RU2794494C2 - Oxazolidinone compounds and methods of their application as antibacterial agents - Google Patents

Abstract

FIELD: pharmaceutical compounds.

SUBSTANCE: invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R¹ is -CH₂N(R²)₂ or -CH₂NR²COOR³; in each occurrence R² is independently selected from H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl; E represents pyridine, where the specified pyridine is substituted by one or two fluorine atoms; A is fragment (a). The invention also relates to a pharmaceutical composition for the treatment of mycobacterial infection, the composition contains a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound of the invention is used to treat mycobacterial infection.

EFFECT: obtaining oxazolidinone compounds applicable for the treatment of mycobacterial infections.

9 cl, 1 tbl, 65 ex

,

Description

The field of technology to which the present invention relates

The present invention relates to novel oxazolidinone compounds useful in the treatment of bacterial infections, in particular mycobacterial infections. The present invention also relates to methods of using oxazolidinone compounds for the treatment of mycobacterial infections, such as those caused by Mycobacteria tuberculosis .

Background of the Invention

Mycobacterium is a genus of bacteria that is neither true Gram positive nor true Gram negative and includes the pathogens responsible for tuberculosis ( M. tuberculosis ) and leprosy ( M. leprae ). Tuberculosis (TB), in particular, despite the availability of anti-TB drugs such as isoniazid and rifampin, is considered one of the most deadly diseases in the world. According to the World Health Organization in 2012, there were 8.6 million new TB cases and 1.3 million TB deaths. See World TB Report 2013 published by the World Health Organization. Worsening the TB epidemic lies in the rising tide of multidrug-resistant strains and the deadly association with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than those who are HIV-negative, and TB causes the death of one in three people with HIV/AIDS worldwide. See, for example, Kaufmann et al. , Trends Microbiol . 1:2-5 (1993), and Bloom et al ., N. Engl. J. Med . 338: 677-678 (1998).

Mycobacteria other than M. tuberculosis are increasingly found in opportunistic infections that affect the AIDS patient. Organisms of the M. avium-intracellulare complex (MAC), especially serotypes four and eight, account for 68% of mycobacterial isolates from AIDS patients. A huge number of MACs (up to 1010 acid-fast bacilli per gram of tissue) are found, and hence the prognosis for an infected AIDS patient is poor.

Oxazolidinones constitute a class of compounds containing a 2-oxazolidone, a 5-membered ring containing nitrogen and oxygen, which are used as antimicrobial agents. Cm., e.g. WO2009157423. In general, oxazolidinones are known to be monoamine oxidase inhibitors and have activity against Gram-positive microorganisms. WO2006022794, Suzuki et al.,Med Chem. Lett.4:1074-1078 (2013), Yang et al.,J. Med. Chem. 58:6389-6409 (2015), Shawet al., Ann. N.Y. Acad. sci. 1241:48-70 (2011). Several oxazolidinone antibiotics have been approved or are in clinical trials for the treatment of Gram-positive bacterial infections, such as those caused by methicillin-resistantStaphylococcus aureus. Examples of oxazolidinone antibiotics include linezolid (Zyvox™, Pfizer Inc., New York, NY) and tedizolid (Sivextro™, Merck Sharp & Dohme Corp., Kenilworth, NJ). Tedizolid is used to treat acute bacterial infections of the skin and skin structures caused by particularly susceptible Gram-positive bacteria. Linezolid is indicated for the treatment of certain infections caused by susceptible gram-positive strains, including nosocomial pneumonia, complicated infections of the skin and skin structures, and community-acquired pneumonia. In addition, it is currently being tested in clinical trials for the treatment of multidrug resistant (MDR) and extensively drug resistant (XDR)Mycobacterium tuberculosis (Mtb). Leeet al.,N. Engl. J.Med 367:1508-18 (2012). Despite clinical efficacy in the treatment of these diseases, long-term use of linezolid has been associated with adverse events, including myelosuppression (including anemia and leukopenia) (Hickeyet al., Therapy 3(4):521-526 (2006), neuropathy and serotonin syndrome. It is believed that such adverse events are associated with inhibition of mitochondrial protein synthesis. Flanaganet al.,Antimicrobial Agents and Chemotherapy 59(1):178-185 (2015).

The development of oxazolidinone antibiotics that are safer than the approved oxazolidinones but at least as effective will be of great benefit to Mtb patients.

Brief description of the present invention

The present invention relates to certain novel oxazolidinone compounds having antibacterial activity. The compounds and their pharmaceutically acceptable salts may be useful, for example, in the treatment of bacterial infections, such as mycobacterial infections. More specifically, the present invention includes compounds of formula I or their pharmaceutically acceptable salts:

Where:

R ¹ is -CH ₂ N(R ² ) ₂ , -CH ₂ NR ² COR ³ , -CH ₂ NR ² COOR ³ , -CH ₂ NR ² CON(R ² ) ₂ , -CH ₂ NR ² CONR ² N (R ² ) ₂ , -CH ₂ NR ² SO ₂ R ³ , -CON(R ² ) ₂ , -C=NOR ³ , -CH ₂ OR ⁴ , -CH ₂ NR ² R ^{4 ,} or -CH ₂ R ⁶ ;

in each occurrence R ² is independently selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl, said C ₂ -C ₆ alkenyl and said C ₃ -C ₆ cycloalkyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl, said C ₂ -C ₆ alkenyl and said C ₃ -C ₆ cycloalkyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ⁴ is a 5- or 6-membered heterocycle which is optionally substituted with R ⁵ ;

R ⁵ is selected from H, halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl and C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl, said C ₃ -C ₆ alkenyl and said C ₃ - C ₆ cycloalkyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ⁶ is H, C ₁ -C ₆ alkyl or a 5-membered heterocycle, said 5-membered heterocycle being optionally substituted with up to two R ⁷ ;

R ⁷ is H, halogen, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl and said C ₃ -C ₆ cycloalkyl may optionally be substituted with one to four substituents independently selected from halo OCH ₃ , OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

E is a 6-membered aryl or a 5- or 6-membered heteroaryl containing one to three heteroatoms independently selected from S, O and N, said aryl and said heteroaryl being optionally substituted with up to four substituents independently selected from halogen -CN, -CF ₃ , -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHCOCH ₃ , -OCF ₃ , -OCHF ₂ , -OH, -O-(C ₁ -C ₆ ) alkyl, C ₁ - C ₆ alkyl and C ₃ -C ₆ cycloalkyl;

A is a heterocycle optionally substituted with up to four R ⁸ , or aryl substituted with up to four R ⁸ ;

in each occurrence R ⁸ is independently selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , =O, -CN , -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N( R ² ) ₂ , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl and benzyl are optionally substituted with F, -OCH ₃ , -OH, =O, NH ₂ , NHCH ₃ and N (CH ₃ ) ₂ up to four; And

in each occurrence R ⁹ is independently selected from H, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl.

The present invention also relates to a pharmaceutical composition for the treatment of a bacterial infection in a subject, in particular an M. tuberculosis infection, comprising an oxazolidinone compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

Compounds of formula (I) (also referred to herein as "oxazolidinone compounds") and their pharmaceutically acceptable salts may be useful, for example, for growth inhibitionMycobacterium tuberculosis and/or for the treatment or prevention of tuberculosis in a patient. Without being bound by any particular theory, it is believed that the use of the oxazolidinone compounds of the present invention for the treatment of tuberculosis is likely to cause less myelosuppression than known oxazolidinone compounds such as linezolid, since they are not associated with a high degree of inhibition of mitochondrial protein synthesis (see example 65) . In addition, the oxazolidinone compounds of the present invention are more selective than known oxazolidinone compounds with weaker Gram-positive antibacterial activity and high activity againstM. tuberculosis.

The present invention also relates to 1) methods of treating tuberculosis in a subject in need of such treatment, comprising administering to the subject an effective amount of an oxazolidinone compound; and 2) uses of the oxazolidinone compound for the treatment of tuberculosis.

Embodiments, sub-embodiments and features of the present invention are either described below or will be made apparent in the following description, examples and appended claims.

Detailed disclosure of the present invention

Oxazolidinones were originally developed for use in the treatment of Gram-positive bacterial infections, in particular methicillin-resistant S. aureus infections. As shown in the examples, in vitro testing of the oxazolidinone compounds of formula I demonstrated that such compounds are highly effective in inhibiting the growth of Mycobacteria tuberculosis , but do not show strong activity against Gram-positive bacteria. In addition, the oxazolidinone compounds of the present invention are not associated with a high degree of inhibition of mitochondrial protein synthesis. Thus, the compounds of formula I and their pharmaceutically acceptable salts are believed to be useful in the treatment of mycobacterial tuberculosis (Mtb) but do not cause the side effects such as myelosuppression associated with the oxazolidinone linezolid approved for the treatment of Gram-positive infections. Therefore, such compounds will have significant advantages over linezolid and analogues as therapeutic agents against Mtb.

Compounds of formula (I)

In one aspect, the present invention includes compounds of formula I:

and their pharmaceutically acceptable salts, where A, E and R ¹ are defined above for compounds of formula (I); wherein the compounds may be suitable for use in the treatment of bacterial infections, in particular mycobacterial infections.

The first embodiment of the present invention (Embodiment E1) relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is aryl optionally substituted with up to four R ⁸ ; and where all other variables are defined at the beginning (i.e., as defined in formula I in the summary of the present invention).

According to a sub-variant of the implementation of the embodiment of E1 A is a 5-membered aryl. According to a further sub-embodiment, A is a 6-membered aryl. In still further sub-embodiments, A is 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aryl.

The second embodiment (Embodiment E2) relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl, where 1 to 4 ring atoms are independently O, N, or S and the remaining ring atoms are carbon atoms, and all other variables are defined in the brief description of the present invention.

According to a sub-embodiment of the embodiment, E2 A is a 5-membered heteroaryl containing one heteroatom. In a further sub-embodiment, A is a 5-membered heteroaryl containing two heteroatoms. According to another sub-embodiment, A is a 5-membered heteroaryl containing three heteroatoms. According to another sub-embodiment, A is a 5-membered heteroaryl containing four heteroatoms. According to another sub-embodiment, A is a 6-membered heteroaryl containing one heteroatom. In a further sub-embodiment, A is a 6-membered heteroaryl containing two heteroatoms. According to another sub-embodiment, A is a 6-membered heteroaryl containing three heteroatoms. According to another sub-embodiment, A is a 6-membered heteroaryl containing four heteroatoms. According to still further sub-embodiments, A is a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heteroaryl containing one to four heteroatoms selected from N, O, and S.

A third embodiment (Embodiment E3) relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is a monocyclic saturated or partially unsaturated ring optionally substituted with up to four R ⁸ , where 1 to 4 ring atoms are independently O , N or S, and the remaining ring atoms are carbon atoms, and all other variables are defined in the summary of the present invention.

According to a sub-variant of the implementation of the option implementation of E3 A is a 5-membered monocyclic saturated or partially unsaturated ring containing one heteroatom. In a further sub-embodiment, A is a 5-membered monocyclic saturated or partially unsaturated ring containing two heteroatoms. According to another sub-embodiment, A is a 5-membered monocyclic saturated or partially unsaturated ring containing three heteroatoms. According to another sub-embodiment, A is a 5-membered monocyclic saturated or partially unsaturated ring containing four heteroatoms. According to another sub-embodiment, A is a 6-membered monocyclic saturated or partially unsaturated ring containing one heteroatom. In a further sub-embodiment, A is a 6-membered monocyclic saturated or partially unsaturated ring containing two heteroatoms. According to another sub-embodiment, A is a 6-membered monocyclic saturated or partially unsaturated ring containing three heteroatoms. According to another sub-embodiment, A is a 6-membered monocyclic saturated or partially unsaturated ring containing four heteroatoms.

A fourth embodiment (Embodiment E4) relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is a bicyclic saturated or partially unsaturated ring system optionally substituted with up to four R ⁸ , wherein 1 to 4 ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms, and all other variables are defined in the summary of the present invention.

According to a sub-variant of implementation of the embodiment E4 A is a bicyclic saturated or partially unsaturated ring system containing one heteroatom. In a further sub-embodiment, A is a bicyclic saturated or partially unsaturated ring system containing two heteroatoms. According to another sub-embodiment, A is a bicyclic saturated or partially unsaturated ring system containing three heteroatoms. According to another sub-embodiment A is a bicyclic saturated or partially unsaturated ring system containing four heteroatoms.

In Embodiments E1-E4 and sub-embodiments of Embodiments E1-E4, A is optionally substituted with up to four R ⁸ substituents. According to the sub-embodiments of embodiments E1-E4 and their previous sub-embodiments, A is substituted with four R ⁸ substituents as defined at the beginning. In another sub-embodiment, A is substituted with three R ⁸ substituents. In a further sub-embodiment, A is substituted with two R ⁸ substituents. In yet another further sub-embodiment, A is substituted with one R ⁸ substituent. According to alternative embodiments of embodiments E1-E4, A is unsubstituted.

The fifth embodiment (Embodiment E5) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

where R ⁸ represents up to four optional substituents, which may be the same or different; and where R ⁸ and all other variables are defined in the brief description of the present invention.

According to sub-options for the implementation of embodiments, E5 A is substituted with four substituents R ⁸ . In another sub-embodiment, A is substituted with three R ⁸ substituents. In a further sub-embodiment, A is substituted with two R ⁸ substituents. In yet another further sub-embodiment, A is substituted with one R ⁸ substituent. According to an alternative sub-variant of the implementation of the embodiment of E5 A is unsubstituted.

The sixth embodiment (Embodiment E6) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

Where:

m=equal to 0, 1, 2 or 3;

in each occurrence, R ⁸ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , =O, -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl and benzyl are optionally substituted with F, -OCH ₃ , -OH, =O, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ up to four;

R ¹⁰ is selected from H, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein said C ₁ -C ₆ alkyl and said C ₃ -C ₆ cycloalkyl are optionally substituted with one to four substituents which are independently selected from F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ¹¹ is selected from H, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, -COR ⁹ , -COOR ⁹ , -CON(R ⁹ ) ₂ and -SO ₂ R ⁹ ;

in each occurrence R ¹² is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N (R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , with said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and benzyl are optionally substituted with up to four F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ¹³ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , with the specified C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and benzyl are optionally substituted with up to four F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ; And

W is selected from O, S, SO, SO ₂ and S(=O)(=NH); And

where --- represents a double or single bond,

where all other variables are defined in the brief description of the present invention.

According to Embodiments E1-E6 and sub-embodiments of Embodiments E1-E6, each occurrence of R ⁸ is independently selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , =O, -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=CH ₂ )C ₁ -C ₆ alkyl, -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl and benzyl are optionally substituted with up to four F, -OCH ₃ , -OH, ═O, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ .

According to a specific sub-embodiment of embodiments E1-E6, one or more R ⁸ substituents are selected from: -H, -OH, -CN, -CH ₃ , -CH ₂ NH ₂ , -CONH ₂ , C(CH ₃ ) ₂ OH, - COOC(CH ₃ ) ₂ CH ₃ , -SCH ₃ , -OCH ₃ , -Cl, -F, -CHF ₂ , =O, -cyclopropyl, NO ₂ , -NHSO ₂ CH ₃ , -SO ₂ N(CH ₃ ) ₂ , -S(=O)(=NH)CH ₃ , -SO ₂ CH ₃ , -SOCH ₃ and -SO ₂ NH ₂ .

According to another specific sub-embodiment of Embodiments E1-E6, one or more R ⁸ substituents are selected from:

A seventh embodiment (Embodiment E7) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of embodiments E1-E6, E is a 6-membered aryl, said aryl being optionally substituted up to four substituents independently selected from halo -CN, -CF ₃ , -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHCOCH ₃ , -OCF ₃ , -OCHF ₂ , -OH, -O-(C ₁ -C ₆ )alkyl, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and all other variables are defined in the brief description of the present invention.

An eighth embodiment (Embodiment E8) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is a 5-membered heteroaryl containing one to three heteroatoms independently selected from S, O and N, wherein said heteroaryl is optionally substituted with up to four substituents independently selected from halo -CN, -CF ₃ , -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHCOCH ₃ , -OCF ₃ , -OCHF ₂ , -OH, -O-(C ₁ -C ₆ )alkyl, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and all other variables are defined in the summary of the present invention.

The ninth embodiment (Embodiment E9) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, where A is defined in the summary of the present invention or in any of embodiments E1-E6, E is a 6-membered heteroaryl containing one to three heteroatoms independently selected from S, O and N, said aryl being optionally substituted with up to four substituents independently selected from halo -CN, -CF ₃ , -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHCOCH ₃ , -OCF ₃ , -OCHF ₂ , -OH, -O-(C ₁ -C ₆ )alkyl, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and all other variables are defined in the summary of the present invention.

The tenth embodiment (Embodiment E10) refers to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is:

; и все другие переменные определены в кратком описании настоящего изобретения.

; and all other variables are defined in the brief description of the present invention.

An eleventh embodiment (Embodiment E11) relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is:

; и все другие переменные определены в кратком описании настоящего изобретения.

; and all other variables are defined in the brief description of the present invention.

The twelfth embodiment (Embodiment E12) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is:

; и все переменные определены в начале.

; and all variables are defined at the beginning.

The thirteenth embodiment (Embodiment E13) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ selected from -CH ₂ N(R ² ) ₂ , -CH ₂ NR ² COR ³ , -CH ₂ NR ² COOR ³ , -CH ₂ NR ² CON(R ² ) ₂ , -CH ₂ NR ² CONR ² N(R ² ) ₂ , -CH ₂ NSO ₂ R ³ , -CON(R ² ) ₂ , -C=NOR ³ , -CH ₂ OR ⁴ , -CH ₂ NR ² R ⁴ and -CH ₂ R ⁶ .

The fourteenth embodiment (Embodiment E14) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ N(R ² ) ₂ .

According to a sub-embodiment of embodiment E14, in one instance R ² is H and in one instance R ² is C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl being optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

According to a further sub-embodiment of embodiment E14, in one instance R ² is H and in one instance R ² is C ₂ -C ₆ alkenyl, said C ₂ -C ₆ alkenyl being optionally substituted with up to four substituents independently selected from halogen -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

According to another sub-embodiment of embodiment E14, in one case R ² is H and in one case R ² is C ₃ -C ₆ cycloalkyl, said C ₃ -C ₆ cycloalkyl being optionally substituted with up to four substituents which are independently selected from the halogen -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

A fifteenth embodiment (Embodiment E15) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² COR ³ .

The sixteenth embodiment (Embodiment E16) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² COOR ³ .

The seventeenth embodiment (Embodiment E17) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² CON(R ² ) ₂ .

According to a sub-variant of the implementation of the embodiment E17 R ¹ represents -CH ₂ NHCON(R ² ) ₂ .

According to a further sub-variant, R ¹ is -CH ₂ NR ² CONH(R ² ).

According to another sub-variant, R ¹ is -CH ₂ NR ² CONH ₂ .

The eighteenth embodiment (Embodiment E18) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² CONR ² N(R ² ) ₂ .

According to a sub-variant of the implementation of the embodiment E18 R ¹ represents -CH ₂ NHCONR ² N(R ² ) ₂ .

According to a sub-variant of the implementation of the embodiment E18 R ¹ represents -CH ₂ NR ² CONHN(R ² ) ₂ .

According to another sub-variant of the implementation of the embodiment E18 R ¹ represents -CH ₂ NR ² CONR ² NH(R ² ).

According to a further sub-option of the implementation of the embodiment E18 R ¹ represents -CH ₂ NHCONHN(R ² ) ₂ .

According to a sub-variant of the implementation of the embodiment E18 R ¹ represents -CH ₂ NR ² CONR ² NH ₂ .

According to a sub-variant of the implementation of the embodiment E18 R ¹ represents -CH ₂ NR ² CONHNH ₂ .

According to a sub-option of the implementation of the E18 R ¹ represents -CH ₂ NHCONR ² NH ₂ .

The nineteenth embodiment (Embodiment E19) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² SO ₂ R ³ .

The twentieth embodiment (Embodiment E20) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CON(R ² ) ₂ .

In a sub-embodiment of embodiment E20, in one instance R ² is H and in one instance R ² is C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl being optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

According to a further sub-embodiment of embodiment E20, in one instance R ² is H and in one instance R ² is C ₂ -C ₆ alkenyl, said C ₂ -C ₆ alkenyl being optionally substituted with up to four substituents independently selected from halogen -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

According to another sub-embodiment of embodiment E20, in one case R ² is H and in one case R ² is C ₃ -C ₆ cycloalkyl, wherein said C ₃ -C ₆ cycloalkyl is optionally substituted with up to four substituents which are independently selected from the halogen -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ .

The twenty-first embodiment (Embodiment E21) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -C=NOR ³ .

According to sub-embodiments of embodiments E15, E16, E19 and E21, R ³ is H.

According to sub-embodiments of embodiments E15, E16, E19 and E21, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N (CH ₃ ) ₂ .

According to sub-embodiments of embodiments E15, E16, E19 and E21, R ³ is C ₂ -C ₆ alkenyl, wherein said C ₂ -C ₆ alkenyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N (CH ₃ ) ₂ .

According to sub-embodiments of embodiments E15, E16, E19 and E21, R ³ is C ₃ -C ₆ cycloalkyl, wherein said C ₃ -C ₆ cycloalkyl may be optionally substituted with up to four substituents independently selected from halo -OCH ₃ , -OH, -NH ₂ , -NHCH ₃ and -N (CH ₃ ) ₂ .

The twenty-second embodiment (Embodiment E22) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ OR ⁴ .

The twenty-third embodiment (Embodiment E23) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NR ² R ⁴ .

According to sub-options for implementing embodiments E22 and E23, R ⁴ is a 5-membered heterocycle optionally substituted with R ⁵ .

According to sub-options for the implementation of embodiments E22 and E23 R ⁴ is a 6-membered heterocycle, optionally substituted with R ⁵ .

According to sub-embodiments of embodiments E15, E16, E19 and E23, R ² is H.

According to additional sub-options for the implementation of embodiments E15, E16, E19 and E23 R ² represents C ₁ -C ₆ alkyl, and the specified C ₁ -C ₆ alkyl is optionally substituted with up to four substituents, which are independently selected from halogen -OCH ₃ , - OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ .

In other sub-embodiments of embodiments E15, E16, E19 and E23, R ² is C ₂ -C ₆ alkenyl, wherein said C ₂ -C ₆ alkenyl is optionally substituted with up to four substituents independently selected from halo -OCH ₃ - OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ .

In alternative sub-embodiments of embodiments E15, E16, E19 and E23, R ² is C ₃ -C ₆ cycloalkyl, wherein said C ₃ -C ₆ cycloalkyl is optionally substituted with up to four substituents independently selected from halo -OCH ₃ - OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ .

The twenty-fourth embodiment (Embodiment E24) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ R ⁶ .

According to a sub-embodiment of the E24 embodiment, R ⁶ is H.

According to a sub-variant of the implementation of the embodiment E24 R ⁶ represents C ₁ -C ₆ alkyl.

According to a sub-variant of the implementation of the option of implementation of E24 R ⁶ represents a 5-membered heterocycle, and the specified 5-membered heterocycle is optionally substituted with one or two R ⁷ .

The twenty-fifth embodiment (Embodiment E25) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the Summary of the Invention or any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NH ₂ .

The twenty-sixth embodiment (Embodiment E26) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NHC(O)CH ₃ .

The twenty-seventh embodiment (Embodiment E27) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NHC(O)-cyclopropyl.

The twenty-eighth embodiment (Embodiment E28) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NHCOOCH ₃ .

The twenty-ninth embodiment (Embodiment E29) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is -CH ₂ NHCOCH ₂ NH ₂ .

The thirtieth embodiment (Embodiment E30) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is CH ₂ NHCOCHCH ₂ CH ₃ .

The thirty-first embodiment (Embodiment E31) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is CH ₂ NHC(O)NHN(CH ₃ ) ₂ .

The thirty-second embodiment (Embodiment E32) relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, and R ¹ is:

The thirty-third embodiment (Embodiment E33) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E13, and R ¹ is:

The thirty-fourth embodiment (Embodiment E34) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E13, and R ¹ is:

The thirty-fifth embodiment (Embodiment E35) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E13, and R ¹ is:

The thirty-sixth embodiment (Embodiment E36) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the Summary of the Invention or any of Embodiments E1-E6, E is defined in any of Embodiments E7-E13, and R ¹ is:

The thirty-seventh embodiment (Embodiment E37) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in the summary of the present invention or in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E13, and R ¹ is:

The thirty-eighth embodiment (Embodiment E38) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, R ¹ is -CH ₂ OR ⁴ or -CH ₂ NR ² R ⁴ ; And

R ⁴ selected from:

The thirty-ninth embodiment (Embodiment E39) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is defined in any of Embodiments E1-E6, E is defined in any of Embodiments E7-E12, R ¹ is CH ₂ R ⁶ and R ⁶ selected from:

The fortieth embodiment (Embodiment E40) refers to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is:

where R ⁸ represents up to four carbon ring substituents, which may be the same or different, E is defined in any of embodiments E7-E12 and R ¹ is defined in any of embodiments E13-E37.

The forty-first embodiment (Embodiment E41) refers to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein E is defined in any of Embodiments E7-E12, R ¹ is defined in any of Embodiments E13-E37, A is:

Where:

m=equal to 0, 1, 2 or 3;

in each occurrence, R ⁸ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , =O, -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl and benzyl are optionally substituted with F, -OCH ₃ , -OH, =O, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ up to four;

R ¹⁰ is selected from H, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein said C ₁ -C ₆ alkyl and said C ₃ -C ₆ cycloalkyl are optionally substituted with one to four substituents which are independently selected from F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ¹¹ is selected from H, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, -COR ⁹ , -COOR ⁹ , -CON(R ⁹ ) ₂ and -SO ₂ R ⁹ ;

in each occurrence R ¹² is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N (R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , with said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and benzyl are optionally substituted with up to four F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ;

R ¹³ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, -OCF ₃ , -OCHF ₂ , -OR ³ , -CN, -NO ₂ , -SR ³ , -SF ₅ , -SCF ₃ , -SOR ³ , -SO ₂ R ³ , -S(=O)(=NH)R ² , -N(R ² ) ₂ , -NR ² COR ³ , -SO ₂ N(R ² ) ₂ , -NR ² SO ₂ R ³ , -COOH, -COR ⁹ , -COOR ³ , -CON(R ² ) ₂ and -C(R ⁹ ) ₂ N(R ² ) ₂ , with the specified C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and benzyl are optionally substituted with up to four F, -OCH ₃ , -OH, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ ; And

W is selected from O, S, SO, SO ₂ and S(=O)(=NH); And

where --- represents a double or single bond and where all other variables are defined in the brief description of the present invention.

The forty-second embodiment (Embodiment E42) refers to a compound of formula IA or a pharmaceutically acceptable salt thereof of the formula:

Where:

R ¹ is -CH ₂ NH ₂ , -CH ₂ NHC(O)CH ₃ , -CH ₂ NHC(O)-C ₃ -C ₆ cycloalkyl or CH ₂ R ⁶ ; A is defined in any of embodiments E1-E6; and R ⁶ is defined in the summary of the present invention.

The forty-third embodiment (Embodiment E43) refers to a compound of formula IB or a pharmaceutically acceptable salt thereof of the formula:

Where:

R ¹ is -CH ₂ NH ₂ , -CH ₂ NHC(O)CH ₃ , -CH ₂ NHC(O)-C ₃ -C ₆ cycloalkyl or CH ₂ R ⁶ ; A is defined in any of embodiments E1-E6; and R ⁶ is defined in the summary of the present invention.

According to sub-embodiments of embodiments E42 and E43, R ¹ is -CH ₂ NH _2.

где R8 представляет собой заместители углеродного кольца в количестве до четырех, которые могут быть одинаковыми или разными.According to additional sub-embodiments of embodiments E42 and E43, A is:

where R8 represents up to four carbon ring substituents, which may be the same or different.

Reference to various embodiments with respect to compounds of formula I specifically includes various embodiments of formula I, such as formula IA and formula IB, sub-embodiments of formula IA and formula IB, other embodiments provided herein, and individual compounds, described in the present invention.

Other embodiments of the present invention include the following:

(a) a pharmaceutical composition containing an effective amount of a compound of formula I, IA or IB as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(b) a pharmaceutical composition (a) further comprising a second compound, the second compound being an antibiotic.

(c) pharmaceutical composition (b), wherein the second compound is selected from the group consisting of: ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, protionamide, cycloserine, terididone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, thioacetazone, meropenem-clavulanate and thioridazine.

(d) a pharmaceutical composition comprising (i) a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, and (ii) a second compound, the second compound being an antibiotic, wherein each compound of formula I, IA or IB and each second compound has been used in an amount that makes the combination effective for treating or preventing a bacterial infection.

(e) combination (d), where the second compound is selected from the group consisting of: ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylic acid , clofazimine, clarithromycin, amoxicillin-clavulanate, thioacetazone, meropenem-clavulanate and thioridazine.

(f) a method of treating a bacterial infection in a subject, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof.

(g) a method for preventing and/or treating a bacterial infection which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof.

(h) a method of treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of composition (a), (b), (c), (d) or (e).

(i) a method for treating a bacterial infection as set forth in (f), (g) or (h), wherein the bacterial infection results from Mycobacterium tuberculosis.

(j) a method for preventing and/or treating a mycobacterial infection, which comprises administering to a subject in need of such treatment an effective amount of a composition containing an oxazolidinone compound or a pharmaceutically acceptable salt thereof.

(k) a method for treating a mycobacterial infection as set forth in (j), wherein the mycobacterial infection is caused by M. tuberculosis .

(l) a method for treating a mycobacterial infection as set forth in (j), wherein the composition is composition (a), (b), (c), (d) or (e).

The present invention also includes a compound of formula I, Ia or Ib or a pharmaceutically acceptable salt thereof (i) for use in (ii) for use as a medicament for or (iii) for use in the preparation (or manufacture) of a therapeutic drug or treating a bacterial infection, in particular a mycobacterial infection. In such applications, the compounds of the present invention may optionally be used in combination with one or more second therapeutic agents, including ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, thioacetazone, meropenem-clavulanate, and thioridazine.

Additional embodiments of the present invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(l) above and the uses set forth in the previous paragraph, where the compound of the present invention used is a compound of one of the described embodiments, sub-embodiments , classes or subclasses. The compound may optionally be used in the form of a pharmaceutically acceptable salt in such embodiments.

According to the embodiments of the compounds and salts presented herein, it is understood that each embodiment can be combined with one or more other embodiments to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. In addition, it is understood that embodiments of the compositions and methods presented above as (a)-(l) include all embodiments of compounds and/or salts, including such embodiments that result from a combination of embodiments.

Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods, and uses set forth in the preceding paragraphs, wherein the compound of the present invention, or salt thereof, is substantially pure. With respect to a pharmaceutical composition comprising a compound of formula I, IA or IB or a salt thereof and a pharmaceutically acceptable carrier and optionally one or more excipients, the term "substantially pure" is meant to refer to a compound of formula I IA or IB or a salt thereof directly; i.e., to the purity of the active substance in the composition.

Definitions and abbreviations

The terms used in the present description have their usual meaning, and the meaning of such terms in each case is independent. That being said, and except where noted otherwise, the following definitions are used throughout the specification and claims. Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If a chemical compound is directed to use both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure is predominant. These definitions are used regardless of whether the term is used on its own or in combination with other terms, unless otherwise noted. Therefore, the definition of "alkyl" refers to "alkyl" as well as the "alkyl" parts in "hydroxyalkyl", "haloalkyl",
"-O-alkyl", etc.

Used in the present description and throughout the disclosure, the following terms, unless otherwise noted, should be understood as having the following meanings:

"Alkyl" means saturated carbon chains, which may be straight or branched, or combinations thereof, unless the carbon chain is otherwise defined. Other "alk" groups, such as alkoxy and alkanoyl, may also be straight or branched, or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and the like.

"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond and which may be straight or branched, or combinations thereof, unless otherwise noted. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

"Antibiotic" refers to a compound or composition that reduces the viability of a microorganism or that inhibits the growth or proliferation of a microorganism. The expression "inhibits growth or proliferation" means an increase in the generation time (ie, the time required to divide a bacterial cell or to double the population) by at least 2 times. Preferred antibiotics are those that can increase the generation time by at least 10-fold or more (eg, at least 100-fold or even limitlessly, as in complete cell death). It is contemplated that the antibiotic used in the present disclosure further includes an antibacterial, bacteriostatic, or bactericidal agent.

"Approximately" when modifying an amount (e.g., kg, l, or equivalents) of a substance or composition, or a value of a physical property, or a value of a parameter characterizing a process step (e.g., the temperature at which the process step was performed) or the like, refers to variation in numerical a value that may occur, for example, during normal measurement, processing and selection procedures that are involved in obtaining, characterizing and/or using a substance or composition; with the inevitable error in such procedures; differences in the manufacture, source, or purity of ingredients used to make or use compositions or procedures; and the like. According to certain embodiments, "about" may mean a variation of ± 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4, 0 or 5.0 of the corresponding unit. In certain embodiments, "about" can mean a ±1%, 2%, 3%, 4%, 5%, 10%, or 20% variation.

"Aromatic ring system" means a monocyclic, bicyclic or tricyclic aromatic ring or a ring system containing 5-14 ring atoms, where at least one of the rings is aromatic. As used herein, aromatic ring systems encompass aryls and heteroaryls. The term may be used to describe a carbocyclic ring fused to an aryl group. For example, a 5-7 membered cycloalkyl may be fused through two adjacent ring atoms with a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms in ring atoms selected from N, O, and S. In another example, a heteromonocyclic ring is fused through two ring atoms with a phenyl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

"Aryl" means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, where at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl.

"Cycloalkyl" means a saturated monocyclic, bicyclic or bridged carbocyclic ring containing the specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "heterocycloalkyl" refers to a non-aromatic saturated monocyclic or polycyclic ring system containing 3 to 11 ring atoms, where 1 to 4 ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms. The heterocycloalkyl group may be attached via a ring carbon atom or a ring nitrogen atom (if present). In one embodiment, the heterocycloalkyl group is monocyclic and contains from about 3 to about 7 ring atoms. In another embodiment, the heterocycloalkyl group is monocyclic and contains from about 4 to about 7 ring atoms. In another embodiment, the heterocycloalkyl group is bicyclic and contains from about 7 to about 11 ring atoms. According to another embodiment, the heterocycloalkyl group is monocyclic and contains 5 or 6 ring atoms. According to one embodiment, the heterocycloalkyl group is monocyclic. According to another embodiment, the heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms in the ring system. Any –NH group on the heterocycloalkyl ring may exist as a protected group such as, for example, -N(BOC), -N(Cbz), -N(Tos) group, etc.; such protected heterocycloalkyl groups are considered part of the present invention. The term "heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined above, that is fused to an aryl (eg, benzene) or heteroaryl ring. The heterocycloalkyl group may optionally be substituted with one or more "ring system substituents" which may be the same or different and are defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl (if present) may optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine, etc., and all their isomers.

Used in the present description, for example, in the definition of R ¹ ,
"-CH ₂ NR ² COR ³ " means "-CH ₂ NR ² C=OR ³ ".

"Drug resistance" in relation to a mycobacterium means a mycobacterium that is no longer sensitive to at least one previously effective drug; which has developed the ability to resist the effects of an antibiotic from at least one previously effective drug. A drug-resistant strain can pass on this ability to resist to its offspring. Said resistance may arise due to random genetic mutations in a bacterial cell that change its sensitivity to one drug or to different drugs.

"Halogen" includes fluorine, chlorine, bromine and iodine.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic ring system containing from about 5 to about 14 ring atoms, where 1 to 4 ring atoms are independently O, N, or S and the remaining ring atoms are carbon atoms, where at least one of the heteroatom containing rings is aromatic. In one embodiment, the heteroaryl group contains 5 to 10 ring atoms. According to another embodiment, the heteroaryl group is monocyclic and contains 5 or 6 ring atoms. According to another embodiment, the heteroaryl group is bicyclic. The heteroaryl group may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are defined herein below. The heteroaryl group is attached via a ring carbon atom and any heteroaryl nitrogen atom may optionally be oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl , pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl , thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzothiazolyl, and the like, and all isomeric forms thereof. According to another embodiment of the present invention, the heteroaryl is pyridine. Examples of bicyclic rings include:

"Heterocycle" means a monocyclic or bicyclic saturated, partially unsaturated or unsaturated ring system containing 5-10 atoms and containing at least one ring heteroatom selected from N, S and O. According to selected embodiments, the ring system contains 1-4 heteroatoms, selected from N, S and O. If the heterocycle contains two rings, the rings may be fused, bridged or spirocyclic. Examples of monocyclic heterocyclic rings include piperazine, piperidine and morpholine. Examples of bicyclic heterocyclic rings include 1,4-diazabicyclo[2,2,2]octane and 2,6-diazaspiroheptane.

"Oxo" means an oxygen atom connected to another atom through a double bond, and it can be represented as "=O".

"Tuberculosis" includes a disease state usually associated with infections caused by mycobacterium species including the M. tuberculosis complex. The term tuberculosis is also associated with mycobacterial infections caused by mycobacteria other than M. tuberculosis (MOTT). Other mycobacterial species include M. avium-intracellulare , M. kansarii , M. fortuitum , M. chelonae , M. leprae , M. africanum and M. microti , M. avium paratuberculosis , M. intracellulare , M. scrofulaceum , M xenopi , M. marinum and M. ulcerans .

Another embodiment of the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined at the outset or as defined in any of the above embodiments, sub-embodiments, aspects, classes or sub-classes, wherein the compound or salt thereof is in its basic pure form. Used in the present description, "substantially pure" means that, respectively, at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt. .% (for example, from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (for example, from about 95 wt.% to about 99 wt.% or from about 98 wt. .% to 100 wt.%) and most preferably at least about 99 wt.% (for example, 100 wt.%) of a product containing a compound of formula I, IA or IB or a salt of formula I, IA or IB (for example, a product isolated from the reaction mixture to give a compound or salt) consists of a compound or salt. The purity levels of compounds and salts can be determined using standard analysis methods such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography and/or mass spectrometry. If more than one assay method was used and the methods provided experimentally significant differences at a given purity level, then the method that provides the highest level of purity is preferred. A 100% pure compound or salt is one that contains no detectable impurities, as determined by a standard assay method. With respect to a compound of the present invention which has one or more centers of asymmetry and may occur as mixtures of stereoisomers, a substantially pure compound may be either a substantially pure mixture of stereoisomers or a substantially pure individual diastereomer or enantiomer.

The present invention embraces all stereoisomeric forms of the compounds of formula I, formula IA and formula IB. Unless a specific stereochemistry is noted, the present invention is intended to cover all such isomeric forms of such compounds. The centers of asymmetry that are present in the compounds of formula I, formula IA and formula IB can all independently of each other have the (R) configuration or (S) configuration. If the bonds to the chiral carbon atom in the structural formulas of the present invention are shown as straight lines, it is clear that both configurations (R) and (S) of the chiral carbon atom and thus both enantiomers and mixtures thereof are covered within the formula. Similarly, if the name of the compound is indicated without the chiral designation of the chiral carbon atom, it is understood that both the (R) and (S) configurations of the chiral carbon atom, and thus the individual enantiomers and mixtures thereof, are covered by the name. The formation of specific stereoisomers or mixtures thereof can be determined in the examples in which such stereoisomers or mixtures were obtained, but this does not limit the inclusion of all stereoisomers or mixtures thereof from being within the scope of the present invention.

The present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, eg mixtures of enantiomers and/or diastereomers in all ratios. Thus, the enantiomers are the object of the present invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of two enantiomers in all ratios. In the case of cis/trans isomerism, the present invention includes both the cis form and the trans form, as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if necessary, by separating the mixture by conventional means, for example by chromatography or crystallization using stereochemically homogeneous synthetic starting materials, or by stereoselective synthesis. Derivatization may optionally be carried out prior to separation of the stereoisomers. The separation of a mixture of stereoisomers may be carried out at an intermediate stage during the synthesis of a compound of formula I, formula IA or formula IB, or may be carried out with the final racemic product. The absolute stereochemistry can be determined by X-ray diffraction crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. If the compounds of the present invention are capable of tautomerization, all individual tautomers, as well as mixtures thereof, are included within the scope of the present invention. Unless a particular isomer, salt, solvate (including hydrates), or solvated salt of such racemate, enantiomer, diastereomer, or tautomer is noted, the present invention includes all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers. , diastereomers and tautomers and mixtures thereof.

If any variable (eg, R1, Ra, etc.) occurs more than once in any term or formula I, its definition in each instance is independent of its definition in every other instance. Combinations of substituents and/or variables are also allowed, only if such combinations result in stable compounds. The wavy line across the bond in the substituent variable represents the attachment point.

In the standard nomenclature used throughout this disclosure, the end portion of said side chain is described last, preceded by an adjacent functional group near the point of attachment.

In selecting the compounds of the present invention, the person skilled in the art will take into account that the various substituents, ie. R1, R2, etc., are selected in accordance with the well-known principles of attachment capacity and chemical structure stability.

The term "substituted" means that one or more hydrogen atoms on one designated atom is replaced by a selected variant from the specified group, provided that the normal valency of the designated atom under existing conditions is not exceeded and that the substitution results in a stable compound. It is believed that the term substituted includes several degrees of substitution of the specified substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound may independently be substituted with one or more of the disclosed or claimed substituent moieties, either alone or in multiples. By independently substituted is meant that the (two or more) substituents may be the same or different.

"Stable compound" and "stable structure" are meant to mean a compound that is sufficiently stable to remain after isolation to an acceptable degree of purity from a reaction mixture, and whose structure and properties remain, or may be caused to remain, unchanged over a period of time. time that is sufficient to allow the use of the compound for the purposes described in the present invention (eg, therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds which are included in formula I.

If a group, such as C ₁ -C ₈ alkyl, is designated as substituted, such substitutions can also occur if such a group is part of a larger substituent, such as -C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl and -C ₁ -C ₈ alkylaryl.

In compounds of formula I, IA and IB, the atoms may exhibit their natural isotopic composition, or one or more atoms may be artificially enriched in a particular isotope with the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly occurring in nature. The present invention is intended to include all acceptable isotopic variants of the compounds of formula I, IA and IB. For example, various isotopic forms of hydrogen (H) include protium ( ¹ H) and deuterium ( ² H or D). Protium is the predominant isotope of hydrogen found in nature. Enrichment with deuterium may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage, or may provide a compound useful as a standard for characterization of biological samples. Isotopically enriched compounds of formulas I, IA and IB can be prepared without inappropriate experimentation by conventional methods well known to those skilled in the art, or by methods similar to those described in the examples herein using the appropriate isotopically enriched reagents and/or intermediates.

Unless expressly stated otherwise in a particular context, any of the various cyclic rings or ring systems described in the present invention may be attached to the remainder of the compound at any ring atom (i.e., any carbon atom or any heteroatom), provided that this results in a stable connection.

Unless expressly stated otherwise, all ranges mentioned herein are inclusive. For example, a heteroaromatic ring described as having "1 to 4 heteroatoms" means that the ring may contain 1, 2, 3, or 4 heteroatoms. It is also understood that any range referred to herein includes within its scope all subranges within that range. Thus, for example, a heterocyclic ring described as having "1 to 4 heteroatoms" is intended to include as its aspects heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms and 4 heteroatoms. Similarly, C ₁ - ₆ when used with a chain, for example an alkyl chain, means that the chain may contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all the ranges it contains, including C ₁ - ₅ , C ₁ - ₄ , C ₁ - ₃ , C ₁ - ₂ , C ₂ - ₆ , C ₃ - ₆ , C ₄ - ₆ , C ₅ - ₆ and all other possible combinations.

It should also be noted that it is assumed that any carbon atom, as well as heteroatom with unsaturated valences in the presented text, schemes, examples and tables contains a sufficient number of hydrogen atom(s) to saturate the valences.

If any substituent or variable (for example, alkyl, R ⁸ , R ^{11 ,} etc.) occurs more than once in any constituent or in formula (I), its definition in each case is independent of its definition in every other case, unless otherwise noted.

The term "compound" refers to the free compound and, to the extent that they are stable, to any hydrate or solvate thereof. A hydrate is a compound that forms a complex with water, and a solvate is a compound that forms a complex with an organic solvent.

As indicated above, the compounds of the present invention may be used in the form of pharmaceutically acceptable salts. It will be understood that, when used herein, the compounds of the present invention may also include pharmaceutically acceptable salts, as well as salts that are not pharmaceutically acceptable when used as starting materials with respect to the free compounds or their pharmaceutically acceptable salts or during other manipulations during synthesis.

The term "pharmaceutically acceptable salt" refers to a salt that has the efficacy of the parent compound and that is not biologically or otherwise undesirable (eg, is neither toxic nor otherwise harmful to the patient). The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds, which are encompassed by the term "pharmaceutically acceptable salt", refers to non-toxic salts of the compounds of the present invention, which are usually obtained by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, without limitation, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic acid salt, digluconate, dihydrochloride, dodecylsulfonate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic acid salt, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid salt, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucat, 2-naphthalenesulfonate, Napsilate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic acid salt, phenylpropionic acid salt, polygalacturonate, propionate, salicylate, stearate, sulfate , subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate, and the like. derived from inorganic bases including aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, ferric manganese, ferrous manganese, potassium, sodium, zinc, and the like. Especially preferred are the salts of ammonium, calcium, magnesium, potassium and sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2 -diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, 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 the like. Also included are basic nitrogen-containing groups which can be quaternized by means such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as
dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and steryl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others.

Such salts can be obtained by known methods, for example, mixing the compound of the present invention with an equivalent amount and a solution containing the desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and their salts may form solvates with a solvent such as water, ethanol or glycerol. The compounds of the present invention can form an acid addition salt and a base salt at the same time according to the type of side chain substituent.

The compounds of the present invention may also be used in the form of a prodrug. For example, the hydrogen atom in –COOH can be a replacement for any of the following groups: C _1-6 alkyl, C _3-6 cycloalkyl, –C _1-6 alkyl-C _3-6 cycloalkyl, C _3-7 cycloheteroalkyl, –C _{1- 6} alkyl-C _3-7 cycloheteroalkyl, aryl, -C _1-10 alkylaryl, heteroaryl, and -C _1-10 alkyl-heteroaryl. Any C _1-6 alkyl, C _3-6 cycloalkyl or C _3-7 cycloheteroalkyl may also be substituted. Any aryl or heteroaryl may also be substituted, as noted.

As set forth above, the present invention includes pharmaceutical compositions comprising a compound of formula I, IA or IB of the present invention, optionally one or more other active ingredients, and a pharmaceutically acceptable carrier. Characteristics of the media will depend on the route of administration. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other, not interfere with the effectiveness of the active(s) ingredient(s) and not be harmful (eg, toxic) to the patient. Thus, the compositions of the present invention may, in addition to the inhibitor, contain diluents, excipients, salts, buffers, stabilizers, solubilizers, and other substances well known in the art.

Also as set forth above, the present invention includes a method of treating a bacterial infection, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof. Used in the present description, the term "subject" (or, alternatively, "patient") refers to an animal, preferably a mammal, most preferably a human, who was the object of treatment, observation or experiment. The term "administration" and variations thereof (eg, "administration" of a compound) in relation to a compound of formula I, IA or IB means providing the compound or a pharmaceutically acceptable salt thereof to a patient in need of treatment. When a compound or salt thereof is provided in combination with one or more other active agents, "administering" and variations thereof is meant to include providing the compound or salt thereof and the other agents at the same time or at different times. If the combination agents were administered at the same time, they may be administered together in the same composition, or they may be administered separately. It is understood that a "combination" of active agents may be a single composition containing all active agents, or multiple compositions each containing one or more active agents. In the case of two active agents, the combination may be either as a single composition containing both agents, or as two separate compositions each containing one of the agents; in the case of three active agents, the combination may be either one composition containing all three agents, three separate compositions each containing one of the agents, or two compositions, one containing two agents and the other containing a third agent; and so on.

The compositions and combinations of the present invention are suitably administered in effective amounts. The term "effective amount" as used herein with respect to an oxazolidinone compound means an amount of the active compound sufficient to cause a bactericidal or bacteriostatic effect. In one embodiment, an effective amount is a "therapeutically effective amount", which means an amount of active compound that can overcome bacterial drug resistance and that is sufficient to inhibit bacterial reduplication and/or kill bacteria. When the active compound (i.e., active ingredient) is administered as a salt, references to the amount of active ingredient refer to the free acid or free base form of the compound.

Suitable administration for a composition according to the present invention is parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular or intrarectal, the composition being suitably formulated for administration by the chosen route using formulation methods well known in the art, including, for example, the methods for preparing and administering the formulations described in chapters 39, 41, 42, 44, and 45 of Remington - The Science and Practice of Pharmacy, 21 ^st edition, 2006. In one embodiment, the compounds of the present invention are administered intravenously in a hospital setting. In another embodiment, the administration is oral in the form of a tablet or capsule or the like. The dosage of the compounds according to the present invention and their pharmaceutically acceptable salts may vary widely and must of course be adjusted on a case-by-case basis in accordance with the individual conditions and the pathogenic agents to be controlled. In general, for use in the treatment of bacterial infections, the daily dose may be from 0.005 mg/kg to 100 mg/kg, from 0.01 mg/kg to 10 mg/kg, from 0.05 mg/kg to 5 mg/kg, from 0.05 mg/kg to 1 mg/kg.

In some embodiments, a compound of the present invention is provided in a pharmaceutical formulation for oral, intravenous, intramuscular, nasal, or topical administration. Thus, in some embodiments, the formulation may be in dosage form such as, without limitation, a tablet, capsule, liquid (solution or suspension), suppository, ointment, cream, or aerosol. In some embodiments, an object disclosed herein provides such compounds and/or formulations that have been lyophilized and that can be reconstituted into pharmaceutically acceptable formulations for administration, for example, by intravenous or intramuscular injection.

Intravenous administration of a compound of the present invention may be accomplished by reconstituting the powder form of the compound in a suitable solvent. Suitable solvents include, for example, saline solutions (for example, 0.9% saline for injection) and sterile water (for example, sterile water for injection, bacteriostatic water for injection with methyl paraben and propyl paraben, or bacteriostatic water for injection with 0.9 % benzyl alcohol). The powder form of the compound can be prepared by treating the compound with gamma irradiation or by lyophilizing a solution of the compound, after which the powder can be stored (eg in a stoppered vial) at or below room temperature until reconstituted. The concentration of the compound in the reconstituted IV solution may be, for example, in the range of about 0.1 mg/mL to about 20 mg/mL.

The methods of the subject matter disclosed herein are applicable to the treatment of such conditions in which they suppress the manifestation, development or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of the subject affected by the condition or at risk of contracting the condition. Thus, in accordance with the subject matter disclosed herein, the terms "treat", "treatment" and their grammatical variations, as well as the phrase "method of treatment" encompass any desired therapeutic intervention, including, without limitation, a method of treating an existing infection in a subject and a method prevention (ie prevention) of infection, for example, in a subject who has been exposed to the microbe disclosed herein or who is expected to be exposed to the microbe disclosed herein.

Infections that can be treated with the compounds of the present invention may be caused by a variety of microbes, including fungi, algae, protozoa, bacteria, and viruses. In some embodiments, the infection is a bacterial infection. Representative microbial infections that can be treated by the methods of the present invention include, without limitation, infections caused by one or more of Staphylococcus aureaus, Enterococcus faecalis, Bacillus anthracis , Streptococcus species (e.g., Streptococcus pyogenes and Streptococcus pneumoniae ), Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia , Proteus species (e.g. Proteus mirabilis and Proteus vulgaris ), Klebsiella pneumoniae, Acinetobacter baumannii, Strenotrophomonas maltophillia, Mycobacterium tuberculosis, Mycobacterium bovis , other Mycobacterium tuberculosis complex, and nontuberculous mycobacteria ulceriumansbacterium .

In some embodiments, the infection is an infection with a Gram-positive bacterium. In some embodiments, the infection is selected from mycobacterial infection, Bacillus anthracis infection, Enterococcus faecalis infection, and Streptococcus pneumoniae infection.

In some embodiments, a compound of formula I, IA, or IB is administered prophylactically to prevent or reduce the incidence of one of (a) Mycobacterium tuberculosis infection in a subject at risk of infection; (b) recurrence of Mycobacterium tuberculosis infection; and (c) combinations thereof. In some embodiments, a compound of Formula I, IA, or IB is administered to treat an existing Mycobacterium tuberculosis infection. In some embodiments, a compound of formula I, IA, or IB is administered to treat infection with a multidrug-resistant strain of Mycobacterium tuberculosis (i.e., a strain that is resistant to two or more previously known anti-tuberculosis drugs such as isoniazid, ethambutol, rifampicin , kanamycin, capreomycin, linezolid and streptomycin). In some embodiments, the compound of formula (I) has a minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis of 25 µg/mL or less. In some embodiments, a compound of formula I, IA, or IB is administered to treat an infection with a multidrug-resistant strain of Mycobacterium tuberculosis .

Thus, the methods of the subject matter disclosed herein may be useful in the treatment of tuberculosis in that they inhibit the onset, development, or spread of a TB infection, cause regression of a TB infection, cure a TB infection, or otherwise improve the general well-being of a subject afflicted with or undergoing tuberculosis. the risk of becoming infected.

Subjects suffering from M. tuberculosis infection or other tuberculosis-associated infection can be detected by a number of techniques, such as sputum smear, chest x-ray, tuberculin skin test (i.e. Mantoux test or PPD test), and/or the presence of other clinical symptoms (eg, chest pain, coughing up blood, fever, night sweats, loss of appetite, fatigue, etc.). If necessary, bacterial RNA, DNA, or proteins can be isolated from a subject suspected of having TB, analyzed by methods known in the art, and compared with known nucleic acid or amino acid sequences of the bacterial RNA, DNA, or protein.

In some embodiments, a compound of formula I, IA, or IB has a minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis of 25 μg/mL or less. MICs can be determined by methods known in the art, such as those described in Hurdle et al ., 2008, J. Antimicrob. Chemother. 62:1037-1045.

In some embodiments, the methods of the present invention further comprise administering to the subject an additional therapeutic compound. In some embodiments, a compound of the present invention is administered to a subject before, after, or simultaneously with one or more additional therapeutic compounds. In some embodiments, the additional therapeutic compound is an antibiotic. In some embodiments, the additional therapeutic compound is an anti-tuberculosis therapeutic agent. In some embodiments, the additional therapeutic compound is selected from the group consisting of isoniazid, ethambutol, rifampicin, kanamycin, capreomycin, linezolid, and streptomycin.

The present invention, therefore, according to the following aspect relates to a combination containing a compound of formula I, IA or IB, or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents. Examples of such one or more additional therapeutic agents are antituberculous agents, including, without limitation, amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, pyrazinamide, rifamycins (such as rifampin, rifapentine and rifabutin), streptomycin, clarithromycin , azithromycin, oxazolidinones, and fluoroquinolones (such as ofloxacin, ciprofloxacin, moxifloxacin, and gatifloxacin). Such chemotherapy is determined at the discretion of the attending physician using the preferred drug combinations. First-line chemotherapy agents used to treat Mycobacterium tuberculosis infection that is not drug-resistant include isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide. Second line chemotherapeutic agents used to treat Mycobacterium tuberculosis infection that has demonstrated resistance to one or more first line drugs include ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin, and capreomycin. In addition to the above, there are a number of new anti-tuberculous therapeutics emerging from clinical studies that can also be used as one or more additional therapeutics in combination with a compound of Formula I, IA or IB, including but not limited to TMC-207, OPC-67683 , PA-824, LL-3858 and SQ-109.

Thus, another antibiotic that can be combined with compounds of formula I, IA or IB is, for example, rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; moxifloxacin; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; quinolones/fluoroquinolones such as, for example, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as, for example, clarithromycin, clofazimine, amoxicillin with clavulanic acid; rifamycins; rifabutin; rifapentine.

According to the following aspect, one or more additional therapeutic agents are, for example, an agent useful for the treatment of tuberculosis in a mammal, therapeutic vaccines, antibacterial agents, antiviral agents; antibiotics and/or HIV/AIDS medications. Examples of such therapeutic agents include isoniazid (INH), ethambutol, rifampin, pyrazinamide, streptomycin, capreomycin, ciprofloxacin, and clofazimine.

In one aspect, the one or more additional therapeutic agents is a therapeutic vaccine. A compound of formula I, IA or IB, or a pharmaceutically acceptable salt thereof, can thus be administered in combination with a vaccination against a mycobacterial infection, in particular a vaccination against a Mycobacterium tuberculosis infection. Existing vaccines against mycobacterial infection include Bacillus Calmette-Guerin (BCG). Vaccines currently being developed to treat, prevent, or alleviate mycobacterial infection include modified strains of BCG that recombinantly express additional antigens, cytokines, and other agents designed to improve efficacy or safety; attenuated mycobacteria that express a range of antigens more similar to Mycobacterium tuberculosis than to BCG; and subunit vaccines. Subunit vaccines may be administered in the form of one or more individual protein antigens, or in the form of a fusion or fusions of several protein antigens, which either may optionally be added as an adjuvant or may be in the form of a polynucleotide encoding one or more individual protein antigens or encoding a fusion or fusion of several protein antigens, for example, if the polynucleotide is introduced into an expression vector. Examples of subunit vaccines include, without limitation, M72, a fusion protein derived from the Mtb32a and Mtb39 antigens; HyVac-1, a fusion protein derived from antigen 85b and ESAT-6; HyVac-4, a fusion protein derived from antigen 85b and Tb10.4; MVA85a, modified Ankara vaccine virus expressing 85a antigen; and Aeras-402, an adenovirus 35 expressing a fusion protein derived from 85a antigen, 85b antigen and Tb10.4.

Abbreviations used in this specification include the following:

ACN=acetonitrile; CBZ-Cl=benzyl chloroformate; CDCl ₃ =deuterated chloroform; DCM=dichloromethane; DIAD=diisopropyldiazodicarboxylate, DIEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; DMSO=dimethyl sulfoxide; Et=ethyl; EtOAc=ethyl acetate; EtOH=ethanol; GFP=green fluorescent protein; HATU=(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HET=heterocycle; H ₂ =hydrogen gas, HPLC=high performance liquid chromatography; LC-MS=liquid chromatography/mass spectrometry; Me=methyl; MeOH=methanol; MIC=minimum inhibitory concentration; MW=molecular weight; MS=mass spectrometry; Mtb = Mycobacterium tuberculosis ; Pd-C=palladium catalyst on a carbon carrier; k. t. = room temperature; TB=tuberculosis; TEA=triethylamine; TFA=trifluoroacetic acid; THF=tetrahydrofuran and TBDMS=tert-butyldimethylsilyl.

Methods for obtaining compounds of formula (I):

Compounds of formula (I) may be prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. In such reactions, it is also possible to use variations that are per se known to those skilled in the art, but not mentioned in more detail. Alternative synthetic routes and similar structures will be apparent to those skilled in the art of organic synthesis in view of the following reaction schemes and examples.

Scheme A shows a method applicable to the preparation of oxazolidinone compounds of formula A7 which correspond to compounds of formula (I) wherein R ¹ is CH ₂ NH ₂ and A is defined in the summary of the present invention. The scheme below shows the synthesis of oxazolidinone analogs where A is introduced via a coupling reaction. The synthesis scheme has been discussed in detail in the literature ( Org. Proc. Res. Dev . 2003 , 533). Oxyzolidinone A3 can be formulated in one step from oxirane S1 and carbamate A2 . Further modification of the hydroxy group with the azide intermediate A5 can give the amine A6 . In the final step, the desired compound A7 was obtained by means of a Suzuki coupling reaction, which can be used to synthesize compounds where R ¹ is a derivative of CH ₂ NH ₂ .

Scheme A

Scheme B shows a method applicable to the preparation of oxazolidinone compounds of formula B4 which correspond to compounds of formula (I) wherein R ¹ is a heterocycle such as imidazole, triazole or tetrazole and A is defined in the summary of the present invention. In Scheme B, compound B1 was converted to compound B2 by a Suzuki coupling reaction followed by heterocycle introduction by substitution of the mesylate intermediate B3 to give compound B4 .

Scheme B

Compounds of formula A7 and B4 can be further processed using methods that will be well known to those skilled in the art of organic synthesis or, for example, the methods described in the examples below, to obtain the full scope of the compounds of formula (I).

Example 1

Synthesis of (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one.

Step A: Synthesis of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one.

To a solution of benzyl (4-bromo-3-fluorophenyl) carbamate (50.0 g, 154 mmol) in THF (600 ml) was added lithium tert-butoxide (37.0 g, 463 mmol) at 0°C. The mixture was stirred at 20°C for 2 hours and then (R)-oxiran-2-ylmethylbutyrate (44.5 g, 309 mmol) was added at 20°C. The resulting mixture was stirred at 20°C for 16 hours and then concentrated HCl was added to adjust the pH to 7. The organic solvent was removed under reduced pressure and the residue was diluted with EtOAc (400 ml), washed with water (400 ml x 2) and brine solution (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain the crude product, which was purified by column chromatography (SiO ₂ , PE:EtOAc=1:1) to obtain the product (R)-3-(4- bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one as a solid.

Step B: Synthesis of (R)-(3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate.

N -ethyl- N -isopropylpropan-2-amine (1.2 ml, 6.89 mmol) and methanesulfonyl chloride (5.17 mmol) at 0°C. The reaction mixture was stirred at 28°C for 2 hours and then diluted with water (20 ml), extracted with DCM (20 ml x 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-(3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate as an oil. MS (ESI) m/z: 368.2, 370.2 [M+H+].

Step C: (R)-5-(azidomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one

Sodium azide (2 .5 g, 38.1 mmol) and the resulting mixture was stirred at 70°C for 4 hours. The mixture was then diluted with EtOAc (200 ml), washed with water (200 ml x 2) and brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give crude (R)-5-(azidomethyl)-3- (4-bromo-3-fluorophenyl)oxazolidin-2-one, which was carried to the next step without purification.

Step D: (S)-5-(aminomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one

Water (5, 72 ml, 317 mmol) and triphenylphosphine (20.81 g, 79 mmol), then the mixture was stirred at 70° C. for 12 hours. The reaction mixture was evaporated to remove the organic solvent, then water (20 ml) was added and the pH was adjusted to 4 using 1 M HCl. The resulting mixture was extracted with EtOAc (30 ml x3), then the pH of the aqueous layer was brought to 10 with Na ₂ CO ₃ (3M). The aqueous layer was extracted with EtOAc (40 mL x4), the combined organic solvents were dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give crude (S)-5-(aminomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin- 2-one as a solid, which was used in the next step without further purification. MS (ESI) m/z: 288.9, 290.9 [M+H ⁺ ].

Step E: (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one

To a solution of (S)-5-(aminomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one (3.0 g, 9.34 mmol), (4-(methylthio)phenyl)boronic acid (1.9 g, 11.21 mmol) and tribasic potassium phosphate (9.3 ml, 18.68 mmol) in THF (40 ml) were added ^2nd generation xphos precatalyst (0.7 g, 0.93 mmol ) in an N2 atmosphere. The mixture was degassed and refilled with N ₂ (3x). The mixture was stirred at 60°C for 16 hours. The mixture was then concentrated to give a crude product which was purified by column chromatography (SiO ₂ , PE:EtOAc=1:1 to DCM:MeOH=10:1) to give the desired product (S)-5-(aminomethyl)-3-( 2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one 1 as a solid. MS (ESI) m/z: 333.1 [M+H ⁺ ] (calc. 333.1).

The following compounds were obtained using the methods described in example 1, with the replacement of the appropriate reagents and/or reagents.

Examples Structure Name IUPAC Mass. M+H ⁺ 2

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-4-carboxamide 3330.1 3

(5S)-5-(aminomethyl)-3-[2-fluoro-3'-(methylsulfanyl)
biphenyl-4-yl]-1,3-oxazolidin-2-one 3333.1 4

(5S)-5-(aminomethyl)-3-[2-fluoro-4'-(methylsulfonyl)
biphenyl-4-yl]-1,3-oxazolidin-2-one 3365 5

(5S)-5-(aminomethyl)-3-(3-fluoro-4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)-1,3-oxazolidin-2-one 3328.1 6

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-4-sulfonamide 3366 7

(5S)-5-(aminomethyl)-3-[2-fluoro-4'-(methylsulfinyl)
biphenyl-4-yl]-1,3-oxazolidin-2-one 3349.1 8

(5S)-5-(aminomethyl)-3-(3-fluoro-4-[1,2,4]triazolo[1,5-a]pyridin-7-ylphenyl)-1,3-oxazolidin-2-one 3328.1 9

(5S)-5-(aminomethyl)-3-(3-fluoro-4-[1,2,4]triazolo[4,3-a]pyridin-6-ylphenyl)-1,3-oxazolidin-2-one 3328.1 10

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-3-carboxamide 3330 eleven

(5S)-5-(aminomethyl)-3-(2-fluoro-4'-hydroxybiphenyl-4-yl)-1,3-oxazolidin-2-one 3303.1 12

(5S)-5-(aminomethyl)-3-(3-fluoro-4-furan-3-ylphenyl)-1,3-oxazolidin-2-one 2277.1 13

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-3-carbonitrile 3312.1 14

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluoro-N,N-dimethylbiphenyl-4-sulfonamide 3394 15

(5S)-5-(aminomethyl)-3-(3-fluoro-4-thiophen-3-ylphenyl)-1,3-oxazolidin-2-one 2292.8 16

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-pyrazol-5-yl)phenyl]-1,3-oxazolidin-2-one 2277 17

N-{4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-4-yl}methanesulfonamide 3380 18

4'-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2'-fluorobiphenyl-4-carbonitrile 3312 19

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(6-fluoropyridin-3-yl)phenyl]-1,3-oxazolidin-2-one 3306.1 20

(5S)-5-(aminomethyl)-3-(2-fluoro-3'-nitrobiphenyl-4-yl)-1,3-oxazolidin-2-one 3332 21

(5S)-5-(aminomethyl)-3-[3'-(1,1-dioxidothiomorpholin-4-yl)-2-fluorobiphenyl-4-yl]-1,3-oxazolidin-2-one 4420 22

(5S)-5-(aminomethyl)-3-[4-(6-chloropyridin-3-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one 3322 23

(5S)-5-(aminomethyl)-3-{3-fluoro-4-[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl]phenyl}-1,3-oxazolidine -2-he 3352 24

(5S)-5-(aminomethyl)-3-(3-fluoro-4-pyridin-3-ylphenyl)-1,3-oxazolidin-2-one 2288 25

(5S)-5-(aminomethyl)-3-(3-fluoro-4-pyrimidin-5-ylphenyl)-1,3-oxazolidin-2-one 2289 26

tert-butyl-4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}-3,6-dihydropyridine-1(2H) -carboxylate N 27

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-indol-6-yl)phenyl]-1,3-oxazolidin-2-one 3326.1 28

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(2-methoxypyrimidin-5-yl)phenyl]-1,3-oxazolidin-2-one 3319.1 29

(5S)-5-(aminomethyl)-3-{3-fluoro-4-[2-(1,4-oxazepan-4-yl)pyrimidin-5-yl]phenyl}-1,3-oxazolidin-2- He 3388.1 thirty

(5S)-5-(aminomethyl)-3-[4-(2-chloropyridin-4-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one 3322.2 31

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-1,3-oxazolidin-2-one 3327.1 32

(5S)-5-(aminomethyl)-3-{3-fluoro-4-[2-(methylsulfanyl)pyrimidin-5-yl]phenyl}-1,3-oxazolidin-2-one 3335.1 33

(5S)-5-(aminomethyl)-3-[4-(6-cyclopropylpyridin-3-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one 3328.1 34

5-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}-2,3-dihydro-1H-isoindol-1-one 3342.1 35

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-1,3-oxazolidin-2-one 3327.1 36

(5S)-5-(aminomethyl)-3-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluorophenyl}-1,3-oxazolidin-2-one 3327.1 37

(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1,3-oxazolidin-2-one 2291.1 38

(5S)-5-(aminomethyl)-3-(3-fluoro-4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-1,3-oxazolidin-2-one 3328 39

(5S)-5-(aminomethyl)-3-(2-fluorobiphenyl-4-yl)-1,3-oxazolidin-2-one 2287

Example 40

Synthesis of (S)-N-((3-(5-fluoro-6-(4-(methylthio)phenyl)pyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide.

Step A: Synthesis of (S,E)-1-(benzylideneamino)-3-chloropropan-2-ol.

Ammonia hydrate (4.9 g, 140 mmol) and benzaldehyde (5.98 g, 56 .4 mmol) and the resulting mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated to give (S,E)-1-(benzylideneamino)-3-chloropropan-2-ol as a solid, which was used in the next step without purification.

Step B: Synthesis of (S)-1-amino-3-chloropropan-2-ol hydrochloride

HCl (6.8 ml, 83 mmol) and the resulting mixture was stirred at 35°C for 4 hours. The reaction mixture was concentrated to a smaller volume, washed with water (20 ml) and the aqueous extract was lyophilized to give (S)-1-amino-3-chloropropan-2-ol hydrochloride as a solid. The crude product was carried to the next step without further purification.

Step C: Synthesis of (S)-1-acetamido-3-chloropropan-2-yl acetate

To a solution of (S)-1-amino-3-chloropropan-2-ol hydrochloride (28.0 g, 153 mmol) in DCM (100 ml) was added acetic anhydride (36.0 g, 353 mmol), pyridine (15. 3 g, 193 mmol) and the resulting mixture was stirred at 35° C. for 16 hours. K ₂ CO ₃ (42.0 g, 304 mmol) was then added in portions while maintaining the temperature at 5-7°C, then 0.5 N HCl (250 ml) was added, the resulting mixture was diluted with H ₂ O (250 ml) and extracted with DCM (200 ml x 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-1-acetamido-3-chloropropan-2-yl acetate as a solid. The crude product was used directly in the next step without further purification. MS (ESI) m/z: 217.3 [M+Na ⁺ ].

Step D: Synthesis of (S)-N-((3-(6-chloro-5-fluoropyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide

To a solution of benzyl(6-chloro-5-fluoropyridin-3-yl)carbamate (6 g, 21.38 mmol) in DMF (20 ml) was added MeOH (1.730 ml, 42.8 mmol) and then the solution was added dropwise lithium tert-butoxide (5.1 g, 64.1 mmol) in THF (30 ml) at 0°C. The resulting mixture was slowly heated to 16°C and stirred for 2 hours. Then, (S)-1-acetamido-3-chloropropan-2-yl acetate (8.3 g, 42.8 mmol) was added to this reaction mixture and stirred at 16° C. for 12 hours. The mixture was concentrated to remove THF and diluted with EtOAc (20 ml), the organic layer was washed with H ₂ O (25 ml x 3), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography ( 0-90% DCM/MeOH) to give (S)-N-((3-(6-chloro-5-fluoropyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide as a solid. MS (ESI) m/z: 287.8[M+H ⁺ ].

Step E: Synthesis of (S)-N-((3-(5-fluoro-6-(4-(methylthio)phenyl)pyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide 40

To a solution of (S)-N-((3-(6-chloro-5-fluoropyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide (80.0 mg, 0.278 mmol), (4- (methylthio)phenyl)boronic acid (46.7mg, 0.278mmol) and tribasic potassium phosphate (118.0mg, 0.556mmol) in THF (2mL) was added xphos 2nd generation pre-catalyst (21.9mg, 0.028 mmol) in an N2 atmosphere. The mixture was degassed and refilled with N ₂ (3x). The mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated to give the crude product, which was purified by reverse phase prep-HPLC to give (S)-N-((3-(5-fluoro-6-(4-(methylthio)phenyl)pyridin-3-yl) -2-oxooxazolidin-5-yl)methyl)acetamide 40 as a solid. LC/MS=376.1 [M+H ⁺ ].

Example 41

Synthesis of (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)cyclopropanecarboxamide.

To a solution of cyclopropanecarboxylic acid (14.2 mg, 0.165 mmol) in DMF (2 ml) was added DIEA (53 ml, 0.301 mmol) and HATU (62.9 mg, 0.165 mmol). The mixture was stirred at 20°C for 15 minutes and then (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl) was added oxazolidin-2-one (50.0 mg, 0.150 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl] -4-yl)-2-oxooxazolidin-5-yl)methyl)cyclopropanecarboxamide as a solid. LC/MS=401.1 [M+H ⁺ ].

Example 42

Synthesis of (S)-N-((3-(4-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide.

Step A: Synthesis of benzyl(4-bromophenyl)carbamate:

To a solution of 4-bromoaniline (50.0 g, 291 mmol) in acetone (500 ml) at 0° C. was added benzyl chloroformate (54.5 g, 320 mmol) to form a white slurry. Then sodium bicarbonate solution (581 ml, 581 mmol) was added slowly. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 hours. The organic solvent was removed under reduced pressure and the precipitated solid was collected by filtration and washed with water (200 mL × 2). The solid was then dried to give benzyl(4-bromophenyl)carbamate as a solid.

Step B: Synthesis of (S)-N-((3-(4-bromophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide:

A solution of lithium 2-methylpropan-2-olate (7.8 g, 98.0 mmol) in THF (60 ml) at 0°C, followed by the addition of (S)-1-acetamido-3-chloropropan-2-yl acetate (12.6 g, 65.3 mmol). The mixture was heated to 20°C and stirred for 16 hours. The mixture was concentrated to give a residue which was poured into ice water (100 ml) and a solid precipitated. The mixture was filtered and the solid was washed with 100 ml of PE and dried in vacuo to give (S)-N-((3-(4-bromophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide as a solid. MS (ESI) m/z: 313.0 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO-d6) d 8.30 - 8.22 (m, 1H), 7.60 - 7.54 (m, 2H), 7.54 - 7.48 (m, 2H), 4.72 (dd, J = 6.0, 8.2 Hz, 1H ), 4.10 (t, J =8.9 Hz, 1H), 3.73 (dd, J =6.6, 8.8 Hz, 1H), 3.41 (t, J =5.4 Hz, 2H), 1.83 (s, 3H). MS (ESI) m/z: 313.0, 315.0 [M+H ⁺ ].

Step C: Synthesis of (S)-N-((3-(4-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)phenyl) -2-oxooxazolidin-5-yl)methyl)acetamide

To a solution of (S)-N-((3-(4-bromophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (100.0 mg, 0.319 mmol), 5,6,7,8-tetrahydro-[ 1,2,4]triazolo[1,5-a]pyrazine (150.0 mg, 1.208 mmol) and Cs ₂ CO ₃ (312.0 mg, 0.958 mmol) in 1,4-dioxane (2 ml) was added preliminary 2nd generation ruphos catalytic converter (12.4 mg, 0.016 mmol) under N2 atmosphere. The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-N-((3-(4-(5,6-dihydro-[1,2,4]triazolo[1,5 -a]pyrazin-7(8H)-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide as a solid. MS(ESI) m/z: 357.1 [M+H+].

Example 43

Synthesis of (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4 -yl)oxazolidin-2-one.

Step A: Synthesis of (R)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-5-(hydroxymethyl)oxazolidin-2-one.

To a solution of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (5.0 g, 17.24 mmol) and (4-(methylthio)phenyl)boronic acid (3.5 g, 20.68 mmol) in THF (60 mL) was added aqueous potassium phosphate (17.2 mL, 34.5 mmol) followed by a 2nd generation xphos pre-catalyst (0.7 g, 0.862 mmol) in N atmosphere₂. The resulting mixture was stirred at 60°C for 16 hours. The mixture was then filtered and concentrated to give a residue which was purified by silica gel chromatography (20%-100% EtOAc in PE) to give (R)-3-(2-fluoro-4'-(methylthio)-[1,1' -biphenyl]-4-yl)-5-(hydroxymethyl)oxazolidin-2-one as a solid. ¹H NMR (400 MHz, DMSO-d6) d 7.66-7.32 (m, 7H), 5.25-5.22 (m, 1H), 4.74-4.70 (m, 1H), 4.13-4.08 (m, 1H), 3.87-3.83 (m, 1H), 3.70-3.65 ( m, 1H), 3.58-3.54 (m, 1H), 2.47 (s, 3H).

Step B: (R)-(3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl methanesulfonate

To a solution of (R)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-5-(hydroxymethyl)oxazolidin-2-one (500.0 mg, 1.50 mmol) in DCM (10 ml) was added DIEA (0.5 ml, 3.00 mmol) and MsCl (0.2 ml, 2.25 mmol) at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with water (5 ml) and then diluted with DCM (20 ml), washed with water (20 ml x 2) and then with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain the crude product (R)-(3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl methanesulfonate as a solid. The crude material was used in the next step of the synthesis without further purification.

Step C: Synthesis of (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl ]-4-yl)oxazolidin-2-one.

K ₂ CO ₃ (50.4 mg, 0.36 mmol) and (R)-( 3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50.0 mg, 0.12 mmol). The resulting mixture was stirred at 20°C for 24 hours. The reaction mixture was quenched with saturated NH ₄ Cl (5 ml) and then diluted with EtOAc (20 ml), washed with water (20 ml x 2) and brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain a residue , which was purified by reverse phase prep-HPLC to give (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-fluoro-4'-(methylthio) -[1,1'-biphenyl]-4-yl)oxazolidin-2-one as a solid. LC/MS, m/z: 385.0 [M+H ⁺ ].

The following compounds were obtained using the methods described in example 43, with the replacement of the appropriate reagents and/or reagents.

Example Structure Name IUPAC (M+H) 44

(5R)-3-[2-fluoro-4'-(methylsulfanyl)
biphenyl-4-yl]-5-(1H-tetrazol-1-ylmethyl)-1,3-oxazolidin-2-one 3386.1 45

(5R)-3-[2-fluoro-4'-(methylsulfanyl)
biphenyl-4-yl]-5-(1H-imidazol-1-ylmethyl)-1,3-oxazolidin-2-one 3384.1 46

(5R)-3-[2-fluoro-4'-(methylsulfanyl)
biphenyl-4-yl]-5-(1H-pyrazol-1-ylmethyl)-1,3-oxazolidin-2-one 3384.1

Example 47

Synthesis of (S)-N-((3-(2,6-difluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)acetamide .

Step A: Synthesis of benzyl(4-bromo-3,5-difluorophenyl)carbamate.

To a stirred solution of 4-bromo-3,5-difluoroaniline (20 g, 96 mmol) in acetone (200 ml) at 0°C was added benzyl chloroformate (18.04 g, 106 mmol) to form a white slurry. Then sodium bicarbonate (192 ml, 192 mmol) was added in portions. After the addition, the mixture was allowed to warm to 25° C. and stirred for 16 hours. The organic solvent was removed under reduced pressure, the precipitated solid was collected by filtration and washed with water (50 ml × 2). The solid was then dried to give benzyl(4-bromo-3,5-difluorophenyl)carbamate as a solid.¹HNMR (CDCl₃, 400 MHz) d 7.39-7.37 (m, 5H), 7.11-7.09 (dd,J=2.0, 6 Hz, 2H), 5.20 (s, 2H).

Step B: (S)-N-((3-(4-bromo-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide:

A solution of 2-methylpropan-2 lithium -olate (5.62 g, 70.1 mmol) in THF (48 ml). The resulting mixture was cooled to 5° C., then (S)-1-acetamido-3-chloropropan-2-yl acetate (9.06 g, 46.8 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours and then extinguished by adding saturated NH ₄ Cl (50.0 ml). The precipitated solid was collected, washed with water (50 ml) and dried to give (S)-N-((3-(4-bromo-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide as solid. MS (ESI) m/z: 348.8, 350.8 [M+H ⁺ ].

Step C: (S)-N-((3-(2,6-difluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl )acetamide 47 :

To a solution of (S)-N-((3-(4-bromo-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (40.0 mg, 0.12 mmol), (4- (methylthio)phenyl)boronic acid (28.9 mg, 0.17 mmol), aqueous potassium phosphate (0.23 ml, 0.23 mmol) in THF (1 ml) was added xphos 2nd generation pre-catalyst (4 .5 mg, 5.73 µmol) under N2 atmosphere. The mixture was stirred at 60°C for 16 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-N-((3-(2,6-difluoro-4'-(methylthio)-[1,1'- biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)acetamide as a solid. LC/MS, m/z: 393.1 [M+H ⁺ ].

Example 48

Synthesis of (S)-5-(aminomethyl)-3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)oxazolidin-2-one.

Step A: Synthesis of 4-(3-fluoro-5-nitropyridin-2-yl)thiomorpholine.

To a solution of 2-chloro-3-fluoro-5-nitropyridine (3.0 g, 15.3 mmol) in DMF (30 ml) was added thiomorpholine (1.6 g, 15.3 mmol) and DIEA (5.3 ml , 30.6 mmol). The mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature and then diluted with water (50 ml). The precipitated solid was collected by filtration and dried to give 4-(3-fluoro-5-nitropyridin-2-yl)thiomorpholine as a solid.¹HNMR d 8.87 (s, 1H), 7.98 (dd,J=2.0, 13.6Hz, 1H), 4.15-4.12 (m, 4H), 2.76-2.74 (m, 4H).

Step B: Synthesis of 5-fluoro-6-thiomorpholinopyridine-3-amine.

Iron (4.1 g, 74 .0 mmol). The resulting mixture was stirred at 60°C for 4 hours. The reaction mixture was concentrated and then diluted with EtOAc (100 ml), washed with saturated NaHCO ₃ (80 ml x 2) and then brine (80 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 5-fluoro-6-thiomorpholinopyridine-3-amine as a solid. The crude material was used in the next step without further purification.

Step C: Synthesis of benzyl (5-fluoro-6-thiomorpholino-pyridin-3-yl) carbamate.

To a stirred solution of 5-fluoro-6-thiomorpholinopyridine-3-amine (3.1 g, 13.1 mmol) in acetone (30 ml) at 0°C was added CBZ-Cl (2.2 ml, 15.7 mmol) with the formation of a suspension. Then sodium bicarbonate solution (26.2 ml, 26.2 mmol) was added slowly. After the addition, the mixture was allowed to warm to 20° C. and stirred for 16 hours. The organic solvent was removed under reduced pressure and the precipitated solid was collected by filtration, washed with water (40 mL x 2) and dried to give benzyl(5-fluoro-6-thiomorpholino-pyridin-3-yl) carbamate as a solid.¹HNMR (CDCl₃, 400 MHz) d 7.83 (s, 1H), 7.75-7.72 (m, 1H), 7.39-7.35 (m, 5H), 6.61 (s, 1H), 5.20 (s, 2H), 3.71-3.68 (m, 4H), 2.75 -2.67 (m, 4H).

Step D: Synthesis of (S)-N-((3-(5-fluoro-6-thiomorpholinopyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide.

To a solution of benzyl (5-fluoro-6-thiomorpholinopyridin-3-yl) carbamate (4.1 g, 10.6 mmol) in a mixture of DMF (15 ml) and MeOH (0.9 ml, 21.2 mmol) was added a solution lithium tert-butoxide (2.6 g, 31.9 mmol) in THF (30 ml) at 0°C. The resulting mixture was stirred at 20°C for 0.5 hour, and then (S)-1-acetamido-3-chloropropan-2-yl acetate (4.1 g, 21.2 mmol) was added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. The mixture was quenched with concentrated HCl (10 ml) and then concentrated to give the crude product, which was purified by column chromatography (SiO ₂ , PE:EtOAc=1:1-DCM:MeOH=10:1) to give (S)-N- ((3-(5-fluoro-6-thiomorpholinopyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide as a solid. ¹ HNMR (CDCl ₃ , 400 MHz) d 8.06 (d, J = 2 Hz, 1H), 7.90 (dd, J = 2.4, 14.8 Hz, 1H), 4.84-4.78 (m, 1H), 4.14-4.12 (m, 1H), 3.81-3.70 (m, 5H), 3.57-3.56 (m, 2H), 2.74-2.71 (m, 4H), 1.97 (s, 3H).

Step E: Synthesis of (S)-N-((3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide.

To a solution of (S)-N-((3-(5-fluoro-6-thiomorpholinopyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide (300 mg, 0.76 mmol) in MeOH (3 ml) and water (1.5 ml) was added oxon (703 mg, 1.14 mmol) at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by prep-HPLC to give (S)-N-((3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)-2-oxooxazolidin- 5-yl)methyl)acetamide as a solid.¹HNMR (DMSO-d6, 400 MHz) d 8.25-8.22 (m, 1H), 8.13 (s, 1H), 7.93 (dd,J=1.6, 14.8Hz, 1H), 4.77-4.72 (m, 1H), 4.11-4.07 (m, 1H), 3.84 (s, 4H), 3.73-3.69 (m, 1H), 3.41-3.39 (m, 2H ), 3.20 (s, 4H), 1.82 (s, 3H). MS (ESI) m/z: 387.0 [M+H⁺].

Step F: (S)-5-(aminomethyl)-3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)oxazolidin-2-one 48

To a solution of (S)-N-((3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)-2-oxooxazolidin-5-yl)methyl)acetamide (150 mg, 0.39 mmol) in MeOH (2 ml) and water (0.5 ml) was added HCl (0.5 ml, 6.09 mmol). The mixture was stirred at 70°C for 16 hours. The mixture was concentrated to give the crude product, which was purified by reverse phase prep-HPLC to give (S)-5-(aminomethyl)-3-(6-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)oxazolidine -2-she48 in the form of a solid.¹HNMR (CDCl₃, 400 MHz) d 8.21 (s, 3H), 8.11 (s, 1H), 7.92 (dd,J=2.0, 14.8Hz, 1H), 4.95-4.88 (m, 1H), 4.18-4.14 (m, 1H), 3.84-3.77 (m, 5H), 3.23-3.19 (m, 6H). MS (ESI) m/z: 345.0 [M+H⁺].

Examples 49 and 50

Synthesis of (R)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2-one .

Step A: (R)-3-(4-bromo-3-fluorophenyl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2-one and (R)-2-((3-(4- bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)isoxazol-3(2H)-one

To a solution of triphenylphosphine (2.2 g, 8.3 mmol) in dry THF (50 ml) was added DIAD (1.6 ml, 8.3 mmol) and the resulting mixture was stirred for 0.5 hour. Isoxazol-3-ol (645 mg, 7.6 mmol) was added to this reaction mixture and the mixture was stirred for 0.5 hour, and then (R)-3-(4-bromo-3-fluorophenyl)-5- (hydroxymethyl)oxazolidin-2-one (2.0 g, 6.9 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with EtOAc (200 ml), washed with hydrochloric acid (1M, 50 ml) then water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , PE-EtOAc) to give (R)-3-(4-bromo-3-fluorophenyl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2-one as solid (main product) and (R)-2-((3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)isoxazol-3(2H)-one as a solid ( by-product).

(R)-3-(4-bromo-3-fluorophenyl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2-one ¹ H NMR (CDCl ₃ , 400 MHz) d 8.16 (d, J = 1.6 Hz, 1H), 7.66 (dd, J =7.2, 11.6 Hz, 1H), 7.39-7.58 (m, 4H), 7.17 (dd, J =1.6, 8.8 Hz, 1H), 6.00 (d, J =1.6 Hz, 1H), 4.89–5.11 (m, 2H), 4.43–4.63 (m, 2H), 4.15 (t, J =8.8 Hz, 1H), 3.96 (dd, J =6.4, 8.8 Hz, 1H).

(R)-2-((3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)isoxazol-3(2H)-one¹H NMR (CDCl₃, 400 MHz) d 7.88 (d,J=2.4 Hz, 1H), 7.40-7.59 (m, 3H), 7.04-7.17 (m, 1H), 5.82 (d,J=2.4 Hz, 1H), 4.91–5.02 (m, 1H), 4.17–4.38 (m, 2H), 4.11 (t,J=8.8 Hz, 1H), 3.96 (dd,J=5.6, 9.2 Hz, 1H).

Step B: (R)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2 -He:

2nd generation xphos pre-catalyst (66.1 mg, 0.08 mmol) was added to the mixture of (R)-3-(4-bromo-3-fluorophenyl)-5-((isoxazol-3-yloxy)methyl) oxazolidin-2-one (300.0 mg, 0.84 mmol), (4-(methylthio)phenyl)boronic acid (155 mg, 0.924 mmol), tribasic potassium phosphate (357.0 mg, 1.68 mmol) in THF (5 ml) and water (1.5 ml) under N ₂ atmosphere. The mixture was stirred at 70°C for 16 hours. Most of the starting material was consumed by LCMS and 50% of the desired product was formed. The mixture was cooled, water (10 ml) was added and the mixture was extracted with ethyl acetate (20 ml × 2). The combined organic fractions were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase prep-HPLC to give (R)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-5-((isoxazol-3 -yloxy)methyl)oxazolidin-2-one, Example 49, as a solid. ¹ H NMR (CDCl ₃ , 400 MHz) d 8.71 (d, J = 1.6 Hz, 1H), 7.64-7.58 (m, 2H), 7.51-7.47 (m, 3H), 7.36 (d, J = 8.4 Hz, 2H), 6.40 (d, J =1.6 Hz, 1H), 5.12-5.11 (m, 1H), 4.53-4.48 (m, 2H), 4.25-4.23 (m, 1H), 4.00-3.96 (m, 1H) , 2.50 (s, 3H). MS (ESI) m/z: 401.0 [M+H ⁺ ].

(R)-2-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)isoxazol-3( 2H)-one, example compound50, prepared from (R)-2-((3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)isoxazol-3(2H)-one based on the protocol described in step B in Method above, as a solid. (CDCl₃, 400 MHz) d 8.56 (d,J=2.4 Hz, 1H), 7.58-7.48 (m, 4H), 7.36-7.34 (m, 3H), 5.98 (d,J=2.4 Hz, 1H), 4.91–5.02 (m, 1H), 4.27–4.20 (m, 3H), 3.90–3.88 (m, 1H), 2.50 (s, 3H). MS (ESI) m/z: 401.1 [M+H⁺].

Example 54

Synthesis of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(6-(piperazin-1-yl)pyridin-3-yl )phenyl)oxazolidin-2-one.

Step A: Synthesis of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one.

2,5-Norbornadiene (13.2 g, 143 mmol) was added to a solution of (R)-5-(azidomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one (9.0 g, 28 .6 mmol) in dioxane (200 ml), then the mixture was stirred at 110°C for 17 hours. The reaction mixture was then concentrated and the crude product was purified by silica gel column chromatography (SiO ₂ , DCM-DCM:MeOH=95:5) to give (R)-5-((1H-1,2,3-triazole-1 -yl)methyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one as a solid, as well as 2.0 g of crude product (<80% pure). MS (ESI) m/z: 382.1, 384.1 [M+ACN+H ⁺ ].

Stage B: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(6-(piperazin-1-yl)pyridin-3 -yl)phenyl)oxazolidin-2-one

To a solution of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one (50.0 mg, 0 .15 mmol), (6-(piperazin-1-yl)pyridin-3-yl)boronic acid (36.4 mg, 0.18 mmol) and aqueous tribasic potassium phosphate (1M, 0.23 ml, 0.29 mmol) in THF (1 mL) was added xphos 2nd generation pre-catalyst (5.8 mg, 7.33 µmol) under N2 atmosphere. The mixture was stirred at 60°C for 16 hours. The mixture was filtered and concentrated to give a residue which was purified by reverse phase prep-HPLC to give (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro -4-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)oxazolidin-2-one, compound of Example 54, as a solid. MS (ESI) m/z: 424.2 [M+H ⁺ ].

The following connection was obtained using the methods described in example 54, with the replacement of the appropriate reagents and/or reagents.

Example Structure Name IUPAC Observation (M+H) 55

(5R)-3-[5'-(aminomethyl)-2,2'-difluorobiphenyl-4-yl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin- 2nd 3386.1

Example 56

Synthesis of (S)-5-(aminomethyl)-3-(3-fluoro-4-(thiophen-2-yl)phenyl)oxazolidin-2-one

To a solution of (S)-5-(aminomethyl)-3-(4-bromo-3-fluorophenyl)oxazolidin-2-one (70.0 mg, 0.24 mmol), tributyl(thiophen-2-yl)stannan ( 108.0 mg, 0.29 mmol) and tribasic potassium phosphate (0.48 ml, 0.48 mmol) in THF (2 ml) were added xphos 2nd generation pre-catalyst (19.0 mg, 0.02 mmol ) in an N ₂ atmosphere. The mixture was degassed and refilled three times with N ₂ . The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated to give the crude product, which was purified by reverse phase prep-HPLC to give (S)-5-(aminomethyl)-3-(3-fluoro-4-(thiophen-2-yl)phenyl)oxazolidin-2 -one, the compound of example 54, as a solid. MS (ESI) m/z: 293.0 [M+H ⁺ ].

Example 57

Synthesis of (S)-4'-(5-((2-aminoacetamido)methyl)-2-oxooxazolidin-3-yl)-2'-fluoro-[1,1'-biphenyl]-4-carboxamide.

Step A: Synthesis of (S)-tert-butyl(2-(((3-(4'-carbamoyl-2-fluoro-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl )methyl)amino)-2-oxoethyl)carbamate.

DIEA (0.05 ml, 0.27 mmol) and HATU (78 .0 mg, 0.20 mmol). The mixture was stirred at 20°C for 10 minutes, then (S)-4'-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2'-fluoro-[1,1'-biphenyl]- was added 4-carboxamide, compound of example 2 (50.0 mg, 0.14 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-tert-butyl(2-(((3-(4'-carbamoyl-2-fluoro-[1,1' -biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)amino)-2-oxoethyl)carbamate as a solid.

Step B: (S)-4'-(5-((2-aminoacetamido)methyl)-2-oxooxazolidin-3-yl)-2'-fluoro-[1,1'-biphenyl]-4-carboxamide

To a solution of (S)-tert-butyl(2-(((3-(4'-carbamoyl-2-fluoro-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl )amino)-2-oxoethyl)carbamate (70.0 mg, 0.13 mmol) in DCM (5 ml) was added TFA (0.1 ml, 1.30 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-4'-(5-((2-aminoacetamido)methyl)-2-oxooxazolidin-3-yl)-2' -fluoro-[1,1'-biphenyl]-4-carboxamide as a solid. MS (ESI) m/z: 386.9 [M+H+].

Example 58

Synthesis of (S)-tert-butyl(2-(((3-(4'-carbamoyl-2-fluoro-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl) amino)-2-oxoethyl)carbamate.

To a solution of (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one (50.0 mg, 0.15 mmol) in DMF (2 ml) was added DIEA (0.05 ml, 0.30 mmol) and isocyanatoethane (12.8 mg, 0.18 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated to give a residue which was purified by reverse phase prep-HPLC to give (S)-1-ethyl-3-((3-(2-fluoro-4'-(methylthio)-[1,1'- biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)urea, compound of Example 56, as a solid. MS (ESI) m/z: 403.9 [M+H ⁺ ].

Example 59

Synthesis of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one (compound of Example 59) .

Step A: Synthesis of 4-(2,6-difluoro-4-nitrophenyl)morpholine.

Potassium carbonate (1.3 g, 9.63 mmol) and morpholine (0.8 g, 8.75 mmol) at 20°C. The reaction mixture was stirred at 50°C for 10 hours. The reaction mixture was poured into EtOAc (50 ml) and washed with brine (50 ml x 3). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(2,6-difluoro-4-nitrophenyl)morpholine as a solid. ¹ H NMR (CDCl ₃ , 400 MHz) d 7.22 (m, 4H), 4.98 (br s, 2H), 3.97 (m, 2H), 3.00 (m, 2H), 1.59 (m, 4H). MS (ESI) m/z: 244.8 [M+H ⁺ ].

Step B: Synthesis of 3,5-difluoro-4-morpholinoaniline.

To a solution of 4-(2,6-difluoro-4-nitrophenyl)morpholine (2.3 g, 9.42 mmol) in MeOH (25 ml) was added Pd-C (10% wt., 0.3 g, 2. 82 mmol) at 20°C. The reaction mixture was stirred under H ₂ atmosphere at 20°C for 10 hours. The reaction mixture was filtered and the filtrate was concentrated to give 3,5-difluoro-4-morpholinoaniline as a solid. ¹ H NMR (CDCl ₃ , 400 MHz) d 6.17 (m, 2H), 3.79 (m, 4H), 3.07 (m, 4H). MS (ESI) m/z: 214.9 [M+H+].

Step C: Synthesis of benzyl(3,5-difluoro-4-morpholinophenyl)carbamate

To a solution of 3,5-difluoro-4-morpholinoaniline (1.8 g, 8.40 mmol) in acetone (20 ml) was added benzyl chloroformate (2.2 g, 12.60 mmol) at 20°C, followed by the hydrogen carbonate solution sodium (1.4 g, 16.81 mmol) in water (20 ml). The reaction mixture was stirred at 20°C for 10 hours and then evaporated and dissolved in EtOAc (50 ml). The organic phase was washed with water (50 ml × 3), dried over Na₂SO₄ and concentrated to give benzyl(3,5-difluoro-4-morpholinophenyl)carbamate as a solid.¹H NMR (CDCl₃, 400 MHz) d 7.37 (m, 7H), 6.96 (d,J=10.4 Hz, 2H), 5.19 (s, 2H), 4.70 (s, 1H), 3.79 (m, 4H), 3.13 (brs, 4H). MS (ESI) m/z: 349.3[M+H⁺].

Step D: Synthesis of (R)-3-(3,5-difluoro-4-morpholinophenyl)-5-(hydroxymethyl)oxazolidin-2-one

To a solution of benzyl(3,5-difluoro-4-morpholinophenyl)carbamate (2.1 g, 6.03 mmol) in THF (30 mL) was added lithium 2-methylpropan-2-olate (1.4 g, 18.09 mmol). The reaction mixture was stirred at 20° C. for 0.5 hour and then (R)-oxiran-2-ylmethyl butyrate (1.7 g, 12.06 mmol) was added. The resulting mixture was stirred at 20°C for 10 hours. The solvent was removed and the crude product was purified by column chromatography (SiO ₂ , EtOAc:PE=2:1) to give (R)-3-(3,5-difluoro-4-morpholinophenyl)-5-(hydroxymethyl)oxazolidin-2 - It is in the form of a solid. ¹ H NMR (CDCl ₃ , 400 MHz) d 7.08 (m, 2H), 4.73 (m, 1H), 3.97 (m, 3H), 3.80 (m, 4H), 3.72 (dd, J = 3.5, 12.9 Hz, 1H), 3.22 (br s, 2H), 3.13 (br s, 4H). MS (ESI) m/z: 314.9 [M+H ⁺ ].

Step E: Synthesis of (R)-(3-(3,5-difluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate.

Methansulfonyl chloride (191 mg , 1.67 mmol) and triethylamine (225 mg, 2.227 mmol) at 0°C. The reaction mixture was stirred at 23°C for 10 hours. The mixture was washed with water (20 ml x 3). The organic phase was then dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-(3-(3,5-difluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate as a solid. MS (ESI) m/z: 392.9 [M+H ⁺ ].

Step F: Synthesis of (R)-5-(azidomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one.

To a solution of (R)-(3-(3,5-difluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (100.0 mg, 0.26 mmol) in DMF (1 ml) was added sodium azide (21.5 mg, 0.33 mmol). The reaction mixture was stirred at 70°C for 5 hours. The mixture was diluted with EtOAc (20 ml), washed with brine (15 ml × 3). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-5-(azidomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one as an oil. MS (ESI) m/z: 339.9 [M+H ⁺ ].

Step G: Synthesis of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one.

To a solution of (R)-5-(azidomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one (86 mg, 0.23 mmol) in a mixture of THF (2 ml) and water (0 .1 ml) triphenylphosphine (120 mg, 0.46 mmol) was added. The reaction mixture was stirred at 70°C for 10 hours. Then the solvent was removed under vacuum and EtOAc (20 ml) was added to the residue. The organic phase was washed with brine (15 ml × 3), dried over Na₂SO₄, filtered and concentrated to give the crude product, which was purified by reverse phase prep-HPLC to give (S)-5-(aminomethyl)-3-(3,5-difluoro-4-morpholinophenyl)oxazolidin-2-one in the form of a solid.¹H NMR (CDCl₃, 400 MHz) d 7.22 (m, 2H), 4.2 (t,J=9.2 Hz, 1H), 3.77 (m, 4H), 3.35 (m, 3H), 3.11 (br s, 3H). MS (ESI) m/z: 313.9 [M+H⁺].

Example 60

Synthesis of (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)-2, 2-dimethylhydrazinecarboxamide (Example 60)

Step A: Synthesis of (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl) -1H-imidazole-1-carboxamide.

To a solution of (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one (350 mg, 1, 05 mmol) in DMF (5 ml) was added DIEA (817 mg, 6.32 mmol) and CDI and the resulting mixture was stirred at 20°C for 16 hours. The crude material was used directly in the next step. MS (ESI) m/z: 426.9 [M+H ⁺ ].

Step B: Synthesis of (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl) -2,2-dimethylhydrazinecarboxamide.

To a solution of (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)-1H -imidazole-1-carboxamide (100 mg, 0.23 mmol) in DMF (2 ml) was added 1,1-dimethylhydrazine (85 mg, 1.41 mmol) and the resulting mixture was stirred at 40°C for 12 hours. The reaction mixture was evaporated to dryness and the crude product was purified by reverse phase prep-HPLC to give (S)-N-((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4- yl)-2-oxooxazolidin-5-yl)methyl)-2,2-dimethylhydrazinecarboxamide as a solid. MS (ESI) m/z: 441.0 [M+Na ⁺ ].

Example 62

Synthesis of (S)-methyl((3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)carbamate (example compound 62) .

To a solution of (S)-5-(aminomethyl)-3-(2-fluoro-4'-(methylthio)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one in DMF (2 ml) DIEA (0.08 ml, 0.451 mmol) and methyl chloroformate were added under N2 atmosphere. The resulting mixture was degassed and refilled three times with N ₂ . The reaction mixture was stirred at 15°C for 16 hours, then diluted with water (5 ml) and extracted with EtOAc (10 ml x3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by reverse phase prep-HPLC to give (S)-methyl((3-(2-fluoro-4'-(methylthio)-[ 1,1'-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)methyl)carbamate as a solid. LC/MS：MS (ESI) m/z: 391.1 [M+H ⁺ ]

The following connection was obtained using the methods described in example 62, with the replacement of the appropriate reagents and/or reagents.

Example Structure Name IUPAC O(M+H) 63

ethyl({(5S)-3-[2-fluoro-4'-(methylsulfanyl)
biphenyl-4-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)carbamate 4405.0

Example 64

Synthesis of (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(2-fluoro-4'-(S-methylsulfonimidoyl)-[1,1'-biphenyl] -4-yl)oxazolidin-2-one (compound 64) .

To a solution of (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(2-fluoro-4'-(methylsulfinyl)-[1,1'-biphenyl]- 4-yl)oxazolidin-2-one (40.0 mg, 0.10 mmol) (generally prepared using the method of Example 54) and sodium azide (9.7 mg, 0.15 mmol) in CHCl ₃ (2 ml) H ₂ SO ₄ (1 µl, 0.02 mmol) was added. The mixture was stirred at 45°C for 5 hours. The mixture was quenched with saturated Na ₂ CO ₃ (1 ml). The mixture was concentrated and purified by reverse phase prep-HPLC to give (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(2-fluoro-4'-(S -methylsulfonimidoyl)-[1,1'-biphenyl]-4-yl)oxazolidin-2-one as a solid. ¹ H NMR (400 MHz, CD ₃ OD) d 8.40 (s, 1H), 8.25 (d, J =8.4 Hz, 2H), 8.14 (s, 1H), 8.00 (d, J= 7.9 Hz, 2H), 7.69 -7.59 (m, 2H), 7.42 (d, J =7.9 Hz, 1H), 5.25 (br s., 1H), 5.10-5.00 (m, 2H), 4.38 (t, J =8.9 Hz, 1H), 4.08 (dd, J =5.3, 8.6 Hz, 1H), 3.93 (s, 3H). MS (ESI) m/z: 416.2 [M+H ⁺ ].

Example 65

Biological analyzes

Mycobacterium tuberculosis ( Mtb ) growth assay

Growth inhibition of Mycobacterium tuberculosis (Mtb) was evaluated on two in vivo -corresponding carbon sources, glucose and cholesterol, at pH 6.8. For glucose as the carbon source, the medium consisted of Middlebrook 7H9 broth supplemented with 4 g/l glucose, 0.08 g/l NaCl, 5 g/l BSA fraction V, and 0.05% tyloxapol. For cholesterol as a carbon source, medium consisted of Middlebrook 7H9 broth supplemented with 97 mg/l cholesterol, 0.08 g/l NaCl, 5 g/l BSA fraction V, and 0.05% tyloxapol. Mtb expressing green fluorescent protein ( Mtb -GFP; H37Rv pMSP12::GFP) was preadapted to grow on an appropriate carbon source in Middlebrook 7H9 broth base supplemented with bovine serum albumin and tyloxapol prior to screening. Bacteria were distributed into 384-well microtiter plates at approximately 2 x 10 ⁴ actively growing cells in 24 μl volumes per well. Microtiter plates were pre-spread with 0.2 μl of compound, dimethyl sulfoxide (negative control) or rifampicin (25 μM; positive control). Cells were exposed to compounds at 2-fold serial dilutions from 50 μM to 0.049 μM. In some experiments, compounds were tested at lower concentrations. Growth inhibition was assessed after a 7 day growth period by measuring fluorescence using a spectrophotometer. In the negative control wells, cells were still actively growing at the time of reading. The lowest concentration of test compound required to inhibit 95% of bacterial growth was defined as MITC95. All studies were performed in the BSL3 laboratory.

Growth analysis of Staphylococcus aureus

Growth inhibition of Staphylococcus aureus (methicillin-resistant, MB5393, COL) was assessed in Mueller-Hinton broth II standardized cation content (CAMHB) in 384-well microtiter plates. Bacteria were distributed into microtiter plates at approximately 5 x 10 ⁵ actively growing cells in 49 μl volumes per well. Cells were exposed to compounds at 2-fold serial dilutions from 200 μM to 0.195 μM and growth was compared to no drug control. Dilutions of compounds were prepared in 100% dimethyl sulfoxide and added to microtiter plates in volumes of 1 μl per well. Full growth control wells contained DMSO and bacteria. Control wells with no growth contained DMSO and CAMHB, but no bacteria. Growth inhibition was assessed after a 22 hour growth period by measuring optical density using a spectrophotometer. The lowest concentration of test compound required to inhibit 95% of bacterial growth was defined as MITC95. All studies were performed in the BSL2 laboratory.

Analysis of mitochondrial protein synthesis

Inhibition of mitochondrial protein synthesis was assessed in HepG2 cells by comparing the levels of two subunits of oxidative phosphorylation enzyme complexes, the complex IV subunit I (COX-I) and the complex II 70-kDa subunit (SDH-A). COX-I is encoded by mitochondrial DNA and SDH-A is encoded by nuclear DNA. HepG2 cells were seeded in 96-well collagen-coated plates at 8000 cells per well and subjected to compounds with 2-fold serial dilutions from 100 μM to 6.25 μM. Microtiter plates were incubated for approximately 5 replication cycles (4 days) prior to protein assessment using the kit as prescribed by the manufacturer (ab110217 MitoBiogenesis In Cell ELISA Kit, Abcam, Cambridge, MA). Inhibition of mitochondrial protein synthesis was expressed as the ratio of COX-1 to SDH-A.

Mycobacterium tuberculosis ( Mtb ) growth assay

Growth inhibition of Mycobacterium tuberculosis (Mtb) was evaluated on two in vivo -corresponding carbon sources, glucose and cholesterol, at pH 6.8. For glucose as the carbon source, the medium consisted of Middlebrook 7H9 broth supplemented with 4 g/l glucose, 0.08 g/l NaCl, 5 g/l BSA fraction V, and 0.05% tyloxapol. For cholesterol as a carbon source, medium consisted of Middlebrook 7H9 broth supplemented with 97 mg/l cholesterol, 0.08 g/l NaCl, 5 g/l BSA fraction V, and 0.05% tyloxapol. Mtb expressing green fluorescent protein ( Mtb -GFP; H37Rv pMSP12::GFP) was preadapted to grow on an appropriate carbon source in Middlebrook 7H9 broth base supplemented with bovine serum albumin and tyloxapol prior to screening. Bacteria were distributed into 384-well microtiter plates at approximately 2 x 10 ⁴ actively growing cells in 24 μl volumes per well. Microtiter plates were pre-spread with 0.2 μl of compound, dimethyl sulfoxide (negative control) or rifampicin (25 μM; positive control). Cells were exposed to compounds at 2-fold serial dilutions from 50 μM to 0.049 μM. In some experiments, compounds were tested at lower concentrations. Growth inhibition was assessed after a 7 day growth period by measuring fluorescence using a spectrophotometer. In the negative control wells, cells were still actively growing at the time of reading. The lowest concentration of test compound required to inhibit 95% of bacterial growth was defined as MITC95. All studies were performed in the BSL3 laboratory.

Growth analysis of Staphylococcus aureus

Growth inhibition of Staphylococcus aureus (methicillin-resistant, MB5393, COL) was assessed in Mueller-Hinton broth II standardized cation content (CAMHB) in 384-well microtiter plates. Bacteria were distributed into microtiter plates at approximately 5 x 10 ⁵ actively growing cells in 49 μl volumes per well. Cells were exposed to compounds at 2-fold serial dilutions from 200 μM to 0.195 μM and growth was compared to no drug control. Dilutions of compounds were prepared in 100% dimethyl sulfoxide and added to microtiter plates in volumes of 1 μl per well. Full growth control wells contained DMSO and bacteria. Control wells with no growth contained DMSO and CAMHB, but no bacteria. Growth inhibition was assessed after a 22 hour growth period by measuring optical density using a spectrophotometer. The lowest concentration of test compound required to inhibit 95% of bacterial growth was defined as MITC95. All studies were performed in the BSL2 laboratory.

Analysis of mitochondrial protein synthesis

Inhibition of mitochondrial protein synthesis was assessed in HepG2 cells by comparing the levels of two subunits of oxidative phosphorylation enzyme complexes, the complex IV subunit I (COX-I) and the complex II 70-kDa subunit (SDH-A). COX-I is encoded by mitochondrial DNA and SDH-A is encoded by nuclear DNA. HepG2 cells were seeded in 96-well collagen-coated plates at 8000 cells per well and subjected to compounds with 2-fold serial dilutions from 100 μM to 6.25 μM. Microtiter plates were incubated for approximately 5 replication cycles (4 days) prior to protein assessment using the kit as prescribed by the manufacturer (ab110217 MitoBiogenesis In Cell ELISA Kit, Abcam, Cambridge, MA). Inhibition of mitochondrial protein synthesis was expressed as the ratio of COX-1 to SDH-A.

Example Mtb Cho MITC95_mkM Mtb Glu MITC95_µM MRSA COL MITC95, µM MPS IC50_µM 1 0.03 0.04 25 12.2 2 0.03 0.02 200 > 25 3 0.78 1.14 100 > 20 4 0.09 0.04 200 22 5 0.09 0.04 200 > 20 6 0.04 0.04 100 > 20 7 0.09 0.04 200 > 20 8 0.04 0.04 200 > 20 9 0.14 0.09 200 > 20 10 0.09 0.09 200 > 20 eleven 0.14 25.1 200 NA 12 1.14 1.14 200 NA 13 0.19 0.19 200 > 20 14 1.14 0.78 200 NA 15 0.58 1.14 200 NA 16 0.39 0.19 200 > 20 17 0.29 0.09 200 > 20 18 0.09 0.04 50 > 20 19 0.09 0.485 200 > 20 20 0.58 0.14 200 > 20 21 1.5 0.39 200 25 22 0.19 0.04 100 > 20 23 0.19 0.19 200 > 20 24 0.09 0.04 200 > 20 25 0.19 0.04 200 > 20 26 1.5 0.78 200 > 20 27 0.78 0.39 200 > 50 28 1.14 0.3 200 > 100 29 1.5 0.39 200 > 25 thirty 0.39 0.09 200 > 20 31 0.78 0.39 200 > 20 32 0.29 0.24 200 > 20 33 0.19 0.845 200 > 20 34 0.04 0.04 200 > 20 35 0.58 1.14 200 NA 36 0.48 1.5 200 NA 37 0.39 0.29 200 > 20 38 0.39 0.14 200 > 20 39 0.78 0.585 200 > 20 40 0.09 0.076 4.688 > 15 41 0.04 0.04 200 8 42 1.5 1.5 200 > 20 43 0.19 0.58 200 > 20 44 0.04 0.19 200 > 20 45 0.39 1.14 200 NA 46 0.29 0.585 200 > 20 47 0.01 0.03 0.7813 > 20 48 0.78 0.39 200 > 100 49 0.58 0.58 200 > 20 50 0.58 0.29 200 > 20 54 0.215 0.24 2.34 > 20 55 0.19 0.19 50 > 20 56 0.39 0.39 100 > 20 57 0.535 0.29 25 50 58 0.19 0.58 200 > 20 59 0.39 0.09 200 > 20 60 1.14 2.3 200 NA 62 0.04 0.04 200 10 63 0.19 0.29 200 18 64 0.09 0.09 0.39 > 20 linezolid 3.14 4.58 6.25 8

Claims (17)

1. Compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: R ¹ is -CH ₂ N(R ² ) ₂ , or -CH ₂ NR ² COOR ³ ; in each occurrence R ² is independently selected from H or C ₁ -C ₆ alkyl; R ³ is H or C ₁ -C ₆ alkyl; E represents pyridine, where the specified pyridine is substituted by one or two fluorine atoms; A represents

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is -CH ₂ NR ² COOR ³ and in each case R ² and R ³ are independently selected from hydrogen and C ₁ -C ₆ alkyl. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CH ₂ NHCOOCH ₃ . 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure:

5. A pharmaceutical composition for the treatment of mycobacterial infection, which contains a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 6. The use of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of a mycobacterial infection. 7. Use according to claim 6, wherein the mycobacterial infection is caused by Mycobacterium tuberculosis. 8. Use according to claim 7, wherein M. tuberculosis is a drug-resistant mycobacterial strain. 9. Application according to paragraphs. 6-8, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, or topically.