measured on a microplate fluorimeter in bottom-reading mode with excitation at 530 nm and emission at 590 nm. For fluorimetrically determined MICs, the lowest drug concentration at which >90% inhibition was achieved was taken as the MIC. The results of MIC determination are presented in table. 1 above.

Example 10.

Study of inhibition of mitochondrial protein synthesis in vitro H9C2 cells were incubated in DMEM (Hyclone, GE LifeSciences) with 10% FBS (Gibco, Life Technologies) and 1χ glutamine (Gibco, Life Technologies) and NEAA (Gibco, Life Technologies) at 37°C , 5% CO ₂ at 1500 cells per well in a 384-well plate. The test compound was added after 18 hours of incubation and then incubated for 5 days. Reductions in COX-1 (cyclooxygenase I) and SDH-A (succinate dehydrogenase-A) protein production were determined by ELISA assay (MitoBiogenesisTM In-Cell ELISA KIT (Colorimetric, Abcam). The results of the assay for MPS are presented in Table 1 above.

Example 11.

Specific compounds synthesized according to general methods.

OTV-107.

- 31 043707 (R)-5-[(1H-1,2,3-triazol-1-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl] -oxazolidin-2-one o

F ¹ H-NMR (400 MHz, CDCI3) 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). ¹³ C-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] ⁺ calculated value for C ₁₇ H ₂₁ O ₂ N ₅ FS: 378.1395; experimental value: 378.1396.

OTV-106.

(R)-5-[(2H-1,2,3-triazol-2-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-oxazolidin- 2-he

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). ¹³ C-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. MC-BP (ESI): m/z [M+H]+ calculated value for C ₁₇ H ₂₁ O ₂ N ₅ FS: 378.1395; experimental value: 378.1403.

OTV-109.

(S)-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-5-[(methylamino)methyl]oxazolidin-2-one o

F ¹ H-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] ⁺ calculated value for C16H ₂₃ O ₂ N ₃ FS: 340.1490; experimental value: 340.1484.

OTV-108.

(C)-[3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methylbutyrate o

o ¹ H-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). ¹³ C-NMR (125 MHz, CDQ3) 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. MC-BP (IERTOF): m/z [M+H]+ calculated value for C ₁₉ H ₂₆ O4N ₂ FS: 397.1592; experimental value: 397.1613.

OTV-111.

(S)-N-[(3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-2-oxooxazolidin-5-yl)methyl]furan-2-carboxamide o

¹ H-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 ). ¹³ C-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. MC-BP (IER-TOF): m/z

- 32 043707

[M+H]+ calculated value for C ₂₀ H ₂₃ O ₄ N ₃ FS: 420.1388; experimental value: 420.1400.

OTV-112.

(S)-N-[(3-[3-fluoro-4-(1,4-thiazepan-4-ul)phenyl]-2-oxooxazolidin-5-yl)methyl]thiophene-2-carboxamide

¹ H-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, CDQ3) 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. MC-BP (ESI-TOF): m/z [M+H] ⁺ calculated value for C18H ₂₅ O ₃ N ₃ FS: 382.1595; experimental value: 382.1620.

OTV-115.

(S)-N-[[3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-pivalamide

¹ H-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, CDCb) 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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C ₂₀ H ₂₉ O ₃ N ₃ FS: 410.1908; experimental value: 410.1942.

OBD-005.

(S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)-butyramide

^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, 7 N), 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]+.

OTB-116.

(R)-N-[[3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-butan-1-sulfonamide

¹ H-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, CDC^) 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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C ₁₉ H ₂₉ O ₄ N ₃ FS ₂ : 446.1578; experimental value: 446.1623.

OTV-119.

(R)-5-[(1H-1,2,4-triazol-1-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-oxazolidin- 2-he

¹ H-NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C17H21O2N5FS: 378.1395; experimental value: 378.1421.

- 33 043707

OTV-412.

Methyl-(S)-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl)-methyl)carbamate

¹ H-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, CDC^) 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] ⁺ calculated value for C17H23C4N3FS: 384.1388; experimental value: 384.1371.

OTV-413.

(S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)-cyclopropanecarboxamide

¹ H-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] ⁺ calculated value for C19H ₂₅ O ₃ N ₃ FS: 394.1595; experimental value: 394.1580.

OTV-414.

(S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)-cyclobutanecarboxamide

¹ H-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] ⁺ calculated value for C20H ₂₇ O ₃ N ₃ FS: 408.1752; experimental value: 408.1736.

OTV-407.

(S)-N-((3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl)-methyl)acetamide

¹ H-NMR (400 MHz, CDCl3) δ: 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). ¹³ CNMR (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] ⁺ calculated value for Ci ₇ H ₂₂ O3N3F ₂ S: 386.1344; experimental value: 386.1330.

OTV-410.

Methyl-(S)-((3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)carbamate

¹ H-NMR (500 MHz, CDCl ₃ ) δ: 7.09 (d, J = 10.0 Hz, 2H), 5.09 (m, 1H), 4.76 (m, 1H), 3.99 (t, J = 9.0 Hz,

- 34 043707

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). ¹³ C-NMR (125 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₂₂ O ₄ N ₃ F ₂ S: 402.1297; experimental value: 402.1287.

OTV-408.

(8)-5-((cyclopropylamino)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)-oxazolidin-2-one

1H-NMR (400 MHz, CDCl3) x: 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), 1.371.39 (m, 1H), 0.97 (m, 1H), 0.93 (m, 1H), 0.77-0.79 (m, 2H). ¹³ C-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] ⁺ calculated value for C19H ₂₄ O ₃ N ₃ F ₂ S: 412.1501; experimental value: 412.1485.

OTV-409.

(S)-5-((cyclobutylamino)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one

1H-NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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] ⁺ calculated value for C ₂₀ H ₂₆ O ₃ N ₃ F ₂ S: 426.1658; experimental value: 426.1643.

OTV-411.

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine -2-he

1H-NMR (400 MHz, CDCI3) 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), 2.762.79 (m, 2H), 1.91-1.97 (m, 2H ). 13C-NMR (125 MHz, CDCl ₃ ) 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]+ calculated value for C ₁₇ H ₂₀ O ₂ N ₅ F ₂ S: 396.1300; experimental value: 396.1296.

OTV-126.

[(5R)-3-[3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl]methylbutyrate

¹ H-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). ¹³ C-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] ⁺ calculated value for C19H ₂₆ O ₅ N ₂ FS: 413.1541; experimental value: 413.1573.

OTV-127.

- 35 043707

N-[[(5S)-3-(3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl]methyl]furan-2-carboxamide o

o ¹ H-NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C20H23O5N3FS: 436.1337; experimental value: 436.1371.

OTV-137.

(5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl )oxazolidin-2-one o

F ¹ H-NMR (400 MHz, CDCl ₃ ) 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]+ calculated value for C ₁₇ H ₂₁ O ₃ N ₅ FS: 394.1344; experimental value: 394.1328.

OTV-138.

(5R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl )oxazolidin-2-one O

¹ H-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]+ calculated value for C ₁₇ H ₂₁ O ₃ N ₅ FS: 394.1344; experimental value: 394.1338.

OTV-140.

(5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl )oxazolidin-2-one o

F ¹ H-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), 5.024.99 (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), 3.453.38 (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] ⁺ calculated value for C ₁₇ H ₂₁ O ₃ N ₅ FS: 394.1344; experimental value: 394.1339.

OBD-006.

N-(((5S)-3-(3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)butyramide

¹ H-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, 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.

(S)-N-((3 -(4-(1,1-dioxido-1,4-thiazepan-4-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide

- 36 043707 ¹ H-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, 7 H), 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]+.

OTV-110.

(R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl butyrate

¹ I-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). ¹³ CNMR (125 MHz, CDCl ₃ ) 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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C ₂₀ H ₂₈ O ₄ N ₂ FS: 411.1748; experimental value: 411.1786.

OTV-113.

(R)-5 -[(2H-1,2,3-triazol-2-yl)methyl]-3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-oxazolidin- 2-he

¹ I-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). ¹³ C-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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C ₁₈ H ₂₃ O ₂ N ₅ FS: 392.1551; experimental value: 392.1590.

OTV-114.

(R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide

¹ H-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). ¹³ C-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. MC-BP (ESI-TOF): m/z [M+H]+calculated value for C ₁₈ H ₂₅ O ₃ N ₃ FS: 382.1595; experimental value: 382.1620.

OTV-117.

(S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-furan-2-carboxamide

¹ H-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). ¹³ C-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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C21H25O4N3FS: 434.1544; experimental value: 434.1581.

OTV-118.

(S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-thiophene-2-carboxamide

¹ I-NMR (400 MHz, CDCl ₃ ) δ: 7.54 (m, 1H), 7.52 (m, 1H), 7.34 (m, 1H), 7.10 (m, 1H), 7.04 (m, 1H), 7.00

- 37 043707 (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). ¹³ C-NMR (125 MHz, CDCI3) 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. MC-BP (ESI-TOF): m/z [M+H] ⁺ calculated value for C21H25C4N4FS2: 450.1316;

experimental value: 450.1356.

OTV-120.

(R)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-butan-1-sulfonamide

'H-NMR (400 MHz, CDCI3) 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, 1H), 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). ¹³ C-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, J = 26.8 Hz), 71.5, 53.1, 47.9, 47.4, 45.5, 31.9, 29.6, 25.6, 21.5, 13.5. MC-BP (ESI-TOF): m/z [M+H] ⁺ calculated value for C20H ₃₁ O ₄ N ₃ FS ₂ : 460.1735; experimental value: 460.1778.

OTV-121.

(S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl]methyl]-pivalamide

¹ H-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, 1H), 4H), 2.74 (m, 4H), 1.98 (m, 4H), 1.17 (s, 9H). ¹³ CNMR (125 MHz, CDCI3) 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. MC-BP (ESI-TOF): m/z [M+H] ⁺ calculated value for C21H ₃₁ O ₃ N ₃ FS: 424.2065; experimental value: 424.2096.

OBD-001.

(R)-5 -((1H-1,2,3-triazol-1 -yl)methyl)-3 -(3-fluoro-4-(1,5-thiazocan-5 -yl)phenyl)-oxazolidin- 2-he

¹ H-NMR (300 MHz, CDCI3) 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] ⁺ .

OBD-003.

(S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)-butyramide

¹ H-NMR (300 MHz, CDCI3) 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] ⁺ .

OBD-008.

(R)-5 -((1H-1,2,4-triazol-1-yl)methyl)-3 -(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-oxazolidin- 2-he

¹ H-NMR (300 MHz, CDCI3) 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]+.

- 38 043707

OTV-124.

(S)-N-[[3-(3-fluoro-4-(1-oxido-1,5-thiazocan-5-ul)phenyl)-2-oxooxazolidin-5-yl]methyl]acetamide

¹ H-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). ¹³ C-NMR (125 MHz, CDCh) 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] ⁺ calculated value for C ₁₈ H ₂₅ O ₄ N ₃ FS: 398.1544; experimental value: 398.1540.

OBD-002.

(R)-5 -((1H-1,2,3-triazol-1-yl)methyl)-3 -(3-fluoro-4-(1-oxido-1,5-thiazocan-5-yl)phenyl )oxazolidin-2-one

¹ H-NMR (300 MHz, CDClj) 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] ⁺ .

OBD-004.

(S)-N-((3-(3-fluoro-4-(1-oxido-1,5-thiazocan-5-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)butyramide

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). LCMS (ESI): m/z = 425.8 [M+H] ⁺ .

OBD-009.

(R)-5 -((1H-1,2,4-triazol-1-yl)methyl)-3 -(3-fluoro-4-(1-oxido-1,5-thiazocan-5-yl)phenyl )oxazolidin-2-one

1H-NMR (300 MHz, CDCl ₃ ) 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] ⁺ .

OTV-227.

N-(((5S)-3-(4-(3-thia-6-azabicyclo[3,1,1]heptan-6-yl)-3-fluorophenyl)

-2-oxooxazolidin-5-yl)methyl)acetamide

¹ H-NMR (400 MHz, CDCI3) 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 (broad s, 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 ). ¹³ CNMR (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, J = 24.9 Hz ), 71.9, 60.8, 47.8, 41.9, 29.4, 25.3, 23.2. MCBP (ESI-TOF ⁺ ): m/z [M+H] ⁺ calculated value for C ₁₇ H ₂₁ FN ₃ O ₃ S: 366.1288; experimental value: 366.1277.

OTV-501.

- 39 043707 (R)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-5-(hydroxymethyl)oxazolidin-2-one

¹ H-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). MSHR (ESI): m/z [M+H]+ calculated value for C ₁₆ H ₂₀ N ₂ O ₃ FS: 339.1179; experimental value: 339.1169.

OTV-502.

N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-2-oxooxazolidin-5-yl)methyl)acetamide

¹ H-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, CDCl ₃ ) 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. MC-BP (ESI-TOF): m/z [M+H]+ calculated value for C ₁₈ H ₂₃ N ₃ O ₃ FS: 380.1444; experimental value: 380.1435.

OTV-504.

(R)-5 -((1H-1,2,3-triazol-1-yl)methyl)-3 -(4-(( 1 R,5S)-3-thia-8-azαbicyclo [3,2, 1]octan-8-yl)-3-fluorophenyl)oxazolidin-2-one

¹ H-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, 6 N). HR-MS (ESI-TOF): m/z [M+H] ⁺ calculated value for C18H ₂₁ N ₅ O ₂ FS: 390.1400; experimental value: 390.1385.

OTV-236.

N-(((R)-3-(3-((1R,5S)-3-Thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-2-oxooxazolidin-5-yl)methyl)methanesulfonamide

¹ H-NMR (400 MHz, CDQ3) δ: 7.47-7.41 (m, 1H), 7.13 (d, J = 9.6 Hz, 1H), 7.02 (t, J = 9 .6 Hz, 1H), 4.764.70 (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] ⁺ calculated value for C ₁₇ H ₂₃ N ₃ O ₄ FS ₂ : 416.1114; experimental value: 416.1097.

OTV-237.

Methyl (((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxo-oxazolidine -5-yl)methyl)carbamate

¹ H-NMR (400 MHz, CDCI3) 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 (broad s, 1H), 4.74 (broad s, 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] ⁺ calculated value for C ₁₈ H ₂₃ N ₃ O ₄ FS: 396.1393; experimental value: 396.1388.

OBD-016.

- 40 043707

N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-2-oxooxazolidin-5-yl)methyl)butyramide

Ή-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]+.

OBD-021.

(R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-((1R,5S)-3-thia-8-azabicyclo

[3,2,1]octan-8-yl)-3-fluorophenyl)oxazolidin-2-one

Ή-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 = 389.9 [M+H] ⁺ .

OTV-506.

N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin- 5yl)methyl)cyclopropanecarboxamide

Ή-NMR (400 MHz, CDCl ₃ ) δ: 7.37 (d, J = 13.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.85 (br. s, 1H), 6.22 (t, J = 6.0 Hz, 1H), 4.79-4.73 (m, 1H), 4.41 (broad s, 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, 6 H), 1.43-1.37 (m, 1H), 0.98-0.90 (m, 2H), 0.82-0.75 (m, 2H). HR-MS (IERTOF): m/z [M+H] ⁺ calculated value for C ₂₀ H ₂₅ N ₃ O ₃ FS: 406.1595; experimental value: 406.1527.

OTV-507.

N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-2-oxooxazolidin-5-yl)methyl)cyclobutanecarboxamide

Ή-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 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, 10 H), 1 .95 (m, 1H), 1.85 (m, 1H). ¹³ C-NMR (100 MHz, CDCl3) δ: 175.9, 154.3, 153.0 (d, J = 242.9 Hz), 131.2, 127.0, 118.6 (d, J = 4.4 Hz), 114.5 (d, J = 2.9 Hz), 108.3 (d, J = 27.1 Hz), 71.9, 58.2, 47.7, 41.9, 39.6, 30.3, 28.3, 25.4, 25.3, 18.1. MCBP (IER): m/z [M+H] ⁺ calculated value for C21H ₂₇ N ₃ O ₃ SF: 420.1757; experimental value: 420.1736.

OTV-510.

N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl) - 2-oxooxazolidin-5-yl)methyl)acetamide

Ή-NMR (400 MHz, CDCl ₃ ) δ: 7.08 (m, 2H), 6.00 (m, 1H), 4.76 (m, 1H), 4.24 (br s, 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). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for Ci8H ₂₂ N ₃ O ₃ SF ₂ : 398.1350; experimental value: 398.1329.

- 41 043707

OTV-512.

Methyl (((S)-3 -(4-(( 1 R,5S)-3 -thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)

-2-oxooxazolidin-5-yl)methyl)carbamate

^-NMR (400 MHz, CDCl ₃ ) δ: 7.09 (m, 2H), 5.08 (m, 1H), 4.76 (m, 1H), 4.24 (broad s, 2H), 3.98 (t, J = 8.8 Hz, 1H), 3.75-3.50 (m, 6 H), 3.38 (m, 2H), 2.20 (m, 2H), 2, 14 (s, 4H). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C18H ₂₂ N ₃ O ₄ SF ₂ : 414.1294; experimental value: 414.1278.

OTV-511.

(R)-5-(( 1H-1,2,3-triazol-1 -yl)methyl)-3 -(4-(( 1 R,5S)-3 -thia-8-azabicyclo [3,2, 1]octan-8-yl)-3,5-difluorophenyl)oxazolidin-2-one

'll-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 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, 6 H). ¹³ C-NMR (100 MHz, CDCl ₃ ) 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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₈ H ₂₀ N ₅ O ₂ SF ₂ : 408.1300; experimental value: 408.1295.

OTV-508.

N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)

-2-oxooxazolidin-5-yl)methyl)cyclopropanecarboxamide

L-NMR (400 MHz, CDCl ₃ ) δ: 7.05 (m, 2H), 6.12 (m, 1H), 4.76 (m, 1H), 4.21 (br s, 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). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C20H ₂₄ N ₃ O ₃ SF ₂ : 420.1506; experimental value: 424.1484.

OTV-509.

N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl) - 2-oxooxazolidin-5-yl)methyl)cyclobutanecarboxamide

L-NMR (400 MHz, CDCl ₃ ) δ: 7.09 (m, 2H), 5.78 (m, 1H), 4.75 (m, 1H), 4.23 (br s, 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). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C21H ₂₆ N ₃ O ₃ SF ₂ : 438.1663; experimental value: 438.1642.

OTV-503.

N-(((5 S)-3 -(3-fluoro-4-(( 1R,5S)-3-oxido-3-thia-8-azabicyclo[3,2,1]octan-8-yl)phenyl ) -2-oxooxazolidin-5-yl)methyl)acetamide o

^! H-NMR (400 MHz, CDCl ₃ ) 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 =

- 42 043707

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 (IERTOF): m/z [M+H]+ calculated value for C ₁₈ H ₂₃ N ₃ O ₄ FS: 396.1388; experimental value:

396.1379.

OTV-505.

(5R)-5-(( 1R-1,2,3-triazol-1 -yl)methyl)-3 -(3-fluoro-4-(( 1E,5 S)-3-oxido-3-thia- 8-azabicyclo[3,2,1]octan-8-yl)phenyl)oxazolidin-2-one

¹ H-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 (IERTOF): m/z [M+H] ⁺ calculated value for C18H ₂₁ N ₅ O ₃ FS: 406.1349; experimental value: 406.1339.

OTV-513.

N-(((5S)-3-(3,5-difluoro-4-((1R,5S)-3-oxido-3-thia-8-αzabicyclo[3,2,1]octan-8-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)cyclobutanecarboxamide

¹ H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 12.0 Hz, 2H), 5.97 (br s, 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, J = 9.2 Hz, 2H), 3.02 (m, 1H), 2.91 (d, J = 12.0 Hz, 2H), 2.26-2.11 (m, 6H), 1.99-1.92 (m, 1H), 1.87-1.85 (m, 3H). MSHR (ESI): m/z [M+H]+ calculated value for C ₂₁ H ₂₆ N ₃ O ₄ SF ₂ : 454.1606; experimental value: 454.1588.

OTV-514.

N-(((5S)-3-(3,5-difluoro-4-((1R,5S)-3-oxido-3-thia-8-azαbicyclo[3,2,1]octan-8-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

¹ H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 12.0 Hz, 2H), 6.15 (br s, 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). MSHR (ESI): m/z [M+H] ⁺ calculated value for C18H ₂₂ N ₃ O ₄ SF ₂ : 414.1293; experimental value: 414.1275.

OBD-017.

N-(((5S)-3-(3-fluoro-4-((1R,5S)-3-oxido-3-thia-8-azabicyclo[3,2,1]octan-8-yl)phenyl) -2-oxooxazolidin-5-yl)methyl)butyramide

¹ H-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]+.

OBD-018.

(5R)-5-((1H-1,2,4-triαzol-1-yl)methyl)-3-(3-fluoro-4-((1R,5S)-3-oxido-3-thia-8 -azabicyclo

[3,2,1]octan-8-yl)phenyl)oxazolidin-2-one

^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 =

- 43 043707

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]+.

OTV-260.

(R)-3 -(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-5 (hydroxymethyl)oxazolidin-2-one

¹ H-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 (broad s, 1H), 4.02 (s, 4H), 3.99-3.89 (m, 3H), 3.76-3.73 (m, 1H), 3.42 (s, 4H). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C ₁₅ H ₁₈ FN ₂ O ₃ S: 325.1022; experimental value: 325.1010.

OTV-261.

(S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 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). MSVR (IER): m/z [M+H]+ calculated value for C ₁₇ H ₂₁ FN ₃ O ₃ S: 366.1288; experimental value: 366.1274.

OTV-241.

(R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-(2-thia-6-azaspiro

[3,3]heptan-6-yl)phenyl)oxazolidin-2-one

¹ H-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). ¹³ C-NMR (100 MHz, CDCl) 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. MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₁₉ FN ₅ O ₂ S: 376.1244; experimental value: 376.1231.

OTV-516.

(R)-3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)

-5-(hydroxymethyl)oxazolidin-2-one

¹ H-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). MSHR (ESI): m/z [M+H] ⁺ calculated value for C15H ₁₇ N ₂ O ₃ SF ₂ : 343.0922; experimental value: 343.0912.

OTV-515.

(S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)acetamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.98 (d, J = 11.6 Hz, 2H), 5.99 (broad s, 1H), 4.74-4.72 (m, 1H), 4.16 (s, 4H), 3.94 (t, J = 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, CDCl ₃ ) 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 =

- 44 043707

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. MCBP (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₂₀ N ₃ O ₃ SF ₂ : 384.1188; experimental value: 384.1168.

OTV-242.

Methyl-(S)-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)

-2-oxo-oxazolidin-5-yl)methyl)carbamate

1H NMR (400 MHz, CDCl3) δ: 7.00 (d, J = 11.6 Hz, 2H), 5.16 (broad s, 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). MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₂₀ F ₂ N ₃ O ₄ S: 400.1143; experimental value: 400.1125.

OTV-245.

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptane -6yl)phenyl)oxazolidin-2-one

1H NMR (400 MHz, CDQ3) 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). MSHR (ESI): m/z [M+H] ⁺ calculated value for C ₁₇ H ₁₈ F ₂ N ₅ O ₂ S: 394.1149; experimental value: 394.1129.

OTV-243.

(S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)cyclopropanecarboxamide

1H NMR (400 MHz, CDCl ₃ ) 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). MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₉ H ₂₂ F ₂ N ₃ O ₃ S: 410.1350; experimental value: 410.1331.

OTV-244.

(S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)cyclobutanecarboxamide

1H NMR (400 MHz, CDCI3) δ: 6.99 (d, J = 11.6 Hz, 2H), 5.83 (broad s, 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). MSHR (IER): m/z [M+H] ⁺ calculated value for C ₂₀ H ₂₄ F ₂ N ₃ O ₃ S: 424.1506; experimental value:. 424.1483.

OTV-201.

(R)-3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

¹ H-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). ¹³ CNMR (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. MCBP (IER): m/z [M+H] ⁺ calculated value for C15H ₁₈ FN ₂ O ₄ : 309.1251; experimental value: 309.1269.

OTV-202.

- 45 043707 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)acetamide

¹ H-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, CDCl ₃ ) 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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₇ H ₂₁ FN ₃ O ₄ : 350.1516; experimental value: 350.1497.

OTV-203.

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxa-6-azaspiro

[3,3]heptan-6-yl)phenyl)oxazolidin-2-one

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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₇ H ₁₉ FN ₅ O ₃ : 360.1472; experimental value: 360.1451.

OTV-204.

(R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(2-oxa-6-azaspiro

[3,3]heptan-6-yl)phenyl)oxazolidin-2-one

¹ H-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), 3.983.92 (m, 1H). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C17H ₁₉ FN ₅ O ₃ : 360.1472; experimental value: 360.1451.

OTV-205.

(S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)furan-2-carboxamide

¹ H-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 (broad s, 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). ¹³ C-NMR (100 MHz, CDCl ₃ ) 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. MCBP (IER): m/z [M+H]+ calculated value for C ₂₀ H ₂₁ FN ₃ O ₅ : 402.1465; experimental value: 402.1561.

OTV-206.

(S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide

1H-NMR (400 MHz, CDCl ₃ ) δ: 7.53 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 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). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 162.9, 154.7, 152.5 (d, J = 241.1 Hz), 150.1, 140.8, 138.1,

- 46 043707

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. MCBP (IER): m/z [M+H]+ calculated value for C ₂₀ H ₂₁ FN ₃ O ₄ S: 418.1237; experimental value: 418.1331.

OTV-222.

(R)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)methanesulfonamide

¹ H-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^) 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. MCBP (IER): m/z [M+H] ⁺ calculated value for C ₁₆ H ₂₁ FN ₃ O ₅ S: 386.1186; experimental value: 386.1185.

OTV-223.

Methyl (S)-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl) carbamate

¹ H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 14.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.61 (t, J = 9.2 Hz, 1H), 5.11 (broad. s, 1H), 4.84 (broad. s, 4H), 4.73 (broad. s, 1H), 4.16 (broad. 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). MSHR (ESI): m/z [M+H] ⁺ calculated value for C17H ₂₁ FN ₃ O ₅ : 366.1465; experimental value: 366.1466.

OTV-238.

(S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)cyclopropanecarboxamide

¹ H-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 (broad s, 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. MCBP (IER): m/z [M+H] ⁺ calculated value for C19H ₂₃ FN ₃ O ₄ : 376.1673; experimental value: 376.1652.

OTV-239.

(S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)cyclobutanecarboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 1H), 4.86 (s, 4H), 4.76 (broad s, 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, CDCl ₃ ) 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. MCBP (IER): m/z [M+H] ⁺ calculated value for C20H25FN3C4: 390.1829; experimental value: 390.1808.

OTV-229.

(R)-3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)

-5-(hydroxymethyl)oxazolidin-2-one

¹ H-NMR (400 MHz, CDCl3) δ: 7.03 (d, J = 10.8 Hz, 2H), 4.82 (s, 4H), 4.72 (broad s, 1H), 4, 28 (s, 4H),

- 47 043707

3.99-3.85 (m, 3H), 3.75-3.72 (m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) 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.

MCBP (IER): m/z [M+H]+ calculated value for C ₁₅ H ₁₇ F ₂ N ₂ O ₄ : 327.1156; experimental value:

327.1135.

OTV-230.

(S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )acetamide

1H-NMR (400 MHz, CDCl ₃ ) δ: 6.97 (d, J = 10.0 Hz, 2H), 6.49 (broad s, 1H), 4.81 (s, 4H), 4, 75 (broad s, 1H), 4.27 (s, 4H), 3.94 (t, J = 8.8 Hz, 1H), 3.70-3.63 (m, 3H), 2.02 (s, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) 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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₇ H ₂₀ F ₂ N ₃ O ₄ : 368.1422; experimental value: 368.1418.

OTV-231.

Methyl-(S)-((3 -(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidin-5-yl )methyl)carbamate

1H-NMR (400 MHz, CDCl ₃ ) δ: 7.04 (d, J = 10.8 Hz, 2H), 5.08 (broad s, 1H), 4.83 (s, 4H), 4, 74 (broad s, 1H), 4.34 (s, 4H), 3.96 (t, J = 9.2 Hz, 1H), 3.72-3.51 (m, 6H). ¹³ C-NMR (100 MHz, CDCl ₃ ) 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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₇ H ₂₀ F ₂ N ₃ O ₅ : 384.1371; experimental value: 384.1367.

OTV-232.

(R)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)methanesulfonamide

1H-NMR (400 MHz, DMSO-d ₆ ) 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). ¹³ C-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. MCBP (IER): m/z [M+H]+ calculated value for C ₁₆ H ₂₀ F ₂ N ₃ O ₅ S: 404.1092; experimental value: 404.1087.

OTV-233.

(S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )cyclopropanecarboxamide

¹ H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J = 10.0 Hz, 2H), 6.36 (br s, 1H), 4.82 (s, 4H), 4, 75 (broad s, 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). ¹³ C-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. MCBP (IER): m/z [M+H] ⁺ calculated value for C ₁₉ H ₂₂ F ₂ N ₃ O ₄ : 394.1578; experimental value: 394.1575.

OTV-234.

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptane -6-yl)phenyl)oxazolidin-2-one

1H-NMR (400 MHz, CDCl ₃ ) δ: 7.77 (s, 1H), 7.75 (s, 1H), 6.86 (d, J = 11.6 Hz, 2H), 5.03- 5.02 (m, 1H),

- 48 043707

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). ¹³ C-NMR (100 MHz,

CDCl ₃ ) 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. MCBP (IER): m/z [M+H] ⁺ calculated value for

C ₁₇ H ₁₈ F ₂ N ₅ O ₃ : 378.1378; experimental value: 378.1365.

OTV-240.

(S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )cyclobutanecarboxamide

1H-NMR (400 MHz, CDCI3) 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), 1.991.82 (m, 2H). MSHR (IER): m/z [M+H] ⁺ calculated value for C ₂₀ H ₂₄ F ₂ N ₃ O ₄ : 408.1735; experimental value: 408.1716.

OTV-701.

(R)-N-((3-(3-fluoro-4-(2,6-diazaspiro[3,3]heptan-2-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)acetamide

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). ¹³ C-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. MSVR (IER): m/z [M+H] ⁺ calculated value for C17H ₂₂ FN ₄ O ₃ : 349.1671; experimental value: 349.1662.

OTV-702.

(R)-N-((3-(3-fluoro-4-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )acetamide

1H-NMR (400 MHz, CDCl ₃ ) 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). ¹³ C 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. MSHR (ESI): m/z [M+H] ⁺ calculated value for C ₁₈ H ₂₄ FN ₄ O ₃ : 363.1827, experimental value: 363.1819.

OTV-704.

(R)-N-((3-(3,5-difluoro-4-(2,6-diazaspiro[3,3]heptan-2-yl)phenyl)

-2-oxooxazolidin-5-yl)methyl)acetamide

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). ¹³ C 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. MSHR (ESI): m/z [M+H] ⁺ calculated value for C17H ₂₁ F ₂ N ₄ O ₃ : 367.1583, experimental value: 367.1576.

OTV-705.

(R)-N-((3-(3,5-difluoro-4-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-2-oxooxazolidin-5-yl )methyl)acetamide

¹ H-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). ¹³ C-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. MSVR (IER): m/z [M+H] ⁺ calculated

- 49 043707 value for C18H23F2N4O3: 381.1733, experimental value: 381.1725.

Example 12.

Synthesis of compounds according to additional embodiments of the present invention.

Methods for obtaining (6).

Experiments.

Ethyl 5-oxothiepane-4-carboxylate (2).

To a solution of tetrahydrothiopyran-4-one (100 g, 862 mmol) in Et ₂ O (150 ml) was added BF ₃ -Et ₂ O (120 ml, 948 mmol) at -30°C, then the reaction mixture was stirred at -30° C for 2 hours under nitrogen gas, after which a solution of ethyl 2-diazoacetate (147 g, 1293 mmol) in Et ₂ O (100 ml) was added to the resulting mixture at -30° C., then the mixture was warmed to room temperature and stirred overnight. Quenched with K2CO3, the solvent was concentrated and dried to give ethyl 5oxothiepane-4-carboxylate (2) (80 g, 46%) as a brown oil.

Tiepan-4-on (3)

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 drops) was stirred at 180°C in for 2 hours. The resulting reaction mixture was cooled to room temperature and poured into ice water, extracted with EA, and the organic layer was concentrated under reduced pressure to give tiepan-4-one (3) (15.9 g crude, 31%) as brown solid.

(7)-thiepan-4-onoxime (4).

To a solution of tiepan-4-one (3) (15.9 g, 122 mmol) in EtOH (150 ml) and H ₂ O (50 ml) was added NH2OHHCl (8.47 g, 122 mmol), then the reaction mixture was stirred at 75°C for 4 hours under nitrogen gas, then the mixture was concentrated and dried to give (2)-thiepan-4-onoxime (4) (9.97 g, 56%) as a brown solid.

1,5-thiazocan-4-one (5).

A mixture of (7)-thiepan-4-onoxime (4) (9.97 g, 68.7 mmol) and polyphosphoric acid (50 g) was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature and poured into ice water, adjusted to pH = 8 using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to give 1,5-thiazocan4-one (5) (3 g crude, 30%) as brown solid matter.

1,5-thiazocane (6).

To a solution of 1,5-thiazocan-4-one (5) (3 g, 20.7 mmol) in THF (100 ml) was added BH ₃ (31 ml, 31.1 mmol) in THF at 0°C, then boiled under reflux for 12 hours. The reaction mixture was quenched with CH ₃ OH (50 ml). The solvent was evaporated to give 1,5-thiazocane (6) as a white oil (1.7 g, 63%) and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 132 [M+H]+.

- 50 043707

Step 1. Preparation of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (8) s^^n-^~^-no ₂

F

K ₂ CO was added 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) ₃ (1.05 g, 7.6 mmol) at 25 °C, then the resulting reaction mixture was stirred at 80 °C for 2 h under nitrogen gas and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 5-(2-fluoro-4nitrophenyl)-1,5-thiazocane (8) (1.5 g , 74%) in the form of a yellow solid. LC-MS (ESI) m/z = 271 [M+H]+.

Step 2. 3-fluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) s^^n-^~^-nh ₂

F 9

A solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.5 g, 5.7 mmol) and palladium on carbon (200 mg) in MeOH (15 ml) was created with a gaseous atmosphere hydrogen and stirred the reaction mixture at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 3-fluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.2 g, 91%) as a white oil, and the resulting crude material was used for the next reaction without additional cleaning. LC-MS (ESI) m/z = 241 [M+H]+.

Step 3. Benzyl 3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10)

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) benzyl chlorofomate (1.76 g, 10.4 mmol) was added at -20°C under nitrogen gas, then the reaction mixture was stirred at 0°C for 30 minutes, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl 3-fluoro-4-(1,5thiazocan-5 -yl)phenylcarbamate (10) (740 mg, 38%) as a white solid. LC-MS (ESI) m/z = 375 [M+H]+.

Step 4. (R)-3-(3-fluoro-4-(1,5-thiazokαn-5-yl)phenyl)-5-(hydroxymethyl)oxαzolidin-2-one (11)

To a solution of benzyl-3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (740 mg g, 1.97 mmol) in THF (10 ml) at -78 °C in an atmosphere of nitrogen gas n-BuLi (1.3 ml, 2.96 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which a solution of (R)oxiran-2-ylmethylbutyrate (427 mg, 2. 96 mmol) in THF at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (R)-3-(3- fluoro-4-(1,5-thiazocan-5-yl)phenyl)-5(hydroxymethyl)oxazolidin-2-one (11) (382 mg, 57%) as a white solid. LC-MS (ESI) m/z = 341 [M+H]+.

Step 5. (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl-4methylbenzenesulfonate (12)

F

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 Et ₃ N (222 mg, 2.2 mmol) in DCM (10 ml), 4-methylbenzene-1sulfonyl chloride (418 mg, 2.2 mmol) was added at 0° C. under nitrogen gas and the resulting reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (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] ⁺ .

Step 6. (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4(1,5-thiazocan-5-yl)phenyl)oxazolidine -2-on (OBD-001) o

OBD-001

To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl-4methylbenzenesulfonate (12) (200 mg, 0. 4 mmol) and 1H-1,2,3-triazole (56 mg, 0.8 mmol) in DMF (5 ml), K2CO3 (110 mg, 0.8 mmol) was added at 25°C, then the reaction mixture was stirred at 80 °C for 2 hours under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 2:1) to give (R)-5-((1H-1.2 ,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5yl)phenyl)oxazolidin-2-one (OBD-001) (70 mg, 45%) in 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]+.

Stage 7. Receiving (OBD-002) o

F

OBD-002

To a solution of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5yl)phenyl)oxazolidin-2 -one (OBD-001) (50 mg, 0.13 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (80 mg, 0.13 mmol) was added at 0°C, then the reaction mixture was stirred at 0° C for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (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]+.

rt °» κ.Λ ^0Η <3

^s \__/ V-7 vA. OTs V / K ₂ CO ₃ , ¹² DMF stage 1 ' rssN ⁰ '° b '' / ⁼ \ -Μ J νΑ^,Ν.^ F ^N THF, H ₂ O, 0°С-к. t., / ^N OBD-008 OBD-009 30 min stage 2

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Step 1. (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)

OBD-008

To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl-4methylbenzenesulfonate (12) (200 mg, 0. 4 mmol) and III-1,2,4-triazole (56 mg, 0.8 mmol) in DMF (5 ml), K ₂ CO ₃ (110 mg, 0.8 mmol) was added at 25°C, then the reaction mixture stirred at 80°C for 2 hours under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 2:1) to give (R)-5-((1H-1.2 ,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5yl)phenyl)oxazolidin-2-one (OBD-008) (84 mg, 54%) in 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] ⁺ .

Stage 2. Receipt (OBD-009)

To a solution of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5yl)phenyl)oxazolidin-2 -one (OBD-008) (50 mg, 0.13 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (80 mg, 0.13 mmol) was added at 0°C, then the reaction mixture was stirred at

0°C for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (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] ⁺ .

stage 4

Step 1. (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13) o

F

To a solution of (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4methylbenzenesulfonate (12) (800 mg, 1.62 mmol) and sodium azide (105 mg, 1.62 mmol) in DMF (10 ml), K ₂ CO ₃ (447 g, 3.24 mmol) was added at 25°C, then the reaction mixture was stirred at 80°C for 1 h under nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (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] ⁺ .

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Step 2. (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14)

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 ) palladium on carbon (100 mg) was added to MeOH (10 ml) at 25°C, then the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (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 (ESI) m/z = 340 [M+H]+.

Step 3. (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-005)

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 hours in an atmosphere of nitrogen gas and monitored by TLC.

Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (S)-N-((3-(3- fluoro-4-(1,5-thiazocan-5yl)phenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-003) (252 mg, 56%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) 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] ⁺ .

Stage 4. Obtaining (OBD-004) o O /=\ Xo O=S n—k L—N i H \__y ^f I OBD-004

To a solution of (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5 yl)methyl)butyramide (OBD-003) (150 mg, 0.37 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (225 mg, 0.37 mmol) was added at 0°C, then the reaction mixture was stirred at 0°C for 2 hours, controlled using TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (OBD-004) (48 mg, 31%) as a white solid.

1H NMR (301 MHz, CDCl ₃ ) 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). LCMS (ESI) m/z = 425.8 [M+H]+.

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Step 1. Preparation of 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocane (8)

E s nA And,

F 8

To a solution of 1,5-thiazocane (6) (1 g, 7.6 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1.35 g, 7.6 mmol) in DMF (10 ml) was added K ₂ CO ₃ (2.1 g, 15.2 mmol) at 25°C, then the resulting reaction mixture was stirred at 80°C for 2 hours under nitrogen gas, monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 5-(2,6-difluoro-4nitrophenyl)-1,5-thiazocane (8) (1, 64 g, 75%) as a yellow solid. LC-MS (ESI) m/z = 289 [M+H]+.

Step 2. 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzenamine (9)

F.

s nA Anh ₂

F 9

In a solution of 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocane (8) (1.64 g, 5.7 mmol) and palladium on carbon (200 mg) in MeOH (15 ml) atmosphere of hydrogen gas and stirred the reaction mixture at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.4 g, 94%) as a white oil and the resulting crude material was used for the following reactions without further purification. LC-MS (ESI) m/z = 259 [M+H] ⁺ .

Step 3. Benzyl 3,5-difluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10)

To a suspension of 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzenamine (9) (1.4 g, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in DCM (200 ml) was added benzyl chloroformate (1.87 g, 10.6 mmol) at -20°C under nitrogen gas, then the reaction mixture was stirred at 0°C for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl-3,5difluoro-4-(1,5- thiazocan-5-yl)phenylcarbamate (10) (872 mg, 42%) as a white solid. LC-MS (ESI) m/z = 393 [M+H] ⁺ .

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Step 4. (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)

-5-(hydroxymethyl)oxazolidin-2-one (11)

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 in a gaseous atmosphere n-BuLi (1.4 ml, 3.34 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which (R)oxiran-2-ylmethylbutyrate (480 mg, 3. 34 mmol) in THF at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH

70:1), yielding (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5 (hydroxymethyl)oxazolidin-2-one (11) (519 mg , 65%) in the form of a white solid. LC-MS (ESI) m/z = 359 [M+H] ⁺ .

Step 5. (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12)

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 Et ₃ N (292 mg, 2.9 mmol) in DCM (10 ml), 4-methylbenzene-1sulfonyl chloride (550 mg, 2.9 mmol) was added at 0° C. under nitrogen gas and the reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (R)-(3-(3,5-difluoro -4-(1,5-thiazocan-5-yl)phenyl)-2oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (12) (594 mg, 80%) as a white solid. LC-MS (ESI) m/z = 513 [M+H] ⁺ .

Step 6. (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (13)

To a solution of (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4methylbenzenesulfonate (12) (594 g, 1 .2 mmol) and sodium azide (75 mg, 1.2 mmol) in DMF (10 ml), K ₂ CO ₃ (160 mg, 2.4 mmol) was added at 25°C, then the reaction mixture was stirred at 80°C in for 1 hour under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (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] ⁺ .

Step 7. (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidin-2-one (14)

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 on carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (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]+.

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Step 8. (S)-N-((3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2oxooxazolidin-5-yl)-methyl)butyramide (OBD-026 ) E O )=\ ^*o S N-& d-Y I N ^F O

OBD-026

To a solution of (8)-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 resulting reaction mixture was stirred at 25°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (8)-No((3-(3.5 -difluoro-4-(1,5thiazocan-5-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-026) (82 mg, 42%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) 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]+.

Step 9. N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidine -5-yl)methyl)butyramide (OBD-027)

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 resulting reaction mixture was stirred at 25°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give N-(((S)-3-(4- (3-thua-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-027) (82 mg, 45 %) in the form of a white solid.

1H NMR (301 MHz, CDCls) 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] ⁺ .

Synthesis scheme.

NH ₂ OHHCI Г > PPA ВНз, ΤΓΦi

U----► ψ —--” k J ^H Г NH

P N ₂ O, EtOH, Ji 70 °C, 2 h ΤΓΦ, arr. cold, ^rt \__

O ^N *OH arr. cold ^u current nights

34

Experiments.

Tetrahydrothiopyran-4-onoxime (2).

To a solution of tetrahydrothiopyran-4-one (20 g, 172 mmol) in EtOH (150 ml) and H2O (50 ml) was added NH ₂ OH-HCl (11.9 g, 172 mmol), then the resulting reaction mixture was stirred at 75° C for 4 hours under nitrogen gas, then the mixture was concentrated and dried to give tetrahydrothiopyran-4-one oxime (2) (14.7 g, 66%) as a brown solid.

1,4-thiazepan-5-one (3).

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 hours. The reaction mixture was cooled to room temperature and poured into ice water, the pH was adjusted to pH = 8, using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to obtain 1,4thiazepan-5-one (3) (11.9 g crude, 81%) as a brown solid.

1,4-thiazepane (4).

To a solution of 1,4-thiazepan-5-one (3) (11.9 g, 105 mmol) in THF (100 ml) was added BH ₃ (158 ml, 158 mol) in THF at 0°C, then refluxed refrigerator for 12 hours. The reaction mixture was quenched with CH ₃ OH (50 ml). The solvent was evaporated to give 1,4-thiazepane (4) as a white oil (10.7 g, 87%) and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 118 [M+H] ⁺ .

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Step 1. Preparation of 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6)

K2CO3 (16 .5 g, 119.6 mmol) at 25°C and then the reaction mixture was stirred at 80°C for 2 hours under nitrogen gas and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 4-(2-fluoro-4-nitrophenyl)-1,4thiazepane (6) (10 g, 65 %) in the form of a yellow solid. LC-MS (ESI) m/z = 257 [M+H]+.

Step 2. 3-fluoro-4-(1,4-thiazepan-4-yl)benzenamine (7)

A solution of 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6) (8 g, 31.2 mmol) and palladium on carbon (500 mg) in MeOH (15 ml) was prepared, then the reaction mixture was stirred at room temperature overnight under hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure to give 3-fluoro-4-(1,4-thiazepan-4-yl)benzenamine (7) (6.4 g, 93%) as a white oil, and the resulting crude material was used for the next reaction without additional cleaning. LC-MS (ESI) m/z = 227 [M+H] ⁺ .

Step 3. Benzyl 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate (8)

To a suspension of 3-fluoro-4-(1,4-thiazepan-4-yl)benzenamine (7) (6.4 g, 28.3 mmol) and triethylamine (5.7 g, 56.6 mmol) in DCM ( 200 ml) benzyl chlorofomate (9.6 g, 56.6 mmol) was added at -20°C under nitrogen gas, then the reaction mixture was stirred at 0°C for 30 minutes, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl-3-fluoro-4-(1,4thiazepan- 4-yl)phenylcarbamate (8) (2.34 g, 23%) as a white oil. LC-MS (ESI) m/z = 361 [M+H] ⁺ .

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Step 4. (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)

-5-(hydroxymethyl)oxazolidin-2-one (9) o

F

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 in a gaseous atmosphere n-BuLi (4 ml, 9.7 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which a solution of (R)-oxiran-2ylmethylbutyrate (1.4 g, 9. 7 mmol) in THF at -78°C, then the mixture was warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (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 (ESM) m/z = 327 [M+H]+.

Step 5. (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (10) o

F

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 Et ₃ N (727 mg, 7.2 mmol) in DCM (10 ml) was added 4-methylbenzene-1sulfonyl chloride (1.4 g, 7.2 mmol) at 0° C. under nitrogen gas and the reaction mixture stirred at room temperature overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (R)-(3-(3-fluoro-4 -(1,4-thiazepan-4-yl)phenyl)-2oxooxazolidin-5-yl)methyl-4-methylbenzenesulfonate (10) (1.41 g, 41%) as a white solid. LC-MS (ESI) m/z = 481 [M+H] ⁺ .

Step 1. (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (11) o

F

To a solution of (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl-4methylbenzenesulfonate (10) (1.41 g, 2.95 mmol) and sodium azide (190 mg, 2.95 mmol) in DMF (10 ml) was added K ₂ CO ₃ (814 g, 5.9 mmol) at 25 ° C, then the resulting reaction mixture was stirred at 80 ° C for 1 hour under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (R)-5-(azidomethyl)-3-( 3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin2-one (11) (830 mg, 80%) as a white solid. LC-MS (ESI) m/z = 352 [M+H] ⁺ .

Step 2. (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidin-2-one (12) o

F

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 ) palladium on carbon (100 mg) was added to MeOH (10 ml) at 25°C, then the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (8)-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] ⁺ .

- 59 043707

Step 3. (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)butyramide (OBD-005) O

OBD-005

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), HOBt (405 mg, 3 mmol), EDCI (764 mg, 4 mmol) and DIPEA (516 mg, 4 mmol) were added at 25°C, then the reaction mixture stirred at 25°C for 2 hours under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (S)-N-((3-(3- fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2oxooxazolidin-5-yl)methyl)butyramide (OBD-005) (286 mg, 34%) as a white solid.

^1H NMR (300 MHz, CDCl ₃ ) 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]+.

Stage 4. Receipt (OBD-006 and OBD-007)

To a solution of (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxooxazolidin-5yl)methyl)butyramide (OBD-005) (150 mg , 0.38 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (233 mg, 0.38 mmol) was added at 0°C, then the reaction mixture was stirred at 0°C for 2 hours, monitored by TLC . Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (OBD-006) (50 mg, 32%) as a white solid and (OBD-007) (24 mg, 15%) as a white solid colors.

(OBD-006).

1H NMR (301 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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] ⁺ .

Methods for obtaining R.

_Rr Ng, 10%P(Iu,4a™,

Z^COOEt ΒΓ1ΝΗ2, K2СО3 kxCOOEt * η Ν η . toluene/H ₂ O, ^υ Βη ^υ arr. cold Stage 2 1 ^T A^L^ ^0T5 „ ^TsCl . Et ₃ N, DMAP _Η0 Cbz DCM, grade 6 stage 5 _e Na ₂ S 9 H2O stage 6 ^g EtOH, arr. cold _s /I ^TMSI ' ^CH 2C1 ₂ . 0 °C to bc , * , Cbz stage 7 / 50°C, 5h MeOH, CH ₃ COOH stage 2 / \ q|_| CaCI ₂ , NaBH ₄ EUN/MeOH, θβ ^ζ stage 4 5. HI'^'NH

- 60 043707

Step 1. Preparation of (2S,5R)-diethyl-1-benzylpyrrolidine-2,5-dicarboxylate (2)

A mixture of (2R,5S)-diethyl-2,5-dibromohexanedioate (1) (100 g, 278 mmol), BnNH ₂ (44.6 g, 416 mmol) and

K2CO3 (76.84 g, 556 mmol) in toluene/H ₂ O was stirred at 110°C overnight, monitored by TLC. The resulting mixture was extracted with EtOAc, washed with water and brine and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S,5R)-diethyl-1-benzylpyrrolidine-2,5-dicarboxylate (2) (63 .75 g, 75%) as a white oil. LC-MS (PER) m/z = 306 [M+H]+.

Stage 2. (2S,R)-diethylpyrrolidine-2,5-dicarboxylate (3) // Ν \\ IT

To a solution of (2S,5R)-diethyl-1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 209 mmol) and palladium on carbon (2 g) in MeOH (15 ml) was added CH3COOH (5 ml ), then the reaction mixture was stirred at 50°C in an atmosphere of hydrogen gas, 4 atm for 5 hours, monitored by TLC. Filtered and concentrated under reduced pressure and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 216 [M+H] ⁺ .

Stage 3. (2S,5R)-1-benzyl-2,5-diethylpyrrolidine-1,2,5-tricarboxylate (4) 1^0 Г^z ⁰ ^ ° Cbz °

To a solution of (2S,5R)-diethylpyrrolidine-2,5-dicarboxylate (3) (62 g, 288 mmol) and Et ₃ N (58 g, 577 mmol) in DCM (100 ml) was added benzyl chlorophosphate (98 g, 577 mmol ) at -20°C in an atmosphere of nitrogen gas, then the resulting reaction mixture was stirred at room temperature for 5 hours and 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 give (2S,5R)-1-benzyl-2,5-diethylpyrrolidine-1,2,5tricarboxylate (4 ) (80 g, 80%) as a white oil. LC-MS (ESI) m/z = 350 [M+H] ⁺ .

Step 4. (2S,5R)-benzyl-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (5) IHO P OH

Cbz 5

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) CaCl ₂ (76 g, 688 mmol) and NaBH4 (43 g, 1146 mmol) at room temperature under nitrogen gas, then the resulting reaction mixture was stirred for 5 hours, monitored by TLC. H2O (5 ml) was added and the resulting mixture was stirred for another 15 minutes. The mixture was then concentrated under vacuum. The resulting mixture was extracted with EtOAc, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S,5R)-benzyl-2,5bis(hydroxymethyl)pyrrolidine-1-carboxylate (5) (32 g, 52% ) as a white oil. LC-MS (ESI) m/z = 266 [M+H] ⁺ .

Step 5. (2S,5R)-benzyl-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate (6) ^T5O x^C~)^ ^OT5

Cbz 6

To a stirred solution of (2S,5R)-benzyl-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (5) (32 g, 121 mmol) and Et ₃ N in DCM (200 ml) was added 4-methylbenzene-1 -sulfonyl chloride (92 g, 483 mmol) at 0° C. under nitrogen gas, then the reaction mixture was allowed to warm to room temperature and stirred for 5 hours, monitored by TLC. The resulting mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (EA:PE = 2:1) to give (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] ⁺ .

- 61 043707

Step 6. 8-benzyl-3-thia-8-aza-bicyclo[3,2,1]octane-1-carboxylate (7)

Sodium sulfide hydrate 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). (38 g, 157 mmol) at room temperature, then the resulting reaction mixture was stirred at 90°C for 2 hours, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give 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]+.

Step 7. 3-thia-8-aza-bicyclo[3,2,1]octane hydroiodide (8)

Iodotrimethylsilane (15 g, 75 mmol) at 0°C under nitrogen gas, then the resulting 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 resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give 3-thia-8-aza-bicyclo [3,2,1]octane hydroiodide (8) (8.13 g, 84%) as a brown solid. LC-MS (ESI) m/z = 130 [M+H] ⁺

stage 7

Step 1. Preparation of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3,2,1]octane (10)

To a solution of 3-thia-8-aza-bicyclo[3,2,1]octane hydroiodide (8) (5.58 g, 21.7 mmol) and 1,2-difluoro-4nitrobenzene (3.8 g, 23. 8 mmol) in DMF (10 ml), K2CO3 (6 g, 43.4 mmol) was added at 25 °C under nitrogen gas and the reaction mixture was stirred at 80 °C for 2 h, monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 8-(2-fluoro-4nitrophenyl)-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] ⁺ .

Step 2. 4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorobenzenamine (11)

- 62 043707

In 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 on carbon ( 200 mg) in MeOH (15 ml) was created with an atmosphere of hydrogen gas and the reaction mixture was stirred at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 4-(3-thia-8-aza-bicyclo[3,2,1]octan-8yl)-3-fluorobenzenamine (11) (4.08 g, 94%) as a white oil and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 239 [M+H]+.

Step 3. Benzyl 4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenylcarbamate (12)

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 ) 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (6.38 g, 25.6 mmol) was added at 0°C under nitrogen gas and the resulting reaction mixture was stirred at 50°C for 5 hours, monitored with TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl-4-(3-thia-8-aza-bicyclo[3,2,1]octane- 8-yl)-3-fluorophenylcarbamate (12) (4.34 g, 68%) as a white solid. LC-MS (ESI) m/z = 373 [M+H] ⁺ .

Step 4. (5R)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2- he (13)

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 nitrogen gas atmosphere, p-BuLi (7.3 ml, 17.5 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which a solution of (R )-oxiran-2-ylmethylbutyrate (2.5 g, 17.4 mmol) in THF at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (5R)-3-(4-(3-thia -8-aza-bicyclo[3,2,1]octan-8-yl)-3fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (3.03 g, 77%) as a white solid colors. LC-MS (ESI) m/z = 339 [M+H] ⁺ .

Step 5. ((R)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5 -yl) methyl 4-methylbenzenesulfonate (14)

F

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 Et ₃ N (1.8 g, 17.9 mmol) in DCM (10 ml) was added 4-methylbenzene-1-sulfonyl chloride (3.41 g, 17. 9 mmol) at 0°C under nitrogen gas and the resulting reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give ((R)-3-(4-(3- thia8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl-4-methylbenzenesulfonate (14) (3.74 g, 85%) in as a white solid. LC-MS (ESI) m/z = 493 [M+H] ⁺ .

Step 6. (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) λ o

OBD-021

To a solution of ((R)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5yl)methyl-4 -methylbenzenesulfonate (14) (500 mg, 1 mmol) and 1H-1,2,4-triazole (140 mg, 2 mmol) in DMF (10 ml) was added K ₂ CO ₃ (280 mg, 2 mmol) at 25° C, then the resulting reaction mixture was stirred at 80°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with EA, concentrated the organic layer under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 2:1) to give (5R)-5-((1H -1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia8-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]+.

Stage 7. Receipt (OBD-018)

OBD-018

To a solution of (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia-8-aza-bicyclo[3,2,1] octane -8-yl)-3fluorophenyl)oxazolidin-2-one (OBD-021) (100 mg, 0.26 mmol) in THF (10 ml) and 10 drops of water was added with potassium peroxomonosulfate (157 mg, 0.26 mmol) at 0°C, then the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (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] ⁺ .

^S ^N №^DMFA ^S c4h QTs * / 60 °C, 2 hours 13 stage 1 M /=vk ^F Г ⁴ OBD-017 /)-NY Ά\^ΝΗ ₂ F OBD-085 h-°D ^0H 5 ^u stage 5 THF, H2O, 0 °C ⁰ /I ⁰ /=\ Pd/CH, At? y ⁼ V 1-4 NI V-^ _N _z \_ _N γ V _{c he} ^v ^nh ₂ FF 15 stage 2 OBD-081 EDCI 0 HOBt _H0 A^ 0 stage 3 . to <----------------- Y h THF,H2O,0°C )-/ F D stage 4 OBD-016 ⁰

- 64 043707

Step 1. (5R)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)

-5-(azidomethyl)oxazolidin-2-one (15)

To a solution of ((R)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5yl)methyl-4 -methylbenzenesulfonate (14) (2 g, 4 mmol) and sodium azide (265 mg, 4 mmol) in DMF (10 ml) was added K ₂ CO ₃ (1.1 g, 8 mmol) at 25°C, then the resulting reaction the mixture was stirred at 80°C for 1 hour under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (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 solid white. LC-MS (ESI) m/z = 364 [M+H]+.

Step 2. (5S)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2- he (OBD-081)

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 on carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored with TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (58)-3-(4-(3-thia-8-aza-bicyclo[3,2 ,1]octan-8-yl)-3fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (OBD-081) (800 mg, 85%) as a white solid. LC-MS (ESI) m/z = 338 [M+H]+.

Step 3. 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)

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 resulting reaction mixture was stirred at 25°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give N-(((S)-3-(4- (3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl)butyramide (OBD-016) (156 mg, 65%) in the form of a white solid.

1H NMR (300 MHz, DMSO-I6) 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, 8 h), 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]+.

Stage 4. Receipt (OBD-017)

OBD-017

To a solution of N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3-fluorophenyl)-2-oxooxazolidin-5yl) methyl)butyramide (OBD-016) (100 mg, 0.25 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (157 mg, 0.26 mmol) was added at 0°C, then the resulting reaction mixture was stirred at 0°C for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (OBD-017) (16 mg, 15%) as a white solid. 1H NMR (301 MHz, CDCl ₃ ) δ 7.39 (dd, J = 15.8, 2.3 Hz, 1H), 7.03 (d, J

- 65 043707 = 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]+.

Stage 4. Receipt (OBD-085)

/)-NI 9 VS^NH ₂

F

OBD-085

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 of water, potassium peroxomonosulfate (182 mg, 0.29 mmol) was added at 0°C, then the resulting reaction mixture was stirred at 0°C for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (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), 2.171.99 (m, 2H), 1.79 (dd, J = 17.3, 9.5 Hz, 4H). LC-MS (ESI) m/z = 354 [M+H] ⁺ .

Step 1. Preparation of 8-(2,6-difluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3,2,1]octane (10)

To a solution of 3-thia-8-aza-bicyclo[3,2,1]octane hydroiodide (8) (5.0 g, 19.4 mmol) and 1,2,3-trifluoro-5 nitrobenzene (4.13 g , 23.3 mmol) in DMF (10 ml), K ₂ CO ₃ (5.35 g, 38.8 mmol) was added at 25°C, then the reaction mixture was stirred at 80°C for 2 hours in an atmosphere of nitrogen gas, monitored using TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 8-(2,6difluoro-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] ⁺ .

Step 2. 4-(3-thia-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorobenzenamine (11)

In 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 on carbon ( 200 mg) in MeOH (15 ml), create an atmosphere of hydrogen gas and stir the reaction mixture at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5difluorobenzenamine (11) (2.9 g, 90%) as a white oil and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 257 [M+H]+.

Step 3. Benzyl 4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenylcarbamate (12)

To a suspension of 4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorobenzenamine (11) (2.9 g, 11.2 mmol) in THF (30 ml ) 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (5.57 g, 22.4 mmol) was added at 0°C under nitrogen gas and the resulting reaction mixture was stirred at 50°C for 5 hours, monitored with TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl-4-(3-thia-8-azabicyclo[3,2,1]octane-8- yl)-3,5difluorophenylcarbamate (12) (3.0 g, 68%) as a white solid. LC-MS (ESI) m/z = 391 [M+H]+.

Step 4. (5R)-3-(4-(3-thia-8-azabiclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(hydroxymethyl)oxazolidin-2-one (13)

To a solution of benzyl 4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenylcarbamate (12) (3.0 g, 7.7 mmol) in THF ( 10 ml) at -78°C under nitrogen gas atmosphere, n-BuLi (4.8 ml, 11.5 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which a solution of (R )-oxiran-2-ylmethylbutyrate (1.66 g, 11.5 mmol) in THF at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (5R)-3-(4-(3-thia -8azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (2.3 g, 84%) as a white solid colors. LC-MS (ESI) m/z = 357 [M+H] ⁺ .

Step 5. ((R)-3-(4-(3-thia-8-azabiclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl) methyl 4-methylbenzenesulfonate (14)

To a suspension of (5R)-3-(4-(3-thia-8-azabiclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(hydroxymethyl)oxazolidin-2-one ( 13) (2.3 g, 6.5 mmol) and Et ₃ N (1.3 g, 13 mmol) 4-methylbenzene-1-sulfonyl chloride (2.45 g, 13 mmol) was added to DCM (10 ml) at 0°C under nitrogen gas atmosphere and the resulting reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give ((R)-3-(4-(3- thia-8azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl-4-methylbenzenesulfonate (14) (2.81 g, 85%) in as a white solid. LC-MS (ESI) m/z = 511 [M+H] ⁺ .

Step 6. (5R)-3-(4-(3-thia-8-azabiclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidin-2- he (15)

To a solution of ((R)-3-(4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5yl)methyl-4 -methylbenzenesulfonate (14) (2.81 g, 5.52 mmol) and sodium azide (360 mg, 5.52 mmol) in DMF (10 ml) was added K ₂ CO ₃ (1.52 mg, 11.04 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 hour in an atmosphere of nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated at

- 67 043707 under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (5R)-3-(4-(3-thia-8-azabicyclo[3,2,1 ]octan-8-yl)-3,5difluorophenyl)-5-(azidomethyl)oxazolidin-2-one (15) (1.85 g, 88%) as a white solid.

LC-MS (ESI) m/z = 382 [M+H]+.

Step 7. (5S)-3-(4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(aminomethyl)oxazolidin-2-one (OBD-083)

F

OBD-083

To a solution of (5R)-3-(4-(3-thia-8-azabiclo[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 on carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored with TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM; MeOH = 50:1) to give (58)-3-(4-(3-thia-8-azabicyclo[3,2,1 ]octan-8-yl)-3,5difluorophenyl)-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] ⁺ .

Stage 8. Receipt (OBD-087)

OBD-087

To a solution of (5S)-3-(4-(3-thia-8-azabicyclo[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 of water, potassium peroxomonosulfate (173 mg, 0.28 mmol) was added at 0°C, then the resulting reaction mixture was stirred at 0°C in for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (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] ⁺ .

Step 9. N-(((S)-3-(4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5 -yl)methyl)butyramide (OBD-029)

OBD-029 O

To a solution of (5S)-3-(4-(3-thia-8-azabicyclo[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) was 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 hours under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give N-(((S)-3-(4- (3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5yl)methyl)butyramide (OBD-029) (119 mg, 50%) in the form of 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]+.

- 68 043707

Stage 10. Receipt (OBD-242)

To a solution of N-(((S)-3-(4-(3-thia-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2oxooxazolidin-5-yl) methyl)butyramide (OBD-029) (100 mg, 0.23 mmol) in THF (10 ml) and 10 drops of water, potassium peroxomonosulfate (144 mg, 0.23 mmol) was added at 0°C, then the resulting reaction mixture was stirred at 0°C for 2 hours, monitored by TLC. Quenched with sodium thiosulfate and the resulting crude material was purified by preparative HPLC to give (OBD242) (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), 1.511.40 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H). LC-MS (ESI) m/z = 442 [M+H]+.

Stage 1. Receiving (3).

3-Bromo-2,2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) at 25°C, the reaction mixture was then stirred at 100°C for 48 hours. The mixture was concentrated under reduced pressure and the resulting crude material was poured into potassium hydroxide solution (75 ml) and stirred for 2 hours, leaving a residue of filter (3) (10 g, 59%) as a white solid. LCMS (ESI) m/z = 254 [m+H] ⁺ .

Stage 2. Obtaining (4).

A mixture of (3) (10 g, 39.5 mmol) and magnesium (6.7 g) in methanol (15 ml) was treated with ultrasound for 1 h at 40°C, after which the solvent was removed under reduced pressure, obtaining a viscous residue gray color, Et ₂ O and sodium sulfate were added and the resulting gray mixture was stirred vigorously for 30 minutes and then filtered. A solution of oxalic acid in ethanol was added to the filtrate. A fine white precipitate formed immediately and was the desired product (4) (3.7 g, 50%) and the resulting crude material was used for the next reaction without further purification.

Stage 3. Obtaining (5).

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 K ₂ CO ₃ (5.38 g, 39 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 2 hours under nitrogen gas, monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give (5) (1.9 g, 38%) as a yellow solid. LC-MS (ESI) m/z = 257 [M+H] ⁺ .

Stage 4. Obtaining (6).

A solution of (5) (1.9 g, 7.4 mmol) and palladium on carbon (200 mg) in methanol (15 ml) was created with an atmosphere of hydrogen gas and the resulting reaction mixture was stirred at room temperature overnight, monitored by TLC . The filtrate was concentrated under reduced pressure to give (6) (1.5 g, 90%) as a white oil, and the resulting crude material was used for the next reaction without further purification.

LC-MS (ESI) m/z = 227 [M+H] ⁺ .

Stage 5. Obtaining (7).

- 69 043707

To a suspension of (6) (1.5 g, 6.7 mmol) in THF (30 ml) was added 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (3.3 g, 13.3 mmol) at 0°C in an atmosphere nitrogen gas and the resulting reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give (7) (1.6 g, 68%) as a white solid.

LC-MS (ESI) m/z = 361 [M+H]+.

Stage 6. Obtaining (8).

To a solution of (7) (1.6 g, 4.6 mmol) in THF (10 ml) at -78°C under nitrogen gas, n-BuLi (2.8 ml, 6.8 mmol) was added, then the mixture was stirred at -78°C for 30 min, after which a solution of (R)-oxiran-2-ylmethylbutyrate (980 mg, 6.8 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (8) (1.2 g, 84%) as a white solid. LC-MS (ESI) m/z = 327 [M+H] ⁺ .

Stage 7. Obtaining (9).

To a suspension (8) (560 mg, 1.7 mmol), tert-butylisoxazol-3-ylcarbamate (380 mg, 2.1 mmol) and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 ml) was added ( E)-N1,N1,N2-trimethyldiazene-1,2dicarboxamide (443 mg, 2.6 mmol) at 0°C under nitrogen gas atmosphere and then the resulting reaction mixture was stirred at 60°C overnight, monitored with TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give (9) (309 mg, 37%) as a white solid. LC-MS (ESI) m/z = 493 [M+H] ⁺ . Stage 8: Receiving (OBD-061):

Trifluoroacetic acid (1 ml) was added to a solution (9) (309 g, 0.6 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C, then the resulting mixture was stirred at 0°C for 30 min, controlled with using TLC. Quenched with ammonium chloride, extracted with CH ₂ Cl ₂ , the organic layer was concentrated under reduced pressure and the resulting crude material was purified by preparative HPLC to give (OBD-061) (93 mg, 38%) as a white solid.

Ή NMR (300 MHz, CDCl ₃ ) 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] ⁺ .

Stage 1. Obtaining (9).

To a suspension of (8) (2.3 g, 6.5 mmol) and Et ₃ N (1.3 g, 13 mmol) in DCM (10 ml) was added 4-methylbenzene1-sulfonyl chloride (2.45 g, 13 mmol) at 0°C and then the resulting reaction mixture was stirred at room temperature overnight under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (9) (2.65 g, 85%) as a white solid. LC-MS (ESI) m/z = 481 [M+H] ⁺ .

Stage 2. Obtaining (10).

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 K ₂ CO ₃ (1.52 mg, 11.04 mmol) at 25°C, then the resulting reaction mixture was stirred at 80°C for 1 hour in an atmosphere of nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give (10) (1.7 g, 88%) as a white solid. LC-MS (ESI) m/z = 352 [M+H] ⁺ .

Stage 3. Receipt (OBD-062).

Palladium on carbon (100 mg) was added to a solution (10) (1.7 g, 4.86 mmol) in MeOH (10 ml) at 25°C, then the reaction mixture was stirred at room temperature overnight under a gas atmosphere. 043707 hydrogen was monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (OBD-062) (1.3 g, 85%) as a white solid.

^1H NMR (400 MHz, DMSOL) 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]+.

Cb-Oe.THF stage 3 /=\ Cbz >4 r ^NH

F

F

Stage 1. Receiving (3).

K ₂ CO ₃ (5 .38 g, 39 mmol) at 25°C, then the resulting reaction mixture was stirred at 80°C for 2 hours under nitrogen gas and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give (3) (1.7 g, 38%) as a yellow solid. LC-MS (ESI) m/z = 239 [M+H]+.

Stage 2. Obtaining (4).

A solution of (3) (1.7 g, 7.4 mmol) and palladium on carbon (200 mg) in methanol (15 ml) was created with an atmosphere of hydrogen gas and the reaction mixture was stirred at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give (4) (1.4 g, 90%) as a white oil, and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 209 [M+H] ⁺ .

Stage 3. Obtaining (7).

To a suspension (6) (1.4 g, 6.7 mmol) in THF (30 ml) at 0°C under nitrogen gas was added 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (3.3 g, 13 .3 mmol) and the resulting reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give (7) (1.6 g, 70%) as a white solid. LC-MS (ESI) m/z = 343 [M+H] ⁺ .

Stage 4. Obtaining (8).

To a solution of (7) (1.6 g, 4.7 mmol) in THF (10 ml) at -78°C under nitrogen gas, n-BuLi (2.9 ml, 7.0 mmol) was added, then the resulting mixture stirred at -78°C for 30 min, after which a solution of (R)-oxiran-2-ylmethylbutyrate (1 g, 7.0 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (8) (1.2 g, 84%) as a white solid. LC-MS (ESI) m/z = 309 [M+H] ⁺ .

Stage 5. Obtaining (9).

To a suspension (8) (523 mg, 1.7 mmol), tert-butylisoxazol-3-ylcarbamate (380 mg, 2.1 mmol) and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 ml) was added ( E)-N ₁ ,N ₁ ,N ₂ -trimethyldiazene-1,2dicarboxamide (443 mg, 2.6 mmol) at 0°C under nitrogen gas atmosphere and then the resulting reaction mixture was stirred at 60°C overnight, monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give (9) (298 mg, 37%) as a white solid. LC-MS (ESI) m/z = 475 [M+H] ⁺ .

Stage 6. Receipt (OBD-056).

Trifluoroacetic acid (1 ml) was added to a solution (9) (298 mg, 0.6 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C, then the resulting mixture was stirred at 0°C for 30 min, controlled with using TLC.

- 71 043707

Quenched with ammonium chloride, extracted with CH2C12, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by preparative HPLC to give (OBD-056) (84 mg, 38%) as a white solid.

1H NMR (301 MHz, CDCl ₃ ) 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, 8 h), 3.05 (dd, J = 23.2, 11.2 Hz, 5H), 2.13-1, 88 (m, 5H). LC-MS (ESI) m/z = 375 [M+H]+.

Step 1. Preparation of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3,2,1]octane (3).

To a solution of 8-oxa-3-azabicyclo[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 resulting reaction mixture was stirred at 80°C for 2 hours in an atmosphere of nitrogen gas, monitored by TLC . The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 3-(2,6difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3,2 ,1]octane (3) (9.3 g, 78%) as a yellow solid. LC-MS (ESI) m/z = 271 [M+H] ⁺ .

Step 2. Preparation of 4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorobenzenamine (4).

In a solution of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3,2,1]octane (3) (9.3 g, 34.4 mmol) and palladium on carbon ( 1 g) in MeOH (15 ml) was created with an atmosphere of hydrogen gas and the reaction mixture was stirred at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5difluorobenzenamine (4) (7.8 g, 95%) as a white oil and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 241 [M+H] ⁺ .

Step 3. Preparation of benzyl-4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenylcarbamate (5).

To a suspension of 4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorobenzenamine (4) (7.8 g, 32.5 mmol) in THF (100 ml ) 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (12 g, 48.7 mmol) was added at 0°C under nitrogen gas and the resulting reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 10:1) to give benzyl-4-(8-oxa-3-azabicyclo[3,2,1]octane-3- yl)-3,5difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid. LC-MS (ESI) m/z = 375 [M+H] ⁺ .

Step 4. Preparation of 3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-5(hydroxymethyl)oxazolidin-2-one (OBD- 114).

To a solution of benzyl 4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF ( 10 ml) at -78°C under nitrogen gas atmosphere, n-BuLi (13.8 ml, 33.1 mmol) was added, then the resulting mixture was stirred at -78°C for 30 min, after which a solution of (R )-oxiran-2-ylmethylbutyrate (4.7 g, 33.1 mmol) in THF at -78°C, then the mixture was warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give 3-(4-(8-oxa-3-azabicyclo [3,2,1]octan-3yl)-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] ⁺ .

Step 5. Preparation of (3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-2-72 043707 oxooxazolidin-5-yl)methyl -4-methylbenzenesulfonate (7).

To a suspension of 3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-5(hydroxymethyl)oxazolidin-2-one (OBD-114) (4.5 g, 13.3 mmol) and Et ₃ N (2.7 g, 26.6 mmol) in DCM (10 ml) was added 4-methylbenzene-1-sulfonyl chloride (5 g, 26.6 mmol) at 0°C under nitrogen gas atmosphere and the reaction mixture was stirred at room temperature overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to give (3-(4-(8-oxa-3azabicyclo[ 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 colors. LC-MS (ESI) m/z = 495 [M+H]+.

Step 6. Preparation of 5-(( 1H-1,2,3 -triazol-1 -yl)methyl)-3 -(4-(8-oxa-3 -azabicyclo[3,2,1]octan-3 -yl )3,5-difluorophenyl)oxazolidin-2-one (OBD-054).

To a solution of (3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5yl)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 K ₂ CO ₃ (166 mg, 1.2 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 hour in an atmosphere of nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, concentrated the organic layer under reduced pressure and the resulting crude material was purified by preparative HPLC to give 5-((1H-1,2,3-triazol-1-yl)methyl)-3 -( 4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5difluorophenyl)oxazolidin-2-one (OBD-054) (82 mg, 35%) as a white solid colors.

^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] ⁺ .

Step 1. Preparation of 3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-5(azidomethyl)oxazolidin-2-one (8) .

To a solution of (3-(4-(8-oxa-3-azabicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5yl)methyl-4-methylbenzenesulfonate (7 ) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 ml), K2CO3 (2.2 mg, 16 mmol) was added at 25°C, then the resulting reaction mixture was stirred at 80°C in for 1 hour under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give 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] ⁺ .

Step 2. Preparation of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3,5-difluorophenyl)-5(aminomethyl)oxazolidin-2-one ( OBD-115).

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 on carbon (300 mg) at 25°C, then the resulting reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octane3 -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

- 73 043707 (s, 2H), 2.04-1.94 (m, 2H), 1.88-1.71 (m, 2H). LC-MS (ESI) m/z = 340 [M+H]+.

Stage 3. Receipt (OBD-048, 049, 252, 253, 254).

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 hours under nitrogen gas, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH=80:1) to give (OBD-048, 049, 252, 253, 254) in the form of a white solid.

OBD-048.

^1H NMR (300 MHz, CDCl ₃ ) 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] ⁺ .

OBD-049.

1H NMR (301 MHz, CDCl ₃ ) 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]+.

OBD-252.

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] ⁺ .

OBD-253.

1H NMR (301 MHz, CDCl ₃ ) 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), 2.382.10 (m, 6H), 2.00-1.79 (m, 4H). LC-MS (ESI) m/z = 422.1 [M+H] ⁺ .

OBD-254.

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] ⁺ .

Step 1. Preparation of 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3,2,1]octane (3).

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 resulting reaction mixture was stirred at 80°C for 2 hours in an atmosphere of nitrogen gas, monitored by TLC . The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 5:1) to give 3-(2fluoro-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] ⁺ .

Step 2. Preparation of 4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorobenzenamine (4).

- 74 043707

In a solution of 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-aza-bicyclo[3,2,1]octane (3) (9.1 g, 36.2 mmol) and palladium on carbon ( 1 g) in MeOH (15 ml) was created with an atmosphere of hydrogen gas and the reaction mixture was stirred at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3fluorobenzenolamine (4) (7.3 g, 91%) as a white oil and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 223 [M+H]+.

Step 3. Preparation of benzyl-4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenylcarbamate (5).

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 ) 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (16.4 g, 65.88 mmol) was added at 0°C under nitrogen gas and the reaction mixture was stirred at 50°C for 5 hours, monitored by TLC . The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 10:1) to give benzyl-4-(8-oxa-3-aza-bicyclo[3,2,1]octane- 3-yl)-3-fluorophenylcarbamate (5) (7.1 g, 61%) as a white solid. LC-MS (ESI) m/z = 357 [M+H] ⁺ .

Step 4. Preparation of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-5(hydroxymethyl)oxazolidin-2-one (OBD- 112).

To a solution of benzyl-(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 nitrogen gas atmosphere, n-BuLi (12.5 ml, 30.1 mmol) was added, then the mixture was stirred at -78°C for 30 min, after which a solution of (R)oxirane- 2-ylmethylbutyrate (4.3 g, 30.1 mmol) in THF at -78°C, then the mixture was warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give 3-(4-(8-oxa-3-aza -bicyclo[3,2,1]octan-3-yl)-3fluorophenyl)-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] ⁺ .

Step 5. Preparation of (3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl-4-methylbenzenesulfonate (7).

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 Et ₃ N (1.2 g, 24 mmol) in DCM (10 ml) was added 4-methylbenzene-1-sulfonyl chloride (2.3 g, 24 mmol) at 0°C in nitrogen gas atmosphere and the resulting reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH=50:1) to give (3-(4-(8-oxa-3aza- 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 colors. LC-MS (ESI) m/z = 477 [M+H] ⁺ .

Step 6. Preparation of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-5(azidomethyl)oxazolidin-2-one (8) .

To a solution of (3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-2-oxooxazolidin-5yl)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 the mixture was stirred at 80°C for 1 hour under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 2:1) to give 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] ⁺ .

Step 7. Preparation of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-5(aminomethyl)oxazolidin-2-one (OBD- 113).

To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin2-one (8) (2, 97 g, 8.5 mmol) in MeOH (10 ml) was added palladium on carbon (300 mg) at 25°C, then the resulting reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octane -3-yl)-3-fluorophenyl)-5(aminomethyl)oxazolidin-2-one (OBD-113) (2.2 g, 81%) as a white solid.

- 75 043707

1H NMR (301 MHz, CDCl ₃ ) 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]+.

Stage 8. Receipt (OBD-110, 111).

To a solution of 3-(4-(8-oxa-3-aza-bicyclo[3,2,1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin2-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 resulting reaction mixture was stirred at 25°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (OBD-110, 111) as a white solid .

OBD-110.

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, 8 h). LC-MS (ESI) m/z = 426 [M+H] ⁺ .

OBD-111.

1H NMR (301 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.03 (s, 1H), 6.17 (s, OH), 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] ⁺ .

Step 1. Preparation of 8-(2,6-difluoro-4-nitrophenyl)-3-oxa-8-aza-bicyclo[3,2,1]octane (3).

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 K ₂ CO ₃ (12.2 g, 88.4 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 2 hours in an atmosphere of nitrogen gas, monitored by TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (EA:PE = 3:1) to give 8-(2,6-difluoro-4nitrophenyl)-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] ⁺ .

Step 2. Preparation of 4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorobenzenamine (4).

In 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 on charcoal (1 g) in MeOH (15 ml) created an atmosphere of hydrogen gas and stirred the reaction mixture at room temperature overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to give 4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5difluorobenzenamine (4) (7.8 g, 95%) as white oil and the resulting crude material was used for the next reaction without further purification. LC-MS (ESI) m/z = 241 [M+H] ⁺ .

Step 3. Preparation of benzyl-4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenylcarbamate (5).

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) 2,5-dioxo-1-pyrrolidinylcarboxylic acid phenylmethyl ester (12 g, 48.7 mmol) was added at 0°C under nitrogen gas and the resulting reaction mixture was stirred at 50°C for 5 hours, monitored with TLC. The mixture was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (PE:EA = 10:1) to give benzyl-4-(3-oxa-8-aza-bicyclo[3,2, 1]octan-8-yl)-3,5difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid. LC-MS (ESI) m/z = 375

[M+N]+.

Step 4. Preparation of (5R)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(hydroxymethyl)oxazolidin- 2-she (6).

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 nitrogen gas, n-BuLi (13.8 ml, 33.1 mmol) was added, then the mixture was stirred at -78 °C for 30 min, after which the solution (R)- Oxiran-2ylmethylbutyrate (4.7 g, 33.1 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 70:1) to give (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 white solid. LC-MS (ESI) m/z = 341 [M+H] ⁺ .

Step 5. Preparation of ((R)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2oxooxazolidin-5-yl )methyl-4-methylbenzenesulfonate (7).

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- she (6) (4.5 g, 13.3 mmol) and Et ₃ N (2.7 g, 26.6 mmol) in DCM (10 ml) was added 4-methylbenzene-1-sulfonyl chloride (5 g, 26. 6 mmol) at 0°C under nitrogen gas and the reaction mixture was stirred at room temperature overnight and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, concentrated the organic layer under reduced pressure, and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give ((R)-3-(4-(3- Oxa-8-azabicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl-4-methylbenzenesulfonate (7) (5.58 g, 85% ) in the form of a white solid. LC-MS (ESI) m/z = 495 [M+H] ⁺ .

Step 6. Preparation of (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1 ]octan8-yl)-3,5-difluorophenyl)oxazolidin-2-one (OBD-055).

To a solution of ((R)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin5-yl)methyl K ₂ CO ₃ (166 mg, 1.2 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 hour under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with EA, concentrated the organic layer under reduced pressure and the resulting crude material was purified by prep-HPLC to give (5R)-5-((III-1,2,3-triazol-1-yl)methyl )-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5difluorophenyl)oxazolidin-2-one (OBD-055) (82 mg, 35 %) in the form of a white solid.

^1H NMR (301 MHz, CDCl ₃ ) 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] ⁺ .

Step 1. Preparation of (5R)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(azidomethyl)oxazolidin- 2-she (8).

To a solution of ((R)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-2-oxooxazolidin5-yl)methyl -4-methylbenzenesulfonate (7) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 ml) was added K ₂ CO ₃ (2.2 g, 16 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 hour in an atmosphere of nitrogen gas and monitored by TLC. Extinguished with ammonium chloride,

- 77 043707 extraction was carried out with EA, the organic layer was concentrated under reduced pressure and the resulting crude material was purified using silica gel column chromatography (PE:EA = 2:1) to give (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 solid white substances. LC-MS (ESI) m/z = 366 [M+H]+.

Step 2. Preparation of (5S)-3-(4-(3-oxa-8-aza-bicyclo[3,2,1]octan-8-yl)-3,5-difluorophenyl)-5(aminomethyl)oxazolidin- 2-she (9).

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- she (8) (2.4 g, 6.5 mmol) in MeOH (10 ml), palladium on carbon (300 mg) was added at 25 ° C, then the resulting reaction mixture was stirred at room temperature overnight in an atmosphere of hydrogen gas, monitored by TLC. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give (58)-3-(4-(3-oxa-8-azabicyclo[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] ⁺ .

Stage 3. Receipt (OBD-051, 052).

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- she (9) (200 mg, 0.59 mmol) and R-OH (0.59 mmol) in DCM (10 ml) 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 resulting reaction mixture was stirred at 25°C for 2 hours under nitrogen gas and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to give (OBD-051, 052) as a white solid .

OBD-051.

1H NMR (301 MHz, CDCl ₃ ) 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, 8 h). LC-MS (ESI) m/z = 381.9 [M+H] ⁺ .

OBD-052.

1H NMR (301 MHz, CDCl ₃ ) 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] ⁺ .

Example 13.

Synthesis of compounds according to additional embodiments of the present invention.

In the same manner as disclosed above in Examples 8 and 12, the following compounds were prepared:

OTV-518

Methyl-(((5 S)-3 -(3-fluoro-4-(( 1 R,5 S)-3 -oxido-3-thia-8-azabicyclo[3,2,1 ]octan-8-yl )phenyl)-2oxooxazolidin-5-yl)methyl)carbamate.

1H-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 2H), 4.02 (t, J = 8.4 Hz, 1H), 3.77 (t, J = 8.0 Hz, 1H), 3.693.53 (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).

MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₈ H ₂₃ FN ₃ O ₅ S: 412.1344; experimental value: 412.1359.

OTV-519

Methyl-(((5 S)-3 -(3,5-difluoro-4-(( 1 R,5 S)-3 -oxido-3 -thia-8-azabicyclo[3,2,1 ]octane-8 -yl)phenyl)-2oxooxazolidin-5-yl)methyl)carbamate.

'H-NMR (400 MHz, CDCl ₃ ) δ: 7.13 (d, J = 12.4 Hz, 2H), 5.10 (m, 1H), 4.80-4.74 (m, 1H) , 4.46 (broad s, 2H), 3.98 (t, 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).

MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₈ H ₂₂ F ₂ N ₃ O ₅ S: 430.1248; experimental value: 430.1259.

- 78 043707

(5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-((1R,5S)-3-oxido-3-thia -8-azabicyclo[3,2,1]octan-8-yl)phenyl)oxazolidin-2-one ¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad s, 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).

MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₈ H ₂₀ F ₂ N ₅ O ₃ S: 424.1249; experimental value: 424.1271

(S)-N-((3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl )acetamide.

¹ H-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).

MSVR (IER): m/z [M+H]+ calculated value for C ₁₇ H ₂₁ FN ₃ O ₄ S: 382.1237; experimental value: 382.1217.

(S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)acetamide .

H NMR (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]+ calculated value for C ₁₇ H ₁₉ F ₂ N ₃ O ₃ S: 383.1115; experimental value: 384.0.

(S)-methyl-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)carbamate.

H NMR (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, 6 N), 3.42 (s, 4 H).

m/z [M+Na] ⁺ calculated value for C ₁₇ H ₂₀ FN ₃ O ₄ S: 381.1159; experimental value: 404.1.

(S)-methyl-((3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl )carbamate.

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 (broad s, 1H), 4.76 (broad s, 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).

MSHR (ESI): m/z [M+H]+ calculated value for C ₁₇ H ₂₁ FN ₃ O ₅ S: 398.1186; experimental value: 398.1166.

- 79 043707

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3 ]heptan-6yl)phenyl)oxazolidin-2-one.

H NMR (400 MHz, CDCI3) 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]+ calculated value for C ₁₇ H ₁₈ FN ₅ O ₃ S: 391.1114; experimental value: 392.0.

About TV-249

(S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)cyclopropanecarboxamide.

1H-NMR (400 MHz, SPS13) 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 (broad s, 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), 0.970.91 (m, 2H), 0.78-0.76 (m, 2H).

MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₉ H ₂₃ FN ₃ O ₃ S: 392.1444; experimental value: 392.1426.

OTV-255

(S)-N-((3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5 yl) methyl)cyclopropanecarboxamide.

¹ H-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 (broad s, 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).

MSVR (IER): m/z [M+H] ⁺ calculated value for C ₁₉ H ₂₃ FN ₃ O ₄ S: 408.1393; experimental value: 408.1378.

OTV-250

(S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5 yl)methyl)cyclobutanecarboxamide.

H NMR (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] ⁺ calculated value for C ₂₀ H ₂₄ FN ₃ O ₃ S: 405.1522; experimental value: 428.2.

OTV-254

(S)-N-((3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl )cyclobutanecarboxamide.

¹ H-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 (broad s, 1H), 4.73 (broad s, 1H), 4.00 (d, J = 12.0 Hz, 4H), 3, 95-3.92 (m, 3H), 3.76-3.72 (m, 1H), 3.653.62 (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).

MSVR (IER): m/z [M+H] ⁺ calculated value for C ₂₀ H ₂₅ FN ₃ O ₄ S: 422.1549; experimental value: 422.1531.

- 80 043707

(R)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)methanesulfonamide.

H NMR (400 MHz, CDCI3) 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] ⁺ calculated value for C ₁₆ H ₂₀ FN ₃ O ₄ S ₂ : 401.0879; experimental value: 402.1.

(R)-N-((3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl )methanesulfonamide.

H NMR (400 MHz, CDCl ₃ ) 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, 8 h), 3.93 (dd, J = 9.6, 3 .2 Hz, 1H), 3.43-3.40 (m, 3H), 3.02 (s, 3H).

m/z [M+H] ⁺ calculated value for C ₁₆ H ₂₀ FN ₃ O ₅ S ₂ : 417.0828; experimental value: 418.0.

(K)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6yl )phenyl)oxazolidin-2-one.

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₁₈ FN ₅ O ₂ S: 375.1165; experimental value: 376.1.

(K)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3 ]heptan-6yl)phenyl)oxazolidin-2-one.

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₁₈ FN ₅ O ₃ S: 391.1114; experimental value: 392.1.

(R)-(3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methylmethylcarbamate.

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₂₀ FN ₃ O ₄ S: 381.1159; experimental value: 382.0.

- 81 043707

(R)-(3-(3-fluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methylmethylcarbamate.

H NMR (400 MHz, CDCy δ: 7.35 (dd, J = 2.0, 11.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.42 (t , 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] ⁺ calculated value for C ₁₇ H ₂₀ FN ₃ O ₅ S: 397.1108; experimental value: 398.0.

OTV-520

(S)-N-((3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl )methyl)acetamide.

1H-NMR (400 MHz, CDCl ₃ ) δ: 7.02 (d, J = 12.0 Hz, 2H), 5.92 (broad s, 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).

MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₂₀ F ₂ N ₃ O ₄ S: 400.1143; experimental value: 400.1158.

About TV-253

^)-methyl-((3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin5 -yl) methyl)carbamate.

1H-NMR (400 MHz, CDCl ₃ ) 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).

MSHR (ESI) calculated value for C ₁₇ H ₂₀ F ₂ N ₃ O ₅ S [M+H]+ 416.1086, experimental value: 416.1073.

OTV-522

F

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₁₇ F ₂ N ₅ O ₃ S: 409.1020; experimental value: 410.1.

OTV-252

(S)-N-((3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidine-5 yl)methyl)cyclopropanecarboxamide.

1H-NMR (400 MHz, CDCl ₃ ) 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)

MSHR (ESI) calculated value for C ₁₉ H ₂₂ F ₂ N ₃ O ₄ S [M+H]+ 426.1294, experimental value: 426.1278.

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(S)-N-((3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl )methyl)cyclobutanecarboxamide.

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)

MSHR (ESI) calculated value for C ₂₀ H ₂₄ F ₂ N ₃ O ₄ S [M+H] ⁺ 440.1450, experimental value: 440.1441.

(R)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl)methyl)methanesulfonamide .

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₆ H ₁₉ F ₂ N ₃ O ₄ S ₂ : 419.0785; experimental value: 420.1.

(R)-N-((3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5yl )methyl)methanesulfonamide.

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₆ H ₁₉ F ₂ N ₃ O ₅ S ₂ : 435.0734; experimental value: 436.0.

(C)-(3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxooxazolidin-5-yl)methylmethylcarbamate.

H NMR (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] ⁺ calculated value for C ₁₇ H ₁₉ F ₂ N ₃ O ₄ S: 399.1064; experimental value: 400.1.

(R)-(3-(3,5-difluoro-4-(2-oxido-2-thia-6-azaspiro[3,3]hepgan-6-yl)phenyl)-2-oxooxazolidin-5yl)methylmethylcarbamate.

H NMR (400 MHz, CDCl ₃ ) 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] ⁺ calculated value for C ₁₇ H ₁₉ F ₂ N ₃ O ₅ S: 415.1013; experimental value: 416.0.

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3 -(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptane-6

- 83 043707 yl)phenyl)oxazolidin-2-one.

¹ I-NMR (400 MHz, CDCl ₃ ) 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), 3.983.92 (m, 1H).

MSHR (IER): m/z [M+H] ⁺ calculated value for C ₁₇ H ₁₉ FN ₅ O ₃ : 360.1472; experimental value: 360.1451.

The present invention will now be further described, without limitation, in the following numbered paragraphs:

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof:

where R independently represents 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 independently represents H, C1-C6 alkyl, C3-C8 cycloalkyl, wherein said alkyl, cycloalkyl is optionally substituted with 1-4 groups selected from halogen, hydroxy, C1-C6 alkyl, C1C6 alkyloxy;

each R2 independently represents C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1-4 groups selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;

each R3 and R4 independently represents H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, aryl; or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or heteroaryl with 1-3 additional heteroatoms selected from O, S or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optional substituted with 1-4 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CF ₃ , NO2, CN;

each R ₅ independently represents C1-C6 alkyl, C3-C8 cycloalkyl, _C1 - _C6 alkoxy, heteroaryl, aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1-4 groups selected from halogen, hydroxyl , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN and NH2;

ring A selected from:

where each R6 and R7 independently represents H, F, _CH3 , CH2CH3, CF3, phenyl;

X = O, S, SO, SO2;

Y = O, S, SO, SO2 and NR8;

m is equal to 1 or 2;

n is 1 or 2;

p is 1 or 2;

q is equal to 1 or 2;

R8 independently represents H, C1- _C4 alkyl, C3-C6 cycloalkyl, COCH3 and p-toluenesulfonyl, wherein said alkyl, cycloalkyl is optionally substituted with 1-4 groups selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy , C ₁ -C ₆ acyloxy, CF ₃ , NO2, CN and NH2.

2. A compound according to claim 1, where said compound is represented by formula II:

where R independently represents OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;

R' and R are independently H or F;

R1 independently represents H, C1-C6 alkyl, C3-C6 cycloalkyl;

R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;

R3 and R4 independently represent H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl; or R3 and R4 together with the nitrogen atom to which they are attached form morpholine, thiamorpholine, piperazine and triazole;

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R5 is independently C1-C6 alkyl, C3- _C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl;

R ₆ and R ₇ are independently H, F, CH3, CH ₂ CH3, CF3; X = O, S, SO, SO ₂ ; when X = S, SO,

SO ₂ , R' = H, R = F, R ₅ cannot be CH ₃ .

3. A compound according to claim 1, wherein said compound is represented by formula III:

where R independently represents OR1, OC(O)R ₂ , NR3R4, NHS(O) ₂ R ₂ , NHC(O)R ₅ ;

R' and R are independently H or F;

R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;

R ₂ independently represents C ₁ -C ₆ alkyl, C3-C6 cycloalkyl;

R3 and _R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl or phenyl; or R ₃ and R 4 together with the nitrogen atom to which they are attached 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;

R ₆ and R ₇ independently represent H, F, CH ₃ , CH ₂ CH ₃ , CF3; X = O, S, SO, SO ₂ .

4. A compound according to claim 1, where said compound is represented by formula IV:

where R independently represents OR1, OC(O)R ₂ , NR3R4, NHS(O) ₂ R ₂ , NHC(O)R ₅ ;

R' and R are independently H or F;

R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;

R ₂ independently represents C ₁ -C ₆ alkyl, C3-C6 cycloalkyl;

R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R ₃ and R ₄ together with the nitrogen atom to which they are attached 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. A compound according to claim 1, wherein said compound is represented by formula V:

where R independently represents OR _b OC(O)R ₂ , NR3R4, NHS(O) ₂ R ₂ , NHC(O)R ₅ ;

R' and R are independently H or F;

R1 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl;

R ₂ independently represents C1-C6 alkyl, C3-C6 cycloalkyl;

R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R ₃ and R ₄ together with the nitrogen atom to which they are attached form morpholine, thiamorpholine, piperazine and triazole;

R ₅ is independently C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5- or 6-membered heteroaryl or phenyl; and X = O, S, SO, SO ₂ .

6. A compound according to claim 1, where said compound is represented by formula VI:

7. A compound according to claim 6, wherein said compound is represented by formula VII, formula VIII or formula IX:

- 85 043707

where R independently represents OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5;

R' and R are independently H or F;

R1 independently represents H, C ₁ -C ₆ alkyl, C3-C6 cycloalkyl;

R2 is independently C1-C6 alkyl, C3-C6 cycloalkyl;

R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl or phenyl; or R3 and R4 together with the nitrogen atom to which they are attached 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. A compound according to claim 1, wherein said compound is represented by formulas IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa or IXb:

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IXb where R independently represents OH, OCH ₃ , OCH2CH ₃ , OS(O)CH ₃ , NH2, NHCH3, NHC6H5, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole , NHS(O)2R2, NHC(O)R5;

R2 independently represents C1-C6 alkyl;

- 87 043707

R5 is independently C1-C6 alkyl, C3-C6 cycloalkyl, _C1 - _C6 alkoxy, furan, thiophene or phenyl; in formula IIa, R5 cannot be CH3; and X = O, S, SO, SO2.

9. The connection according to claim 1, where the specified connection is:

OTV-107 o s' \ /=4 n= ⁿ . 1 N—ά //—NI 1 \ \^/ y F OTV-106 ABOUT s'^S /=4 N^\ 1 N—К /)—N I 1 λ F OTV-109 z^L /=\ to 1 Ν—(\ />—Ν I N k / ν // OH, F OTV-108 ABOUT /=\ / 1 Ν—(x Ν I ---/ y/ F O otv-sh s' \ /=4 ko °L ^F J OTV-112 About 4 fr OTV-115 4=4 k, 1 N—<\ /)—NI N ^F o OBD-005 /=\ k / 1 N—G // ^- Ν I N ---/ o__/ 4 // F O OTV-116 O s-Λ /=\ ko 1 N—G />—Ν I N O k / V Y ν--1 \ ^F th

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OTB-119 O /=4 Ko g^H 1 N—(\ /DN I / L ABOUT F OTV-412 O s' \ /=\ Do k/ Ush/ O / p ^F O OTV-413 О ε ^/ Ά / ⁼ \ Do _l ^F o OTV-414 IZ .у 0 0 TV-407 )=° IZ A 0 0 TV-410 ^F O /=\ Up to 1 Ν—G />—Ν 1 N <7 VA O / p ^F o 0 TV-408 \ ° ε^Ά _у=\ Do _l ^F o 0 TV-409 ^F O S ^Z \ /=\ To 1 ^N— (\ /D ^N 1 ⁿ / / S___/ y // ^F O OTV-411 F O s^ N= ⁿ . 1 ^N— (\ /А ^N 1 ¹ а к / у У F OTV-126 1 Ν—G />—Ν 1 ---/ __/ V_у F O

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OTV-127 ° ⁱ s ^z \ /=4 Хo oG ^f I OTV-137 o °*s ^z \ /=4 Xo n= ⁿ . 1 n—G //—NI 1 4 F About TV-138 °%' ^/ \ / ⁼ \Xo N^\ 1 N—G //—NI 1 4 F OTV-140 o .A 0 and about OBD-006 %^4 /=4 Vo 1 N—G /)—N I H . / 4___/ A/F O OBD-007 /=4 to _z °\> ^N p'UJy' ⁷ F O otv-by ABOUT O /=\ K„ . S N—G /)—N I ---Z y__J A // χ^-Ι^,ο-^Ζ F O otv-pz LA /=\ Ko Ν _Λ SN—G /)—Ν I 1 4 F OTV-114 0 O /=\ Ko ^s N—G //—Ν I N / F 0 OTV 124 O /=.4-0 0=S N—G U-N I N / F 0

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OTB-117 AL /=\ k o _L ^s Ν—ά // ^- Ν I Η 1 V \ / V_у ^F O OTV-118 О /=\ Vo s ₄ ^s Ν—ά /)—Ν 1 Η 1 V \ / \_// \^-Α^Α^Αα/ ^F Ο OTV-120 /=\ to s Ν—<\ />—Ν 1 Η 0 \ / ν '/ 7—' s ^F 0 OTV-121 ΙΖ V0 OBD-001 ο /=4 No. ^ν . S Ν—(\ />—Ν 1 1 Λ F OBD-002 Ο /=\ No. ^ν . O=S Ν—/>—Ν 1 1 λ V / Αχ/ΝΑ F OBD-003 Ο Al τ-ν A . s ν—/An ι η F Ο OBD-004 0 O /=\ Ko / O = S Ν—ά F 0 OBD-008 4—/ )-27 GX ν,,/ Α \-Ά ^ν Α F OBD-009 Ο ° = Ν -Ζ \ F

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OBD-027 Vo S N—ά λ—N I H / F 0 OBD-240 oVo O U^ F O OBD-026 x U. Vo . ^S N—< NIH yS ___у У // F O OBD-241 ABOUT II 0 Ύ ϊ OTB-227 γ/=ν to ХУу—ά Λ—Ν 1 Η / sY У^ ^ ^Ν Υ F Ο OTB-501 Ο X /=\ Χθ Χ^Ν —/)—Ν 1 >>V ν' ^.ΟΗ S</ /- F OBD-081 0 <Y X=V Co Χ^Ν—ά >—Ν 1 F OBD-085 0 X 7=\ Χο Χ^Ν—(\ E—Ν 1 o=s</ /— ^{J 2} F OTB-502 X /=\ Vo X>M—(\ />— NI N / xm ^ ⁿ Y F O OTB-503 ABOUT %Х=\ У о-зУ F 0

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0 TV-504 AA n= ⁿ . TOn—G />—Ν ί । l s</ /—' F 0 TV-505 0 F 0 TV-23 6 ω Г ΖΙ ο=ω=ο \ 0 TV-23 7 7^11—/ V- 'Γ? Η FT F Ο OTV-518 <χ /-ν k 70 Ν—< ύ—Ν Ι Η yj F Ο OBD-016 F Ο OBD-017 Ο F Ο OBD-021 0 Ck ΑΑ r^ ^N . ΤΟν—(\ /)—Ν I ι λ S^/ /- — Ν F OBD-018 Ο _/ ⁼ \_ f^ ^N \ ₀ _- _s 7r rG F 0 TV-506 F O

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0 TV-507 _S ^ ^N x F O OTV-510 <\ J=\ Vo X^N—// ^- N 1 Η / Y/ y // ,Ν^Ζ /— X ^x v F O OTV-514 F P ABOUT OTV-512 F O ^N ΐ ^H θ'- F O OTV-519 F 0 _O _ _S >-0~£W' F O OTV-511 F 0 <4%^ z^on= ⁿ . Λ^Ν—(\ />— ^N 1 ' A siy /— X ^x F OTV-517 F 0 F 0 TV-508 F 0 ₃ У^>\Хй-У F 0 0 TV-509 F 0 OTV-513 Fll ABOUT

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OBD-083 F 0 F OBD-087 F OBD-029 F O OBD-242 . Λ^Ν—< K-N I H / Jr \ // o=s</ /—' D F 0 OTB-260 ABOUT /=v Ko v v y // F OTB-261 O Z Z. /lKo SXN—//—NIH Y Ά _v ^F o OTB523 o AL /-V Ko O=s'XN—< Λ—NIH \ZX y // ^F o OTB-515 O YES /=\ Κθ ^s XN—/)— NIH \Z\z / T ^F o OTB-256 ZAZA /=\ to O=S _V XN—(\ /)—NIH \Z\z _F / T ^F o

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0 TV-241 o ll /=\ Co F 0 TV-247 /uch /-\Ko °=A XN—S L—NI / _N yG F 0 TV-249 O /uch /=\ _Col s XN—(χ /)—NI Η L VXZ A Y '^Κ _4Χ Ν _χ >- ^{Δ F} o 0 TV-255 /uch Co. O=S _V XN—(χ Λ—NI Η L ^F 0 0 TV-250 o /uch /=\ Ko SXN—(x /)—NI N /7 \/\/ A // ^F J 0 TV-254 /uch /=\Ko ^s XN—(\ />—NI n /7 \Z\z A // ^F J OTV-260-2A 0 /yjyk A X N—< L—N I N V v A_/ y F 0**0 OTV-260-2V \<P TZ O./ To 8 II o OTV-260-5A /uch /=\ to Ν _Λ θν X Ν—< λ—Ν 1 / \ F OTV-260-5V Ο Ζ\Ζ\ /=4 Ko Ν=\ °=Α X ,Ν—4 Λ—Ν 1 / \ F

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OTB-260-4A S' XN—G ύ—N 1 Η / ϊ ^F 0 OTB-260-4B ^F 0 OTB-516 F. O >=\ Xo l//'H /)—NI ^vv fP ^χ,ΟΗ F OTV-515 ^Υν k _o ^s XN—G /)—NIH XZXZ // ^F 0 0 TV-520 Yv to O=S ₄ XN—G ύ—NIH \z\z y // ^F 0 0 TV-242 Yv to s XN—G /)—NIH x/X/ YY / T ^F O 0 TV-253 llХК O=S, XN—G /)—NIH Λ 0. ^F 0 0 TV-245 -. ⁿ >---' N F 0 TV-522 Yv Ko O=S ₄ XN—G E—NI 1 _N VV Ά # \ N. <· ^v 7-^ ------ 'N F 0 TV-243 ^F \_ X \X>-y> ^F 0

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OTV-252 aa k\ k l O=S' X N—4 Λ—N I Η L 0 TV-244 k. k η s XN—G /)—Ν I N /7 ν ν A // ^F o 0 TV-251 LA_kk °=A XN—4 Λ—NI N /7 \Z\z A_/ ^F O OTV-516-2A A^ksk s; X n—4 km I n \Z x/ A / / / OTV-516-2V o II I Z to °4/ ^ΖΧ Ho ο ^Ζζ \ OTV-516-6A to to /X /X / \ /О №=\ θκ X Ν—G >—Ν I / \ F OTV-516-6V k k 0=8^4^ ⁴ Ν—ZN ? / ¹ ^F OTV-516-4A llksk XX Ν—ά kN 1 Η Г ^Ύ ^Ν ' ^F o OTV-516-4V Axkvk O=S _V X Ν—G /)—Ν 1 Η 0 TV-201 ΑΑ /=\ to ° X Ν—G /k Ν I \XX/ y xA^on F

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OBD-057 O /=\ Co O X N—< Λ—N I XZ XZ y / F 0 TV-202 O LA /=\ K ⁰ XN—ά /)—Ν I N χζΧζ A y ^F O 0 TV-203 LA /=\k O X Ν—(\ /)—N I 1 L J-Γ lF 0 TV-204 aa /=\ to 1=4 /—'N F 0 TV-205 A A /=\k O XN—G />—NI n I A XZXz A_y \—%/ ⁿ x/k/ ^F o 0 TV-206 o ^Xy^ / ⁼ \ θ-Ά ^F o OBD-056 0 /-\Ho O _h X Ν—ά L—NI N XzXZ A / X? 0 TV-222 0 ll 7=\ to ° X ^N— (\ />— NIH 0 Х/X/ У // xN^H/ /—' S F ΰ 0 TV-223 ABOUT AL /=\ Xo o X Ν—<\ />—Ν 1 Η χ/Χζ γ_7 /Υ F Ο 0 TV-23 8 Ο ⁰ X Ν—//—Ν 1 Η Λ ΧΖ\Ζ U // ^F O

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0 TV-23 9 χχ /=\ ko O XN—(\ /)—NI n /7 x/X/ A // ^F o 0 TV-229 χχ to to O X N—//—N I vv A // xA^on F OBD-062 XX Αχ ko A XN—< I—NIVV A_/ \_A^^nh ₂ F 0 TV-230 XX JAko ⁰ XN—ά /)—Ν I N ΧΖ X/ A // ^F O 0 TV-231 XX k\ ko vXz -у^ ^ _Νγ Ο. ^g about 0 TV-232 _V to ko ⁰ XN—G /)—Ν I N O X/ XZ A_// -NJI/ ^F O 0 TV-233 /x/x )=\ k _l ^F o 0 TV-234 XX X ko χχ °AC ⁿ ~\j~ SMLy >—' n F OBD-061 AL to co F k/° 0 TV-240 XX Ako o X Ν—ά //—NIH /7 X/Х/ A // ^F O

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OBD-051 F o F O OBD-052 F O OBD-055 F ⁰ Ko No. ^ν . Α^Ν—(\ λ— Ν 1 / \ F OBD-112 ABOUT OBD-113 ABOUT OBD-110 ABOUT OBD-111 ABOUT /--\ Ko />M—4 />—N I n 4 n OBD-114 F O 4%^ OBD-115 OBD-048 J-ν Ko 4 ν Άτ OBD-049 /4ν—ά λ—Ν I Η 4 g OBD-252 47^4 OBD-253 OBD-054 F O . /=\ Co OBD-254 4->%v^

10. A pharmaceutical composition containing 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. A pharmaceutical composition of a compound of formula I or a salt, hydrate or solvate thereof, further containing one or more additional anti-infective agents.

12. A method for preventing and treating microbial infections in humans by administering therapeutic

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Claims (10)

a commercially effective amount of a compound of formula I or a salt, hydrate or solvate thereof to a patient in need thereof. 13. The method according to claim 12, wherein said microbial infection is caused by Mycobacterium tuberculosis. * * * It should be understood that the present invention is not limited to the specific embodiments described above, since changes may be made to specific embodiments, and such changes are also included within the scope of the appended claims. CLAIM 1. A compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof: S; (I) where R is OR1, OC(O) _R2 , NHS( _{O)2R2 , NR3R4} or NHC(O)R5; R' and R are independently H, F or Cl; each R1 represents H; each R2 is C1-C6 alkyl; R ₃ and R ₄ are each independently C1-C6 alkyl; each R5 is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from O and ring A selected from: where each R ₆ and R ₇ represents H; X represents O, S, SO or SO2; m is equal to 1 or 2; n is 1 or 2. 2. A compound according to claim 1, where said compound is represented by formula II: II where R is OR1, OC(O)R ₂ , NHS(O) ₂ R ₂ , NR ₃ R4 or NHC(O)R ₅ ; R' and R are independently H or F; R1 represents H; R2 is C1-C6 alkyl; R ₃ and R 4 independently represent C1-C6 alkyl; R5 is a 5- or 6-membered heteroaryl with 1-3 heteroatoms selected from O and S; R ₆ and R ₇ represent H; X represents O, S, SO or SO2. 3. A compound according to claim 1, wherein said compound is represented by formula III: III where R is OR1, OC(O)R2, NHS(O^R2, NR3R4 or NHC(O)R5; R' and R are independently H or F; R ₁ represents H; R2 is C1-C6 alkyl; R ₃ and R 4 independently represent C1-C6 alkyl; R5 is a 5- or 6-membered heteroaryl with 1-3 heteroatoms selected from O and S; R6 and R7 represent H; X represents O, S, SO or SO2. 4. A compound according to claim 1, where said compound is represented by formula IV: - 102 043707 where R is OR ₁ , OC(O)R ₂ , NHS(O) ₂ R ₂ , NR3R4 or NHC(O)R ₅ ; R' and R are independently H or F; R ₁ represents H; R ₂ represents C ₁ -C ₆ alkyl; R ₃ and R 4 independently represent C ₁ -C ₆ alkyl; R ₅ is a 5- or 6-membered heteroaryl with 1-3 heteroatoms selected from O and S; And X represents O, S, SO or SO ₂ . 5. A compound according to claim 1, wherein said compound is represented by formula V: where R is OR ₁ , OC(O)R ₂ , NHS(O) ₂ R ₂ , NR3R4 or NHC(O)R ₅ ; R' and R are independently H or F; Ri R2 R3 R ₅ represents H; independently represents C ₁ -C ₆ alkyl; and R4 independently represent C1-C6 alkyl; independently represents a 5- or 6-membered heteroaryl with 1-3 heteroatoms selected from O and S; And X represents O, S, SO or SO ₂ . 6. A compound according to claim 1, wherein said compound is represented by formula IX: where R is OR ₁ , OC(O)R ₂ , NHS(O) ₂ R ₂ , NR3R4 or NHC(O)R ₅ ; R' and R are independently H or F; R ₁ represents H; R ₂ represents C ₁ -C ₆ alkyl; R ₃ and R 4 independently represent C ₁ -C ₆ alkyl; And R ₅ independently represents a 5- or 6-membered heteroaryl with 1-3 heteroatoms selected from O and S. 7. A compound according to claim 1, wherein said compound is represented by formulas IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, IXa or IXb: - 103 043707 Sha IXb where R represents OH, OC(O)CH3, NHS/O^ or NHC(O)R5; R2 is C1- _C6 alkyl; R5 is furan or thiophene; And X represents O, S, SO or SO2. 8. The connection according to claim 1, where the specified connection is: - 104 043707 OTV-108 F O hole s' \ /=4 Ο-λ 1 N—<\ /)—N 1 n 1 k / y U ^F O OTV-112 /=\ Xo s—λ ^F o OTV-116 s-Λ /=\ k 1 N—4 /)—NI N O k / V // \___< ^F ά OTV-126 kZukkyi-A F O OTV-127 °*s ^x \ /=4 +° Λ ^F o otv-po o/=\ k . SN—<\ /)—N t /--U ___/ A // F O OTV-117 O /=\ k o _L SN—4 />—N 1 Η 1 A \ / V__у ^F O OTV-118 XX / ⁼ \ Х° θΆ ^F о OTV-120 O /=\k s N—/)—NI N O \/4/S ^F th OTV-501 A to TOMACH An I >/ K ^_ ___k/ ^{he S} A /— F OTV-236 /=\ to UAAch An I n about si7 / O OBD-112 A^-buon / OR OBD-114 .fk% - 105 043707 9. Pharmaceutical composition for the prevention and treatment of microbial infections caused by Mycobacterium tuberculosis containing a therapeutically effective amount of at least one compound of formula I at π. 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutically acceptable carriers and/or additives. 10. A method of preventing and treating microbial infection caused by Mycobacterium tuberculosis in humans by administering a therapeutically effective amount of a compound of formula I at π. 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof to a patient in need thereof. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 106-