NZ738702B2 - Substituted phenyloxazolidinones for antimicrobial therapy - Google Patents

Substituted phenyloxazolidinones for antimicrobial therapy Download PDF

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NZ738702B2
NZ738702B2 NZ738702A NZ73870216A NZ738702B2 NZ 738702 B2 NZ738702 B2 NZ 738702B2 NZ 738702 A NZ738702 A NZ 738702A NZ 73870216 A NZ73870216 A NZ 73870216A NZ 738702 B2 NZ738702 B2 NZ 738702B2
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New Zealand
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otb
mmol
obd
alkyl
independently
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NZ738702A
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NZ738702A (en
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Christopher B Cooper
Nader Fotouhi
Haihong Huang
Takushi Kaneko
Doongfeng Zhang
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The Global Alliance For Tb Drug Development Inc
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Priority to NZ773022A priority Critical patent/NZ773022B2/en
Priority claimed from PCT/US2016/042486 external-priority patent/WO2017015106A1/en
Publication of NZ738702A publication Critical patent/NZ738702A/en
Publication of NZ738702B2 publication Critical patent/NZ738702B2/en

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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
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    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

Abstract

The present invention relates to novel oxazolidinones (Formula I): or a pharmaceutically acceptable salt having ring A characterized by N-containing monocyclic, bicyclic or spirocyclic substituents, to their preparation, and to their use as drugs for treatingMycobacterium tuberculosisand other microbial infections, either alone or in combination with other anti-infective treatments.

Description

SUBSTITUTED PHENYLOXAZOLIDINONES FOR ANTIMICROBIAL THERAPY FIELD OF THE INVENTION The invention relates generally to compounds with antibacterial activity and, more specifically, with anti-tuberculosis properties. In particular, it relates to substituted phenyloxazolidinone compounds useful for the treatment of tuberculosis in patients in need thereof.
All documents cited to or relied upon below are expressly incorporated herein by reference.
BACKGROUND OF THE INVENTION Linezolid is the first-in-class drug and was approved in 2000 for a number of clinical applications including the treatment of nosocomial and community-acquired pneumonia and skin infections caused by Staphylococcus aureus/Methicillin-resistant S. aureus, Vancomycin-resistant Enterococci, and Streptococcus pneumoniae (Pen-S). Linezolid exhibits in vitro bacteriostatic activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) and extensively drug resistant (XDR) strains, with a minimum inhibitory concentration (MIC) of less than 1 µg/ml. However, it has demonstrated only modest activity in murine models of tuberculosis. Nonetheless, Linezolid has been used off-label in combination regimens to treat multidrug-resistant tuberculosis.
Oxazolidinones currently in clinical development show bone marrow toxicity in animals after long term administration (i.e., greater than one month) that is believed to be related to mitochondrial protein synthesis (MPS) inhibition, with very narrow safety margins or no safety margins. Since the antimicrobial mode of action of this class of compounds is inhibition of microbial protein synthesis, the MPS inhibition and consequent bone marrow toxicity exhibited by these compounds is considered mechanism specific. These oxazolidinones generally show high clearance and so require administration of high doses in clinical treatment of TB or the other indications for which they are being developed (e.g., 500 mg to 1600 mg daily) to achieve efficacious exposures. Therefore, it would be highly desirable to identify a new generation of oxazolidinones for TB treatment that would demonstrate improved potency and efficacy against TB, reduced systemic clearance to reduce the daily dose below 500 mg, and diminished MPS inhibition and related bone marrow toxicity, resulting in an improved safety margin for long term administration.
SUMMARY OF THE INVENTION The present invention relates to novel oxazolidinones of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein, R is independently OR , OC(O)R , OC(O)NHR , OS(O )R , NHS(O) R , NR R , 1 2 2 2 2 2 2 3 4 NHC(O)R ; R’ and R’’ are independently H, F, Cl or OMe; each R is independently H, C -C alkyl, C -C cycloalkyl, wherein said alkyl, 1 1 6 3 8 cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C -C alkyl, C -C alkyloxy; 1 6 1 6 each R is independently C -C alkyl, C -C cycloalkyl, heterocyclyl, heteroaryl or 2 1 6 3 8 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 each R and R is independently H, C -C alkyl, C -C cycloalkyl, heterocyclyl 3 4 1 6 3 8 heteroaryl, aryl; or R and R taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C -C alkyl, C -C alkoxy, CF , NO , CN; 1 6 1 6 3 2 each R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, heteroaryl, 1 6 3 8 1 6 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 Ring A is selected from: (CH ) (CH ) , , and wherein, each R and R is independently H, F, CH , CH CH , CF , phenyl; 6 7 3 2 3 3 X = O, S, SO, SO ; Y = O, S, SO, SO , and NR ; m is 1, or 2; n is 1, or 2; p is 1, or 2; q is 1, or 2; R in independently H, C -C alkyl, C -C cycloalkyl, COCH , and p-toluenesulfonyl, 8 1 4 3 6 3 wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C alkoxy, C -C acyloxy, CF , NO , CN and 1 6 1 6 1 6 3 2 In a first aspect, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate of: wherein: R is independently OR , OC(O)R , OC(O)NHR , OS(O )R , NHS(O) R , NR R , 1 2 2 2 2 2 2 3 4 NHC(O)R ; R’ and R’’ are independently H, F, Cl or OMe; each R is independently H, C -C alkyl, C -C cycloalkyl, wherein said alkyl, 1 1 6 3 8 cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C -C alkyl, C -C alkyloxy; 1 6 1 6 each R is independently C -C alkyl, C -C cycloalkyl, heterocyclyl, heteroaryl or 2 1 6 3 8 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 each R and R is independently H, C -C alkyl, C -C cycloalkyl, heterocyclyl 3 4 1 6 3 8 heteroaryl, aryl; or R and R taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C -C alkyl, C -C alkoxy, CF , NO , CN; 1 6 1 6 3 2 each R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, heteroaryl, 1 6 3 8 1 6 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 Ring A is selected from: (CH ) (CH ) , , and wherein, each R and R is independently H, F, CH , CH CH , CF , phenyl; 6 7 3 2 3 3 X = O, S, SO, SO ; Y = O, S, SO, and SO ; m is 2; n is 1, or 2; p is 1, or 2; q is 1, or 2; R in independently H, C -C alkyl, C -C cycloalkyl, COCH , and p-toluenesulfonyl, 8 1 4 3 6 3 wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C alkoxy, C -C acyloxy, CF , NO , CN and 1 6 1 6 1 6 3 2 In a second aspect, there is provided a compound, wherein the compound is: OTB-107 S O N OTB-106 S O N OTB-109 N N H OTB-108 OTB-111 S O O N N H OTB-112 S O S N N H OTB-115 N N H OBD-005 N N H OTB-116 N N H O OTB-119 OTB-412 N N H OTB-413 N N H OTB-414 OTB-407 N N H OTB-410 N N H OTB-408 N N H OTB-409 N N H OTB-411 S O N OTB-126 OTB-127 S O O OTB-137 S O N OTB-138 S O N OTB-140 OBD-006 N N H OBD-007 N N H OTB-110 OTB-113 S N N OTB-114 OTB124 OTB-117 S N N H OTB-118 S N N H OTB-120 S N N H O OTB-121 S N N H OBD-001 9825338_1 (GHMatters) P107873.NZ OBD-002 OBD-003 S N N H OBD-004 O S N N H OBD-008 S N N OBD-009 O S N N OBD-027 OBD-240 OBD-026 OBD-241 OTB-227 N N H 9825338_1 (GHMatters) P107873.NZ OTB-501 OBD-081 OBD-085 OTB-502 N N H OTB-503 OTB-504 OTB-505 OTB-236 N N H O OTB-237 N N H O OTB-518 OBD-016 N N H OBD-017 OBD-021 OBD-018 OTB-506 N N H OTB-507 N N H OTB-510 N N H OTB-514 OTB-512 N N H OTB-519 OTB-511 OTB-517 OTB-508 N N H OTB-509 OTB-513 F O OBD-083 OBD-087 OBD-029 OBD-242 OTB-260 S N N OTB-261 S N N H OTB523 OTB-248 S N N H OTB-256 OTB-241 OTB-247 OTB-249 S N N H OTB-255 OTB-250 OTB-254 S N N H OTB-260 OTB-260 OTB-260 OTB-260 OTB-260 OTB-260 OTB-516 OTB-515 N N H OTB-520 OTB-242 S N N H OTB-253 OTB-245 S N N OTB-522 OTB-243 S N N H OTB-252 OTB-244 N N H OTB-251 OTB-516 OTB-516 OTB-516 OTB-516 OTB-516 OTB-516 OTB-201 OBD-057 OTB-202 O N N H OTB-203 OTB-204 O N N OTB-205 OTB-206 O N N H OBD-056 OTB-222 O N N H O OTB-223 O N N H OTB-238 O N N H OTB-239 O N N H OTB-229 OBD-062 OTB-230 O N N H OTB-231 N N H OTB-232 O N N H O OTB-233 OTB-234 O N N OBD-061 OTB-240 F O O N N H OBD-051 OBD-052 OBD-055 OBD-112 OBD-113 OBD-110 OBD-111 OBD-114 OBD-115 OBD-048 OBD-049 OBD-252 OBD-253 OBD-054 OBD-254 or a pharmaceutical acceptable salt, hydrate, or solvate thereof.
In a third aspect, there is provided a compound, wherein said compound is: or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
In a fourth aspect, there is provided a pharmaceutical composition comprising at least one compound according to the first, second or third aspects, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and/or additives.
In a fifth aspect, there is provided a use of a compound according to the first, second or third aspects, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for treating microbial infections in a human.
In a sixth aspect, there is provided a use of a compound according to the first, second or third aspects, or a salt, hydrate, or solvate thereof, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for treating microbial infections in a human, wherein the infection caused by Mycobacterium tuberculosis.
The present disclosure includes pharmaceutical compositions of Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective treatments.
The present disclsoure also relates to a compound in accordance with Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in a human.
DETAILED DESCRIPTION OF THE INVENTION One aspect of the present invention is to provide novel compounds according to Formula I shown and described above. Specifically, the compounds of the invention are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria, Mycobacterium tuberculosis, Mycobacterium avium, and the like. As a result, this invention provides novel 9825338_1 (GHMatters) P107873.NZ compounds according to Formula I, as well as pharmaceutically acceptable salts, hydrates, or solvates thereof. Values for the variables in Formula I are provided in the following paragraphs.
Table 1 below shows some specific examples of the compounds of the invention, by indicating their structures as well as their in vitro activity against Mycobacterium tuberculosis H37Rv strains, and in vitro MPS inhibition activity when tested as described in Example 9 and 10 below, respectively. As shown in Table 1 below, potent anti-tubercular agents demonstrate low MIC values (particular compounds with MIC’s below 1 ?g/mL). Conversely, high MPS inhibition IC ’s indicate diminished mitochondrial protein synthesis activity in vitro, and are indicative of reduced myelosuppression toxicity in vivo. In certain embodiments of the invention, compounds having the best therapeutic index are those demonstrating a 4q [followed by page 5] OTB-116 446.1623 3.812 > 100 N N H O OTB-119 378.1421 0.456 > 100 OTB-412 384.1371 0.199 10 N N H OTB-413 394.1580 0.108 9.13 N N H OTB-414 408.1736 0.171 NA N N H OTB-407 386.1330 0.097 3.079 N N H OTB-410 402.1287 0.125 > 100 N N H OTB-408 412.1485 0.342 3.608 N N H OTB-409 426.1643 0.477 8.51 OTB-411 396.1296 0.124 8.73 OTB-126 413.1573 0.847 35.60 OTB-127 436.1371 1.234 10.15 S O O N N H OTB-137 394.1328 0.277 7.64 S O N OTB-138 394.1338 7.565 > 100 S O N OTB-140 394.1339 3.695 > 100 OBD-006 411.1628 0.49 7.485 N N H OBD-007 427.1577 0.46 19.81 N N H OTB-110 411.1786 0.125 > 100 S N N OTB-113 392.1590 2 > 100 S N N OTB-114 382.1620 0.05-0. 28-29 S N N H OTB-124 398.1540 0.26-1. 94->100 OTB-117 434.1581 0.665 56.32 S N H OTB-118 450.1356 1.548 NA S N N H OTB-120 460.1778 3.877 7.27 S N H O OTB-121 424.2096 2.785 17.63 S N N H OBD-001 391.1478 0.3 12 S N N OBD-002 407.1427 1.6 29 OBD-003 409.1835 0.33 > 100 S N H OBD-004 425.1785 3.338 15.76 O S N N H OBD-008 391.1478 3.513 29.89 S N N OBD-009 407.1427 21.052 > 100 O S N N OBD-027 0.3 NA OBD-240 NA NA OBD-026 0.4 NA OBD-241 NA NA OTB-227 366.1277 0.889 15.22 N N H OTB-501 339.1169 4.5 NA OBD-081 407.9 0.47 77 OBD-085 1.1 >100 OTB-502 380.1435 0.246 13.55 OTB-503 396.1379 0.2-1.3 78->100 OTB-504 390.1385 0.5-0.7 17-> 100 OTB-505 406.1339 1.8-3.5 57->100 OTB-236 416.1097 14.256 NA N N H O OTB-237 396.1388 0,03-0. 15-23 OTB-518 3.5 73 OBD-016 407.1679 0.486 13 N N H OBD-017 423.8 5.8-6.3 41 OBD-021 389.1322 27.456 NA OBD-018 405.1271 > 32 NA OTB-506 406.1527 1 8 N N H OTB-507 420.1736 0.7 10 N N H OTB-510 398.1329 0.03-0. 3-7 N N H OTB-514 414.1275 0.5 25 OTB-512 414.1278 0.063 42.47 N N H OTB-519 0.9 51 OTB-511 408.1295 0.06-0. 9-> 100 OTB-517 1.3-2 30-55 OTB-508 424.1484 0.2 8 N N H OTB-509 438.1642 0.04 5 N N H OTB-513 F 454.1588 1.664 12.96 OBD-083 0.05 20 OBD-087 0.86 >100 OBD-029 0.11 >100 OBD-242 0.61 >100 OTB-260 325.1010 1.49 30.03 S N N OTB-261 366.1274 0.12 2 S N H OTB-523 0.5 4 OTB-515 NA 0.03-0. 23-71 S N N H OTB-256 4 46 OTB-241 376.1231 0.116 19.81 S N N OTB-247 392.0 1.2-1.4 10 OTB-249 392.1426 0.06-0. 7->100 S N N H OTB-255 408.1378 1.9 10 OTB-250 428.2 0.06 10->100 S N N H OTB-254 422.1531 1.8 23 S N N H OTB-260 402.1 0.82 >100 OTB-260 418.0 0.49 >100 OTB-260 376.1 0.44 >100 OTB-260 392.1 >32 >100 OTB-260 382.0 0.39 >100 OTB-260 398.0 20 >100 OTB-516 343.0912 0.465 15.33 OTB-515 384.1168 0.03-0. 14-21 S N N H OTB-520 400.1158 0.4 17 OTB-242 400.1125 0.02-0. 23-71 S N N H OTB-253 416.1073 0.7 10 OTB-245 394.1129 0.03-0. 25-35 S N N OTB-522 410.1 1 38 OTB-243 410.1331 0.03 14 S N H OTB-252 426.1278 0.7 52 OTB-244 424.1483 0.02-0. 6->22 S N N H OTB-251 440.1441 0.9 24 OTB-516 420.1 0.05 >100 OTB-516 436.0 3 >100 OTB-516 400.1 0.03 >100 OTB-516 416.0 4.7 >100 OTB-201 309.1269 16 NA OBD-057 0.4 67 OTB-202 350.1497 0.6-1.2 17-29 N N H OTB-203 360.1451 > 32 NA O N N OTB-204 360.1451 3.2-3.7 > 100 O N N OTB-205 402.1561 3.9 NA O N N H OTB-206 418.1331 2.8 NA O N N H OBD-056 1.9 17 OTB-222 386.1185 7.4 O N N H O OTB-223 366.1466 0.8-2.6 38->100 O N N H OTB-238 376.1652 2-4 20 O N N H OTB-239 390.1808 2.1-3.8 19-67 N N H OTB-229 327.1135 1.9-7.4 > 100 O N N OBD-062 0.1-0.2 21->100 OTB-230 368.1418 0.2 13 O N H OTB-231 384.1367 0.24-0. 37-63 O N N H OTB-232 404.1087 1.5-4 > 100 O N N H O OTB-233 394.1575 0.36-1 8.4-50 O N N H OTB-234 378.1365 0.39-4 43->100 OBD-061 0.8 29 OTB-240 408.1716 0.24-0. 19-67 O N N H OBD-051 381.9 0.6 6 OBD-052 398.0 0.95 13 OBD-055 391.8 1.3 15 OBD-112 3.5 >100 OBD-113 0.39 >100 OBD-110 0.45 7 OBD-111 0.49 7 OBD-114 1.7 >100 OBD-115 0.2=0.3 87->100 OBD-048 0.39 5 OBD-049 0.25-1 6->100 OBD-252 0.47 32.3 OBD-253 0.53 65 OBD-054 0.5 6-31 OBD-254 0.73 36 Definitions As used herein unless otherwise indicated, "alkyl" includes branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified carbon atom numbers. Commonly used abbreviations for alkyl groups are used throughout the application, e.g. methyl may be represented by conventional abbreviations including "Me" or CH or a symbol that is an extended bond without defined terminal group, e.g. , ethyl is represented by "Et" or CH CH , propyl is represented by "Pr" or CH CH CH , butyl can be represented by "Bu" or 2 2 3 CH CH CH CH , etc. "C alkyl" (or "C -C alkyl") means branched or linear 2 2 2 3 1-6 1 6 chain alkyl groups, including all isomers, having the specified number of carbon atoms. C alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is provided, 1-10 carbon atoms are intended for linear or branched alkyl groups. C - alkyl may be unsubstituted or substituted with 1-3 fluorine or 1-3 chlorine atoms.
"Cycloalkyl" means C carbocycles not containing heteroatoms. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, and the like.
"Aryl" means mono- and bicyclic aromatic rings containing 6-12 carbon atoms.
Examples of aryl include, but are not limited to, phenyl, naphthyl, indenyl and so on.
Aryl also includes monocyclic rings fused to an aryl group. Examples include tetrahydronaphthyl, indanyl and the like.
"Heterocyclyl," unless otherwise indicated, means a 4-, 5-, 6-, 7- or 8-membered monocyclic saturated ring containing 1-2 heteroatoms selected from N, O and S, in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclyl" include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, and so on. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1H, 3H)-pyrimidine-2, 4-diones (N-substituted uracils). Heterocyclyl may also include such moieties in charged form, e.g., piperidinium.
"Heteroaryl" means a mono- or bicyclic aromatic ring or ring system having 5 to 10 atoms and containing 1-3 heteroatoms selected from N, O, and S. Examples include, but are not limited to, oxadiazolyl, thiadiazolyl, pyrrolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl, isoxazolyl, triazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, pyridinyl, oxazolyl, thiazolyl, tetrazolyl, and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Additional examples of heteroaryls include, but are not limited to, imidazopyridinyl, imidazopyridazinyl, pyrazolopyrazolyl, indazolyl, thienopyrazolyl, pyrazolopyridinyl, and imidazothiazolyl. Heteroaryl also includes such groups in charged form, such as pyridinium. In an embodiment, heteroaryl is triazolyl, imidazolyl, oxadiazolyl, pyrazolyl, oxazolyl, and pyridinyl.
"Heterocyclic alkyl," unless otherwise indicated, includes both branched- and straight-chain saturated aliphatic hydrocarbon groups which is bonded to a carbon or nitrogen atom of a heterocyclyl, as described above.
"Halogen (or halo)" includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halogen is chlorine or fluorine.
Substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound. A "stable" compound can be prepared and isolated, and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time that allows use of the compound for the described purposes.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C alkyl COOR is equivalent to .
When a variable (e.g., R, R , etc.) occurs more than once in any constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents and/or variables are allowed only if such combinations lead to stable compounds.
In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e. R , R , R, etc., are to be chosen in conformity with common principles of chemical structure connectivity and stability.
The term "substituted" is used to include multiple degrees of substitution by a named substituent. Where multiple substituents are claimed, the substituted compound can be independently substituted by one or more of the disclosed substituents. By independently substituted, it is meant that the (two or more) substituents can be the identical or different.
Where a substituent or variable has multiple definitions, the substituent or variable is defined as being selected from the group consisting of the indicated definitions.
Salts: Compounds of structural Formula I also cover the pharmaceutically acceptable salts. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" means salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases or acids. Pharmaceutically acceptable salts of basic compounds refer to non-toxic salts of the compounds of this invention which are generally prepared by mixing the free base with a suitable organic or inorganic acid.
Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, clavulanate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate and the like.
Suitable pharmaceutically acceptable salts of acids covered by Formula I include, but are not limited to, salts generated from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and so on.
Solvates and hydrates of the compounds of Formula I are also included in the present invention.
The present invention also discloses processes to synthesize the compounds of Formula I, as described below.
One aspect of the invention that is of interest relates to a compound in accordance with Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in a method of treatment of microbial infections in humans.
Another aspect of the invention that is of interest is a method of treating microbial infections in a human patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof to said patient.
In a further aspect, the present invention provides pharmaceutical compositions of Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents.
In still a further aspect, the present invention relates to a compound in accordance with Formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in a human.
While it may be possible for the compounds of the invention to be administered as the raw chemical, it is preferable to present these as a pharmaceutical composition.
Thus, according to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient.
Tablets, capsules, intraocular topical formulations and parenteral solutions are common among aminoglycosides. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Abbreviations Throughout the synthetic schemes and examples below, abbreviations are used with the following meanings unless otherwise indicated: Ac is acetate, or acetyl; aq. is aqueous; Ar is Aryl; Bn is benzyl; BnNH is benzylamine; Boc is tert-butylcarbamoyl; br is broad; Bu is butyl; Bu is tert-butyl; n-BuLi is n-butyllithium; CbzCl is benzyl chloroformate; CFU is colony forming units CO is carbon dioxide COX-1 is cyclooxygenase I Pr is cyclopropyl; DCM is dichloromethane; DIPEA is N,N-diisopropylethylamine; DMAP is 4-dimethylaminopyridine DMEM is Dulbecco’s Modified Eagle Medium DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; ELISA is enzyme-linked immunosorbent assay ESI is electrospray ionization; Et is ethyl; Et N is triethylaimne; Et O is diethyl ether; EtOH is ethanol, EtOAc is ethyl acetate; FBS is Fetal Bovine Serum Halo is a halogen (e.g., fluorine or chlorine); H-NMR is proton nuclear magnetic resonance; C-NMR is carbon nuclear magnetic resonance; H9C2 is a cell line from rat heart myoblasts HPLC is high performance liquid chromatography; HRMS is high-resolution mass spectrometry; Hz is hertz; i is Iso; IC is half-maximum inhibitory concentration; Kg is kilogram; M is molar; Me is methyl; ?g is microgram; MeCN is acetonitrile; MeOH is methanol; MsCl is methanesulfonyl chloride; MHz is megahertz; mm is millimeter; ?L is microliter; mM is milimolar; ? ? is micromolar; mmol is milimoles; MABA is microplate alamar blue assay; MIC is minimum inhibitory concentration; MPS is mitochondrial protein synthesis; m/z is mass to charge ratio; n is normal; NEAA is non-essential amino acids nm is nanometer; nPr is n-propyl; p is para; PE is petroleum ether; Ph is phenyl; Pr is propyl; rt is room temperature; sec is secondary; SDH-A is succinate dehydrogenase-A tert is tertiary; TFA is trifluoroacetic acid; TsCl is p-toluene sulfonyl chloride; TMSI is trimethylsilyl iodide; TPP is triphenylphosphine; TsNH is p-toluenesulfonamide; Tosyl is p-toluenesulfonyl; THF is tetrahydrofuran; TLC is thin layer chromatography.
EXAMPLES Synthetic methods for preparing the representative compounds of the present invention are illustrated in the following Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein. The following Examples are intended to help illustrate the invention, and are not intended to, nor should they be constructed to limit its scope.
Example 1 Preparation of [1, 4]Thiazepane (1a) polyphosphoric acid N LiAlH EtOH/H O,reflux 115 deg.
S HO-NH HCl Step 1: Synthesis of Dihydro-2H-thiopyran-4(3H)-one oxime (1a-1) 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 H O (100 mL) and ethanol (40 mL) was added sodium acetate (13.1 g, 0.16 mol). The mixture was refluxed for 4h, the organic solvent was removed in vacuum and the residue was cooled in an ice bath, 8.92 g solid was obtained in 79% yield by filtration. H-NMR (400 MHz, CDCl ) d: 2.88 (m, 2H), 2.80 (m, 2H), 2.74 (m, 2H), 2.57 (m, 2H).
Step 2: Synthesis of 1,4-Thiazepanone (1a-2) The mixture of dihydro-2H-thiopyran-4(3H)-one oxime (4.01 g, 0.03 mol) in polyphosphoric acid was heated at 115 ? for 15min, and cooled to rt, ice-water was added, then the mixture was extracted with EtOAc 5 times. The combined organic layer was dried over Na SO and concentrated under vacuum to give 2.4 g product as brown solid in 60% yield. H-NMR (400 MHz, CDCl ) d: 6.79 (brs, 1H), 3.63 (m, 2H), 2.94 (m, 2H), 2.74 (m, 4H).
Step 3: Synthesis of 1,4-Thiazepane (1a) To a solution of 1,4-thiazepanone (2.07 g, 15.7 mmol) in dry THF was added LiAlH (0.66 g, 17.3 mmol) at 0 ?, then the mixture was stirred at rt for 4h. H O (0.7 mL), 15% NaOH (0.7 mL) and H O (2.1 mL) were added to the reaction in successively. The mixture was filtrated to give 1.77 g product in 96% yield.
H-NMR (400 MHz, CDCl ) d: 3.07 (m, 2H), 2.98 (m, 2H), 2.75 (m, 4H), 1.93 (m, Example 2 Preparation of 1,5-Thiazocane hydrochloride (1b) LiAlH O N O 2 rt-reflux 3 Na S H O 2 9 2 Br N Br HO N OH CH Cl 3-chlorobutanoyl chloride reflux CH Cl , deg. 2 2 0 Step 1: Synthesis of Dimethyl 3,3'-(benzylazanediyl)dipropanoate (1b-1) O N O A solution of benzylamine (10.7 g, 0.1 mol) in MeOH (50 mL) was added in dropwise to a solution of methyl acrylate (18.9 g, .022 mol) in MeOH (100 mL) at rt.
The result mixture was refluxed for 8h, and evaporated in vacuum to give 27.9 g product in quantitative yield. H-NMR (400 MHz, CDCl ) d: 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(propanol) (1b-2) HO N OH To a solution of dimethyl 3,3'-(benzylazanediyl)dipropanoate (4.47 g, 16.0 mmol) in dry THF was added LiAlH (0.77 g, 20.2 mmol) at 0 ?, then the mixture was stirred at rt for 24h. MeOH (1.5 mL), 15% NaOH (1.0 mL) and H O (1.0 mL) were added to the reaction in successively. The mixture was filtrated to give 3.4 g product in 91% yield. H-NMR (400 MHz, CDCl ) d: 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-Benzylbromo-N-(3-bromopropyl)propanamine (1b-3) Br N Br To a solution of 3,3'-(benzylazanediyl)bis(propanol) (447 mg, 2.0 mmol) in dry CH Cl was added PBr3 in dropwise at 0 ?, then the mixture was stirred at rt for 12h.
The reaction mixture was diluted with water and extracted with CH Cl . The combined organic layer was washed with sat. NaHCO and brine, dried over Na SO , 3 2 4 and concentrated. The 0.43 g product was obtained as yellow oil in 61% yield.
H-NMR (400 MHz, CDCl ) d: 7.27 (m, 5 H), 3.56 (s, 2 H), 3.44 (t, J = 6.8 Hz, 6.4 Hz, 4 H), 2.58 (t, J = 6.4 Hz, 6.4 Hz, 4 H), 2.02 (m, 4 H).
Step 4: Synthesis of 5-Benzyl-1,5-thiazocane (1b-4) To a solution of N-benzylbromo-N-(3-bromopropyl)propanamine (1.0 g, 2.9 mmol) in ethanol was added Na S·9H O (697 mg, 2.9 mmol). The mixture was refluxed for 18 h. The mixture was then cooled to r.t., and the solvent was removed in vacuum. To the residue was added H O and Et O. The aqueous layer was extracted with Et O, and the combined organic layer was washed with brine, dried over Na SO and concentrated under vacuum. 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 Cl was added (6.15 g, 43 mmol) at 0 ?. The mixture was stirred at rt for 6 h. the solvent was evaporated in vacuum and the residue was refluxed in MeOH for 3h. The mixture was concentrated and washed with Et O. The crude product was used without purification.
Example 3 Preparation of (1R,5S)thiaazabicyclo[3.1.1]heptane (1c) NH.HI Br HCl Br Br BnNH EtOOC COOEt EtOH EtOOC COOEt PBr 2 3 O O O O (1) H Pd(OH) MsCl Et N 2 2 3 HO MsO N OH N OH N OMs CaCl (2) CbzCl DIPEA 2 Cbz Bn Cbz LiBr S Na S . 9H O Step 1: Synthesis of diethyl 2,4-dibromopentanedioate (1c-1) Br Br EtOOC COOEt To a solution of dihydro-2H-pyran-2,6(3H)-dione (11.4 g, 0.1mol) and PBr (0.1 mL) was added Br (32 g, 0.2 mol) dropwise at 100°C, the mixture was stirred at 100°C for 7h and cooled to rt. HCl/EtOH (10mL) was added to the reaction mixture and stirred overnight at rt. After EtOH was evaporated, Et O was added to the residue and washed with sat. NaHCO and brine, dried over Na SO , concentrated to give 32 3 2 4 g product was used for next step without purification.
Step 2: Synthesis of (2R,4S)-diethyl 1-benzylazetidine-2,4-dicarboxylate (1c-2) EtOOC COOEt A mixture of (2R,4S)-diethyl 2,4-dibromopentanedioate (54 g, 156 mmol), benzylamine (17 g, 159 mmol) and K CO (25.9 g, 187.2 mmol) in toluene was refluxed for 24h. the mixture was washed with brine, dried over and concentrated.
The crude product was purified by chromatography on silica gel to give 18.39 g product in 41% yield. HRMS (ESI): m/z [M + H] calcd for C H NO : 292.1549; 16 22 4 found: 292.1542.
Step 3: Synthesis of ((2R,4S)benzylazetidine-2,4-diyl)dimethanol (1c-3) To a solution of (2R,4S)-diethyl 1-benzylazetidine-2,4-dicarboxylate (0.8 g, 2.75 mmol) in EtOH/MeOH (9:1; 10 mL) was added CaCl (0.92 g, 8.25 mmol) at r.t. To the resulting stirred mixture was then added NaBH (0.63 g, 16.5 mmol) in portions.
The reaction mixture was stirred for overnight at r.t. Subsequently H O (5 mL) was added, and the mixture was stirred for 30 min. The mixture was then concentrated in vacuum, and partitioned between H O (10 mL) and CH Cl (10 mL). The aqueous 2 2 2 layer was extracted with CH Cl (2 × 10 mL), and the organic layers were combined, washed with brine (10 mL), dried over Na SO , and concentrated in vacuo to give 0.25 g product as yellow oil. This product was used in the next step without further purification. MS (ESI): m/z [M + H] : 208.1477.
Step 4: Synthesis of (2R,4S)-benzyl 2,4-bis(hydroxymethyl)azetidinecarboxylate (1c-4) To a solution of ((2R,4S)benzylazetidine-2,4-diyl)dimethanol (0.52 g, 2.9 mmol) in MeOH (10 mL) was added Pd(OH) (0.13 g), and the mixture was stirred for 2 h under H at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in anhydrous CH Cl (30 mL). To the resulting solution was added DIPEA (0.37 g, 2.9 mmol), and then CbzCl (0.44 g, 2.56 mmol) dropwise. The mixture was stirred for 2 h at r.t., and then quenched with H O (50 mL). The organic layer was washed with brine, dried over Na SO , and concentrated. The crude product was purified by chromatography on silica gel (5% MeOH in CH Cl ) to afford 0.33 g product as a yellow oil in 45% yield.
Step 5: Synthesis of (2R,4S)-benzyl-2,4-bis(((methylsulfonyl)oxy)methyl)azetidine- 1-carboxylate (1c-5) To a solution of (2R,4S)-benzyl 2,4-bis(hydroxymethyl)azetidinecarboxylate (51 mg, 0.2 mmol) in CH Cl (15 mL) was added Et N (61 mg, 0.6 mmol), and then 2 2 3 MsCl (70 mg, 0.6 mmol) dropwise. The mixture was stirred for 5 h at r.t., and the reaction mixture was washed with 1N HCl and brine, dried over Na SO , and concentrated. The crude product was purified by chromatography on silica gel (5% MeOH in CH Cl ) to afford 65 mg product as a yellow oil in 80% yield.
HRMS (ESI): m/z [M + H] calcd for C H NO S : 408.0787; found: 408.0780. 22 8 2 Step 6: Synthesis of (2R,4S)-benzyl-2,4-bis(bromomethyl)azetidinecarboxylate (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 (15mL) was refluxed for 10h. The reaction mixture was evaporated, the residue was added H O (20 mL) and Et O (20 mL). The aqueous layer was extracted with Et O (2 × 20 2 2 2 mL), and the combined organic layer was washed with brine (10 mL), dried over Na SO and concentrated under vacuum to give 51 mg product as yellow oil in 85% yield. HRMS (ESI): m/z [M + H] calcd for C H Br NO : 375.9548; found: 13 15 2 2 375.9558.
Step 7: Synthesis of (1R,5S)-benzyl 3-thiaazabicyclo[3.1.1]heptanecarboxylate (1c-7) To a solution of (2R,4S)-benzyl 2,4-bis(bromomethyl)azetidinecarboxylate (0.77 g, 2.05 mmol) in DMF (5 mL) was added Na S·9H O (0.59 g, 2.46 mmol). The mixture was stirred at rt for 45min. To the solution was added H O (20 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layer was washed with brine (10 mL), dried over Na SO and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20–30% EtOAc in PE) to give 0.15 g product as a colorless oil in 28.7% yield. HRMS (ESI): m/z [M + H] calcd for C H NO S: 250.0902; found: 13 17 2 250.0900.
Step 8: Synthesis of (1R,5S)thiaazabicyclo[3.1.1]heptane iodate (1c) To a solution of (1R, 5S)-benzylthiaazabicyclo[3.1.1]heptanecarboxylate (0.19 g, 0.8 mmol) in anhydrous CH Cl (20 mL) was added TMSI (0.39 g, 1.9 mmol) under Ar at 0 °C. The resulting mixture was stirred at rt for 2 h, and MeOH (5 mL) was added to the reaction dropwise. The result solution was stirred for additional 0.5 h, and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (2:1) to give 0.24 g crude product as a brown solid and was used without purification.
Example 4 Preparation of (1R, 5S)Thiaazabicyclo[3.2.1]octane iodate (1d) NH.HI (1) H 10% Pd/C BnNH K CO 2 2 3 COOEt COOEt EtOOC N COOEt EtOOC COOEt (2) CbzCl Et N Toluene TsCl Et N Na S . 9H O 3 2 2 HO OTs CaCl N Cbz Cbz Step 1: Synthesis of cis-Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (1d-1) EtOOC COOEt To a stirred solution of diethyl 2,5-dibromohexanedioate (10.8 g, 30 mmol) and benzylamine (3.2 g, 30 mmol) in toluene (45 mL) and H O (9 mL) was added K CO (5 g, 36 mmol) at r.t. The mixture was refluxed for 20 h under Ar, and then poured into H O (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), the combined organic layers were washed with brine (20 mL), dried over Na SO , and purified by chromatography on silica gel (10–20% EtOAc in PE) to afford 6.1 g product as a yellow oil in 67% yield.
H-NMR (400 MHz, CDCl ) d: 7.35–7.22 (m, 5 H), 4.06–4.00 (m, 4 H), 3.97 (s, 2 H), 3.46 (brs, 2 H), 2.08–2.04 (m, 4 H), 1.19 (t, J = 7.1 Hz, 6 H). HRMS (ESI): m/z [M + H] calcd for C H NO : 306.1705; found: 306.1695. 17 24 4 Step 2: Synthesis of cisBenzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (1d-2) COOEt EtOOC To a solution of cis-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (5.4 g, 17.7 mmol) in MeOH (100 mL) was added 10% Pd/C (0.54 g), and the mixture was shaken in a Parr Shaker for 4 h at 50 psi under H at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in anhydrous CH Cl (50 mL), and cooled to 0 °C.
To the resulting solution was added Et N (2.2 g, 21.6 mmol), and then CbzCl (3.7 g, 21.6 mmol) dropwise. The mixture was stirred overnight at r.t., and then quenched with H O (50 mL). The organic layer was washed with brine, dried over Na SO , 2 2 4 and concentrated. The crude product was purified by chromatography on silica gel (5–20% EtOAc in PE) to afford 5.22 g product as a yellow oil in 84% yield.
H-NMR (400 MHz, CDCl ) d: 7.33–7.29 (m, 5 H), 5.19–5.10 (m, 2 H), 4.47 (m, 1 H), 4.40 (m, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 2 H), 2.25–2.14 (m, 4 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.17 (t, J = 6.8 Hz, 3 H). HRMS (ESI): m/z [M + H] calcd for C H NO : 350.1604; found: 350.1649. 18 24 6 Step 3: Synthesis of cis-Benzyl 2,5-bis(hydroxymethyl)pyrrolidinecarboxylate (1d-3) To a solution of cisbenzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (5.75 g, 16.4 mmol) in EtOH/MeOH (10:1; 300 mL) was added CaCl (5.5 g, 49.2 mmol) at r.t. To the resulting stirred mixture was then added NaBH (3.75 g, 98.4 mmol) in portions. The reaction mixture was stirred for overnight at r.t. Subsequently H O (50 mL) was added, and the mixture was stirred for 30 min. The mixture was then concentrated in vacuo, and partitioned between H O (100 mL) and EtOAc (100 mL).
The aqueous layer was extracted with EtOAc (2 × 50 mL), and the organic layers were combined, washed with brine (10 mL), dried over Na SO , and concentrated in vacuo to give 4.57 g product as colorless oil. This product was used in the next step without further purification.
H-NMR (400 MHz, CDCl ) d: 7.39–7.33(m, 5 H), 5.16 (s, 2 H), 4.09–3.82 (m, 4 H), 3.56 (d, J = 8.1 Hz, 2 H), 2.91 (brs, 2 H), 2.04–1.97 (m, 4 H). HRMS (ESI): m/z [M + Na] calcd for C H NNaO : 288.1206; found: 288.1196. 14 19 4 Step 4: Synthesis of cis-Benzyl 2,5-bis(tosyloxymethyl)pyrrolidinecarboxylate (1d-4) A solution of compound cis-benzyl 2,5-bis(hydroxymethyl)pyrrolidinecarboxylate (4.35 g, 16.4 mmol), Et N (3.65 g, 36.1 mmol), and DMAP (4.01 g, 32.8 mmol) in CH Cl (50 mL) was cooled to 0 °C. To this mixture was added p-toluenesulfonyl chloride (6.88 g, 36.1 mmol) in one portion and the resulting mixture was stirred overnight at r.t. The mixture was then washed with water and brine, dried over Na SO and concentrated under vacuum. The residue was purified by flash column chromatography (30–40% EtOAc in PE) to give 8.97 g product as a semi-solid in 95% yield.
H-NMR (400 MHz, CDCl ) d: 7.73 (brs, 4 H), 7.36–7.29 (m, 9 H), 5.03–4.96 (m, 2 H), 4.15–3.89 (m, 6 H), 2.44 (s, 6 H), 1.87–1.83 (m, 4 H). C-NMR (100 MHz, CDCl ) d (rotamers): 165.30, 154.49, 144.90, 135.88, 132.61, 129.90, 128.55, 128.19, 127.89, 69.16, 68.87, 67.28, 57.30, 56.56, 26.61, 25.44, 21.63. HRMS (ESI): m/z [M + H] calcd for C H NO S : 574.1564; found: 574.1547. 28 32 8 2 Step 5: Synthesis of (1R, 5S)-Benzylthiaazabicyclo[3.2.1]octanecarboxylate (1d-5) To a solution of cis-benzyl 2,5-bis(tosyloxymethyl)pyrrolidinecarboxylate (4.1 g, 7.1 mmol) in ethanol (25 mL) and H O (25 mL) was added Na S·9H O (5.12 g, 21.3 2 2 2 mmol). The mixture was refluxed for 5 h. The mixture was then cooled to r.t., and the solvent was removed in vacuo. To the residue was added H O (20 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layer was washed with brine (10 mL), dried over Na SO and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20–30% EtOAc in PE) to give 1.38 g product as a colorless oil in 73% yield.
H-NMR (400 MHz, CDCl ) d: 7.37–7.30 (m, 5 H), 5.16 (s, 2 H), 4.52–4.47 (m, 2 H), 3.22 (d, J = 11.6 Hz, 1 H), 3.11 (d, J = 10.8 Hz, 1 H), 2.12 (d, J = 12.8 Hz, 2 H), 2.06 (d, J = 1.2 Hz, 4 H). C-NMR (100 MHz, CDCl ) d: 152.95, 136.59, 128.40, 127.93, 127.80, 66.73, 53.94, 32.72, 32.08, 28.82, 27.99. HRMS (ESI): m/z [M + H] calcd for C H NO S: 264.1058; found: 264.1113. 14 18 2 Step 6: Synthesis of (1R, 5S)Thiaazabicyclo[3.2.1]octane iodate (1d) To a solution of (1R, 5S)-benzylthiaazabicyclo[3.2.1]octanecarboxylate (0.24 g, 0.91 mmol) in anhydrous CH Cl (20 mL) was added TMSI (0.44 g, 2.18 mmol) under Ar at 0 °C. The resulting mixture was stirred at rt for 0.5 h, and MeOH (0.26 mL) was added to the reaction dropwise. The result solution was stirred for additional 0.5 h, and then evaporated to remove the solvent. The residue was washed with PE/EtOAc (1:2) to give 0.21 g product as a yellow solid in 91% yield.
Mp: 208–210?. H-NMR (400 MHz, CDCl ) d: 8.92 (brs, 1 H), 8.72 (brs, 1 H), 4.38 (s, 2 H), 3.78 (d, J = 14.0 Hz, 2 H), 2.41–2.35 (m, 4 H), 2.24–2.22 (d, J = 7.6 Hz, 2 H). C-NMR (100 MHz, CDCl ) d: 55.67, 31.42, 27.23. HRMS (ESI): m/z [M + H] calcd for C H NS: 130.0685; found: 130.0686.
Example 5 Preparation of 2-Thiaaza-spiro[3.3]heptane (1e) Br Br TsNH O , HBr O N S CH , Reflux Et O 0¡æ OH Br TPP CBr HO , Br N S CH N S CH Br Br DCM , r.t.
Na S 9H O S N S CH CH CN/H O 50¡æ 3 2 , MeOH Step 1: Synthesis of 6-Tosyloxaazaspiro[3.3]heptane (1e-1) O N S CH To a solution of KOH (9.04 g, 161 mmol) and 3-bromo-2,2-bis(bromomethyl)propanol (15.3 g, 47.0 mmol) in 500 mL ethanol was added p-tosylamide (17.9 g, 104 mmol) at room temperature and the reaction mixture was refluxed for 20 h. The solvent was removed by evaporation, 100 mL 8% NaOH solution was added and the suspension was stirred for another 2 h. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried to give the title product. Yield: 6.1 g (40.2 %). H-NMR (400 MHz, CDCl ) d: 7.71 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 4.59 (s, 4 H), 3.91 (s, 4 H), 2.46 (s, 3 H). HRMS (ESI-TOF ): m/z [M + H] calcd for C H NO S: 254.0825; found: 254.0851. 12 16 3 Step 2: Synthesis of (3-(bromomethyl)tosylazetidinyl)methanol (1e-2) N S CH To a suspension of 6-(p-toluenesulfonyl)oxaazaspiro[3.3]heptane (1e-1) (9.79 g, 38.7 mmol) in Et O (200 mL) at 0 °C was added a solution of hydrobromic acid (ca. 33% in AcOH) in dropwise. The resulting solution was stirred at room temperature for 30 min, it was adjusted to pH=8 with 1mol/L NaOH. The phases were separated and the aqueous phase was extracted with Et O (3×100 mL). The combined organic layers were dried (Na SO ), filtered, and concentrated in vacuo to afford the title compound as a colorless solid. Yield: 10.0 g (77.4%). H-NMR (400 MHz, CDCl ) d: 7.74 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 3.68 (s, 2 H), 3.68 (s, 2 H), 3.62 (d, J = 8.4 Hz, 2 H), 3.55 (d, J = 8.4 Hz, 2 H), 3.45 (s, 2 H), 2.47 (s, 3 H).
Step 3: Synthesis of 3,3-bis(bromomethyl)tosylazetidine (1e-3) N S CH (3-(Bromomethyl)tosylazetidinyl)methanol (1e-2) (10.0 g, 30.0 mmol) was dissolved in CH Cl and CBr (16.4 g, 49.4 mmol) was added. The resulting solution 2 2 4 was cooled to 0 °C and PPh (17.9 g, 104 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (5 - % EtOAc in PE) to give the pure title compound. Yield: 8.85 g (74.8%). H-NMR (400 MHz, CDCl ) d: 7.73 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 3.59 (s, 4 H), 3.53 (s, 4 H), 2.47 (s, 3 H).
Step 4: Synthesis of 6-tosylthiaazaspiro[3.3]heptane (1e-4) S N S CH To a solution of 3,3-bis(bromomethyl)tosylazetidine (1e-3) (8.82 g, 7.9 mmol) in a mixture of CH CN (90 mL) and H O (9 mL) was added Na S·9H O (10.7 g, 44.7 3 2 2 2 mmol) and the reaction mixture was stirred at 50 °C for 4 h, then it was concentrated to dryness. EtOAc (100 mL) and NaHCO solution (100 mL) were added, and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL).
The organic phase was washed with brine, dried (Na SO ), filtered, and concentrated in vacuo to give the title compound. Yield: 5.46 g (90.1%). H-NMR (400 MHz, CDCl ) d: 7.71 (d J = 8.0 Hz, 2 H), 7.37 (d J = 8.0 Hz, 2 H), 3.78 (s, 4 H), 3.14 (s, 4 H), 2.46(s, 3 H). HRMS (ESI-TOF ): m/z [M + H] calcd for C H NO S : 12 16 2 2 270.0622; found: 270.0621.
Step 5: Synthesis of 2-thiaazaspiro[3.3]heptane (1e) 6-Tosylthiaazaspiro[3.3]heptane (1e-4) (2.0 g, 7.9 mmol) was dissolved in MeOH (40 mL). To the resulting solution was added magnesium powder (1.0g), and the reaction mixture was sonicated at RT for about 3 hrs. The reaction mixture was concentrated in vacuo, the crude product was used in next step without purification.
Example 6 Preparation of 2-Oxaaza-spiro[3.3]heptane (1f) Br Br , TsNH O N S CH EtOH Reflux MeOH OH Br Step 1: Synthesis of 6-Tosyloxaazaspiro[3.3]heptane O N S CH This product was synthesized as described in Example 5, StepSStep 1.
Step 2: Synthesis of 2-oxaazaspiro[3.3]heptane (1f) 6-Tosyloxaazaspiro[3.3]heptane (6.3 g, 25.0 mmol) was dissolved in MeOH (50 mL). To the resulting solution was added magnesium powder (6.0g), and the reaction mixture was sonicated at RT for about 3 hrs. The reaction mixture was concentrated in vacuo, the crude product was used in next step without purification.
Example 7 Preparation of N-Boc protected 2, 6-Diaza-spiro[3.3]heptane (1g) Step 1: Synthesis of (3-(Bromomethyl)(p-toluenesulfonyl)azetidinyl)methanol (1g-1) To a suspension of 6-(p-toluenesulfonyl)oxaazaspiro[3.3]heptane (6.25 g, 24.7 mmol) (obtained according to Example 5 step 1) in Et O (100 mL) at 0 °C was dropwise added over a period of 15 min a solution of hydrobromic acid (ca. 33% in AcOH; 4.1 mL, 24.7 mmol) in Et O (5 mL). The resulting mixture was warmed to room temperature and stirred for 45 min. The resulting colorless solution was poured into a saturated aqueous solution of NaHCO (100 mL). The organic phase was separated and the aqueous phase was extracted with Et O (100 mL). The combined organic layers were dried (MgSO ), filtered, and concentrated in vacuo to afford the title compound 7.74g as a colorless solid. The crude product was pure enough for further transformations.
Step 2: Synthesis of 3,3-Bis(bromomethyl)(p-toluenesulfonyl)azetidine (1g-2) The above crude product 1g-1 (7.74 g, 23.1 mmol) was dissolved in CH Cl (100 mL) and CBr (13.7 g, 41.2 mmol) was added in one portion. The resulting solution was cooled to 0 °C and PPh (26.26 g, 41.2 mmol) was added in one portion. The reaction mixture turned to a dark orange solution, which was stirred at 0 °C for 1.5 h, then warmed to room temperature and stirred for further 8 h. The mixture was concentrated under reduced pressure to afford a dark orange oil, which was purified by chromatography (hexanes : EtOAc 4:1) to give the title compound 7.61g.
H-NMR (400 MHz, CDCl ) d: 7.73 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 3.60 (s, 4 H), 3.53 (s, 4 H), 2.48 (s, 3 H).
Step 3: Synthesis of 2-Benzyl(p-toluenesulfonyl)-2,6-diazaspiro[3.3]heptane (1g-3) Ts N N Dibromide 1g-2 (7.61 g, 19.1 mmol) was dissolved in CH CN (100 mL).
Benzylamine (4.1 g, 38.3 mmol) and DIPEA (12.4 g, 95.5 mmol) were added to the above mixture and the reaction mixture was heated to reflux for 3 d. Then the yellowish solution was cooled to room temperature and concentrated to about 1/6 of the initial volume. The residue was partitioned between CH Cl (100 mL) and 1 mol/L NaOH (100 mL). The organic phase was separated and the aqueous layer was extracted with CH Cl (50 mL). The combined organic layers were dried (MgSO ), 2 2 4 filtered, and concentrated in vacuo. The residue was purified by chromatography (hexanes : EtOAc : Et3N 1:1:1% to 1:2:1% gradient) to afford the title compound 4.0 g. H-NMR (400 MHz, CDCl ) d: 7.69 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.32-7.11 (m, 5 H), 3.82 (s, 4 H), 3.47 (s, 2 H), 3.13 (s, 4 H), 2.44 (s, 3 H).
Step 4: Synthesis of tert-Butyl 6-(p-toluenesulfonyl)-2,6-diazaspiro[3.3]heptane carboxylate (1g-5) N N Boc Benzyl azetidine 1g-3 (2.70 g, 7.88 mmol) was dissolved in MeOH (40 mL), and Pd/C (10% on charcoal; 0.54 g) was added to the above mixture. A hydrogen atmosphere (50 PSI) was built up and the mixture was heated to 45 °C and stirred at this temperature for 48 h. Then the reaction mixture was cooled to room temperature and filtered over celite. The filter cake was washed thoroughly with MeOH (2 × 20 mL). To the above solution of the intermediate Ts-protected azetidine (1g-4) in MeOH (ca. 80 mL) was added Boc O (1.77 g, 7.88 mmol). The resulting solution was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by chromatography (hexanes : EtOAc 1:1 to 1:2 gradient) to furnish the pure title compound. H-NMR (400 MHz, CDCl ) d: 7.71 (d, J = 7.6 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 3.85 (s, 4 H), 3.84 (s, 4 H), 2.46 (s, 3 H), 1.39 (s, 9 H).
Step 5: Synthesis of tert-Butyl 2,6-diazaspiro[3.3]heptanecarboxylate (1g) HN N Boc The above product 1g-5 (3.50 g, 10.0 mmol) was dissolved in MeOH (30 mL). Mg powder (1.92 g, 80.0 mmol) was added, and the mixture was sonicated for 6 h. The reaction mixture was concentrated in vacuo to afford a dark gray solid, which can be . used for the further reaction without purification.
Example 8 General Synthetic Methods: preparation of oxazolidinone compounds DIPEA R1 Pd-C\H R1 R2 + N NO 2 CH CN or THF R2 R2 reflux O N X 3 CBZ-Cl, NaHCO THF-H O X n-BuLI -78 deg MsCl Et N 3 O NaN OSO CH 2 3 DMF, 65 deg.
R COCl Pd-C, H R1 3 Et N/ DCM THF R2 2 3 N R3 R1 R2 wherein, represents ring A as previously defined in Formula I; X = H, or F.
General procedures for the preparation of (S)-N-((3-(3-fluoro(1,5-thiazocanyl) phenyl)oxooxazolidinyl)methyl)acetamide (OTB-114) and its sulfoxide (OTB-124), are provided below.
S N O S N OTB-114 OTB-124 Step A: 5-(2-Fluoronitrophenyl)-1,5-thiazocane A solution of 3,4-difluoronitrobenzene (4.92 g, 31 mmol) and N,N-diisopropylethylamine (8.81 g, 68 mmol) in CH CN (30 mL) was treated with 1,5-thiazocane hydrochloride (5.2 g, 31 mol) at ambient temperature and the reaction mixture heated to reflux for 24 h. The reaction mixture was cooled to rt and concentrated. The residue was diluted with H O and CH Cl , aqueous layer was 2 2 2 extracted with CH Cl (50mL*3). The organic layer was dried over Na SO , filtered, 2 2 2 4 and concentrated. The crude product was purified by chromatography on silica gel (PE/CH Cl =10:1) to give 3.36 g (40%) of the title compound as a yellow solid. H-NMR (400 MHz, CDCl ) d: 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(1,5-thiazocanyl)phenyl)carbamate To a solution of 5-(2-fluoronitrophenyl)-1,5-thiazocane (3.0 g, 12.5 mmol) in MeOH/THF was added 10% Pd/C (0.3 g), and the mixture was shaken 4 h under H at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in THF/H O (50 mL). To the resulting solution was added NaHCO (2.12 g, 25.2 mmol), and then CbzCl (2.58 g, 15.1 mmol) dropwise. The mixture was stirred overnight at r.t., and concentrated. The residue was added H O (50 mL) and extracted with CH Cl . The organic layer was washed with brine, dried over Na SO , 2 2 2 4 and concentrated. The crude product was purified by chromatography on silica gel (PE/EtOAc=5:1) to afford 4.6 g product as a colorless solid in 98% yield. H-NMR (400 MHz, CDCl ) d: 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(1,5-thiazocaneyl)phenyl]oxooxazolidinyl]methanol A solution of benzyl(3-fluoro(1,5-thiazocanyl)phenyl)carbamate (2.44 g, 6.5 mmol) in dry THF (20 mL) was cooled to -78 °C (dry ice/acetone bath) under N . n-Butyllithium (2.5 M solution in hexanes, 2.9 mL, 7.2 mmol) was added to the reaction mixture over 10 min. The resultant light yellow solution was stirred at -78 °C for 50 min and then treated with (R)-(-)-glycidyl butyrate (0.95 mL, 6.9 mmol) dropwise. The reaction mixture was stirred for an additional 30 min at -78 °C, and then the cooling bath was removed. The reaction mixture was allowed to warm to ambient temperature overnight. Saturated aqueous NH 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 SO , filtered, and concentrated. The residue was purified by by chromatography on silica gel (PE/EtOAc=1:2) to afford 1.33 g product as a colorless solid in 59% yield. H-NMR (400 MHz, CDCl ) d: 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: (R)-[3-[3-Fluoro(1,5-thiazocaneyl)phenyl]oxooxazolidinyl] methyl methanesulfonate A solution of (R)-[3-[3-Fluoro(1,5-thiazocaneyl)phenyl]oxooxazolidinyl] methanol (1.0 g, 2.94 mmol) in dry CH Cl was cooled with an ice bath and treated with Et N (446 mg, 4.41 mmol) and methanesulfonyl chloride (404 mg, 3.53 mmol).
The mixture was stirred for 2h at rt, and was washed with H O, saturated aqueous NaHCO , and brine. The organic layer was then dried over Na SO , filtered, and 3 2 4 concentrated. The product was used in next step without purification.
Step E: (R)-[3-[3-Fluoro(1,5-thiazocaneyl)phenyl]oxooxazolidinyl] methyl azide A solution of (R)-[3-[3-Fluoro(1,5-thiazocaneyl)phenyl]oxooxazolidinyl] methyl methanesulfonate (859 mg, 2.1 mmol) in dry DMF was treated with solid NaN (683 mg, 10.5 mmol) at rt. The mixture was then heated to 65 °C for 8 h, after cooling to rt; the reaction mixture was quenched with H O and was extracted with EtOAc. The combined organic layer was washed with H O and brine, dried over Na SO , filtered, and concentrated. The product was used in next step without purification.
Step F: (S)-N-((3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl) methyl)acetamide To a solution of (R)-[3-[3-fluoro(1,5-thiazocaneyl)phenyl]oxo oxazolidinyl]methyl azide (216 mg, 0.59 mmol) in MeOH/THF was added 10% Pd/C (22 mg), and the mixture was shaken 4 h under H at r.t. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed in vacuo. The residue was dissolved in CH Cl and was treated with Et N (121 mg, 1.2 mmol) and AcCl (56 mg, 1.2 mmol). The reaction mixture was quenched with H O and extracted with CH Cl . The combined organic extracts were 2 2 2 washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by chromatography on silica gel (CH Cl /MeOH=100:1) to afford 0.1 g product as a colorless solid in 44% yield. mp 78-80 C. [a] -15.4 (c 0.25, CHCl ).
H-NMR (400 MHz, CDCl ) d: 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). C-NMR (125 MHz, CDCl ) d: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M+H] calcd for C H O N FS: 382.1595; found: 382.1620. 18 25 3 3 Step G: (S)-N-[[3-(3-fluoro(1-oxido-1,5-thiazocanyl)phenyl)oxo-oxazolidin- -yl]methyl]acetamide O S N A solution of sodium metaperiodate (30 mg, 0.14 mmol) in H O (2 mL) was cooled to 0 °C. (S)-N-((3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl) methyl)acetamide (50 mg, 0.13 mmol) was added and then MeOH (3 mL). The reaction mixture was stirred at 0 °C for 2 h, and was concentrated. H O was added to the residue and then extracted with CH Cl The combined organic layer was washed with brine, dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by chromatography on silica gel (CH Cl /MeOH=100:1) to afford 39 mg product as a colorless solid in 75% yield. mp 69-70 C. H-NMR (400 MHz, CDCl ) d: 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). C-NMR (125 MHz, CDCl ) d: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J = 26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2. HR-MS (ESI): m/z [M+H] calcd for C H O N FS: 398.1544; found: 398.1540. 18 25 4 3 Example 9 In Vitro Assay for Antimicrobial Susceptibility Antimicrobial susceptibility testing was performed in 96-well microplates.
Initial drug dilutions (6.4 mg/ml) were prepared in dimethyl sulfoxide, and subsequent two-fold dilutions were performed in 0.1 ml of 7H9 broth media (BD) in the microplates. The final drug concentrations were about 0.008 µg/ml. Every concentration of test compounds was added to two wells. Control wells consisted of bacteria and positive drug (Linezolid). Plates were incubated at 37°C. The final bacterial titers were 1×10 CFU/ml for H Rv. Starting at day 7 of incubation, 20µl of 10× Alamar blue solution (Life Technologies) and 12.5µl of 20% Tween 80 (Sigma-Aldrich) were added to each well and the plates were reincubated at 37°C.
Wells were observed at 24h and the colors of all were recorded. Visual MICs were defined as the lowest amount of drug that prevented a color change from blue to pink.
Fluorescence was measured in a microplate fluorometer in bottom-reading mode with excitation at 530 nm and emission at 590 nm. For fluorometric MICs, the lowest drug concentration effecting an inhibition of =90% was considered the MIC.
The MIC results are provided in Table 1 above.
Example 10 In Vitro Assay for MPS Inhibition H9C2 cells were incubated in DMEM (Hyclone, GE LifeSciences) with 10% FBS (Gibco, Life Technologies) and 1× Glutamine (Gibco, Life Technologies) and NEAA (Gibco, Life Technologies) at 37°C, 5% CO2 at 1500 cells/well in a 384-well plate.
Test compound was added after 18 hr incubation, and then incubated for 5 days.
COX-1 protein (cyclooxygenase I) and SDH-A (succinate dehydrogenase-A) formation reduction were measured by ELISA assay (MitoBiogenesisTM In-Cell ELISA Kit (Colorimetric, Abcam). MPS assay results are provided in Table 1 above.
Example 11 Specific Compounds Synthesized According to General Methods OTB-107 (R)[(1H-1,2,3-Triazolyl)methyl][3-fluoro(1,4-thiazepanyl)phenyl]oxa zolidinone H-NMR (400 MHz, CDCl ) d: 7.94 (s, 1 H), 7.75 (s, 1 H), 7.17 (dd, J = 15.2 Hz, 1.2 Hz, 1 H), 6.89 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 6.82 (t, J = 9.6 Hz, 8.8 Hz, 1 H), .03 (m, 1 H), 4.78 (s, 2 H), 4.10 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.87 (m, 1 H), 3.68 (m, 4 H), 2.87 (m, 2 H), 2.68 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.06 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 153.4, 151.0, 134.3, 124.9, 116.8, 115.1, 108.7 (d, J = 27.3 Hz), 70.2, 56.1, 51.9, 51.3, 47.4, 34.0, 31.5, 30.3. HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 378.1395; found: 378.1396. 17 21 2 5 OTB-106 (R)[(2H-1,2,3-Triazolyl)methyl][3-fluoro(1,4-thiazepanyl)phenyl]oxa zolidinone H-NMR (400 MHz, CDCl ) d: 7.65 (s, 2 H), 7.27 (m, 1 H), 7.01 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 6.84 (t, J = 9.2 Hz, 9.2 Hz, 1 H), 5.11 (m. 1 H), 4.85 (dd, J = 14 Hz, 4.8 Hz, 1 H), 4.74 (dd, J = 14 Hz, 6.8 Hz, 1 H), 4.05 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.95 (m, 1 H), 3.67 (m, 4 H), 2.87 (m, 2 H), 2.69 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.06 (m, 2 H). C-NMR (125 MHz, CDCl ) d: 153.7, 152.4 (d, J = 241.8 Hz), 135.0, 134.7, 129.1, 116.9 (d, J = 5.1 Hz), 114.7 (d, J = 2.9 Hz), 108.4 (d, J = 27.4 Hz), 69.9, 56.2, 56.1, 51.4, 48.2, 34.1, 31.6, 30.4. HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 378.1395; found: 378.1403. 17 21 2 5 OTB-109 (S)[3-Fluoro(1,4-thiazepanyl)phenyl][(methylamino)methyl]oxazolidin-2 H-NMR (400 MHz, CDCl ) d: 7.30 (dd, J = 15.6 Hz, 2.4 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 6.82 (t, J = 9.6 Hz, 9.6 Hz, 1 H), 4.83 (m, 1 H), 4.02 (t, J = 8.8 Hz, 8.4 Hz, 1 H), 3.79 (t, J = 8.0 Hz, 7.2 Hz, 1 H), 3.67 (m, 4 H), 2.97 (m, 2 H), 2.87 (m, 2 H), 2.68 (m, 2 H), 2.54 (s, 3 H), 2.05 (m, 2 H). HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 340.1490; found: 340.1484. 16 23 2 3 OTB-108 (R)-[3-[3-Fluoro(1,4-thiazepanyl)phenyl]oxooxazolidinyl]methyl butyrate H-NMR (400 MHz, CDCl ) d: 7.34 (dd, J = 15.6 Hz, 2.4 Hz, 1 H), 7.05 (dd, J = 9.2 Hz, 2.0 Hz, 1 H), 6.89 (m, 1 H), 4.84 (m, 1 H), 4.37 (dd, J = 16.0 Hz, 4.0 Hz, 1 H), 4.31 (dd, J = 12.0 Hz, 4.8 Hz, 1 H), 4.06 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.76 (m, 1 H), 3.68 (m, 4 H), 2.89 (m, 2 H), 2.70 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.34 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 2.08 (m, 2 H), 1.65 (m, 2 H), 0.94 (t, J = 7.6 Hz, 7.2 Hz, 3 H).
C-NMR (125 MHz, CDCl ) d: 173.3, 154.4, 152.7 (d, J = 241.6 Hz), 134.9 (d, J = 8.3 Hz), 129.5 (d, J = 10.1 Hz), 117.2 (d, J = 5.4 Hz), 114.7 (d, J = 2.9 Hz), 108.5 (d, J = 27.5 Hz), 70.2, 64.1, 56.3, 51.7, 47.5, 36.0, 34.4, 31.9, 30.7, 18.4, 13.7. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 397.1592; found: 397.1613. 19 26 4 2 OTB-111 (S)-N-[(3-[3-Fluoro(1,4-thiazepanyl)phenyl]oxo-oxazolidinyl)methyl]fur ancarboxamide H-NMR (400 MHz, CDCl ) d: 7.47 (s, 1 H), 7.32 (dd, J = 16.0 Hz, 2.0 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.01 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 6.87 (m, 1 H), 6.81 (m, 1 H), 6.52 (s, 1 H), 4.82 (m, 1 H), 4.04 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.89 (m, 1 H), 3.76 (m, 2 H), 3.67 (m, 4 H), 2.88 (m, 2 H), 2.69 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.07 (m, 2 H). C-NMR (125 MHz, CDCl ) d: 159.0, 154.4, 152.6 (d, J = 241.9 Hz), 147.1, 144.5, 134.5, 129.3, 117.2, 115.1, 114.7, 112.3, 108.5 (d, J = 27.4 Hz), 71.9, 56.3, 51.7, 47.9, 41.6, 34.1, 31.7, 30.5. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 420.1388; found: 420.1400. 23 4 3 OTB-112 (S)-N-[(3-[3-Fluoro(1,4-thiazepanyl)phenyl]oxo-oxazolidinyl)methyl] thiophenecarboxamide H-NMR (400 MHz, CDCl ) d: 7.34 (m, 1 H), 7.02 (m, 2 H), 6.23 (m, 1 H), 4.75 (m, 1 H), 4.00 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.73 (m, 2 H), 3.64 (m, 1 H), 3.36 (t, J = 6.4 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 2.04 (s, 3 H), 1.97 (m, 4 H). C-NMR (125 MHz, CDCl ) d: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 382.1595; found: 382.1620. 18 25 3 3 OTB-115 (S)-N-[[3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl]methyl]piv alamide H-NMR (400 MHz, CDCl ) d: 7.34 (dd, J = 15.6 Hz, 2.0 Hz, 1 H), 7.01 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.89 (m, 1 H), 6.12 (m, 1 H), 4.74 (m, 1 H), 3.99 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.74 (m, 1 H ), 3.67 (m, 6 H), 2.89 (t, J = 5.6 Hz, 5.2 Hz, 2 H), 2.70 (t, J = 6.4 Hz, 6.4 Hz, 2 H), 2.08 (m, 2 H), 1.17 (s, 9H). C-NMR (125 MHz, CDCl ) d: 179.7, 154.6, 152.7 (d, J = 241.6 Hz), 134.8, 129.5, 117.2 (d, J = 5.4 Hz), 114.7 (d, J = 2.9 Hz), 108.5 (d, J = 27.6 Hz), 72.1, 56.3, 51.7, 48.0, 42.4, 39.0, 34.4, 31.9, 30.7, 27.7. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 410.1908; found: 29 3 3 410.1942.
OBD-005 (S)-N-((3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)buty ramide H-NMR (300 MHz, CDCl ) d: 7.42-7.23 (m, 2 H), 7.01 (dd, J = 8.9, 2.3 Hz, 1 H), 6.04 (s, 1 H), 4.75 (ddd, J = 9.0, 7.9, 4.6 Hz, 1 H), 4.00 (t, J = 9.0 Hz, 1 H), 3.79-3.05 (m, 7 H), 2.91 (dd, J = 16.2, 10.1 Hz, 2 H), 2.70 (t, J = 6.3 Hz, 2 H), 2.28-2.13 (m, 2 H), 2.13-1.97 (m, 2 H), 1.82-1.25 (m, 3 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.01 (s, 1 H).
LC-MS (ESI): m/z = 395.9 [M+H] .
OTB-116 (R)-N-[[3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl]methyl]but anesulfonamide H-NMR (400 MHz, CDCl ) d: 7.33 (d, J = 15.6 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 1 H), 6.88 (m, 1 H), 4.92 (t, J = 6.8 Hz, 6.4 Hz, 1 H), 4.78 (m, 1 H ), 4.02 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.90 (m, 1 H), 3.69 (m, 4 H), 3.54 (m, 1 H), 3.43 (m, 1 H), 3.07 (m, 2 H), 2.94 (m, 2 H), 2.69 (m, 2 H), 2.08 (m, 2 H), 1.79 (m, 2 H), 1.46 (m, 2 H), 0.95 (t, J = 7.2 Hz, 7.2 Hz, 3 H). C-NMR (125 MHz, CDCl ) d: 154.2, 152.5 (d, J = 241.8 Hz), 134.8 (d, J = 8.3 Hz), 129.2 (d, J = 10.5 Hz), 117.2, 115.0, 108.6 (d, J = 27.5 Hz), 71.5, 56.3, 53.2, 51.6, 47.5, 45.5, 34.1, 31.7, 30.5, 25.6, 21.5, 13.5. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS : 446.1578; found: 446.1623. 19 29 4 3 2 OTB-119 (R)[(1H-1,2,4-Triazolyl)methyl][3-fluoro(1,4-thiazepanyl)phenyl]oxa zolidinone H-NMR (400 MHz, CDCl ) d: 8.24 (s, 1 H), 7.96 (s, 1 H), 7.22 (m, 1 H), 6.97 (m, 1 H), 6.89 (m, 1 H), 5.02 (m, 1 H), 4.54 (d, J = 4.8 Hz, 2 H), 4.10 (t, J = 9.2 Hz, 9.2 Hz, 1 H), 3.94 (m, 1 H), 3.68 (m, 4 H), 2.89 (m, 2 H), 2.70 (m, 2 H), 2.08 (m, 2 H).
HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 378.1395; found: 17 21 2 5 378.1421.
OTB-412 Methyl (S)-((3-(3-fluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl) methyl) carbamate H-NMR (400 MHz, CDCl ) d: 7.29-7.33 (m, 1 H), 7.03-7.05 (m, 1 H), 6.82 (t, J = 8.8 Hz, 1 H), 5.10 (m, 1 H), 4.73 (m, 1 H), 3.99 (t, J = 9.9 Hz, 1 H), 3.69-3.74 (m, 1 H), 3.67 (s, 3 H), 3.66-3.67 (m, 4 H), 3.61 (m, 1 H), 3.50-3.55 (m, 1 H), 2.87 (m, 1 H), 2.68 (m, 2 H), 2.04-2.07 (m, 2 H). C-NMR (150 MHz, CDCl ) d: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 71.7, 56.2, 56.2, 51.5, 47.7, 43.7, 34.3, 31.8, 30.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 384.1388; found: 384.1371. 17 23 4 3 OTB-413 (S)-N-((3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl)methyl)cyc lopropanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.29-7.33 (m, 1 H), 7.03-7.00 (m, 1 H), 6.81 (t, J = 9.6 Hz, 1 H), 6.09 (m, 1 H), 4.74 (m, 1 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.73-3.74 (m, 1 H), 3.67-3.71 (m, 4 H), 3.62-3.66 (m, 1 H), 2.87 (t, J = 4.8 Hz, 2 H), 2.68 (t, J = .0 Hz, 2 H), 2.04-2.07 (m, 2 H), 1.36-1.43 (m, 1 H), 1.05-1.07 (m, 1 H), 0.93-0.97 (m, 2 H), 0.77-0.78 (m, 1 H). C-NMR (150 MHz, CDCl ) d: 174.5, 154.5, 153.3, 151.7, 134.8, 134.7, 129.2, 129.2, 117.0, 114.7, 108.6, 108.4, 72.0, 56.2, 51.5, 47.8, 42.1, 34.3, 31.8, 30.6, 14.7, 7.7. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 394.1595; found: 394.1580. 19 25 3 3 OTB-414 (S)-N-((3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)cycl obutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.29-7.34 (m, 1 H), 7.03-7.00 (m, 1 H), 6.82 (t, J = 9.6 Hz, 1 H), 5.84 (m, 1 H), 4.75 (m, 1 H), 3.99 (t, J = 8.8 Hz, 1 H), 3.72-3.76 (m, 1 H), 3.67-3.71 (m, 4H), 3.63-3.66 (m, 1 H), 3.14-3.23 (m, 2 H), 2.68 (m, 1 H), 1.89-2.35 (m, 10 H). C-NMR (150 MHz, CDCl ) d: 180.2, 176.0, 154.5, 134.8, 134.8, 129.2, 129.1, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 72.0, 56.2, 56.2, 51.5, 51.5, 47.9, 42.0, 39.7, 37.8, 34.3, 31.8, 30.6, 25.2, 18.4. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 408.1752; found: 408.1736. 27 3 3 OTB-407 (S)-N-((3-(3,5-Difluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl)methyl )acetamide NHCOCH H-NMR (400 MHz, CDCl ) d: 7.07 (d, J = 10.4 Hz, 2 H), 6.08 (m, 1 H), 4.76-4.77 (m, 1 H), 3.98 (t, J = 9.2 Hz, 1 H), 3.59-3.70 (m, 3 H), 3.45-3.48 (m, 4 H ), 2.89 (t, J = 6.0 Hz, 2 H), 2.77-2.80 (m, 2 H), 2.02 (s, 3 H). C-NMR (150 MHz, CDCl ) d: 171.1, 159.8, 159.7, 158.1, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 71.9, 58.8, 54.1, 47.5, 41.9, 36.1, 31.8, 31.6, 23.1. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N F S: 386.1344; found: 386.1330. 17 22 3 3 2 OTB-410 Methyl (S)-((3-(3,5-difluoro(1,4-thiazepanyl)phenyl)oxo-oxazolidinyl) methyl)carbamate H-NMR (500 MHz, CDCl ) d: 7.09 (d, J = 10.0 Hz, 2 H), 5.09 (m, 1 H), 4.76 (m, 1 H), 3.99 (t, J = 9.0 Hz, 1 H), 3.74-3.76 (m, 1 H), 3.73 (s, 3 H), 3.61 (m, 1 H), 3.52-3.55 (m, 1 H), 3.46-3.47 (m, 4 H), 2.90 (t, J = 6.0 Hz, 1 H), 2.78-2.80 (m, 2 H), 1.94-1.98 (m, 2 H). C-NMR (125 MHz, CDCl ) d: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.4, 108.4, 71.3, 56.2, 56.2, 51.5, 47.8, 43.7, 34.3, 31.8, 30.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N F S: 402.1297; found: 402.1287. 17 22 4 3 2 OTB-408 (S)((Cyclopropylamino)methyl)(3,5-difluoro(1,4-thiazepanyl)phenyl)oxa zolidinone H-NMR (400 MHz, CDCl ) d: 7.07 (d, J = 10.8 Hz, 2 H), 6.06 (m, 1 H), 4.76 (m, 1 H), 3.96 (t, J = 8.8 Hz, 1 H), 3.66-3.75 (m, 3 H), 3.43-3.47 (m, 3 H), 2.89 (t, J = 9.2 Hz, 2 H), 2.78-2.80 (m, 3 H), 1.94-1.97 (m, 2 H), 1.37-1.39 (m, 1 H), 0.97 (m, 1 H), 0.93 (m, 1 H), 0.77-0.79 (m, 2 H). C-NMR (150 MHz, CDCl ) d: 174.7, 159.8, 159.7, 158.2, 158.1, 154.0, 133.4, 126.0, 102.6, 102.4, 72.0, 58.8, 54.1, 47.5, 42.0, 36.1, 31.8, 31.6, 14.7, 7.8, 7.7. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N F S: 412.1501; found: 412.1485. 19 24 3 3 2 OTB-409 (S)((Cyclobutylamino)methyl)(3,5-difluoro(1,4-thiazepanyl)phenyl)oxaz olidinone H-NMR (400 MHz, CDCl ) d: 7.07 (d, J = 10.8 Hz, 2 H), 5.81 (m, 1 H), 4.75 (m, 1 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.72-3.76 (m, 1 H), 3.64-3.66 (m, 2 H), 3.45-3.46 (m, 3 H), 3.01 (t, J = 8.8 Hz, 1 H), 2.90 (t, J = 6.4 Hz, 2 H), 2.77-2.80 (m, 2 H), 2.13-2.26 (m, 4 H), 1.92-1.96 (m, 3 H). C-NMR (150 MHz, CDCl ) d: 176.0, 159.8, 159.8, 158.2, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 72.0, 58.8, 54.1, 47.5, 41.9, 39.7, 36.1, 31.8, 31.6, 25.4, 25.3, 18.1. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N F S: 426.1658; found: 426.1643. 26 3 3 2 OTB-411 (R)((1H-1,2,3-triazolyl)methyl)(3,5-difluoro(1,4-thiazepanyl)phenyl)o xazolidinone H-NMR (400 MHz, CDCl ) d: 7.76 (d, J = 11.2 Hz, 2 H), 6.95 (d, J = 10.4 Hz, 2 H), .04-5.07 (m, 1 H), 4.78 (d, J = 4.0 Hz, 2 H), 4.10 (t, J = 9.2 Hz, 1 H), 3.86-3.90 (m, 1 H), 3.44-3.46 (m, 4 H), 2.88 (t, J = 6.4 Hz, 2 H), 2.76-2.79 (m, 2 H), 1.91-1.97 (m, 2H). C-NMR (125 MHz, CDCl ) d: 159.8, 159.8, 157.9, 157.8, 153.0, 134.6, 125.1, 102.8, 102.5, 70.3, 58.7, 54.0, 51.9, 47.1, 36.1, 31.8, 31.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N F S: 396.1300; found: 396.1296. 17 20 2 5 2 OTB-126 [(5R)[3-Fluoro(1-oxido-1,4-thiazepanyl)phenyl)oxo-oxazolidinyl]met hyl butyrate H-NMR (400 MHz, CDCl ) d: 7.45 (dd, J = 14.8 Hz, 1.6 Hz, 1 H), 7.07 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.96 (t, J = 9.2 Hz, 9.2 Hz, 1 H), 4.85 (m, 1 H), 4.37 (dd, J = 12.0 Hz, 4.0 Hz, 1 H), 4.30 (dd, J = 12.4 Hz, 4.8 Hz, 1 H), 4.07 (m, 1 H), 3.78 (m, 2 H), 3.40 (m, 2 H), 3.19 (m, 4 H), 2.98 (m, 1 H), 2.72 (m, 1 H), 2.33 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 2.04 (m, 1 H), 1.63 (m, 2 H), 0.92 (t, J = 7.6 Hz, 7.2 Hz, 3 H). C-NMR (125 MHz, CDCl ) d: 173.2, 154.1, 154.0 (d, J = 241.8 Hz), 136.6, 131.4, 118.1 (d, J = 4.3 Hz), 114.0, (d, J = 2.9 Hz), 107.8 (d, J = 26.9 Hz), 70.1, 63.9, 52.8, 49.6, 47.2, 46.4, 43.7, 35.8, 18.3, 16.2, 13.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 413.1541; found: 413.1573. 19 26 5 2 OTB-127 N-[[(5S)(3-Fluoro(1-oxido-1,4-thiazepanyl)phenyl)oxo-oxazolidinyl] methyl]furancarboxamide H-NMR (400 MHz, CDCl ) d: 7.47 (s, 1 H), 7.42 (m, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.04 (m, 1 H), 6.87 (m, 2 H), 6.51 (m, 1 H), 4.85 (m, 1 H), 4.05 (m, 1 H), 3.81 (m, 4 H), 3.38 (m, 2 H), 3.15 (m, 2 H), 3.04 (m, 3 H), 2.70 (m, 1 H), 2.03 (m, 1 H).
HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 436.1337; found: 23 5 3 436.1371.
OTB-137 (5R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(1-oxido-1,4-thiazepanyl)p henyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.30-7.25 (m, 1 H), 6.91-6.89 (m, 2 H), 5.07-5.02 (m, 1 H), 4.78 (d, J = 4.0 Hz, 2 H), 4.11 (t, J = 9.2 Hz, 1 H), 3.93-3.88 (m, 1 H), 3.82-3.76 (m, 1 H), 3.43-3.36 (m, 2 H), 3.24-2.91 (m, 4 H), 2.75-2.69 (m, 1 H), 2.04-2.02 (m, 2 H). HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 394.1344; found: 394.1328. 17 21 3 5 OTB-138 (5R)((2H-1,2,3-Triazolyl)methyl)(3-fluoro(1-oxido-1,4-thiazepanyl)p henyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.65 (s, 2 H), 7.39 (d, J = 14.4 Hz, 1 H), 7.04-6.98 (m, 2 H), 5.15-5.09 (m, 1 H), 4.86 (dd, J = 14.0, 4.4 Hz, 1 H), 4.75 (dd, J = 14.0, 6.8 Hz, 1 H), 4.06 (dt, J = 9.2, 2.4 Hz, 1 H), 4.00-3.96 (m, 1 H), 3.86-3.82 (m, 1 H), 3.46-3.38 (m, 2 H), 3.29-3.08 (m, 3 H), 3.02-2.96 (m, 1 H), 2.76-2.71 (m, 1 H), 2.04-2.02 (m, 2 H). HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 394.1344; 17 21 3 5 found: 394.1338.
OTB-140 (5R)((1H-1,2,4-Triazolyl)methyl)(3-fluoro(1-oxido-1,4-thiazepanyl)p henyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 8.24 (s, 1 H), 7.94 (s, 1 H), 7.35 (d, J = 14.4 Hz, 1 H), 7.0-6.96 (m, 2 H), 5.02-4.99 (m, 1 H), 4.55 (d, J = 4.4 Hz, 2 H), 4.10 (dt, J = 8.8, 2.0 Hz, 1 H), 3.99-3.95 (m, 1 H), 3.86-3.82 (m, 1 H), 3.45-3.38 (m, 2 H), 3.29-3.09 (m, 3 H), 3.00-2.94 (m, 1 H), 2.77-2.71 (m, 1 H), 2.07-2.03 (m, 2 H). HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 394.1344; found: 394.1339. 17 21 3 5 OBD-006 N-(((5S)(3-Fluoro(1-oxido-1,4-thiazepanyl)phenyl)oxooxazolidinyl)m ethyl)butyramide H-NMR (300 MHz, CDCl ) d: 7.52 (d, J = 15.0 Hz, 1 H), 7.16 (s, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 5.99 (s, 1 H), 4.78 (s, 1 H), 4.02 (t, J = 8.8 Hz, 2 H), 3.88-3.56 (m, 3 H), 3.55-2.92 (m, 7 H), 2.77 (s, 1 H), 2.20 (t, J = 7.1 Hz, 3 H), 1.64 (dd, J = 14.9, 7.4 Hz, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).
LC-MS (ESI): m/z = 411.8 [M+H] .
OBD-007 (S)-N-((3-(4-(1,1-Dioxido-1,4-thiazepanyl)fluorophenyl)oxooxazolidinyl )methyl)butyramide H-NMR (300 MHz, CDCl ) d: 7.51 (d, J = 14.7 Hz, 1 H), 7.10 (d, J = 9.9 Hz, 2 H), .92 (s, 1 H), 4.78 (s, 1 H), 4.03 (t, J = 9.0 Hz, 1 H), 3.87-3.39 (m, 7 H), 3.27 (d, J = .7 Hz, 2 H), 2.39 (d, J = 6.2 Hz, 2 H), 2.20 (t, J = 7.2 Hz, 2 H), 1.64 (dd, J = 14.8, 7.4 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H).
LC-MS (ESI): m/z = 427.8 [M+H] .
OTB-110 (R)-[3-[3-Fluoro(1,5-thiazocanyl)phenyl]oxooxazolidinyl]methyl butyrate S N N H-NMR (400 MHz, CDCl ) d: 7.36 (dd, J = 14.8 Hz, 4.0 Hz, 1 H), 7.09 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 7.04 (t, J = 10.4 Hz, 9.2 Hz, 1 H), 4.85 (m, 1 H), 4.37 (m, 1 H), 4.31 (m, 1 H), 4.08 (m, 1 H), 3.78 (m, 1 H), 3.37 (m, 4 H), 2.75 (m, 4 H), 2.34 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 1.97 (m, 4 H), 1.64 (m, 2 H), 0.93 (t, 7.6 Hz, J = 7.2 Hz, 3 H).
C-NMR (125 MHz, CDCl ) d: 173.3, 155.4 (d, J = 243.5 Hz), 154.3, 134.5 (d, J = 8.3 Hz), 131.1 (d, J = 10.1 Hz), 128.2, 127.1, 120.0 (d, J = 4.9 Hz), 114.3 (d, J = 3.0 Hz), 108.4 (d, J = 26.8 Hz), 70.2, 64.0, 48.1, 47.4, 36.0, 32.1, 29.8, 18.4, 13.7.
HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 411.1748; found: 28 4 2 411.1786.
OTB-113 (R)[(2H-1,2,3-triazolyl)methyl][3-fluoro(1,5-thiazocanyl)phenyl]oxaz olidinone S N N H-NMR (400 MHz, CDCl ) d: 7.65 (s, 2 H), 7.30 (d, J = 14.8 Hz, 1 H), 7.03 (m, 2 H), 5.10 (m, 1 H), 4.85 (dd, J = 14.0 Hz, 4.8 Hz, 1 H), 4.74 (dd, J = 14.0 Hz, 7.2 Hz, 1 H), 4.06 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.97 (m, 1 H), 3.37 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 1.97 (m, 4 H). C-NMR (125 MHz, CDCl ) d: 155.2 (d, J = 243.5 Hz), 135.2, 134.4 (d, J = 8.1 Hz), 130.8 (d, J = 10.3 Hz), 119.8 (d, J = 4.9 Hz), 114.5 (d, J = 3.1 Hz), 108.4 (d, J = 26.6 Hz), 70.0, 56.3, 48.3, 47.9, 31.9, 29.6.
HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 392.1551; found: 18 23 2 5 392.1590.
OTB-114 (R)-[3-[3-Fluoro(1,5-thiazocanyl)phenyl]oxooxazolidinyl]methyl acetamide S N N H-NMR (400 MHz, CDCl ) d: 7.34 (m, 1 H), 7.02 (m, 2 H), 6.23 (m, 1 H), 4.75 (m, 1 H), 4.00 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.73 (m, 2 H), 3.64 (m, 1 H), 3.36 (t, J = 6.4 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 2.04 (s, 3 H), 1.97 (m, 4 H). C-NMR (125 MHz, CDCl ) d: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 382.1595; found: 382.1620. 18 25 3 3 OTB-117 (S)-N-[[3-(3-Fluoro(1,5-thiazocanyl)phenyl)oxo-oxazolidinyl]methyl]fur ancarboxamide S N N H-NMR (400 MHz, CDCl ) d: 7.47 (s, 1 H), 7.36 (d, J = 14.4 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.01 (m, 2 H), 6.78 (m, 1 H), 6.51 (m, 1 H), 4.84 (m, 1 H), 4.05 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.88 (m, 1 H), 3.80 (m, 2 H), 3.36 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 1.96 (m, 4 H). C-NMR (125 MHz, CDCl ) d: 159.0, 155.2 (d, J = 243.6 Hz), 154.3, 147.1, 144.5, 134.3, 130.9, 119.8, 115.1, 114.3 (d, J = 3.0 Hz), 112.3, 108.4 (d, J = 26.8 Hz), 71.9, 47.9, 41.5, 31.9, 29.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 434.1544; found: 434.1581. 21 25 4 3 OTB-118 (S)-N-[[3-(3-Fluoro(1,5-thiazocanyl)phenyl)oxo-oxazolidinyl]methyl]thi ophenecarboxamide S N N H-NMR (400 MHz, CDCl ) d: 7.54 (m, 1 H), 7.52 (m, 1 H), 7.34 (m, 1 H), 7.10 (m, 1 H), 7.04 (m, 1 H), 7.00 (m, 1 H), 6.57 (t, J = 6.0 Hz, 6.0 Hz, 1 H), 4.86 (m, 1 H), 4.07 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 4.07 (m, 1 H), 3.82 (m, 2 H), 3.36 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.74 (m, 4 H), 1.96 (m, 4 H). C-NMR (125 MHz, CDCl ) d: 162.7, 155.2 (d, J = 243.5 Hz), 154.5, 137.9, 130.8, 128.7, 127.8, 119.8, 114.5 (d, J = 3.0 Hz), 108.5 (d, J = 26.8 Hz), 72.1, 48.0, 42.5, 31.9, 29.6. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS : 450.1316; found: 450.1356. 21 25 4 4 2 OTB-120 (R)-N-[[3-(3-Fluoro(1,5-thiazocanyl)phenyl)oxo-oxazolidinyl]methyl]but anesulfonamide S N N H-NMR (400 MHz, CDCl ) d: 7.42 (d, J = 14.4 Hz, 1 H), 7.08 (m, 2 H), 4.94 (m, 1 H), 4.79 (m, 1 H), 4.04 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.93 (m, 1 H), 3.55 (m, 1 H), 3.43 (m, 5 H), 3.07 (m, 2 H), 2.76 (m, 4 H), 2.01 (m, 4 H), 1.80 (m, 2 H), 1.45 (m, 2 H), 0.95 (t, J = 7.6 Hz, 7.2 Hz, 3 H). C-NMR (125 MHz, CDCl ) d: 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. HR-MS (ESI-TOF): m/z [M + H] calcd for C20H31O4N3FS2: 460.1735; found: 460.1778.
OTB-121 (S)-N-[[3-(3-Fluoro(1,5-thiazocanyl)phenyl)oxo-oxazolidinyl]methyl]piv alamide S N N H-NMR (400 MHz, CDCl ) d: 7.39 (d, J = 14.4 Hz, 1 H), 7.04 (m, 2 H), 6.11 (m, 1 H), 4.74 (m, 1 H), 4.00 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.76 (m, 1 H), 3.67 (m, 2 H), 3.39 (m, 4 H), 2.74 (m, 4 H), 1.98 (m, 4 H), 1.17 (s, 9 H). C-NMR (125 MHz, CDCl ) d: 179.6, 155.2 (d, J = 243.6 Hz), 154.4, 134.3 (d, J = 8.0 Hz), 130.9 (d, J = .4 Hz), 128.8, 119.8 (d, J = 4.9 Hz), 114.2 (d, J = 2.9 Hz), 108.2 (d, J = 26.9 Hz), 72.0, 47.9, 47.8, 42.2, 38.9, 31.9, 29.6, 27.5. HR-MS (ESI-TOF): m/z [M + H] calcd for C H O N FS: 424.2065; found: 424.2096. 21 31 3 3 OBD-001 (R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxa zolidinone H-NMR (300 MHz, CDCl ) d: 7.76 (d, J = 17.6 Hz, 2 H), 7.41-7.09 (m, 1 H), 7.11-6.73 (m, 2 H), 5.04 (d, J = 3.0 Hz, 1 H), 4.78 (d, J = 3.4 Hz, 2 H), 4.12 (t, J = 9.2 Hz, 1 H), 3.88 (dd, J = 9.2, 6.1 Hz, 1 H), 3.36 (t, J = 6.0 Hz, 3 H), 2.92-2.59 (m, 4 H), 2.01 (dd, J = 27.9, 7.3 Hz, 4 H).
LC-MS (ESI): m/z = 391.9 [M+H] .
OBD-003 (S)-N-((3-(3-Fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl)buty ramide H-NMR (300 MHz, CDCl ) d: 7.50 (s, 2 H), 7.03 (d, J = 6.1 Hz, 1 H), 5.99 (s, 1 H), 4.77 (d, J = 5.7 Hz, 1 H), 4.02 (t, J = 9.0 Hz, 2 H), 3.70 (ddd, J = 20.7, 15.2, 7.7 Hz, 4 H), 3.48 (s, 4 H), 2.95-2.68 (m, 4 H), 2.20 (t, J = 7.2 Hz, 3 H), 2.06 (d, J = 6.1 Hz, 4 H), 1.64 (dd, J = 14.8, 7.4 Hz, 4 H), 0.91 (t, J = 7.4 Hz, 4 H).
LC-MS (ESI): m/z = 409.9 [M+H] .
OBD-008 (R)((1H-1,2,4-Triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxa zolidinone H-NMR (300 MHz, CDCl ) d: 8.24 (s, 1 H), 7.97 (s, 1 H), 7.00 (s, 2 H), 5.12-4.91 (m, 1 H), 4.56 (d, J = 4.7 Hz, 2 H), 4.24-3.83 (m, 2 H), 3.38 (t, J = 6.0 Hz, 4 H), 2.95-2.59 (m, 4 H), 1.98 (s, 5 H).
LC-MS (ESI): m/z = 391.9 [M+H] .
OTB-124 (S)-N-[[3-(3-Fluoro(1-oxido-1,5-thiazocanyl)phenyl)oxo-oxazolidinyl]m ethyl]acetamide O S N N H-NMR (400 MHz, CDCl ) d: 7.46 (dd, J = 2.8 Hz, 14.8 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 7.07 (m, 1 H), 6.15 (m, 1 H), 4.78 (m, 1 H), 4.03 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.74 (m, 3 H), 3.31 (m, 1 H), 3.18 (m, 4 H), 2.98 (m, 2 H), 2.17 (m, 4 H), 2.03 (s, 3 H). C-NMR (125 MHz, CDCl ) d: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J = 26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2.
HR-MS (ESI): m/z [M + H] calcd for C H O N FS: 398.1544; found: 398.1540. 18 25 4 3 OBD-002 (R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(1-oxido-1,5-thiazocanyl)phe nyl)oxazolidinone H-NMR (300 MHz, CDCl ) d: 7.92-7.67 (m, 2 H), 7.32 (d, J = 16.8 Hz, 1 H), 7.12 (t, J = 9.0 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 5.07 (s, 1 H), 4.81 (d, J = 4.0 Hz, 2 H), 4.15 (t, J = 9.0 Hz, 1 H), 4.01-3.83 (m, 1 H), 3.32 (d, J = 14.2 Hz, 5 H), 3.11-2.87 (m, 2 H), 2.59 (s, 2 H), 2.19 (s, 4 H).
LC-MS (ESI): m/z = 407.8 [M+H] .
OBD-004 (S)-N-((3-(3-Fluoro(1-oxido-1,5-thiazocanyl)phenyl)oxooxazolidinyl)me thyl)butyramide H-NMR (300 MHz, CDCl ) d: 7.44 (dd, J = 14.7, 2.4 Hz, 1 H), 7.19-6.99 (m, 2 H), 6.44 (s, 1 H), 4.84-4.71 (m, 1 H), 4.02 (t, J = 8.9 Hz, 1 H), 3.78 (dd, J = 9.0, 6.6 Hz, 1 H), 3.66 (t, J = 4.6 Hz, 2 H), 3.38-3.09 (m, 6 H), 2.99 (dd, J = 12.6, 6.3 Hz, 2 H), 2.20 (dd, J = 9.4, 5.3 Hz, 6 H), 1.71-1.56 (m, 2 H), 0.91 (dd, J = 9.6, 5.1 Hz, 3 H).
LC-MS (ESI): m/z = 425.8 [M+H] .
OBD-009 (R)((1H-1,2,4-Triazolyl)methyl)(3-fluoro(1-oxido-1,5-thiazocanyl)phe nyl)oxazolidinone H-NMR (300 MHz, CDCl ) d: 8.24 (s, 1 H), 7.93 (s, 1 H), 7.41-7.20 (m, 1 H), 7.19-6.92 (m, 2 H), 5.10-4.92 (m, 1 H), 4.56 (d, J = 4.7 Hz, 2 H), 4.12 (t, J = 9.0 Hz, 1 H), 3.97 (dd, J = 9.2, 6.2 Hz, 1 H), 3.28 (dd, J = 13.0, 6.9 Hz, 2 H), 3.12 (dd, J = 12.5, 5.9 Hz, 4 H), 3.02-2.83 (m, 2 H), 2.22-1.99 (m, 5 H), 1.26 (d, J = 9.4 Hz, 4 H).
LC-MS (ESI): m/z = 407.8 [M+H] .
OTB-227 N-(((5S)(4-(3-Thiaazabicyclo[3.1.1]heptanyl)fluorophenyl)oxo-oxazol idinyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 7.36 (d, J = 14.4 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.60 (t, J = 9.2 Hz, 1 H), 6.35 (brs, 1 H), 4.76-4.74 (m, 1 H), 4.56-4.54 (m, 2 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.76-3.65 (m, 2 H), 3.62-3.57 (m, 1 H), 3.43 (d, J = 12.0 Hz, 2 H), 2.93-2.87 (m, 1 H), 2.74 (d, J = 12.0 Hz, 2 H), 2.09 (s, 1 H), 2.03 (s, 3 H).
C-NMR (100 MHz, CDCl ) d: 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. HRMS (ESI-TOF+): m/z [M + H] calcd for C H FN O S: 366.1288; found: 366.1277. 17 21 3 3 OTB-501 (R)(4-((1R,5S)Thiaazabicyclo[3.2.1]octanyl)fluorophenyl)(hydroxy methyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.39 (d, J = 12.8 Hz, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 6.90 (t, J = 9.2 Hz, 1 H), 4.74 (m, 1 H), 4.43 (s, 2 H), 3.99-3.96 (m, 3 H), 3.79-3.75 (m, 1 H), 3.48 (d, J = 13.2 Hz, 2 H), 2.21-2.10 (m, 6 H). HRMS (ESI): m/z [M + H] calcd for C H N O FS: 339.1179; found: 339.1169. 16 20 2 3 OTB-502 N-(((S)(4-((1R,5S)Thiaazabicyclo[3.2.1]octanyl)fluorophenyl)oxoo xazolidinyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 7.36 (dd, J = 15.2, 2.4 Hz, 1 H), 7.06 (dd, J = 8.8, 1.8 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 6.18 (s, 1 H), 4.77–4.75 (m, 1 H), 4.40 (s, 2 H), 4.00 (t, J = 8.8 Hz, 1 H), 3.76–3.72 (m, 2 H), 3.68-3.62 (m, 1 H), 3.37 (d, J = 12.8 Hz, 2 H), 2.26–2.04 (m, 6 H), 2.02 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 171.1, 154.5, 152.8 (d, J = 241.7 Hz), 132.2 (d, J = 8.6 Hz), 130.2 (d, J = 10.4 Hz), 118.1 (d, J = 5.0 Hz), 114.7, 108.4 (d, J = 27.2 Hz), 71.9 , 57.4, 47.8, 42.0, 30.2, 28.4, 23.1. HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 380.1444; 18 23 3 3 found: 380.1435.
OTB-504 (R)((1H-1,2,3-Triazolyl)methyl)(4-((1R,5S)thiaazabicyclo[3.2.1]octan yl)fluorophenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.80 (s, 1 H), 7.76 (s, 1 H), 7.24 (m, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 6.83 (t, J = 8.8 Hz, 1 H), 5.07–5.04 (m, 1 H), 4.79 (s, 2 H), 4.40 (s, 2 H), 4.11 (t, J = 8.0 Hz, 1 H), 3.90–3.87 (m, 1 H), 3.42 (d, J = 12.8 Hz, 2 H), 2.20– 2.07 (m, 6 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 390.1400; 18 21 5 2 found: 390.1385.
OTB-236 N-(((R)(4-((1R,5S)Thiaazabicyclo[3.2.1]octanyl)fluorophenyl)oxo- oxazolidinyl)methyl)methanesulfonamide H-NMR (400 MHz, CDCl ) d: 7.47-7.41 (m, 1 H), 7.13 (d, J = 9.6 Hz, 1 H), 7.02 (t, J = 9.6 Hz, 1 H), 4.76-4.70 (m, 1 H), 4.34 (s, 2 H), 4.08 (t, J = 9.2 Hz, 1 H), 3.76 (t, J = 8.8 Hz, 1 H), 3.29-3.26 (m, 2 H), 3.11 (d, J = 12.8 Hz, 2 H), 2.93 (s, 3 H), 2.11 (d, J = 12.4 Hz, 2 H), 2.02 (s, 4 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS : 416.1114; found: 416.1097. 17 23 3 4 2 OTB-237 Methyl (((S)(4-((1R,5S)thiaazabicyclo[3.2.1]octanyl)fluorophenyl) Oxo-oxazolidinyl)methyl)carbamate H-NMR (400 MHz, CDCl ) d: 7.36 (d, J = 15.2 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 6.81 (t, J = 9.2 Hz, 1 H), 5.18 (brs, 1 H), 4.74 (brs, 1 H), 4.39 (s, 2 H), 4.01 (t, J = 8.8 Hz, 1 H), 3.76 (t, J = 7.6 Hz, 1 H), 3.69 (s, 3 H), 3.56-3.51 (m, 1 H), 3.33 (d, J = 12.8 Hz, 2 H), 2.18-2.07 (m, 6 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 396.1393; found: 396.1388. 18 23 3 4 OBD-016 N-(((S)(4-((1R,5S)Thiaazabicyclo[3.2.1]octanyl)fluorophenyl)oxoo xazolidinyl)methyl)butyramide H-NMR (300 MHz, DMSO-d ) d: 8.18 (s, 1 H), 7.42 (d, J = 16.0 Hz, 1 H), 7.35-6.88 (m, 2 H), 4.71 (s, 1 H), 4.35 (s, 2 H), 4.07 (t, J = 8.7 Hz, 1 H), 3.77-3.57 (m, 1 H), 3.51-3.27 (m, 2 H), 3.12 (d, J = 12.4 Hz, 2 H), 2.09 (dd, J = 20.9, 12.2 Hz, 8 H), 1.47 (dd, J = 14.0, 7.1 Hz, 2 H), 0.80 (dd, J = 8.0, 6.7 Hz, 3 H).
LC-MS (ESI): m/z = 407.9 [M+H] .
OBD-021 (R)((1H-1,2,4-Triazolyl)methyl)(4-((1R,5S)thiaazabicyclo[3.2.1]octan yl)fluorophenyl)oxazolidinone H-NMR (300 MHz, DMSO-d ) d: 8.57 (s, 1 H), 8.01 (s, 1 H), 7.36 (dd, J = 15.8, 2.1 Hz, 1 H), 7.18-6.92 (m, 2 H), 5.06 (dd, J = 8.9, 4.8 Hz, 1 H), 4.72-4.52 (m, 2 H), 4.36 (s, 2 H), 4.17 (t, J = 9.1 Hz, 1 H), 3.84 (dt, J = 49.3, 24.7 Hz, 1 H), 3.12 (d, J = 12.8 Hz, 2 H), 2.16 (s, 1 H), 2.11 (s, 1 H), 2.04 (s, 4 H).
LC-MS (ESI): m/z = 389.9 [M+H] .
OTB-506 N-(((S)(4-((1R,5S)Thiaazabicyclo[3.2.1]octanyl)fluorophenyl)oxo- oxazolidinyl)methyl)cyclopropanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.37 (d, J = 13.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.85 (brs, 1 H), 6.22 (t, J = 6.0 Hz, 1 H), 4.79–4.73 (m, 1 H), 4.41 (brs, 2 H), 3.99 (t, J = 7.2 Hz, 1 H), 3.77–3.64 (m, 3 H), 3.39 (d, J = 12.8 Hz, 2 H), 2.20–2.09 (m, 6 H), 1.43–1.37 (m, 1 H), 0.98–0.90 (m, 2 H), 0.82–0.75 (m, 2 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 406.1595; found: 406.1527. 25 3 3 OTB-507 N-(((S)(4-((1R,5S)Thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxo- oxazolidinyl)methyl)cyclobutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.45 (d, J = 12.4 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 7.05 (t, J = 8.8 Hz, 1 H) 5.95 (m, 1 H), 4.78 (m, 1 H), 4.51 (brs, 2 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.84-3.74 (m, 3 H), 3.66 (m, 2 H), 3.02 (m, 1 H), 2.28-2.15 (m, 10 H), 1.95 (m, 1 H), 1.85 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 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. HRMS (ESI): m/z [M + H] calcd for C H N O SF: 420.1757; found: 420.1736. 21 27 3 3 OTB-510 N-(((S)(4-((1R,5S)Thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl) oxo-oxazolidinyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 7.08 (m, 2 H), 6.00 (m, 1 H), 4.76 (m, 1 H), 4.24 (brs, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.75-3.60 (m, 3 H), 3.38 (m, 2 H), 2.21 (m, 2 H), 2.14 (s, 4 H), 2.03 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 171.2, 155.3 (dd, J = 241.5, 9.5 Hz), 154.1, 130.6 (t, J = 13.6 Hz), 122.9 (t, J = 12.4 Hz), 102.9 (dd, J = 20.7, 11.3 Hz), 71.9, 60.4, 47.4, 41.9, 33.7, 29.2, 23.1. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 398.1350; found: 398.1329. 18 22 3 3 2 OTB-512 Methyl (((S)(4-((1R,5S)thiaazabicyclo[3.2.1]octanyl)-3,5-difluoro phenyl)oxo-oxazolidinyl)methyl)carbamate H-NMR (400 MHz, CDCl ) d: 7.09 (m, 2 H), 5.08 (m, 1 H), 4.76 (m, 1 H), 4.24 (brs, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.75-3.50 (m, 6 H), 3.38 (m, 2 H), 2.20 (m, 2 H), 2.14 (s, 4 H). C-NMR (100 MHz, CDCl ) d: 157.5, 155.3 (dd, J = 241.6, 9.4 Hz), 153.9, 130.7 (t, J = 13.6 Hz), 122.9 (t, J = 12.3 Hz), 102.9 (dd, J = 20.7, 11.3 Hz), 71.8, 60.4, 52.6, 47.3, 43.6, 33.7, 29.2. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 414.1294; found: 414.1278. 18 22 3 4 2 OTB-511 (R)((1H-1,2,3-Triazolyl)methyl)(4-((1R,5S)thiaazabicyclo[3.2.1]octan yl)-3,5-difluorophenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.78 (s, 1 H), 7.76 (s, 1 H), 6.94 (d, J = 11.6 Hz, 2 H), 5.07-5.04 (m, 1 H), 4.79 (d, J = 3.6 Hz, 2 H), 4.20 (brs, 2 H), 4.09 (t, J = 8.8 Hz, 1 H), 3.88-3.83 (m, 1 H), 3.32 (d, J = 12.8 Hz, 2 H), 2.19-2.11 (m, 6 H). C-NMR (100 MHz, CDCl ) d: 155.3 (d, J = 242.1 Hz), 155.2 (d, J = 242.1 Hz), 153.1, 134.5, 129.9 (t, J = 13.6 Hz), 125.1, 123.3 (t, J = 12.3 Hz), 103.3 (dd, J = 20.7, 11.2 Hz), 70.3, 60.4, 52.0, 47.2, 33.8, 29.2. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 408.1300; found: 408.1295. 18 20 5 2 2 OTB-508 N-(((S)(4-((1R,5S)Thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)o xo-oxazolidinyl)methyl)cyclopropanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.05 (m, 2 H), 6.12 (m, 1 H), 4.76 (m, 1 H), 4.21 (brs, 2 H), 3.95 (t, J = 9.2 Hz, 1 H), 3.72-3.65 (m, 3 H), 3.34 (m, 2 H), 2.21-2.12 (m, 6 H), 1.37 (m, 1 H), 0.99-0.75 (m, 4 H). C-NMR (100 MHz, CDCl ) d: 174.8, 155.3 (dd, J = 241.7, 9.5 Hz), 154.2, 130.5 (t, J = 13.6 Hz), 123.0 (t, J = 12.5 Hz), 103.0 (dd, J = 20.8, 11.4 Hz), 72.1, 60.4, 47.5, 41.9, 33.8, 29.2, 14.6, 7.8, 7.7. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 420.1506; found: 424.1484. 24 3 3 2 OTB-509 N-(((S)(4-((1R,5S)Thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)o xo-oxazolidinyl)methyl)cyclobutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.09 (m, 2 H), 5.78 (m, 1 H), 4.75 (m, 1 H), 4.23 (brs, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.73 (m, 1 H), 3.65 (m, 2 H), 3.36 (m, 2 H), 2.99 (m, 1 H), 2.27-2.14 (m, 9 H), 1.97 (m, 1 H), 1.85 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 176.0, 155.3 (dd, J = 243.4, 9.5 Hz), 154.1, 130.6 (t, J = 13.5 Hz), 122.9 (t, J = 12.2 Hz), 102.9 (dd, J = 20.7, 11.4 Hz), 72.0, 60.4, 47.5, 41.8, 33.7, 29.2, 25.4, 25.3, 18.1. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 438.1663; found: 21 26 3 3 2 438.1642.
OTB-503 N-(((5S)(3-Fluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)pheny l)oxo-oxazolidinyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 7.45 (dd, J = 16.0, 2.8 Hz, 1 H), 7.12 (dd, J = 8.8, 2.0 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 6.14 (s, 1 H), 4.78–4.77 (m, 1 H), 4.61 (s, 2 H), 4.00 (t, J = 8.8 Hz, 1 H), 3.77–3.64 (m, 3 H), 3.45 (d, J = 9.6 Hz, 2 H), 2.85 (d, J = 12.4 Hz, 2 H), 2.22–2.20 (m, 2 H), 2.03 (s, 3 H), 1.92–1.88 (m, 2 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 396.1388; found: 396.1379. 18 23 3 4 OTB-505 (5R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro((1R,5S)oxidothiaaza bicyclo[3.2.1]octanyl)phenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.30 (dd, J = 15.2, 2.0 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.79 (t, J = 9.2 Hz, 1 H), 5.07–5.05 (m, 1 H), 4.79 (s, 2 H), 4.58 (s, 2 H), 4.12 (t, J = 9.2 Hz, 1 H), 3.91–3.89 (m, 1 H), 3.43 (d, J = 11.6 Hz, 2 H), 2.88–2.81 (m, 2 H), 2.21–2.18 (m, 2 H), 1.89–1.87 (m, 2 H). HR-MS (ESI-TOF): m/z [M + H] calcd for C H N O FS: 406.1349; found: 406.1339. 18 21 5 3 OTB-513 N-(((5S)(3,5-Difluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)ph enyl)oxo-oxazolidinyl)methyl)cyclobutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.12 (d, J = 12.0 Hz, 2 H), 5.97 (brs, 1 H), 4.77-4.75 (m, 1 H), 4.45 (s, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.74 (t, J = 8.4 Hz, 1 H), 3.66 (t, J = .2 Hz, 2 H), 3.54 (d, J = 9.2 Hz, 2 H), 3.02 (m, 1 H), 2.91 (d, J = 12.0 Hz, 2 H), 2.26-2.11 (m, 6 H), 1.99-1.92 (m, 1 H), 1.87-1.85 (m, 3 H). HRMS (ESI): m/z [M + H] calcd for C H N O SF : 454.1606; found: 454.1588. 21 26 3 4 2 OTB-514 N-(((5S)(3,5-Difluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)ph enyl)oxo-oxazolidinyl)methyl) acetamide H-NMR (400 MHz, CDCl ) d: 7.12 (d, J = 12.0 Hz, 2 H), 6.15 (brs, 1 H), 4.81-4.75 (m, 1 H), 4.45 (s, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.74-3.63 (m, 3 H), 3.56 (d, J = 9.2 Hz, 2 H), 2.92 (d, J = 12.4 Hz, 2 H), 2.20-2.17 (m, 2 H), 2.03 (s, 3 H), 1.89-1.83 (m, 2 H). HRMS (ESI): m/z [M + H] calcd for C H N O SF : 414.1293; found: 18 22 3 4 2 414.1275.
OBD-017 N-(((5S)(3-Fluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)pheny l)oxooxazolidinyl)methyl)butyramide H-NMR (300 MHz, CDCl ) d: 7.39 (dd, J = 15.8, 2.3 Hz, 1 H), 7.03 (d, J = 6.1 Hz, 2 H), 6.78 (t, J = 9.3 Hz, 1 H), 4.72 (s, 1 H), 4.55 (s, 2 H), 3.94 (t, J = 8.9 Hz, 1 H), 3.81-3.66 (m, 1 H), 3.58 (s, 2 H), 3.42 (d, J = 10.3 Hz, 2 H), 2.77 (d, J = 11.9 Hz, 2 H), 2.17 (dd, J = 25.1, 17.8 Hz, 4 H), 1.84 (d, J = 7.9 Hz, 2 H), 1.56 (dd, J = 14.5, 7.2 Hz, 2 H), 0.83 (t, J = 7.4 Hz, 3 H).
LC-MS (ESI): m/z = 423.8 [M+H] .
OBD-018 (5R)((1H-1,2,4-Triazolyl)methyl)(3-fluoro((1R,5S)oxidothiaaza bicyclo[3.2.1]octanyl)phenyl)oxazolidinone H-NMR (300 MHz, DMSO-d ) d: 12.17 (s, 1 H), 8.69 (d, J = 2.9 Hz, 1 H), 8.20 – 8.03 (m, 1 H), 7.44 (d, J = 16.2 Hz, 1 H), 7.28-7.02 (m, 2 H), 5.08 (dd, J = 8.5, 5.1 Hz, 1 H), 4.68-4.52 (m, 4 H), 4.20 (t, J = 9.1 Hz, 1 H), 3.91 (dd, J = 8.7, 6.0 Hz, 1 H), 3.56 (d, J = 11.1 Hz, 2 H), 2.48 (d, J = 12.3 Hz, 2 H), 2.06 (d, J = 5.1 Hz, 2 H), 1.79 (d, J = 7.6 Hz, 2 H).
LC-MS (ESI): m/z = 405.8 [M+H] .
OTB-260 (R)(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)(hydroxymethyl)oxa zolidinone H-NMR (400 MHz, CDCl ) d:7.38 (d, J = 14.0 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.55 (t, J = 8.8 Hz, 1 H), 4.72 (brs, 1 H), 4.02 (s, 4 H), 3.99-3.89 (m, 3 H), 3.76-3.73 (m, 1 H), 3.42 (s, 4 H). C-NMR (100 MHz, CDCl ) d: 154.8, 152.2 (d, J = 240.8 Hz), 135.9 (d, J = 11.7 Hz), 130.2 (d, J = 9.3 Hz), 114.6 (d, J = 5.2 Hz), 114.5 (d, J = 3.1 Hz), 107.6 (d, J = 23.8 Hz), 72.8, 66.8, 62.8, 46.7, 44.3, 36.8. HRMS (ESI): m/z [M + H] calcd for C H FN O S: 325.1022; found: 325.1010. 18 2 3 OTB-261 (S)-N-((3-(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin-5 -yl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 7.33 (d, J = 14.0 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.48 (t, J = 8.8 Hz, 1 H), 6.20 (brs, 1 H), 4.75-4.73 (m, 1 H), 3.98-3.96 (m, 5 H), 3.73-3.66 (m, 2 H), 3.62-3.57 (m, 1 H), 3.41 (s, 4 H), 2.01 (s, 3 H). HRMS (ESI): m/z [M + H] calcd for C H FN O S: 366.1288; found: 366.1274. 17 21 3 3 OTB-241 (R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(2-thiaazaspiro[3.3]heptan yl)phenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.22 (dd, J = 13.6, 2.0 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.51 (t, J = 9.2 Hz, 1 H), 5.06-5.00 (m, 1 H), 4.78-4.77 (m, 2 H), 4.08 (t, J = 9.2 Hz, 1 H), 4.01 (s, 4 H), 3.89-3.85 (m, 1 H), 3.40 (s, 4 H). C-NMR (100 MHz, CDCl ) d: 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 = .2 Hz), 108.1 (d, J = 23.6 Hz), 70.4, 66.7, 52.1, 47.7, 44.3, 36.8. HRMS (ESI): m/z [M + H] calcd for C H FN O S: 376.1244; found: 376.1231. 17 19 5 2 OTB-516 (R)(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)(hydroxymethyl) oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.03 (d, J = 12.0 Hz, 2 H), 4.74-4.70 (m, 1 H), 4.18 (s, 4 H), 3.98 (dd, J = 12.8, 3.2 Hz, 1 H), 3.93-3.85 (m, 2 H), 3.75 (dd, J = 12.4, 4.0 Hz, 1 H), 3.41 (s, 4 H). HRMS (ESI): m/z [M + H] calcd for C H N O SF : 343.0922; 17 2 3 2 found: 343.0912.
OTB-515 (S)-N-((3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 6.98 (d, J = 11.6 Hz, 2 H), 5.99 (brs, 1 H), 4.74-4.72 (m, 1 H), 4.16 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.71-3.65 (m, 2 H), 3.61-3.55 (m, 1 H), 3.40 (s, 4 H), 2.01 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 171.1, 154.2, 152.6 (dd, J = 240.6, 11.1 Hz), 153.1, 134.5, 128.5 (t, J = 12.6 Hz), 124.7 (t, J = 13.3 Hz), 102.8 (dd, J = 18.2, 10.7 Hz), 71.9, 68.7, 47.6, 45.2, 42.0, 36.5, 23.1. HRMS (ESI): m/z [M + H] calcd for C H N O SF : 384.1188; found: 384.1168. 17 20 3 3 2 OTB-242 Methyl (S)-((3-(3,5-difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxo- oxazolidinyl)methyl)carbamate H NMR (400 MHz, CDCl ) d: 7.00 (d, J = 11.6 Hz, 2 H), 5.16 (brs, 1 H), 4.81–4.67 (m, 1 H), 4.16 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.68 (s, 3 H), 3.56–3.50 (m, 3 H), 3.40 (s, 4 H). HRMS (ESI): m/z [M + H] calcd for C H F N O S: 400.1143; found: 17 20 2 3 4 400.1125.
OTB-245 (R)((1H-1,2,3-Triazolyl)methyl)(3,5-difluoro(2-thiaazaspiro[3.3]heptan yl)phenyl)oxazolidinone H NMR (400 MHz, CDCl ) d: 7.77 (s, 1 H), 7.74 (s, 1 H), 6.87 (d, J = 11.6 Hz, 2 H), .03–5.01 (m, 1 H), 4.77–4.76 (m, 2 H), 4.15 (s, 4 H), 4.06 (t, J = 9.2 Hz, 1 H), 3.86–3.82 (m, 1 H), 3.41 (s, 4 H). HRMS (ESI): m/z [M + H] calcd for C H F N O S: 394.1149; found: 394.1129. 17 18 2 5 2 OTB-243 (S)-N-((3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)cyclopropanecarboxamide H NMR (400 MHz, CDCl ) d: 6.98 (d, J = 11.6 Hz, 2 H), 6.25–6.24 (m, 1 H), 4.77– 4.71 (m, 1 H), 4.16 (s, 4 H), 3.92 (t, J = 8.8 Hz, 1 H), 3.71 – 3.56 (m, 3 H), 3.40 (s, 4 H), 1.40–1.38 (m, 1 H), 1.04–0.87 (m, 2 H), 0.82–0.73 (m, 2 H). HRMS (ESI): m/z [M + H] calcd for C H F N O S: 410.1350; found: 410.1331. 19 22 2 3 3 OTB-244 (S)-N-((3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)cyclobutanecarboxamide H NMR (400 MHz, CDCl ) d: 6.99 (d, J = 11.6 Hz, 2 H), 5.83 (brs, 1 H), 4.82–4.68 (m, 1 H), 4.17 (s, 4 H), 3.93 (t, J = 8.8 Hz, 1 H), 3.72–3.64 (m, 3 H), 3.40 (s, 4 H), 3.03–2.96 (m, 1 H), 2.26–1.85 (m, 6 H). HRMS (ESI): m/z [M + H] calcd for C H F N O S: 424.1506; found:.424.1483 24 2 3 3 OTB-201 (R)(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)(hydroxymethyl)oxaz olidinone H-NMR (400 MHz, CDCl ) d:7.42 (dd, J = 14.0, 2.0 Hz, 1 H), 7.03 (dd, J = 8.8, 2.0 Hz, 1 H), 6.62 (t, J = 8.8 Hz, 1 H), 4.85 (s, 4 H), 4.73 (m, 1 H), 4.17 (s, 4 H), 4.00-3.95 (m, 2 H), 3.93-3.89 (m, 1 H), 3.77-3.74 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 155.2, 152.3 (d, J = 240.7 Hz), 135.9 (d, J = 11.3 Hz), 130.4 (d, J = 8.9 Hz), 114.7 (d, J = 3.0 Hz), 114.6 (d, J = 5.6 Hz), 107.8 (d, J = 23.8 Hz), 81.3, 73.2, 63.1, 62.9, 46.9, 40.1. HRMS (ESI): m/z [M + H] calcd for C H FN O : 309.1251; found: 18 2 4 309.1269.
OTB-202 (S)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)acetamide H-NMR (300 MHz, CDCl ) d: 7.35 (d, J = 14.1 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 6.51 (t, J =9.0 Hz, 1 H), 6.03(s, 1 H), 4.84 (s, 4 H), 4.74 (m, 1 H), 4.12 (s, 4 H), 3.99 (t, J =8.7 Hz, 1 H), 3.73-3.69 (m, 2 H), 3.61 (m, 1 H), 2.02 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 171.4, 154.8, 152.4 (d, J = 240.8 Hz), 136.1 (d, J = 11.9 Hz), 130.1 (d, J = 9.2 Hz), 114.7 (d, J = 3.1 Hz), 114.6 (d, J = 5.0 Hz), 107.9 (d, J = 23.6 Hz), 81.2, 72.1, 63.1, 48.1, 42.2, 40.1, 23.4. HRMS (ESI): m/z [M + H] calcd for C H FN O : 350.1516; found: 350.1497. 17 21 3 4 OTB-203 (R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(2-oxaazaspiro[3.3]heptany l)phenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.78 (s, 1 H), 7.75 (s, 1 H), 7.18 (d, J = 13.6 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.46 (t, J = 9.2 Hz, 1 H), 5.03 (m, 1 H), 4.83 (s, 4 H), 4.78 (m, 2 H), 4.10-4.07 (m, 5 H), 3.91-3.85 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 153.6, 152.1 (d, J = 241.4 Hz), 136.1 (d, J = 10.6 Hz), 134.5, 129.2 (d, J = 9.3 Hz), 125.1, 115.0 (d, J = 2.9 Hz), 114.5 (d, J = 4.7 Hz), 108.1 (d, J = 23.7 Hz), 81.0, 70.4, 62.9, 52.1, 47.7, 39.8. HRMS (ESI): m/z [M + H] calcd for C H FN O : 360.1472; 17 19 5 3 found: 360.1451.
OTB-204 (R)((2H-1,2,3-Triazolyl)methyl)(3-fluoro(2-oxaazaspiro[3.3]heptany l)phenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.65 (s, 2 H), 7.31 (d, J = 14.4, 2.4 Hz,1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.59 (t, J = 9.2 Hz, 1 H), 5.14-5.07 (m, 1 H), 4.88-4.83 (m, 5 H), 4.77-4.71 (m, 1 H), 4.16 (s, 4 H), 4.07-4.02 (m, 1 H), 3.98-3.92 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 158.99, 154.38, 147.08, 144.53, 135.18, 115.11, 114.43, 112.30, 107.91, 107.87, 81.04, 71.85, 70.04, 62.91, 48.38, 48.02, 41.57, 39.85. HRMS (ESI): m/z [M + H] calcd for C H FN O : 360.1472; found: 360.1451. 17 19 5 3 OTB-205 (S)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)furancarboxamide H-NMR (400 MHz, CDCl ) d: 7.46 (s, 1 H), 7.32 (dd, J = 14.0, 2.4 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.81 (t, J = 6.4 Hz, 1 H), 6.51 (d, J = 3.2 Hz, 1 H), 6.45 (t, J = 9.2 Hz, 1 H), 4.83 (brs, 5 H), 4.08 (s, 4 H), 4.03 (t, J = 8.8 Hz, 1 H), 3.92-3.85 (m, 1 H), 3.79-3.73 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 159.2, 154.6, 152.4 (d, J = 240.8 Hz), 147.3, 144.7, 136.5, 130.5 (d, J = 9.4 Hz), 115.3, 114.7 (d, J = 3.1 Hz), 112.5, 109.9, 107.9 (d, J = 23.9 Hz), 81.2, 72.1, 63.1, 48.2, 41.8, 40.1.
HRMS (ESI): m/z [M + H] calcd for C H FN O : 402.1465; found: 402.1561. 21 3 5 OTB-206 (S)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)thiophenecarboxamide H-NMR (400 MHz, CDCl ) d: 7.53 (d, J = 3.2 Hz, 1 H), 7.50 (d, J = 4.8 Hz, 1 H), 7.32 (d, J = 14.0 Hz, 1 H), 7.09-6.96 (m, 2 H), 6.66 (m, 1 H), 6.45 (t, J = 9.2 Hz, 1 H), 4.82 (s, 4 H), 4.09-4.01 (m, 6 H), 3.81-3.79 (m, 1 H), 3.78-3.73 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 162.9, 154.7, 152.5 (d, J = 241.1 Hz), 150.1, 140.8, 138.1, 130.9, 128.9, 128.0, 114.9 (d, J = 2.8 Hz), 114.2 (d, J = 3.2 Hz), 108.1 (d, J = 23.9 Hz), 81.20 72.2, 63.2, 48.3, 42.7, 40.0. HRMS (ESI): m/z [M + H] calcd for C H FN O S: 418.1237; found: 418.1331. 21 3 4 OTB-222 (R)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)methanesulfonamide O N N H-NMR (400 MHz, CDCl ) d: 7.44-7.35 (m, 1 H), 7.07- 6.97 (m, 1 H), 6.69-6.59 (m, 1 H), 4.98-4.91 (m, 1 H), 4.85 (s, 4 H), 4.81-4.75 (m, 1 H), 4.24-4.14 (m, 4 H), 4.13-4.09 (m, 1 H), 4.06-3.98 (m, 1 H), 3.92-3.86 (m, 1 H), 3.63-3.53 (m, 1 H), 3.47-3.36 (m, 1 H), 3.03 (s, 3 H). C-NMR (100 MHz, DMSO-d ) d: 154.5, 151.7 (d, J = 237.7 Hz), 135.9 (d, J = 11.0 Hz), 130.5 (d, J = 9.4 Hz), 115.2 (d, J = 5.4 Hz), 115.1 (d, J = 2.8 Hz), 107.3 (d, J = 23.8 Hz), 80.2, 71.7, 62.7, 47.6, 45.5. HRMS (ESI): m/z [M + H] calcd for C H FN O S: 386.1186; found: 386.1185. 16 21 3 5 OTB-223 Methyl (S)-((3-(3-fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo- oxazolidinyl)methyl)carbamate H-NMR (400 MHz, CDCl ) d: 7.39 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.61 (t, J = 9.2 Hz, 1 H), 5.11 (brs, 1 H), 4.84 (s, 4 H), 4.73 (brs, 1 H), 4.16 (s, 4 H), 3.99 (t, J = 8.8 Hz, 1 H), 3.77-3.75 (m, 1 H), 3.68 (s, 3 H), 3.64-3.60 (m, 1 H), 3.55-3.50 (m, 1 H). HRMS (ESI): m/z [M + H] calcd for C H FN O : 366.1465; 17 21 3 5 found: 366.1466.
OTB-238 (S)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)cyclopropanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.35 (dd, J = 14.0, 2.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.51 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.84 (s, 4 H), 4.75-4.73 (m, 1 H), 4.12 (s, 4 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.75-3.65 (m, 3 H), 1.39-1.36 (m, 1 H), 0.97-0.91 (m, 2 H), 0.79-0.75 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 174.8, 154.6, 151.6 (d, J = 240.8 Hz), 136.0 (d, J = 11.3 Hz), 129.8 (d, J = 9.2 Hz), 114.5 (d, J = 3.1 Hz), 114.6 (d, J = 3.1 Hz), 114.3 (d, J = 5.2 Hz), 107.8 (d, J = 23.8 Hz), 81.1, 72.1, 62.9, 47.9, 42.0, 39.9, 14.6, 7.7. HRMS (ESI): m/z [M + H] calcd for C H FN O : 376.1673; 19 23 3 4 found: 376.1652.
OTB-239 (S)-N-((3-(3-Fluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin yl)methyl)cyclobutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.49 (d, J = 14.4 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.85 (t, J = 9.2 Hz, 1 H), 5.82 (brs, 1 H), 4.86 (s, 4 H), 4.76 (brs, 1 H), 4.27 (s, 4 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.78-3.65 (m, 3 H), 3.03-2.99 (m, 1 H), 2.26-2.13 (m, 4 H), 1.99-1.85 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 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 = .2 Hz), 107.7 (d, J = 23.9 Hz), 81.1, 71.9, 62.8, 47.9, 41.9, 39.7, 25.4, 25.3, 18.2.
HRMS (ESI): m/z [M + H] calcd for C H FN O : 390.1829; found: 390.1808. 25 3 4 OTB-229 (R)(3,5-Difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)(hydroxymethyl)o xazolidinone H-NMR (400 MHz, CDCl ) d: 7.03 (d, J = 10.8 Hz, 2 H), 4.82 (s, 4 H), 4.72 (brs, 1 H), 4.28 (s, 4 H), 3.99-3.85 (m, 3 H), 3.75-3.72 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 154.6, 152.6 (dd, J = 240.2, 10.8 Hz), 128.9 (t, J = 12.8 Hz), 124.3 (t, J = 13.3 Hz), 102.8 (dd, J = 18.2, 10.7 Hz), 81.0, 72.9, 64.9, 62.6, 46.3, 40.8. HRMS (ESI): m/z [M + H] calcd for C H F N O : 327.1156; found: 327.1135. 17 2 2 4 OTB-230 (S)-N-((3-(3,5-Difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)acetamide H-NMR (400 MHz, CDCl ) d: 6.97 (d, J = 10.0 Hz, 2 H), 6.49 (brs, 1 H), 4.81 (s, 4 H), 4.75 (brs, 1 H), 4.27 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.70-3.63 (m, 3 H), 2.02 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 171.2, 154.2, 152.5 (dd, J = 240.5, 10.9 Hz), 128.6 (t, J = 12.6 Hz), 124.5 (t, J = 13.4 Hz), 102.8 (dd, J = 18.2, 10.6 Hz), 80.9, 71.9, 64.9, 47.5, 41.9, 40.8, 23.1. HRMS (ESI): m/z [M + H] calcd for C H F N O : 17 20 2 3 4 368.1422; found: 368.1418.
OTB-231 Methyl (S)-((3-(3,5-difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo- oxazolidinyl)methyl)carbamate H-NMR (400 MHz, CDCl ) d: 7.04 (d, J = 10.8 Hz, 2 H), 5.08 (brs, 1 H), 4.83 (s, 4 H), 4.74 (brs, 1 H), 4.34 (s, 4 H), 3.96 (t, J = 9.2 Hz, 1 H), 3.72-3.51 (m, 6 H).
C-NMR (100 MHz, CDCl ) d: 157.5, 154.0, 152.6 (dd, J = 240.4, 10.9 Hz), 128.7 (t, J = 12.8 Hz), 124.5 (t, J = 13.5 Hz), 102.8 (dd, J = 23.3, 15.7 Hz), 80.9, 71.7, 64.8, 52.6, 47.4, 43.6, 40.8. HRMS (ESI): m/z [M + H] calcd for C H F N O : 384.1371; 17 20 2 3 5 found: 384.1367.
OTB-232 (R)-N-((3-(3,5-Difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)methanesulfonamide H-NMR (400 MHz, DMSO-d ) d: 7.8 (d, J = 12.4 Hz, 2 H), 4.74-4.69 (m, 5 H), 4.23 (s, 4 H), 4.06 (t, J = 8.8 Hz, 1 H), 3.74-3.70 (m, 1 H), 3.31-3.27 (m, 2 H), 2.94 (s, 3 H). C-NMR (100 MHz, DMSO-d ) d: 154.3, 152.2 (dd, J = 237.8, 11.3 Hz), 129.5 (t, J = 13.0 Hz), 124.4 (t, J = 13.6 Hz), 102.9 (dd, J = 18.2, 10.5 Hz), 80.0, 71.8, 64.7, 47.4, 45.5, 40.7. HRMS (ESI): m/z [M + H] calcd for C H F N O S: 404.1092; 16 20 2 3 5 found: 404.1087.
OTB-233 (S)-N-((3-(3,5-Difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)cyclopropanecarboxamide H-NMR (400 MHz, CDCl ) d: 6.98 (d, J = 10.0 Hz, 2 H), 6.36 (brs, 1 H), 4.82 (s, 4 H), 4.75 (brs, 1 H), 4.28 (s, 4 H), 3.93 (t, J = 8.8 Hz, 1 H), 3.72-3.65 (m, 3 H), 1.42-1.40 (m, 1 H), 0.96-0.88 (m, 2 H), 0.77-0.75 (m, 2 H). C-NMR (100 MHz, CDCl ) d: 174.9, 154.4, 152.5 (dd, J = 240.4, 10.3 Hz), 128.6 (t, J = 12.7 Hz), 124.4 (t, J = 13.4 Hz), 102.8 (dd, J = 18.2, 10.6 Hz), 80.9, 72.2, 64.8, 47.6, 41.9, 40.8, 14.5, 7.7.
HRMS (ESI): m/z [M + H] calcd for C H F N O : 394.1578; found: 394.1575. 19 22 2 3 4 OTB-234 (R)((1H-1,2,3-Triazolyl)methyl)(3,5-difluoro(2-oxaazaspiro[3.3]heptan yl)phenyl)oxazolidinone H-NMR (400 MHz, CDCl ) d: 7.77 (s, 1 H), 7.75 (s, 1 H), 6.86 (d, J = 11.6 Hz, 2 H), .03-5.02 (m, 1 H), 4.81 (s, 4 H), 4.77-4.76 (m, 2 H), 4.27 (s, 4 H), 4.06 (t, J = 9.2 Hz, 1 H), 3.86-3.82 (m, 1 H). C-NMR (100 MHz, CDCl ) d: 153.2, 152.4 (dd, J = 240.7, 11.0 Hz), 134.5, 127.8 (t, J = 12.8 Hz), 125.1, 124.8 (t, J = 13.3 Hz), 103.1 (dd, J = 18.1, 10.7 Hz), 80.9, 70.4, 64.8, 52.0, 47.3, 40.8. HRMS (ESI): m/z [M + H] calcd for C H F N O : 378.1378; found: 378.1365. 17 18 2 5 3 OTB-240 (S)-N-((3-(3,5-Difluoro(2-oxaazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidi nyl)methyl)cyclobutanecarboxamide H-NMR (400 MHz, CDCl ) d: 7.00 (d, J = 12.0 Hz, 2 H), 5.87 (t, J = 6.0 Hz, 1 H), 4.82 (s, 4 H), 4.77-4.71 (m, 1 H), 4.28 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.72-3.64 (m, 3 H), 3.03-2.99 (m, 1 H), 2.26-2.13 (m, 4 H), 1.99-1.82 (m, 2 H). HRMS (ESI): m/z [M + H] calcd for C H F N O : 408.1735; found: 408.1716. 24 2 3 4 OTB-701 (R)-N-((3-(3-Fluoro(2,6-diazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidiny l)methyl)acetamide N N N H-NMR (400 MHz, CDCl ) d: 7.38 (d, J = 14.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.58 (t, J = 9.2 Hz, 1 H), 4.76 (m, 2 H), 4.30 (s, 4 H), 4.10 (s, 4 H), 3.76 (m, 1 H), 3.54 (m, 2 H), 1.96 (s, 3 H). C-NMR (100 MHz, CDCl ) d: 172.6, 155.4, 153.2, 150.8, 135.6, 130.5, 114.4, 107.3, 72.0, 62.2, 55.0, 48.0, 41.7, 37.2, 21.0. HRMS (ESI): m/z [M+H] calcd for C H FN O :349.1671; found: 349.1662. 17 22 4 3 OTB-702 (R)-N-((3-(3-Fluoro(6-methyl-2,6-diazaspiro[3.3]heptanyl)phenyl)oxo-oxaz olidinyl)methyl)acetamide N N N H H-NMR (400 MHz, CDCl ) d: 7.36 (d, J = 14.4 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.57 (t, J = 9.2 Hz, 1 H), 4.75 (m, 1 H), 4.10 (t, J = 9.2 Hz, 1 H), 4.01 (s, 4 H), 3.74 (m, 1 H), 3,73 (s, 4 H), 3.53 (m, 2 H), 2.52 (s, 3 H), 1.96 (s, 3 H). C NMR (100 MHz, CDCl ) d: 172.6, 155.4, 153.2, 150.8, 136.1, 130.3, 114.4, 107.3, 72.0, 64.9, 62.6, 48.0, 43.0, 41.7, 34.8, 21.0. HRMS (ESI): m/z [M+H] calcd for C H FN O : 363.1827, found: 363.1819. 18 24 4 3 OTB-704 (R)-N-((3-(3,5-Difluoro(2,6-diazaspiro[3.3]heptanyl)phenyl)oxo-oxazolidin- -yl)methyl)acetamide N N N H H-NMR (400 MHz, CD OD) d: 7.12 (d, J = 9.6 Hz, 2 H), 4.76, (m, 1 H), 4.30 (s, 4 H), 4.24 (s, 4 H), 4.06 (m, 1 H), 3.73 (m, 1 H), 3.53 (m, 2 H), 1.96 (s, 3 H).
C NMR (100 MHz, CD OD) d: 172.6, 155.0, 153.7, 151.3, 129.6, 129.4, 102.7, 102.5, 72.0, 64.3, 55.0, 48.0, 41.6, 38.3, 21.0. HRMS (ESI): m/z [M+H] calcd for C H F N O : 367.1583 , found: 367.1576. 17 21 2 4 3 OTB-705 (R)-N-((3-(3,5-Difluoro(6-methyl-2,6-diazaspiro[3.3]heptanyl)phenyl)oxo-o xazolidinyl)methyl)acetamide N N N H H-NMR (400 MHz, CD OD) d: 7.12 (d, J = 10.0 Hz, 2 H), 4.75 (m, 1 H), 4.22 (s, 4 H), 4.05 (m, 1 H), 3.78 (s, 4 H), 3.73 (m, 1 H), 3.53 (m, 2 H), 2.55 (s, 3 H), 1.96 (s, 3 H). C-NMR (100 MHz, CD OD) d: 172.6, 155.0, 153.7, 151.3, 129.4, 102.8, 72.0, 64.7, 64.6, 48.0, 42.7, 41.7, 22.4, 21.0. HRMS (ESI): m/z [M+H] calcd for C H F N O : 381.1733, found: 381.1725. 18 23 2 4 3 Example 12 Synthesis of Additional Embodiments of the Invention Procedures for preparation of (6): LiCl NH HCl-OH O S EtOH, H O, BF -Et O DMSO, H O 3 2 2 reflux step 1 step 2 step 3 1 2 3 4 step 4 BH THF TFH, reflux Experimental step 5 Ethyl 5-oxothiepanecarboxylate (2).
To a solution of tetrahydrothiopyranone (100 g, 862 mmol) in Et O (150 mL) was added BF -Et O (120 mL, 948 mmol) at -30 °C, then the reaction mixture was stirred at -30 °C for 2 h under a nitrogen gas atmosphere, after that the solution of ethyl 2-diazoacetate (147 g, 1293 mmol) in Et O (100 mL) was added to the mixture at -30 °C, then the mixture was warmed to room temperature and stirred for overnight.
Quenched with K CO , the solvent was concentrated and dried to give ethyl -oxothiepanecarboxylate (2) (80 g, 46%) as brown oil.
Thiepanone (3).
A mixture of ethyl 5-oxothiepanecarboxylate (2) (80 g, 396 mmol) and lithium chloride (16.6 g, 396 mmol) in DMSO (100 mL) and H O (5 drop) was stirred at 180°C for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, extracted with EA, the organic layer was concentrated under reduced pressure to afford thiepanone (3) (15.9 g crude, 31%) as brown solid.
(Z)-Thiepanone oxime (4).
To a solution of thiepanone (3) (15.9 g, 122 mmol) in EtOH (150 mL) and H O (50 mL) was added with NH OH-HCl (8.47 g, 122 mmol), then the reaction mixture was stirred at 75 °C for 4 h under a nitrogen gas atmosphere, then mixture was concentrated and dried to give (Z)-thiepanone oxime (4) (9.97 g, 56%) as brown solid. 1,5-Thiazocanone (5).
A mixture of (Z)-thiepanone oxime (4) (9.97 g, 68.7 mmol) and polyphosphoric acid (50 g) was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, adjusted pH = 8 using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to afford 1,5-thiazocanone (5) (3 g crude, 30%) as brown solid. 1,5-Thiazocane (6).
To a solution of 1,5-thiazocanone (5) (3 g, 20.7 mmol) in THF (100 mL) was added BH (31 mL, 31.1 mmol) in THF at 0 °C, followed by refluxing for 12 h. The reaction was quenched with CH OH (50 mL). The solvent was evaporated to afford 1,5-thiazocane (6) as a white oil (1.7 g, 63%), and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 132 [M+H] .
K CO Pd/C, H 2 3 2 NH F NO 2 S N NO S N NH S DMF CH OH step 1 step 2 6 8 9 CbzCl step 3 CH Cl O TsCl O S N NHCbz S N N S N N OTs Et N, 0 °C-rt OH THF, n-BuLi CH Cl F step 4 12 11 step 5 10 DMF N 80 °C step 6 K O S S N N O S N N THF, H O, 0°C-rt, 30 min N 2 N step 7 OBD-002 OBD-001 Step 1: Preparation of 5-(2-fluoronitrophenyl)-1,5-thiazocane (8): S N NO To a solution of 1,5-thiazocane (6) (1 g, 7.6 mmol) and 1,2-difluoronitrobenzene (1.2 g, 7.6 mmol) in DMF (10 mL) was added K CO (1.05 g, 7.6 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 5-(2-fluoronitrophenyl)-1,5-thiazocane (8) (1.5 g, 74%) as a yellow solid.
LC-MS (ESI) m/z = 271 [M+H] .
Step 2: 3-Fluoro(1,5-thiazocanyl)benzenamine (9): S N NH To a solution of 5-(2-fluoronitrophenyl)-1,5-thiazocane (8) (1.5 g, 5.7 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3-fluoro(1,5-thiazocanyl)benzenamine (9) (1.2 g, 91%) as a white oil., and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 241 [M+H] .
Step 3: Benzyl 3-fluoro(1,5-thiazocanyl)phenylcarbamate (10): S N NHCbz Benzyl carbonochloridate (1.76 g, 10.4 mmol) was added to a suspension of 3-fluoro(1,5-thiazocanyl)benzenamine (9) (1.2 g, 5.2 mmol) and triethylamine (1.05 g, 10.4 mmol) in DCM (200 mL) at -20 °C under a nitrogen gas atmosphere, then reaction mixture was stirred at 0 °C for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 3-fluoro(1,5-thiazocanyl)phenylcarbamate (10) (740 mg, 38%) as a white solid.
LC-MS (ESI) m/z = 375 [M+H] .
Step 4: (R)(3-Fluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidinone (11): S N N To a solution of benzyl 3-fluoro(1,5-thiazocanyl)phenylcarbamate (10) (740 mg, 1.97 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (1.3 ml, 2.96 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (427 mg, 2.96 mmol) in THF was added to the mixture at -78 °C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (R)(3-fluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidinone (11) (382 mg, 57%) as a white solid.
LC-MS (ESI) m/z = 341 [M+H] .
Step 5: (R)-(3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12): S N N 4-methylbenzenesulfonyl chloride (418 mg, 2.2 mmol) was added to a suspension (R)(3-fluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidinone (11) (382 mg, 1.1 mmol) and Et N (222 mg, 2.2 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (R)-(3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (407 mg, 75%) as a white solid.
LC-MS (ESI) m/z = 495 [M+H] .
Step 6: (R)((1H-1,2,3-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-001): S N N OBD-001 To a solution of (R)-(3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,3-triazole (56 mg, 0.8 mmol) in DMF (5 mL) was added K CO (110 mg, 0.8 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 2: 1) to afford (R)((1H-1,2,3-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-001) (70 mg, 45%) as a white solid.
H NMR (301 MHz, CDCl ) d 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] .
Step 7: Preparation of (OBD-002): O S N N OBD-002 To a solution of (R)((1H-1,2,3-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-001) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (80 mg, 0.13 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-002) (22 mg, 41%) as a white solid.
H NMR (301 MHz, CDCl ) d 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] .
O O OH O K O S O N O N S N N S N N O S N N OTs N N K CO , DMF THF, H O, 0°C-rt, 30 min 2 3 N 2 F step 2 F step 1 12 OBD-008 OBD-009 Step 1: (R)((1H-1,2,4-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-008): S N N OBD-008 To a solution of (R)-(3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,4-triazole (56 mg, 0.8 mmol) in DMF (5 mL) was added K CO (110 mg, 0.8 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 2: 1) to afford (R)((1H-1,2,4-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-008) (84 mg, 54%) as a white solid.
H NMR (301 MHz, CDCl ) d 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] .
Step 2: Preparation of (OBD-009): O S N N OBD-009 To a solution of (R)((1H-1,2,3-triazolyl)methyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxaz olidinone (OBD-008) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (80 mg, 0.13 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-009) (22 mg, 41%) as a white solid.
H NMR (301 MHz, CDCl ) d 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] .
Pd / C, H2 O S N N S N N S N N K CO , DMF MeOH step 1 step 2 12 13 step 3 HOBt, EDCI K O S O S N N S N N THF, H O, 0°C-rt, 30 min step 4 OBD-004 OBD-003 Step 1: (R)(azidomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13): S N N To a solution of (R)-(3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (800 mg, 1.62 mmol) and sodium azide (105 mg, 1.62 mmol) in DMF (10 mL) was added K CO (447 g, 3.24 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (R)(azidomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13) (470 mg, 80%) as a white solid.
LC-MS (ESI) m/z = 366 [M+H] .
Step 2: (S)(aminomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14): S N N To a solution of (R)(azidomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13) (470 mg, 1.3 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at °C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (S)(aminomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14) (374 mg, 85%) as a white solid.
LC-MS (ESI) m/z = 340 [M+H] .
Step 3: (S)-N-((3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-005): S N N OBD-003 To a solution of (S)(aminomethyl)(3-fluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14) (374 mg, 1.1 mmol) and butyric acid (97 mg, 1.1 mmol) in DCM (10 mL) were added HOBt (223 mg, 1.65 mmol), EDCI (420 mg, 2.2 mmol) and DIPEA (284 mg, 2.2 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (S)-N-((3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-003) (252 mg, 56%) as a white solid.
H NMR (300 MHz, CDCl ) d 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] .
Step 4: Preparation of (OBD-004): O S N N OBD-004 To a solution of (S)-N-((3-(3-fluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-003) (150 mg, 0.37 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (225 mg, 0.37 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-004) (48 mg, 31%) as a white solid.
H NMR (301 MHz, CDCl ) d 7.44 (dd, J = 14.7, 2.4 Hz, 1H), 7.19 – 6.99 (m, 2H), 6.44 (s, 1H), 4.84 – 4.71 (m, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.78 (dd, J = 9.0, 6.6 Hz, 1H), 3.66 (t, J = 4.6 Hz, 2H), 3.38 – 3.09 (m, 6H), 2.99 (dd, J = 12.6, 6.3 Hz, 2H), 2.20 (dd, J = 9.4, 5.3 Hz, 6H), 1.71 – 1.56 (m, 2H), 0.91 (dd, J = 9.6, 5.1 Hz, 3H).
LC-MS (ESI) m/z = 425.8 [M+H] .
K CO Pd/C, H 2 3 2 NH F NO 2 S N NO S N NH S DMF CH OH step 1 step 2 6 8 9 CbzCl step 3 3 CH Cl F O F O O TsCl O S N NHCbz S N N S N N OTs OH Et N, 0 °C-rt THF, n-BuLi CH Cl F step 4 12 11 step 5 10 step 6 F O O O Pd / C, H2 O O S N N S N N S N N H 3 MeOH HOBt, EDCI step 7 OBD-027 step 8 step 9 HOBt, EDCI S N N H OBD-026 Step 1: Preparation of 5-(2,6-difluoronitrophenyl)-1,5-thiazocane (8): S N NO To a solution of 1,5-thiazocane (6) (1 g, 7.6 mmol) and 1,2,3-trifluoronitrobenzene (1.35 g, 7.6 mmol) in DMF (10 mL) was added K CO (2.1 g, 15.2 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford -(2,6-difluoronitrophenyl)-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(1,5-thiazocanyl)benzenamine (9): S N NH To a solution of 5-(2,6-difluoronitrophenyl)-1,5-thiazocane (8) (1.64 g, 5.7 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3,5-difluoro(1,5-thiazocanyl)benzenamine (9) (1.4 g, 94%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 259 [M+H] .
Step 3: Benzyl 3,5-difluoro(1,5-thiazocanyl)phenylcarbamate (10): S N NHCbz Benzyl carbonochloridate (1.87 g, 10.6 mmol) was added to a suspension of 3,5-difluoro(1,5-thiazocanyl)benzenamine (9) (1.4 g, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in DCM (200 mL) at -20 °C under a nitrogen gas atmosphere, then reaction mixture was stirred at 0 °C for 30 min, monitored by TLC.
Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 3,5-difluoro(1,5-thiazocanyl)phenylcarbamate (10) (872 mg, 42%) as a white solid.
LC-MS (ESI) m/z = 393 [M+H] .
Step 4: (R)(3,5-difluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidino ne (11): S N N To a solution of benzyl 3,5-difluoro(1,5-thiazocanyl)phenylcarbamate (10) (872 mg, 2.23 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (1.4 ml, 3.34 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (480 mg, 3.34 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (R)(3,5-difluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidino ne (11) (519 mg, 65%) as a white solid.
LC-MS (ESI) m/z = 359 [M+H] .
Step 5: (R)-(3-(3,5-difluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12): S N N 4-methylbenzenesulfonyl chloride (550 mg, 2.9 mmol) was added to a suspension (R)(3,5-difluoro(1,5-thiazocanyl)phenyl)(hydroxymethyl)oxazolidino ne (11) (519 mg, 1.45 mmol) and Et N (292 mg, 2.9 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (R)-(3-(3,5-difluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (594 mg, 80%) as a white solid.
LC-MS (ESI) m/z = 513 [M+H] .
Step 6: (R)(azidomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13): S N N To a solution of (R)-(3-(3,5-difluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (12) (594 g, 1.2 mmol) and sodium azide (75 mg, 1.2 mmol) in DMF (10 mL) was added K CO (160 mg, 2.4 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (R)(azidomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13) (400 mg, 87%) as a white solid.
LC-MS (ESI) m/z = 384 [M+H] .
Step 7: (S)(aminomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14): S N N To a solution of (R)(azidomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (13) (400 g, 1.04 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at °C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (S)(aminomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14) (331 g, 89 %) as a white solid.
LC-MS (ESI) m/z = 358 [M+H] .
Step 8: (S)-N-((3-(3,5-difluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl) butyramide (OBD-026): S N N OBD-026 To a solution of (S)(aminomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol) and DIPEA (118 mg, 0.92 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (S)-N-((3-(3,5-difluoro(1,5-thiazocanyl)phenyl)oxooxazolidinyl)methyl) butyramide (OBD-026) (82 mg, 42%) as a white solid.
H NMR (400 MHz, CDCl ) d 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)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazo lidinyl)methyl)butyramide (OBD-027): S N N OBD-027 To a solution of (S)(aminomethyl)(3,5-difluoro(1,5-thiazocanyl)phenyl)oxazolidinone (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol) and DIPEA (118 mg, 0.92 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazo lidinyl)methyl)butyramide (OBD-027) (82 mg, 45%) as a white solid.
H NMR (301 MHz, CDCl ) d 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, LC-MS (ESI) m/z = 400 [M+H] .
The synthesis route: BH THF NH OH HCl PPA H O, EtOH, reflux 70°C, 2 h THF, reflux,overnight 1 2 3 4 Experimental Tetrahydrothiopyranone oxime (2).
To a solution of tetrahydrothiopyranone (20 g, 172 mmol) in EtOH (150 mL) and H O (50 mL) was added with NH OH-HCl (11.9 g, 172 mmol), then the reaction mixture was stirred at 75 °C for 4 h under a nitrogen gas atmosphere, then mixture was concentrated and dried to give tetrahydrothiopyranone oxime (2) (14.7 g, 66%) as brown solid. 1,4-Thiazepanone (3).
A mixture of tetrahydrothiopyranone oxime (2) (14.7 g, 112 mmol) and polyphosphoric acid (50 g) was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and poured into ice water, adjusted pH = 8 using potassium carbonate solution, extracted with EA, the organic layer was concentrated under reduced pressure to afford 1,4-thiazepanone (3) (11.9 g crude, 81%) as brown solid. 1,4-Thiazepane (4).
To a solution of 1,4-thiazepanone (3) (11.9 g, 105 mmol) in THF (100 mL) was added BH (158 mL, 158 mol) in THF at 0 °C, followed by refluxing for 12 h. The reaction was quenched with CH OH (50 mL). The solvent was evaporated to afford 1,4-thiazepane (4) as a white oil (10.7 g, 87%), and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 118 [M+H] .
K CO S Pd/C, H S 2 3 2 S F NO 2 N NO N NH DMF CH OH step 1 step 2 4 5 6 7 CbzCl, Et N step 3 CH Cl S O S O N NHCbz N N N N OTs Et N OH THF, n-BuLi step 5 F step 4 9 8 step 6 60 °C O O O S O S O Pd/C, H N N 2 HO H N N N N CH OH EDCI, HOBt step 7 step 8 11 OBD-005 step 9 N N H N N H OBD-007 OBD-006 Step 1: Preparation of 4-(2-fluoronitrophenyl)-1,4-thiazepane (6): To a solution of 1,4-thiazepane (4) (7 g, 59.8 mmol) and 1,2-difluoronitrobenzene (10.4 g, 65.8 mmol) in DMF (10 mL) was added K CO (16.5 g, 119.6 mmol) at °C and then reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 4-(2-fluoronitrophenyl)-1,4-thiazepane (6) (10 g, 65%) as a yellow solid.
LC-MS (ESI) m/z = 257 [M+H] .
Step 2: 3-Fluoro(1,4-thiazepanyl)benzenamine (7): To a solution of 4-(2-fluoronitrophenyl)-1,4-thiazepane (6) (8 g, 31.2 mmol) and Palladium carbon (500 mg) in MeOH (15 mL), then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 3-fluoro(1,4-thiazepanyl)benzenamine (7) (6.4 g, 93%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 227 [M+H] .
Step 3: Benzyl 3-fluoro(1,4-thiazepanyl)phenylcarbamate (8): N NHCbz Benzyl carbonochloridate (9.6 g, 56.6 mmol) was added to a suspension of 3-fluoro(1,4-thiazepanyl)benzenamine (7) (6.4 g, 28.3 mmol) and triethylamine (5.7 g, 56.6 mmol) in DCM (200 mL) at -20 °C under a nitrogen gas atmosphere, then reaction mixture was stirred at 0 °C for 30 min, monitored by TLC.
Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 3-fluoro(1,4-thiazepanyl)phenylcarbamate (8) (2.34 g, 23%) as a white oil.
LC-MS (ESI) m/z = 361 [M+H] .
Step 4: (R)(3-Fluoro(1,4-thiazepanyl)phenyl)(hydroxymethyl)oxazolidinone To a solution of benzyl 3-fluoro(1,4-thiazepanyl)phenylcarbamate (8) (2.34 g, 6.5 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (4 ml, 9.7 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (1.4 g, 9.7 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (R)(3-fluoro(1,4-thiazepanyl)phenyl)(hydroxymethyl)oxazolidinone (9) (1.16 g, 55%) as a white solid.
LC-MS (ESI) m/z = 327 [M+H] .
Step 5: (R)-(3-(3-Fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (10): 4-Methylbenzenesulfonyl chloride (1.4 g, 7.2 mmol) was added to a suspension of (R)(3-fluoro(1,4-thiazepanyl)phenyl)(hydroxymethyl)oxazolidinone (9) (1.16 g, 3.6 mmol) and Et N (727 mg, 7.2 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (R)-(3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (10) (1.41 g, 41%) as a white solid.
LC-MS (ESI) m/z = 481 [M+H] .
Step 1: (R)(azidomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (11): To a solution of (R)-(3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl 4-methylbenzenesulfonate (10) (1.41 g, 2.95 mmol) and sodium azide (190 mg, 2.95 mmol) in DMF (10 mL) was added K CO (814 g, 5.9 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (R)(azidomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (11) (830 mg, 80%) as a white solid.
LC-MS (ESI) m/z = 352 [M+H] .
Step 2: (S)(aminomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (12): To a solution of (R)(azidomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (11) (830 mg, 2.4 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at °C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (S)(aminomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (12) (654 mg, 85%) as a white solid.
LC-MS (ESI) m/z = 326 [M+H] .
Step 3: (S)-N-((3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-005): N N H OBD-005 To a solution of (S)(aminomethyl)(3-fluoro(1,4-thiazepanyl)phenyl)oxazolidinone (12) (654 mg, 2 mmol) and butyric acid (177 mg, 2 mmol) in DCM (10 mL) were added HOBt (405 mg, 3 mmol), EDCI (764 mg, 4 mmol) and DIPEA (516 mg, 4 mmol) at °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (S)-N-((3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-005) (286 mg, 34%) as a white solid.
H NMR (300 MHz, CDCl ) d 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] .
Step 4: Preparation of (OBD-006 and OBD-007): N N H + OBD-007 OBD-006 To a solution of (S)-N-((3-(3-fluoro(1,4-thiazepanyl)phenyl)oxooxazolidinyl)methyl)buty ramide (OBD-005) (150 mg, 0.38 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (233 mg, 0.38 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-006) (50 mg, 32%) as a white solid and (OBD-007) (24 mg, 15%) as a white solid.
(OBD-006) H NMR (301 MHz, CDCl ) d 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) H NMR (301 MHz, CDCl ) d 7.51 (d, J = 14.7 Hz, 1H), 7.10 (d, J = 9.9 Hz, 2H), .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 = .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] .
Procedures for preparation of R: H , 10% Pd/C, 4 atm, 50 °C, 5h BnNH , K CO O 2 2 2 3 COOEt COOEt MeOH, CH COOH O toluene/H O, reflux step 2 step 1 CbzCl, Et N step 3 -20 °C ~0 °C OTs CaCl , NaBH O TsO TsCl, Et N, DMAP O DCM, rt EtOH/MeOH, rt Cbz Cbz step 5 step 4 Na S • 9 H2O step 6 EtOH, reflux TMSI, CH Cl , 0 C to rt step 7 Step 1: Preparation of (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2): The mixture of (2R,5S)-diethyl 2,5-dibromohexanedioate (1) (100 g, 278 mmol), BnNH (44.6 g, 416 mmol) and K CO (76.84 g, 556 mmol) in toluene/H O was 2 2 3 2 stirred at 110°C for overnight, monitored by TLC. The mixture was extracted with EtOAc, washed with water and brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 75%) as a white oil.
LC-MS (ESI) m/z = 306 [M+H] .
Step 2: (2S,5R)-diethyl pyrrolidine-2,5-dicarboxylate (3): To a solution of (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 209 mmol) and Palladium carbon (2 g) in MeOH (15 mL) was added CH COOH (5 mL), then the reaction mixture was stirred at 50°C under a hydrogen gas atmosphere, 4atm for 5 h, monitored by TLC. The filter was concentrated under reduced pressure, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 216 [M+H] .
Step 3: (2S,5R)benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (4): To a solution of (2S,5R)-diethyl pyrrolidine-2,5-dicarboxylate (3) (62 g, 288 mmol) and Et N (58 g, 577 mmol) in DCM (100 mL) was added benzyl carbonochloridate (98 g, 577 mmol) at -20 °C under a nitrogen gas atmosphere, then the reaction mixture was stirred at rt for 5 h, monitored by TLC. The mixture was extracted with DCM, washed with water and brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (4) (80 g, 80%) as a white oil.
LC-MS (ESI) m/z = 350 [M+H] .
Step 4: (2S,5R)-benzyl 2,5-bis(hydroxymethyl)pyrrolidinecarboxylate (5): CaCl (76 g, 688 mmol) and NaBH (43 g, 1146 mmol) were added to a stirred solution of (2S,5R)benzyl 2,5-diethyl pyrrolidine-1,2,5-tricarboxylate (4) (80 g, 229 mmol) in EtOH-MeOH (9:1; 200 mL) at rt under a nitrogen gas atmosphere, then the reaction mixture was stirred for 5 h, monitored by TLC. H O (5 mL) was added, and the mixture was stirred tor a turther 15 min. The mixture was then concentrated in vacuo. The mixture was extracted with EtOAc, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-benzyl 2,5-bis(hydroxymethyl)pyrrolidinecarboxylate (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)pyrrolidinecarboxylate (6): 4-methylbenzenesulfonyl chloride (92 g, 483 mmol) was added to a stirred solution of (2S,5R)-benzyl 2,5-bis(hydroxymethyl)pyrrolidinecarboxylate (5) (32 g, 121 mmol) and Et N in DCM(200 mL) at 0 °C under a nitrogen gas atmosphere, then the reaction mixture was allowed to warm to room temperature and stirred for 5 h, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 2: 1) to afford (2S,5R)-benzyl 2,5-bis(tosyloxymethyl)pyrrolidinecarboxylate (6) (30 g, 43%) as a white solid.
LC-MS (ESI) m/z = 574 [M+H] .
Step 6: 8-benzylthiaaza-bicyclo[3.2.1]octanecarboxylate (7): Sodium sulfide hydrate (38 g, 157 mmol) was added to a stirred solution of (2S,5R)-benzyl 2,5-bis(tosyloxymethyl)pyrrolidinecarboxylate (6) (30 g, 50 mmol) in EtOH (50 mL) and water (50 mL) at room temperature, then the reaction mixture was stirred at 90 °C for 2 h, monitored by TLC. The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford 8-benzylthiaaza-bicyclo[3.2.1]octanecarboxylate (7) (10 g, 73%) as a white solid.
LC-MS (ESI) m/z = 264 [M+H] .
Step 7: 3-thiaaza-bicyclo[3.2.1]octane hydrogen iodide (8): Iodotrimethylsilane (15 g, 75 mmol) was added to a stirred solution of 8-benzylthiaaza-bicyclo[3.2.1]octanecarboxylate (7) (10 g, 38 mmol) in DCM (200 mL) at 0 °C under a nitrogen gas atmosphere, then the reaction mixture was allowed to warm to room temperature and stirred for 30 min, monitored by TLC.
The mixture was extracted with DCM, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 15: 1) to afford 3-thiaaza-bicyclo[3.2.1]octane hydrogen iodide (8) (8.13 g, 84%) as a brown solid.
LC-MS (ESI) m/z = 130 [M+H] Pd/C, H N NO N NH F NO 2 2 DMF, 70 °C CH OH step 1 F F F step 2 step 3 TsCl S N N N N N NHCbz Et N, 0-rt 3 THF, n-BuLi OTs OH step 5 step 4 80 °C step 6 K O S THF, H O, 0°C-rt, 30 min OBD-021 OBD-018 step 7 Step 1: Preparation of 8-(2-fluoronitrophenyl)thiaaza-bicyclo[3.2.1]octane (10): To a solution of 3-thiaaza-bicyclo[3.2.1]octane hydrogen iodide (8) (5.58 g, 21.7 mmol) and 1,2-difluoronitrobenzene (3.8 g, 23.8 mmol) in DMF (10 mL) was added K CO (6 g, 43.4 mmol) at 25°C under a nitrogen gas atmosphere and the reaction mixture was stirred at 80°C for 2 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 8-(2-fluoronitrophenyl)thiaaza-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-thiaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (11): To a solution of 8-(2-fluoronitrophenyl)thiaaza-bicyclo[3.2.1]octane (10) (4.89 g, 18.2 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (11) (4.08 g, 94%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 239 [M+H] .
Step 3: Benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenylcarbamate (12): N NHCbz Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (6.38 g, 25.6 mmol) was added to a suspension of 4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (11) (4.08 g, 17.1 mmol) in THF (30 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenylcarbamate (12) (4.34 g, 68%) as a white solid.
LC-MS (ESI) m/z = 373 [M+H] .
Step 4: (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl) (hydroxymethyl)oxazolidinone (13): To a solution of benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenylcarbamate (12) (4.34 g, 11.6 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (7.3 ml, 17.5 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (2.5 g, 17.4 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (5R)(4-(3-thiaaza-bicyclo[3.2.1] Octanyl)fluorophenyl)(hydroxymethyl)oxazolidinone (13) (3.03 g, 77%) as a white solid.
LC-MS (ESI) m/z = 339 [M+H] .
Step 5: ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (14): 4-methylbenzenesulfonyl chloride (3.41 g, 17.9 mmol) was added to a suspension (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(hydroxymethyl oxazolidinone (13) (3.03 g, 8.9 mmol) and Et N (1.8 g, 17.9 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (14) (3.74 g, 85%) as a white solid.
LC-MS (ESI) m/z = 493 [M+H] .
Step 6: (5R)((1H-1,2,4-triazolyl)methyl)(4-(3-thiaaza-bicyclo[3.2.1]octanyl) fluorophenyl)oxazolidinone (OBD-021): OBD-021 To a solution of ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl) oxooxazolidinyl)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 CO (280 mg, 2 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 2: 1) to afford (5R)((1H-1,2,4-triazolyl)methyl) (4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxazolidinone (OBD-021) (177 mg, 45%) as a white solid.
H NMR (300 MHz, DMSO-d ) d 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] .
Step 7: Preparation of (OBD-018): OBD-018 To a solution of (5R)((1H-1,2,4-triazolyl)methyl)(4-(3-thiaaza-bicyclo[3.2.1] octanyl)fluorophenyl)oxazolidinone (OBD-021) (100 mg, 0.26 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (157 mg, 0.26 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-018) (52 mg, 50%) as a white solid.
H NMR (300 MHz, DMSO-d ) d 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] .
OBD-085 K O S step 5 THF,H O, 0 °C O NaN , DMF 3 Pd/C, H N N N 60 °C, 2h CH OH step 1 13 OBD-081 step 2 step 3 S K O S O O S N O O THF,H O, 0 °C N step 4 OBD-017 OBD-016 Step 1: (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(azidomethyl)ox azolidinone (15): To a solution of ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl) oxooxazolidinyl)methyl 4-methylbenzenesulfonate (14) (2 g, 4 mmol) and sodium azide (265 mg, 4 mmol) in DMF (10 mL) was added K CO (1.1 g, 8 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl) fluorophenyl)(azidomethyl)oxazolidinone (15) (1.01 g, 70%) as a white solid.
LC-MS (ESI) m/z = 364 [M+H] .
Step 2: (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)o xazolidinone (OBD-081): OBD-081 To a solution of (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl) fluorophenyl)(azidomethyl)oxazolidinone (15) (1.01 g, 2.8 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)o xazolidinone (OBD-081) (800 mg, 85%) as a white solid.
LC-MS (ESI) m/z = 338 [M+H] .
Step 3: N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidi nyl)methyl)butyramide (OBD-016): OBD-016 To a solution of (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)o xazolidinone (OBD-081) (200 mg, 0.59 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol) and DIPEA (115 mg, 0.88 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC.
Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidi nyl)methyl)butyramide (OBD-016) (156 mg, 65%) as a white solid.
H NMR (300 MHz, DMSO-d ) d 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] .
Step 4: Preparation of (OBD-017): OBD-017 To a solution of N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl) oxooxazolidinyl)methyl)butyramide (OBD-016) (100 mg, 0.25 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (157 mg, 0.26 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-017) (16 mg, 15%) as a white solid.
H NMR (301 MHz, CDCl ) d 7.39 (dd, J = 15.8, 2.3 Hz, 1H), 7.03 (d, J = 6.1 Hz, 2H), 6.78 (t, J = 9.3 Hz, 1H), 4.72 (s, 1H), 4.55 (s, 2H), 3.94 (t, J = 8.9 Hz, 1H), 3.81 – 3.66 (m, 1H), 3.58 (s, 2H), 3.42 (d, J = 10.3 Hz, 2H), 2.77 (d, J = 11.9 Hz, 2H), 2.17 (dd, J = 25.1, 17.8 Hz, 4H), 1.84 (d, J = 7.9 Hz, 2H), 1.56 (dq, J = 14.5, 7.2 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H).
LC-MS (ESI) m/z = 423.8 [M+H] .
Step 4: Preparation of (OBD-085): OBD-085 To a solution of (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)o xazolidinone (OBD-081) (100 mg, 0.29 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (182 mg, 0.29 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-085) (28 mg, 28%) as a white solid.
H NMR (400 MHz, DMSO-d ) d 7.52 (dd, J = 16.4, 2.2 Hz, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 7.13 (t, J = 9.6 Hz, 1H), 4.58 (dd, J = 14.1, 4.9 Hz, 3H), 4.04 (t, J = 8.9 Hz, 1H), 3.84 (dd, J = 8.7, 6.5 Hz, 1H), 3.56 (d, J = 10.0 Hz, 2H), 2.81 (dd, J = 9.3, 4.9 Hz, 2H), 2.46 (s, 2H), 2.17 – 1.99 (m, 2H), 1.79 (dd, J = 17.3, 9.5 Hz, 4H).
LC-MS (ESI) m/z = 354 [M+H] .
Pd/C, H K CO 2 S 2 3 F NO N NO HI N NH CH OH DMF, rt 3 9 Step 2 Step 1 11 CbzCl CH Cl Step 3 TsCl, Et N O 3 O NHCbz THF, n-BuLi OTs CH Cl Step 5 F 14 Step 4 F NaN , K CO Step 6 3 2 3 DMF, 80 °C Pd / C, H O N N H MeOH N F HOBt, EDCI, DIPEA Step 7 F Step 9 O OBD-083 OBD-029 130 O K O S K O S Step 8 Step 10 THF / H O, 0 °C 2 THF / H O, 0 °C F O F O N N N N OBD-087 O OBD-242 Step 1: Preparation of 8-(2,6-difluoronitrophenyl)thiaaza-bicyclo[3.2.1]octane (10): To a solution of 3-thiaaza-bicyclo[3.2.1]octane hydrogen iodide (8) (5.0 g, 19.4 mmol) and 1,2,3-trifluoronitrobenzene (4.13 g, 23.3 mmol) in DMF (10 mL) was added K CO (5.35 g, 38.8 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 8-(2,6-difluoronitrophenyl)thiaaza-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-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (11): N NH To a solution of 8-(2-fluoronitrophenyl)thiaaza-bicyclo[3.2.1]octane (10) (3.6 g, 12.5 mmol) and Palladium carbon (200 mg) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (11) (2.9 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 257 [M+H] .
Step 3: benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (12): NHCbz Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (5.57 g, 22.4 mmol) was added to a suspension of 4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (11) (2.9 g, 11.2 mmol) in THF (30 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (12) (3.0 g, 68%) as a white solid.
LC-MS (ESI) m/z = 391 [M+H] .
Step 4: (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxyme thyl)oxazolidinone (13): To a solution of benzyl 4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (12) (3.0 g, 7.7 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (4.8 ml, 11.5 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (1.66 g, 11.5 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5- difluorophenyl)(hydroxymethyl)oxazolidinone (13) (2.3 g, 84%) as a white solid.
LC-MS (ESI) m/z = 357 [M+H] .
Step 5: ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)methyl 4-methylbenzenesulfonate (14): 4-methylbenzenesulfonyl chloride (2.45 g, 13 mmol) was added to a suspension of (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5- difluorophenyl)(hydroxymethyl)oxazolidinone (13) (2.3 g, 6.5 mmol) and Et N (1.3 g, 13 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC.
Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)methyl 4-methylbenzenesulfonate (14) (2.81 g, 85%) as a white solid.
LC-MS (ESI) m/z = 511 [M+H] .
Step 6: (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (15): To a solution of ((R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)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 CO (1.52 mg, 11.04 mmol) at °C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (15) (1.85 g, 88%) as a white solid.
LC-MS (ESI) m/z = 382 [M+H] .
Step 7: (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (OBD-083): OBD-083 To a solution of (5R)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (15) (1.85 g, 4.87 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (OBD-083) (1.6 g, 90 %) as a white solid.
H NMR (400 MHz, DMSO) d 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] .
Step 8: Preparation of (OBD-087): OBD-087 To a solution of (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (OBD-083) (100 mg, 0.28 mmol) in THF (10 mL) and 10 drops water was added potassium peroxomonosulfate (173 mg, 0.28 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC. Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-087) (31 mg, 30 %) as a white solid.
H NMR (400 MHz, DMSO) d 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)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazo lidinyl)methyl)butyramide (OBD-029): OBD-029 To a solution of (5S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (OBD-083) (200 mg, 0.56 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL) were added HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol) and DIPEA (115 mg, 0.88 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC.
Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazo lidinyl)methyl)butyramide (OBD-029) (119 mg, 50%) as a white solid.
H NMR (400 MHz, DMSO-d ) d 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] .
Step 10: Preparation of (OBD-242): OBD-242 To a solution of N-(((S)(4-(3-thiaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazo lidinyl)methyl)butyramide (OBD-029) (100 mg, 0.23 mmol) in THF (10 mL) and drops water was added potassium peroxomonosulfate (144 mg, 0.23 mmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 2 h, monitored by TLC.
Quenched with sodium thiosulfate, and the crude material was purified by prep-HPLC to afford (OBD-242) (30 mg, 15%) as a white solid.
H NMR (400 MHz, DMSO-d ) d 8.19 (d, J = 5.6 Hz, 1H), 7.28 (d, J = 12.7 Hz, 3H), 4.77 – 4.69 (m, 1H), 4.34 (s, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.67 (d, J = 9.0 Hz, 3H), 3.40 (dd, J = 11.0, 5.5 Hz, 1H), 2.56 (d, J = 11.9 Hz, 1H), 2.06 (t, J = 7.3 Hz, 4H), 1.82 – 1.72 (m, 2H), 1.51 – 1.40 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H).
LC-MS (ESI) m/z = 442 [M+H] . 2.1 Mg,MeOH,1h Br Br KOH,EtOH,refulx,48h 2.2 Na SO ,Et O,30min 2 4 2 H C O 2 2 4 HN O S NH S N O Br OH 2.3 EtOH,H C O 2 2 4 step 1 step 2 F 2 K CO , DMF 80 °C step 3 F O O F F F Cbz-Osu, THF Pd/C, H O N NH O N NH O N N O N NO CH OH THF, n-BuLi 3 F F F F step 5 step 4 8 step 6 toluene, 60 °C step 7 O CF COOH Boc O O N N O N N CH Cl N 2 2 N step 8 F O 9 OBD-061 Step 1: Preparation of (3): To a solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 g, 890 mmol) in ethanol (1000 mL) was added 3-bromo-2,2-bis(bromomethyl)propanol (90 g, 270 mmol) at 25°C then the reaction mixture was stirred at 100°C for 48 h. The mixture was concentrated under reduced pressure, and the crude material was poured into solution of potassium hydroxide (75 mL) and stirred for 2 h, to afford filter cake (3) (10 g, 59%) as a white solid.
LC-MS (ESI) m/z = 254 [M+H] .
Step 2: Preparation of (4): A mixture of (3) (10 g, 39.5 mmol) and magnesium (6.7 g) in methanol (15 mL) was sonicated for 1 h at 40 °C, after that the solvent was removed under reduced pressure to afford a viscous grey residue, Et2O and sodium sulfate were added and the resulting grey mixture was stirred vigorously for 30 min before filtration. A solution of oxalic acid in ethanol was added to the filtrate. A think white precipitate formed instantly, which was target product (4) (3.7 g, 50%), and the crude material was used for next reaction without further purification.
Step 3: Preparation of (5): To a solution of (4) (3.7 g, 19.5 mmol) and 1,2,3-trifluoronitrobenzene (3.81 g, 21.5 mmol) in DMF (10 mL) was added K CO (5.38 g, 39 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford (5) (1.9 g, 38%) as a yellow solid.
LC-MS (ESI) m/z = 257 [M+H] .
Step 4: Preparation of (6): To a solution of (5) (1.9 g, 7.4 mmol) and Palladium carbon (200 mg) in methanol (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford (6) (1.5 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 227 [M+H] .
Step 5: Preparation of (7): Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (3.3 g, 13.3 mmol) was added to a suspension of (6) (1.5 g, 6.7 mmol) in THF (30 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford (7) (1.6 g, 68%) as a white solid.
LC-MS (ESI) m/z = 361 [M+H] .
Step 6: Preparation of (8): To a solution of (7) (1.6 g, 4.6 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (2.8 ml, 6.8 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (980 mg, 6.8 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (8) (1.2 g, 84%) as a white solid.
LC-MS (ESI) m/z = 327 [M+H] .
Step 7: Preparation of (9): (E)-N1,N1,N2-trimethyldiazene-1,2-dicarboxamide (443 mg, 2.6 mmol) was added to a suspension of (8) (560 mg, 1.7 mmol), tert-butyl isoxazolylcarbamate (380 mg, 2.1 mmol) and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 mL) at 0 °C under a nitrogen gas atmosphere and then the reaction mixture was stirred at 60 °C for overnight, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford (9) (309 mg, 37%) as a white solid.
LC-MS (ESI) m/z = 493 [M+H] .
Step 8: Preparation of (OBD-061): To a solution of (9) (309 g, 0.6 mmol) in CH Cl (10 mL) at 0 °C was added trifluoroacetic acid (1 ml), then the mixture was stirred at 0 °C for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with CH Cl , the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (OBD-061) (93 mg, 38 %) as a white solid.
H NMR (300 MHz, CDCl ) d 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] .
O F F O NaN , K CO TsCl, Et N 3 2 3 3 O N N N O N N O N OTs N DMF 3 CH Cl step 2 step 1 Pd/ C, H step 3 OBD-062 Step 1: Preparation of (9): 4-methylbenzenesulfonyl chloride (2.45 g, 13 mmol) was added to a suspension of (8) (2.3 g, 6.5 mmol) and Et N (1.3 g, 13 mmol) in DCM (10 mL) at 0 °C and then the reaction mixture was stirred at room temperature for overnight under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (9) (2.65 g, 85%) as a white solid.
LC-MS (ESI) m/z = 481 [M+H] .
Step 2: Preparation of (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 CO (1.52 mg, 11.04 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (10) (1.7 g, 88%) as a white solid.
LC-MS (ESI) m/z = 352 [M+H] .
Step 3: Preparation of (OBD-062): To a solution of (10) (1.7 g, 4.86 mmol) in MeOH (10 mL) was added palladium carbon (100 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (OBD-062) (1.3 g, 85 %) as a white solid.
H NMR (400 MHz, DMSO-d ) d 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] .
Pd/C, H O N NH K CO , DMF O N NO F NO 2 H C O + 2 2 4 CH OH step 1 step 2 Cbz-Osu, THF step 3 O O O Boc O O N NH O N N O N N THF, n-BuLi N N step 4 5 PBu toluene, 60 °C step 5 CF COOH step 6 CH Cl O N N H OBD-056 Step 1: Preparation of (3): To a solution of (1) (3.7 g, 19.5 mmol) and 1,2-difluoronitrobenzene (3.41 g, 21.5 mmol) in DMF (10 mL) was added K CO (5.38 g, 39 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford (3) (1.7 g, 38%) as a yellow solid.
LC-MS (ESI) m/z = 239 [M+H] .
Step 2: Preparation of (4): To a solution of (3) (1.7 g, 7.4 mmol) and Palladium carbon (200 mg) in methanol (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford (4) (1.4 g, 90%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 209 [M+H] .
Step 3: Preparation of (7): Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (3.3 g, 13.3 mmol) was added to a suspension of (6) (1.4 g, 6.7 mmol) in THF (30 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford (7) (1.6 g, 70%) as a white solid.
LC-MS (ESI) m/z = 343 [M+H] .
Step 4: Preparation of (8): To a solution of (7) (1.6 g, 4.7 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (2.9 ml, 7.0 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (1 g, 7.0 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (8) (1.2 g, 84%) as a white solid.
LC-MS (ESI) m/z = 309 [M+H] .
Step 5: Preparation of (9): (E)-N ,N ,N -trimethyldiazene-1,2-dicarboxamide (443 mg, 2.6 mmol) was added to 1 1 2 a suspension of (8) (523 mg, 1.7 mmol), tert-butyl isoxazolylcarbamate (380 mg, 2.1 mmol) and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 mL) at 0 °C under a nitrogen gas atmosphere and then the reaction mixture was stirred at 60 °C for overnight, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford (9) (298 mg, 37%) as a white solid.
LC-MS (ESI) m/z = 475 [M+H] .
Step 6: Preparation of (OBD-056): To a solution of (9) (298 mg, 0.6 mmol) in CH Cl (10 mL) at 0 °C was added trifluoroacetic acid (1 ml), then the mixture was stirred at 0 °C for 30 min, monitored by TLC. Quenched with ammonium chloride, extracted with CH Cl , the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (OBD-056) (84 mg, 38 %) as a white solid.
H NMR (301 MHz, CDCl ) d 7.39 (d, J = 14.4 Hz, 1H), 7.25 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.83 (t, J = 8.9 Hz, 1H), 5.14 (s, 1H), 4.73 (s, 1H), 4.39 (s, 2H), 4.00 (t, J = 8.8 Hz, 1H), 3.84 – 3.42 (m, 8H), 3.05 (dd, J = 23.2, 11.2 Hz, 5H), 2.13 – 1.88 (m, 5H).
LC-MS (ESI) m/z = 375 [M+H] .
DIPEA Pd/C, H NH N NH + F NO O CH CN, rt CH OH/EA O F step 1 3 step 2 Cbz-Osu step 3 F O F TsCl, Et N N N O N N N NH CH Cl , rt O O THF, n-BuLi step 5 OBD-114 step 4 step 6 OBD-054 Step 1: Preparation of 3-(2,6-difluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane (3): To a solution of 8-oxaaza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoronitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL) was added K CO (12.2 g, 88.4 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 3-(2,6-difluoronitrophenyl)oxaaza-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-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4): To a solution of 3-(2,6-difluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane (3) (9.3 g, 34.4 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4) (7.8 g, 95%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 241 [M+H] .
Step 3: Preparation of benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5): Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (12 g, 48.7 mmol) was added to a suspension of 4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 10: 1) to afford benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid.
LC-MS (ESI) m/z = 375 [M+H] .
Step 4: Preparation of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxymethyl)o xazolidinone (OBD-114): To a solution of benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (13.8 ml, 33.1 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (4.7 g, 33.1 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxymethyl)o xazolidinone (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-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (7): 4-methylbenzenesulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxymethyl)o xazolidinone (OBD-114) (4.5 g, 13.3 mmol) and Et N (2.7 g, 26.6 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (7) (5.58 g, 85%) as a white solid.
LC-MS (ESI) m/z = 495 [M+H] .
Step 6: Preparation of -((1H-1,2,3-triazolyl)methyl)(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-di fluorophenyl)oxazolidinone (OBD-054): To a solution of (3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (7) (300 mg, 0.6 mmol) and 1H-1,2,3-triazole (42 mg, 0.6 mmol) in DMF (10 mL) was added K CO (166 mg, 1.2 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford -((1H-1,2,3-triazolyl)methyl)(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-di fluorophenyl)oxazolidinone (OBD-054) (82 mg, 35%) as a white solid.
H NMR (300 MHz, DMSO-d ) d 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 = .7 Hz, 3H), 2.07 – 1.61 (m, 7H).
LC-MS (ESI) m/z = 392 [M+H] .
NaN , K CO 3 2 3 DMF N O CH OH NH O 3 3 F step 2 step 1 F OBD-115 HOBT , EDCI ,DCM step 3 R = O O O O O OBD-048 OBD-049 OBD-252 OBD-253 OBD-254 Step 1: Preparation of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethyl)oxa zolidinone (8): To a solution of (3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidin yl)methyl 4-methylbenzenesulfonate (7) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 mL) was added K CO (2.2 mg, 16 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethyl)oxa zolidinone (8) (2.57 g, 88%) as a white solid.
LC-MS (ESI) m/z = 366 [M+H] .
Step 2: Preparation of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminomethyl)ox azolidinone (OBD-115): To a solution of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethyl)oxa zolidinone (8) (2.57 g, 7 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminomethyl)ox azolidinone (OBD-115) (2.1 g, 85 %) as a white solid.
H NMR (400 MHz, CDCl ) d 7.40 – 7.20 (m, 2H), 4.62 (td, J = 10.9, 4.9 Hz, 1H), 4.28 (s, 2H), 4.02 (t, J = 8.9 Hz, 1H), 3.81 (dd, J = 8.9, 6.3 Hz, 1H), 3.27 (d, J = 10.4 Hz, 2H), 2.81 (ddd, J = 28.3, 18.6, 7.7 Hz, 4H), 2.21 (s, 2H), 2.04 – 1.94 (m, 2H), 1.88 – 1.71 (m, 2H).
LC-MS (ESI) m/z = 340 [M+H] .
Step 3: Preparation of (OBD-048, 049, 252, 253, 254): To a solution of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminomethyl)ox azolidinone (OBD-115) (200 mg, 0.59 mmol) and R-OH (0.59 mmol) in DCM (10 mL) were added HOBt (119 mg, 0.88 mmol), EDCI (225 mg, 1.18 mmol) and DIPEA (152 mg, 1.18 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-048, 049, 252, 253, 254) as a white solid.
OBD-048 H NMR (300 MHz, CDCl ) d 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 = .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 H NMR (301 MHz, CDCl ) d 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, LC-MS (ESI) m/z = 397.7 [M+H] .
OBD-252 H NMR (301 MHz, CDCl ) d 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 H NMR (301 MHz, CDCl ) d 7.07 (d, J = 11.0 Hz, 2H), 5.88 (s, 1H), 4.76 (s, 1H), 4.34 (s,2H), 3.98 (t, J = 9.0 Hz, 1H), 3.79 – 3.59 (m, 3H), 3.45 (d, J = 10.8 Hz, 2H), 3.12 – 2.97 (m, 1H), 2.79 (d, J = 11.3 Hz, 2H), 2.38 – 2.10 (m, 6H), 2.00 – 1.79 (m, LC-MS (ESI) m/z = 422.1 [M+H] .
OBD-254 H NMR (301 MHz, CDCl ) d 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] .
DIPEA Pd/C, H + F NO O CH CN, rt CH OH/EA O F step 1 3 step 2 Cbz-Osu step 3 TsCl, Et N O N N O N N N NH CH Cl , rt O O 2 2 THF, n-BuLi step 5 OBD-112 step 4 NaN , K CO 3 2 3 step 6 N N R OH N N H 3 NH N O CH OH 3 2 O HOBT , EDCI ,DCM step 7 F 8 OBD-113 R = O OBD-110 OBD-111 Step 1: Preparation of 3-(2-fluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane To a solution of 8-oxaaza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2-difluoronitrobenzene (7.7 g, 48.6 mmol) in DMF (10 mL) was added K CO (12.2 g, 88.4 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 5: 1) to afford 3-(2-fluoronitrophenyl)oxaaza-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-oxaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (4): To a solution of 3-(2-fluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane (3) (3) (9.1 g, 36.2 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (4) (7.3 g, 91%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 223 [M+H] .
Step 3: Preparation of benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenylcarbamate (5): Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (16.4 g, 65.88 mmol) was added to a suspension of 4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorobenzenamine (4) (7.3 g, 32.9 mmol) in THF (100 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 10: 1) to afford benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)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-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(hydroxymethyl)oxaz olidinone (OBD-112): To a solution of benzyl 4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenylcarbamate (5) (7.1 g, 20.1 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (12.5 ml, 30.1 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (4.3 g, 30.1 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(hydroxymethyl)oxaz olidinone (OBD-112) (3.9 g, 60%) as a white solid.
H NMR (301 MHz, DMSO-d ) d 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-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidinyl) methyl 4-methylbenzenesulfonate (7): 4-methylbenzenesulfonyl chloride (2.3 g, 24 mmol) was added to a suspension of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(hydroxymethyl)oxaz olidinone (OBD-112) (3.9 g, 12 mmol) and Et N (1.2 g, 24 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidinyl) methyl 4-methylbenzenesulfonate (7) (4.86 g, 85%) as a white solid.
LC-MS (ESI) m/z = 477 [M+H] .
Step 6: Preparation of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(azidomethyl)oxazoli dinone (8): To a solution of (3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)oxooxazolidinyl) methyl 4-methylbenzenesulfonate (7) (4.86 g, 10.2 mmol) and sodium azide (663 mg, .2 mmol) in DMF (10 mL) was added K CO (1.4 g, 20.4 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(azidomethyl)oxazoli dinone (8) (2.97 g, 84%) as a white solid.
LC-MS (ESI) m/z = 348 [M+H] .
Step 7: Preparation of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)oxazol idinone (OBD-113): To a solution of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(azidomethyl)oxazoli dinone (8) (2.97 g, 8.5 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)oxazol idinone (OBD-113) (2.2 g, 81 %) as a white solid.
H NMR (301 MHz, CDCl ) d 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] .
Step 8: Preparation of (OBD-110, 111): To a solution of 3-(4-(8-oxaaza-bicyclo[3.2.1]octanyl)fluorophenyl)(aminomethyl)oxazol idinone (OBD-113) (200 mg, 0.62 mmol) and R-OH (0.62 mmol) in DCM (10 mL) were added HOBt (126 mg, 0.96 mmol), EDCI (237 mg, 1.24 mmol) and DIPEA (160 mg, 1.24 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-110, 111) as a white solid.
OBD-110 H NMR (301 MHz, CDCl ) d 7.51 – 7.32 (m, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 9.1 Hz, 1H), 6.07 (s, 1H), 4.74 (s, 1H), 4.39 (s, 2H), 4.00 (t, J = 8.9 Hz, 1H), 3.85 – 3.49 (m, 3H), 3.05 (dd, J = 23.2, 10.6 Hz, 4H), 2.32 – 1.67 (m, 8H).
LC-MS (ESI) m/z = 426 [M+H] .
OBD-111 H NMR (301 MHz, CDCl ) d 7.41 (s, 1H), 7.03 (s, 1H), 6.17 (s, 0H), 5.20 – 5.02 (m, 1H), 4.85 – 4.62 (m, 1H), 4.41 (s, 1H), 4.01 (s, 1H), 3.68 (s, 3H), 3.09 (d, J = 7.9 Hz, 2H), 2.05 (d, J = 42.7 Hz, 3H), 1.83 – 1.35 (m, 3H).
LC-MS (ESI) m/z = 397.7 [M+H] .
O O Pd/C, H F NO N 2 NH 2 N NO CH OH DIPEA CH CN rt 3 F step 1 step 2 Cbz-Osu step 3 O O Cbz N N N N N N Et N OH H OTs 3 157 THF, n-BuLi step 4 step 5 K CO DMF step 6 OBD-051 Step 1: Preparation of 8-(2,6-difluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane (3): To a solution of 3-oxaaza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoronitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL) was added K CO (12.2 g, 88.4 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 8-(2,6-difluoronitrophenyl)oxaaza-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-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4): To a solution of 3-(2,6-difluoronitrophenyl)oxaaza-bicyclo[3.2.1]octane (3) (9.3 g, 34.4 mmol) and Palladium carbon (1 g) in MeOH (15 mL), then under a hydrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. The filtrate was concentrated under reduced pressure to afford 4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4) (7.8 g, 95%) as a white oil, and the crude material was used for next reaction without further purification.
LC-MS (ESI) m/z = 241 [M+H] .
Step 3: Preparation of benzyl 4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5): Carbonic acid, 2,5-dioxopyrrolidinyl phenylmethyl ester (12 g, 48.7 mmol) was added to a suspension of 4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorobenzenamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at 50°C for 5 h, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 10: 1) to afford benzyl 4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5) (8.2 g, 68%) as a white solid.
LC-MS (ESI) m/z = 375 [M+H] .
Step 4: Preparation of (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxyme thyl)oxazolidinone (6): To a solution of benzyl 4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF (10 mL) at – 78 °C under a nitrogen gas atmosphere was added n-BuLi (13.8 ml, 33.1 mmol), then the mixture was stirred at -78°C for 30 min, after that the solution of (R)-oxiranylmethyl butyrate (4.7 g, 33.1 mmol) in THF was added to the mixture at -78°C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxyme thyl)oxazolidinone (6) (4.5 g, 60%) as a white solid.
LC-MS (ESI) m/z = 341 [M+H] .
Step 5: Preparation of ((R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)methyl 4-methylbenzenesulfonate (7): 4-methylbenzenesulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(hydroxyme thyl)oxazolidinone (6) (4.5 g, 13.3 mmol) and Et N (2.7 g, 26.6 mmol) in DCM (10 mL) at 0 °C under a nitrogen gas atmosphere and the reaction mixture was stirred at room temperature for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford ((R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)methyl 4-methylbenzenesulfonate (7) (5.58 g, 85%) as a white solid.
LC-MS (ESI) m/z = 495 [M+H] .
Step 6: Preparation of (5R)((1H-1,2,3-triazolyl)methyl)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)- 3,5-difluorophenyl)oxazolidinone (OBD-055): To a solution of ((R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)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 CO (166 mg, 1.2 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by prep-HPLC to afford (5R)((1H-1,2,3-triazolyl)methyl)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)- 3,5-difluorophenyl)oxazolidinone (OBD-055) (82 mg, 35%) as a white solid.
H NMR (301 MHz, CDCl ) d 7.76 (d, J = 5.7 Hz, 2H), 6.94 (d, J = 12.1 Hz, 2H), .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] .
F O O O Pd/C H2 NaN , K CO 3 2 3 O N N N DMF N step 2 step 1 step 3 HOBT , EDCI ,DCM N N H R = O OBD-051 OBD-052 Step 1: Preparation of (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (8): To a solution of ((R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)oxooxazolidi nyl)methyl 4-methylbenzenesulfonate (7) (4 g, 8 mmol) and sodium azide (526 mg, 8 mmol) in DMF (10 mL) was added K CO (2.2 g, 16 mmol) at 25°C, then the reaction mixture was stirred at 80°C for 1 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (PE: EA = 2: 1) to afford (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (8) (2.4 g, 82%) as a white solid.
LC-MS (ESI) m/z = 366 [M+H] .
Step 2: Preparation of (5S)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (9): To a solution of (5R)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(azidomethy l)oxazolidinone (8) (2.4 g, 6.5 mmol) in MeOH (10 mL) was added palladium carbon (300 mg) at 25°C, then the reaction mixture was stirred at room temperature for overnight under a hydrogen gas atmosphere, monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to afford (5S)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (9) (1.9 g, 86 %) as a white solid.
LC-MS (ESI) m/z = 340 [M+H] .
Step 3: Preparation of (OBD-051, 052): To a solution of (5S)(4-(3-oxaaza-bicyclo[3.2.1]octanyl)-3,5-difluorophenyl)(aminometh yl)oxazolidinone (9) (200 mg, 0.59 mmol) and R-OH (0.59 mmol) in DCM (10 mL) were added HOBt (119 mg, 0.88 mmol), EDCI (224 mg, 1.18 mmol) and DIPEA (152 mg, 1.18 mmol) at 25 °C, then the reaction mixture was stirred at 25 °C for 2 h under a nitrogen gas atmosphere, monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to afford (OBD-051, 052) as a white solid.
OBD-051 H NMR (301 MHz, CDCl ) d 6.99 (t, J = 9.3 Hz, 2H), 5.38 (s, 1H), 4.84 – 4.69 (m, 1H), 3.98 – 3.86 (m, 4H), 3.75 – 3.60 (m, 4H), 2.24 – 1.97 (m, 8H).
LC-MS (ESI) m/z = 381.9 [M+H] .
OBD-052 H NMR (301 MHz, CDCl ) d 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 Additional Embodiments of the Invention In a manner similar to those disclosed in Examples 8 and 12 above, the following compounds were made: OTB-518 Methyl (((5S)(3-fluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)phenyl)- 2-oxooxazolidinyl) methyl)carbamate 1H-NMR (400 MHz, CDCl3) d: 7.45 (d, J = 16.4 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 5.17-5.12 (m, 1 H), 4.80-4.74 (m, 1 H), 4.62 (brs, 2 H), 4.02 (t, J = 8.4 Hz, 1 H), 3.77 (t, J = 8.0 Hz, 1 H), 3.69-3.53 (m, 4 H), 3.45 (d, J = 10.4 Hz, 2 H), 2.86 (d, J = 12.0 Hz, 2 H), 2.22 (m, 2 H), 1.90-1.88 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H FN O S: 412.1344; found: 412.1359 18 23 3 5 OTB-519 Methyl (((5S)(3,5-difluoro((1R,5S)oxidothiaazabicyclo[3.2.1]octanyl)phenyl)- 2-oxooxazolidinyl) methyl)carbamate 1H-NMR (400 MHz, CDCl3) d: 7.13 (d, J = 12.4 Hz, 2 H), 5.10 (m, 1 H), 4.80-4.74 (m, 1 H), 4.46 (brs, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.76-3.69 (m, 4 H), 3.60-3.49 (m, 3 H), 2.94 (d, J = 12.0 Hz, 2 H), 2.20-2.18 (m, 2 H), 1.87-1.85 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H F N O S: 430.1248; found: 430.1259 18 22 2 3 5 OTB-517 (5R)((1H-1,2,3-Triazolyl)methyl)(3,5-difluoro((1R,5S)oxidothiaazabicyclo[3.2.1] octanyl)phenyl)oxazolidinone 1H-NMR (400 MHz, CDCl3) d: 7.79 (s, 1 H), 7.77 (s, 1 H), 6.98 (d, J = 12.0 Hz, 2 H), 5.10-5.04 (m, 1 H), 4.79 (d, J = 4.0 Hz, 2 H), 4.43 (brs, 2 H), 4.10 (t, J = 9.2 Hz, 1 H), 3.91-3.87 (m, 1 H), 3.55 (d, J = 12.4 Hz, 2 H), 2.92 (d, J = 10.4 Hz, 2 H), 2.19-2.16 (m, 2 H), 1.88-1.83 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H F N O S: 424.1249; found: 424.1271 18 20 2 5 3 OTB-523 (S)-N-((3-(3-Fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)acetamide 1H-NMR (400 MHz, CDCl3) d: 7.34 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.41 (t, J = 8.8 Hz, 1 H), 6.12 (t, J = 6.0 Hz, 1 H), 4.76-4.73 (m, 1 H), 4.01-3.90 (m, 7 H), 3.74-3.66 (m, 2 H), 3.62-3.56 (m, 1 H), 3.45-3.40 (m, 2 H), 2.02 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H21FN3O4S: 382.1237; found: 382.1217 OTB-515 (S)-N-((3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)acetamide HNMR (400 MHz, CDCl3) ?: 7.03-6.94 (m, 2 H), 6.09 (t, J = 5.6 Hz, 1 H), 4.75 (q, J = 3.2 Hz, J = 2.8 Hz, 1 H), 4.16 (s, 4 H), 3.95 (t, J = 8.8 Hz, 1 H), 3.72-3.61 (m, 3 H), 3.40 (s, 4 H), 2.03 (s, 3 H). m/z [M + Na]+ calcd for C H F N O S:383.1115; found: 384.0 17 19 2 3 3 OTB-248 (S)-Methyl ((3-(3-fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl)methyl)carbamate HNMR (400 MHz, CDCl3) ?: 7.33 (q, J = 2.0 Hz, J = 11.6 Hz, 2 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.44 (t, J = 9.2 Hz, 1 H), 5.15 (bs, 1 H), 4.77-4.73 (m, 1 H), 4.01-3.97 (m, 4 H), 3.76-3.52 (m, 6 H), 3.42 (s, 4 H). m/z [M + Na]+ calcd for C H FN O S:381.1159; found: 404.1 17 20 3 4 OTB-256 (S)-Methyl ((3-(3-fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)carbamate 1H-NMR (400 MHz, CDCl3) d: 7.51 (d, J = 14.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.80 (t, J = 8.8 Hz, 1 H), 5.09 (brs, 1 H), 4.76 (brs, 1 H), 4.16 (d, J = 13.2 Hz, 4 H), 4.01-3.98 (m, 3 H), 3.77–3.75 (m, 1 H), 3.69 (s, 3 H), 3.61-3.55 (m, 2 H), 3.46-3.44 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H FN O S: 398.1186; found: 398.1166 17 21 3 5 OTB-247 (R)((1H-1,2,3-Triazolyl)methyl)(3-fluoro(2-oxidothiaazaspiro[3.3]heptanyl) phenyl)oxazolidinone HNMR(400 MHz, CDCl3) ?: 7.78 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 13.6, 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 1.6 Hz, 1H), 6.37 (t, J = 9.2 Hz, 1H), 5.04 - 5.00 (m, 1H), 4.77 (d, J = 3.6 Hz, 2H), 4.08 (t, J = 9.2 Hz, 1H), 3.96 (dd, J = 10.4, 1.6 Hz, 4H), 3.92 - 3.89 (m, 3H), 3.42 - 3.39 (m, 2H). m/z [M + H]+ calcd for C H FN O S: 391.1114; found: 392.0 17 18 5 3 OTB-249 (S)-N-((3-(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) d: 7.33 (d, J = 14.0 Hz, 1 H), 6.99 (d, J = 8.8 Hz, 1 H), 6.47 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.73 (m, 1 H), 3.98-3.95 (m, 5 H), 3.73-3.66 (m, 3 H), 3.42 (s, 4 H), 1.39-1.37 (m, 1 H), 0.97-0.91 (m, 2 H), 0.78-0.76 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H FN O S: 392.1444; found: 392.1426 19 23 3 3 OTB-255 (S)-N-((3-(3-Fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) d: 7.35 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.44 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.74 (m, 1 H), 4.00-3.91 (m, 7 H), 3.75-3.62 (m, 3 H), 3.47-3.41 (m, 2 H), 1.38-1.37 (m, 1 H), 0.97-0.92 (m, 2 H), 0.78-0.76 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H23FN3O4S: 408.1393; found: 408.1378 OTB-250 (S)-N-((3-(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)cyclobutanecarboxamide HNMR (400 MHz, CDCl3) ?: 7.76 (d, J = 8.8 Hz, 2 H), 6.92-6.83 (m, 2 H), 5.04 (m, 1 H), 4.78 (q, J = 0.8 Hz, J = 3.2 Hz 2 H), 4.15 (t, J = 2.4 Hz, 4 H), 3.85 (t, J = 6.0 Hz, 1 H), 3.72-3.63 (m, 3 H), 3.40 (s, 4 H), 3.05-2.99 (m, 1 H), 2.24-2.13 (m, 4 H), 1.97-1.60 (m ,2 H). m/z [M + Na]+ calcd for C H FN O S: 405.1522; found: 428.2 24 3 3 OTB-254 (S)-N-((3-(3-fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)cyclobutanecarboxamide 1H-NMR (400 MHz, CDCl3) d: 7.36 (d, J = 14.4 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.47 (t, J = 9.2 Hz, 1 H), 5.80 (brs, 1 H), 4.73 (brs, 1 H), 4.00 (d, J = 12.0 Hz, 4 H), 3.95-3.92 (m, 3 H), 3.76-3.72 (m, 1 H), 3.65-3.62 (m, 2 H), 3.47-3.41 (m, 2 H), 3.02-2.96 (m, 1 H), 2.26-2.13 (m, 4 H), 1.98-1.84 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C H FN O S: 422.1549; found: 422.1531 25 3 4 OTB2A (R)-N-((3-(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl)methyl) methanesulfonamide HNMR (400 MHz, CDCl3) ?: 7.04 - 6.95 (m, 2H), 5.05 (s, 1H), 4.80 - 4.77 (m, 1H), 4.15 (t, J = 2.4 Hz, 4H), 3.97 (t, J = 8.8 Hz, 1H), 3.86 (dd, J = 6.4, 8.8 Hz, 1H), 3.56 (dd, J = 3.6, 14.4 Hz, 1H), 3.43 - 3.39 (m, 5H), 3.01 (s, 3H). m/z [M + H]+ calcd for C H FN O S : 401.0879; found: 402.1 16 20 3 4 2 OTB2B (R)-N-((3-(3-Fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl)methanesulfonamide HNMR (400 MHz, CDCl ) ?: 7.32 (dd, J = 14.0, 2.4 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.41 (t, J = 9.6 Hz, 1H), 4.86 - 4.77 (m, 2H), 4.04 - 3.95 (m, 8H), 3.93 (dd, J = 9.6, 3.2 Hz, 1H), 3.43 - 3.40 (m, 3H), 3.02 (s, m/z [M + H]+ calcd for C H FN O S : 417.0828; found: 418.0 16 20 3 5 2 OTB5A (R)((2H-1,2,3-Triazolyl)methyl)(3-fluoro(2-thiaazaspiro[3.3]heptanyl) phenyl)oxazolidinone HNMR (400 MHz, CDCl ) ?: 7.64 (s, 2H), 7.24 - 7.21 (m, 1H), 6.99 (dd, J = 8.8, 1.6 Hz, 1H), 6.41 (t, J = 9.6 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.87 - 4.82 (m, 1H), 4.75 - 4.72 (m, 1H), 4.05 - 4.01 (m, 1H), 3.96 - 3.93 (m, 5H), 3.40 (s, 4H). m/z [M + H]+ calcd for C H FN O S: 375.1165; found: 376.1 17 18 5 2 OTB5B (R)((2H-1,2,3-Triazolyl)methyl)(3-fluoro(2-oxidothiaazaspiro[3.3]heptanyl) phenyl)oxazolidinone HNMR (400 MHz, CDCl ) ?: 7.64 (s, 2H), 7.27 - 7.23 (m, 1H), 6.99 (dd, J = 8.8, 2.0 Hz, 1H), 6.39 (t, J = 9.2 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.87 - 4.82 (m, 1H), 4.76 - 4.70 (m, 1H), 4.06 - 4.03 (m, 1H), 3.98 - 3.90 (m, 7H), 3.43 - 3.40 (m, 2H). m/z [M + H]+ calcd for C H FN O S: 391.1114; found: 392.1 17 18 5 3 OTB4A (R)-(3-(3-Fluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl)methyl methylcarbamate HNMR (400 MHz, CDCl ) ?: 7.33 (dd, J = 2.4, 13.6 Hz, 1H), 7.04 (dd, J = 1.6, 8.4 Hz, 1H), 6.44 (t, J = 9.2 Hz, 1H), 4.88 - 4.72 (m, 2H), 4.33 (t, J = 4.0 Hz, 2H), 4.02 (t, J = 9.2 Hz, 1H), 3.97 (d, J = 1.6 Hz, 4H), 3.77 (dd, J = 6.4, 8.8 Hz, 1H), 3.42 (s, 4H), 2.80 (d, J = 4.8 Hz, 3H). m/z [M + H]+ calcd for C H FN O S: 381.1159; found: 382.0 17 20 3 4 OTB4B (R)-(3-(3-Fluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl)methyl methylcarbamate HNMR (400 MHz, CDCl ) ?: 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]+ calcd for C H FN O S: 397.1108; found: 398.0 17 20 3 5 OTB-520 (S)-N-((3-(3,5-Difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)acetamide 1H-NMR (400 MHz, CDCl3) d: 7.02 (d, J = 12.0 Hz, 2 H), 5.92 (brs, 1 H), 4.75-4.74 (m, 1 H), 4.16 (d, J = 12.0 Hz, 4 H), 3.97-3.90 (m, 2 H), 3.72-3.65 (m, 4 H), 3.41-3.37 (m, 2 H), 2.02 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C H F N O S: 400.1143; found: 400.1158 17 20 2 3 4 OTB-253 (S)-Methyl ((3-(3,5-difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)carbamate 1H-NMR (400 MHz, CDCl3) d: 7.00 (d, J = 10.8 Hz, 2H), 5.36 (m, 1H), 4.72 (m, 1H), 4.14 (d, J = 12.0 Hz, 4H), 3.92 (m, 3H), 3.69 (m, 1H), 3.67 (s, 3H), 3.52 (m, 2H), 3.39 (d, J = 12.4 Hz, 2H).
HRMS (ESI) calcd for C H F N O S [M+H]+ 416.1086, found: 416.1073 17 20 2 3 5 OTB-522 HNMR (400 MHz, CDCl ) ?: 7.75 (d, J = 8.0 Hz, 2H), 6.92 - 6.83 (m, 2H), 5.05 - 5.01 (m, 1H), 4.77 (d, J = 4.0 Hz, 2H), 4.15 (dt, J = 11.6, 2.4 Hz, 4H), 4.05 (t, J = 9.2 Hz, 1H), 3.92 - 3.89 (m, 3H), 3.40 - 3.37 (m, 2H). m/z [M + H]+ calcd for C H F N O S: 409.1020; found: 410.1 17 17 2 5 3 OTB-252 (S)-N-((3-(3,5-Difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) d: 6.98 (d, J = 11.6 Hz, 2H), 6.60 (m, 1H), 4.73 (m, 1H), 4.13 (d, J = 12.4 Hz, 4H), 3.91 (m, 3H), 3.70 (m, 1H), 3.64 (m, 2H), 3.79 (d, J = 10.4 Hz, 2H),1.41 (m, 1H), 0.94 (m, 1H), 0.87 (m, 1H), 0.74 (m, 2H) HRMS (ESI) calcd for C H F N O S [M+H]+ 426.1294, found: 426.1278 19 22 2 3 4 OTB-251 (S)-N-((3-(3,5-Difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)cyclobutanecarboxamide 1H-NMR (400 MHz, CDCl3) d: 6.99 (d, J = 10.4 Hz, 2H), 6.06 (m, 1H), 4.74 (m, 1H), 4.14 (d, J = 12.4 Hz, 4H), 3.93 (m, 3H), 3.70 (m, 1H), 3.62 (m, 2H), 3.38 (d, J = 12.4 Hz, 2H), 3.00 (m, 1H), 2.21 (m, 1H), 2.11 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H) HRMS (ESI) calcd for C H F N O S [M+H]+ 440.1450, found: 440.1441 24 2 3 4 OTB2A (R)-N-((3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)methanesulfonamide HNMR (400 MHz, CDCl3) ?: 7.04 - 6.95 (m, 2H), 5.05 (s, 1H), 4.80 - 4.77 (m, 1H), 4.15 (t, J = 2.4 Hz, 4H), 3.97 (t, J = 8.8 Hz, 1H), 3.86 (dd, J = 6.4, 8.8 Hz, 1H), 3.56 (dd, J = 3.6, 14.4 Hz, 1H), 3.43 - 3.39 (m, 5H), 3.01 (s, 3H). m/z [M + H]+ calcd for C H F N O S : 419.0785; found: 420.1 16 19 2 3 4 2 OTB2B (R)-N-((3-(3,5-Difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)- 2-oxooxazolidinyl)methyl)methanesulfonamide HNMR (400 MHz, CDCl3) ?: 7.03 - 7.00 (m, 2H), 4.81 - 4.78 (m, 2H), 4.18 - 4.14 (m, 4H), 3.98 - 3.93 (m, 1H), 3.91 - 3.85 (m, 3H), 3.60-3.41 (m, 4H), 3.40 - 3.37 (m, 3H), 3.02 (s,3H). m/z [M + H]+ calcd for C H F N O S : 435.0734; found: 436.0 16 19 2 3 5 2 OTB4A (R)-(3-(3,5-Difluoro(2-thiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl)methyl methylcarbamate HNMR (400 MHz, CDCl ) ?: 7.08 - 6.91 (m, 2H), 4.91 - 4.70 (m, 2H), 4.38 - 4.28 (m, 2H), 4.16 (t, J = 2.4 Hz, 4H), 3.98 (t, J = 9.2 Hz, 1H), 3.74 (dd, J = 6.4, 8.8 Hz, 1H), 3.43 - 3.37 (m, 4H), 2.81 (d, J = 4.8 Hz, 3H). m/z [M + H]+ calcd for C H F N O S: 399.1064; found: 400.1 17 19 2 3 4 OTB4B (R)-(3-(3,5-Difluoro(2-oxidothiaazaspiro[3.3]heptanyl)phenyl)oxooxazolidinyl) methyl methylcarbamate HNMR (400 MHz, CDCl ) ?: 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, m/z [M + H]+ calcd for C H F N O S: 415.1013; found: 416.0 17 19 2 3 5 OTB-204 (R)((1H-1,2,3-tTriazolyl)methyl)(3-fluoro(2-oxaazaspiro[3.3]heptan-6 -yl)phenyl)oxazolidinone 1H-NMR (400 MHz, CDCl3) d: 7.65 (s, 2 H), 7.31 (d, J = 14.4, 2.4 Hz,1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.59 (t, J = 9.2 Hz, 1 H), 5.14-5.07 (m, 1 H), 4.88-4.83 (m, 5H), 4.77-4.71 (m, 1 H), 4.16 (s, 4 H), 4.07-4.02 (m, 1 H), 3.98-3.92 (m, 1 H) HRMS (ESI): m/z [M + H]+calcd for C H FN O : 360.1472; found: 360.1451 17 19 5 3 The invention will be further described, without limitation, by the following numbered paragraphs: 1. A compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate of: wherein: R is independently OR , OC(O)R , OC(O)NHR , OS(O )R , NHS(O) R , NR R , 1 2 2 2 2 2 2 3 4 NHC(O)R ; R’ and R’’ are independently H, F, Cl or OMe; each R is independently H, C -C alkyl, C -C cycloalkyl, wherein said alkyl, 1 1 6 3 8 cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C -C alkyl, C -C alkyloxy; 1 6 1 6 each R is independently C -C alkyl, C -C cycloalkyl, heterocyclyl, heteroaryl or 2 1 6 3 8 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 each R and R is independently H, C -C alkyl, C -C cycloalkyl, heterocyclyl 3 4 1 6 3 8 heteroaryl, aryl; or R and R taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C -C alkyl, C -C alkoxy, CF , NO , CN; 1 6 1 6 3 2 each R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, heteroaryl, 1 6 3 8 1 6 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 Ring A is selected from: (CH ) (CH ) , , and wherein, each R and R is independently H, F, CH , CH CH , CF , phenyl; 6 7 3 2 3 3 X = O, S, SO, SO ; Y = O, S, SO, SO , and NR ; m is 1, or 2; n is 1, or 2; p is 1, or 2; q is 1, or 2; R in independently H, C -C alkyl, C -C cycloalkyl, COCH , and p-toluenesulfonyl, 8 1 4 3 6 3 wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C alkoxy, C -C acyloxy, CF , NO , CN and 1 6 1 6 1 6 3 2 2. The compound of paragraph 1, wherein the compound is represented by Formula wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, phenyl; or R and R 3 4 1 6 3 6 3 4 taken together with the nitrogen to which they are attached to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 1 6 3 6 1 6 heteroaryl or phenyl; R and R is independently H, F, CH , CH CH , CF ; 6 7 3 2 3 3 X = O, S, SO, SO ; when X = S, SO, SO , R’ = H, R’’ = F, R can not be CH ; 2 2 5 3 3. The compound of paragraph 1, wherein the compound is represented by Formula 7 R'' wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, or phenyl; or R and R 3 4 1 6 3 6 3 4 taken together with the nitrogen to which they are attached to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 1 6 3 6 1 6 heteroaryl or phenyl; R and R is independently H, F, CH , CH CH , CF ; 6 7 3 2 3 3 X = O, S, SO, SO ; 4. The compound of paragraph 1, wherein the compound is represented by Formula wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO .
. The compound of paragraph 1, wherein the compound is represented by Formula wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO . 6. The compound of paragraph 1, wherein the compound is represented by Formula 7. The compound of paragraph 6, wherein the compound is represented by Formula VII, Formula VIII, or Formula IX: X N N O N N wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO . 8. The compound of paragraph1, the compound is represented by Formula IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa, or IXb: R F O X N N X N N X N N O N N VIIIa O N N VIIIb wherein, R is independently OH, OCH , OCH CH , OC(O)CH , NH , NHCH , NHC H , 3 2 3 3 2 3 6 5 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, NHS(O) R , NHC(O)R ; 2 2 5 R is independently C -C alkyl; 2 1 6 R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, furan, thiophene or 1 6 3 6 1 6 phenyl; in Formula IIa, R can not be CH ; and X = O, S, SO, SO . 9. The compound of paragraph 1, wherein the compound is: OTB-107 S O N OTB-106 S O N OTB-109 N N H OTB-108 OTB-111 S O O N N H OTB-112 S O S N N H OTB-115 N N H OBD-005 N N H OTB-116 N N H O OTB-119 OTB-412 N N H OTB-413 N N H OTB-414 N N H OTB-407 OTB-410 N N H OTB-408 N N H OTB-409 N N H OTB-411 S O N OTB-126 OTB-127 S O O N N H OTB-137 S O N OTB-138 S O N OTB-140 OBD-006 N N H OBD-007 N N H OTB-110 OTB-113 S N N OTB-114 N N H OTB124 OTB-117 S N N H OTB-118 S N N H OTB-120 S N N H O OTB-121 N N H OBD-001 OBD-002 OBD-003 S N N H OBD-004 O S N N H OBD-008 S N N OBD-009 O S N N OBD-027 OBD-240 OBD-026 OBD-241 OTB-227 OTB-501 OBD-081 OBD-085 OTB-502 N N H OTB-503 OTB-504 OTB-505 OTB-236 N N H O OTB-237 N N H O OTB-518 OBD-016 N N H OBD-017 OBD-021 OBD-018 OTB-506 N N H OTB-507 N N H OTB-510 N N H OTB-514 OTB-512 N N H OTB-519 OTB-511 OTB-517 OTB-508 OTB-509 OTB-513 F O OBD-083 OBD-087 OBD-029 OBD-242 OTB-260 S N N OTB-261 S N N H OTB523 OTB-515 S N N H OTB-256 OTB-241 OTB-247 OTB-249 S N N H OTB-255 OTB-250 OTB-254 S N H OTB-260 OTB-260 OTB-260 OTB-260 OTB-260 OTB-260 OTB-516 OTB-515 N N H OTB-520 OTB-242 S N H OTB-253 OTB-245 S N N OTB-522 OTB-243 S N N H OTB-252 OTB-244 S N N H OTB-251 OTB-516 OTB-516 OTB-516 OTB-516 OTB-516 OTB-516 OTB-201 O N N OBD-057 OTB-202 O N N H OTB-203 OTB-204 OTB-205 N N H OTB-206 O N H OBD-056 OTB-222 O N H O OTB-223 O N N H OTB-238 O N N H OTB-239 O N N H OTB-229 O N N OBD-062 OTB-230 O N N H OTB-231 O N N H OTB-232 O N N H O OTB-233 O N H OTB-234 O N N OBD-061 OTB-240 F O O N N H OBD-051 OBD-052 OBD-055 OBD-112 OBD-113 OBD-110 OBD-111 OBD-114 OBD-115 OBD-048 OBD-049 OBD-252 OBD-253 OBD-054 OBD-254 . A pharmaceutical composition comprising at least one compound of Formula I, or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and/or additives. 11. The pharmaceutical compositions Formula I, or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective treatments. 12. A method of preventing and treating microbial infections in humans by administering a therapeutically effective amount of a compound of Formula I, or a salt, hydrate, or solvate thereof to a patient in need thereof. 13. The method of paragraph 12, wherein the microbial infection is caused by Mycobacterium tuberculosis.
* * * It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.

Claims (8)

WHAT IS CLAIMED IS:
1. A compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate of: wherein: R is independently OR , OC(O)R , OC(O)NHR , OS(O )R , NHS(O) R , NR R , 1 2 2 2 2 2 2 3 4 NHC(O)R ; R’ and R’’ are independently H, F, Cl or OMe; each R is independently H, C -C alkyl, C -C cycloalkyl, wherein said alkyl, 1 1 6 3 8 cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxy, C -C alkyl, C -C alkyloxy; 1 6 1 6 each R is independently C -C alkyl, C -C cycloalkyl, heterocyclyl, heteroaryl or 2 1 6 3 8 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 each R and R is independently H, C -C alkyl, C -C cycloalkyl, heterocyclyl 3 4 1 6 3 8 heteroaryl, aryl; or R and R taken together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, C -C alkyl, C -C alkoxy, CF , NO , CN; 1 6 1 6 3 2 each R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, heteroaryl, 5 1 6 3 8 1 6 aryl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C 1 6 1 6 alkoxy, C -C acyloxy, CF , NO , CN and NH ; 1 6 3 2 2 Ring A is selected from: (CH ) (CH ) , , and wherein, each R and R is independently H, F, CH , CH CH , CF , phenyl; 6 7 3 2 3 3 X = O, S, SO, SO ; Y = O, S, SO, and SO ; m is 2; n is 1, or 2; p is 1, or 2; q is 1, or 2; R in independently H, C -C alkyl, C -C cycloalkyl, COCH , and p-toluenesulfonyl, 8 1 4 3 6 3 wherein said alkyl, cycloalkyl are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C -C alkyl, C -C alkoxy, C -C acyloxy, CF , NO , CN and 1 6 1 6 1 6 3 2
2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula III: X N N wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, or phenyl; or R and R 3 4 1 6 3 6 3 4 taken together with the nitrogen to which they are attached to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 5 1 6 3 6 1 6 heteroaryl or phenyl; R and R is independently H, F, CH , CH CH , CF ; and 6 7 3 2 3 3 X = O, S, SO, SO .
3. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula IV: wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 5 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO .
4. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula V: wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 5 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO .
5. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula VI:
6. The compound of claim 5, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula VII, Formula VIII, or Formula IX: X N N O N N wherein, R is independently OR , OC(O)R , NR R , NHS(O) R , NHC(O)R ; 1 2 3 4 2 2 5 R’ and R’’ are independently H, or F; R is independently H, C -C alkyl, C -C cycloalkyl; 1 1 6 3 6 R is independently C -C alkyl, C -C cycloalkyl; 2 1 6 3 6 R and R is independently H, C -C alkyl, C -C cycloalkyl, 5- or 6-membered 3 4 1 6 3 6 heteroaryl or phenyl; or R and R taken together with the nitrogen to which they are attached, to form morpholine, thiamorpholine, piperazine and triazole; R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, 5- or 6-membered 5 1 6 3 6 1 6 heteroaryl or phenyl; and X = O, S, SO, SO .
7. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate of, wherein the compound is represented by Formula IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa, or IXb: X N N X N N O N N VIIIa O N N VIIIb wherein, R is independently OH, OCH , OCH CH , OC(O)CH , NH , NHCH , NHC H , 3 2 3 3 2 3 6 5 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, NHS(O) R , NHC(O)R ; 2 2 5 R is independently C -C alkyl; 2 1 6 R is independently C -C alkyl, C -C cycloalkyl, C -C alkoxy, furan, thiophene or 5 1 6 3 6 1 6 phenyl; in Formula IIa, R can not be CH ; and X = O, S, SO, SO .
8. A compound, wherein the compound is: OTB-107 S O N OTB-106 S O N OTB-109 N N H OTB-108 OTB-111 S O O N N H OTB-112 S O S N N H OTB-115 OBD-005 N N H OTB-116 N N H O OTB-119 OTB-412 N N H OTB-413 N N H OTB-414 N N H OTB-407 OTB-410 OTB-408 OTB-409 N N H OTB-411 S O N OTB-126 OTB-127 N N H OTB-137 S O N OTB-138 S O N OTB-140 OBD-006 N N H OBD-007 N N H OTB-110 OTB-113 S N N OTB-114 N N H OTB124 OTB-117 S N N H OTB-118 S N N H OTB-
NZ738702A 2016-07-15 Substituted phenyloxazolidinones for antimicrobial therapy NZ738702B2 (en)

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PCT/US2016/042486 WO2017015106A1 (en) 2015-07-17 2016-07-15 Substituted phenyloxazolidinones for antimicrobial therapy

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