JP2008530192A - Pyrrole derivatives as inhibitors of DNA gyrase and topoisomerase - Google Patents

Abstract

  The compounds of formula (I) and their pharmaceutically acceptable salts are described. The method of manufacture, pharmaceutical compositions containing them, their use as pharmaceuticals and their use in the treatment of bacterial infections are also described.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION The present invention relates to compounds that exhibit antibacterial activity, methods for their production, pharmaceutical compositions containing them as active ingredients, their use as pharmaceuticals, and the treatment of bacterial infections in warm-blooded animals such as humans. Relates to its use in the manufacture of pharmaceuticals of use. In particular, the present invention relates to compounds useful in the treatment of bacterial infections in warm-blooded animals such as humans, and more particularly in the manufacture of pharmaceuticals for use in the treatment of bacterial infections in warm-blooded animals such as humans. About the use of.

  The international microbiological society continues to express serious concern that the evolution of antibiotic resistance may result in strains that render currently available antimicrobials ineffective. In general, bacterial pathogens can be classified as either Gram positive or Gram negative pathogens. Antibiotic compounds with effective activity against both gram positive and gram negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are considered effective against both gram positive pathogens and certain gram negative pathogens.

  Gram-positive pathogens such as staphylococci, enterococci, streptococci, and mycobacteria are particularly important for the development of resistant strains that are difficult to treat and, once established, difficult to expel from the hospital environment. is there. Examples of such strains are methicillin resistant staphylococci (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae, and multidrug resistant Enterococcus faecium.

  A preferred clinically effective antibiotic for the last resort in the treatment of such resistant Gram positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with a variety of toxicities including nephrotoxicity. Furthermore, and most importantly, antimicrobial resistance to Banco machines and other glycopeptides is also emerging. This resistance is increasing at a steady rate, making these drugs increasingly ineffective in the treatment of Gram-positive pathogens. It also develops resistance to drugs such as β-lactams, quinolones, and macrolides used to treat upper respiratory tract infections caused by certain gram-negative strains, including H. influenzae and M. catarrhalis. It is increasing.

  Inevitably, new antibiotics, especially those containing either new mechanisms of action and / or new pharmacophoric groups, to overcome the threat of widespread multi-drug resistant pathogens There is a current need to develop.

Deoxyribonucleic acid (DNA) gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, JJ; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerase uses free energy from adenosine triphosphate (ATP) hydrolysis to introduce transient double-strand breaks into DNA, catalyzing break-strand passage and re-DNA. Modify the topology of the DNA by binding. DNA gyrase is an essential conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA. This enzyme consists of two subunits encoded by gyrA and gyrB, forming a complex of A ₂ B ₂ tetramers. The gyrase A subunit (GyrA) contains conserved tyrosine residues that participate in DNA cleavage and recombination and form a transient covalent linkage to DNA during strand transit. The B subunit (GyrB) catalyzes the hydrolysis of ATP, interacts with the A subunit, translates the free energy from hydrolysis into conformational changes in the enzyme, and allows for strand-passing and DNA recycling. Allows coupling.

  Another conserved essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for isolating linked closed circular bacterial chromosomes produced during replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to GyrA and GyrB. The overall sequence identity between gyrase and topoisomerase IV is high in various bacterial species. Therefore, compounds targeting bacterial type II topoisomerase have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV, as in the case of existing quinolone antibacterial drugs (Maxwell, A. et al. 1997, Trends Microbiol. 5: 102-109).

DNA gyrase is a well-validated antibacterial target that includes quinolones and coumarins. Quinolones (eg, ciprofloxacin) are broad spectrum antibacterial drugs that inhibit the enzyme's DNA cleavage and recombination activities and capture GyrA subunits covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol. Rev. 61: 377-392). Members of this class of antibacterial agents also inhibit topoisomerase IV, and as a result, the primary target of these compounds varies from species to species. Quinolones are successful antibacterials, but resistance produced primarily by mutations in the target (DNA gyrase and topoisomerase IV) is increasingly in several pathogens, including staphylococci and pneumococci It is a problem (Hooper, DC, 2002, The Lancet Infectious Diseases 2: 530-538). In addition, quinolones as a class of chemicals suffer from toxic side effects, including arthropathy that prevents their use in children (Lipsky, BA and Baker, CA, 1999, Clin. Infect. Dis. 28 : 352-364). In addition, the potential for cardiotoxicity predicted by extending the QT _c interval has been noted as a quinolone toxicity concern.

  Several natural product inhibitors of DNA gyrase that compete with ATP for binding to the GyrB subunit are known (Maxwell, A. and Lawson, DM 2003, Curr. Topics in Med. Chem. 3: 283- 303). Coumarins are natural products isolated from Streptomyces spp. Examples are novobiocin, chlorobiocin, and coumermycin A1. Although these compounds are potent inhibitors of DNA gyrase, their therapeutic utility is limited due to toxicity in eukaryotes and poor penetration in gram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). Another natural product class of compounds that target the GyrB subunit is cyclothirizine, isolated from Streptomyces filipensis (Watanabe, J. et al 1994, J. Antibiot. 47: 32-36). Despite its strong activity against DNA gyrase, cyclothirizine is a weak antibacterial agent that is only active against some intrinsic bacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656 -2661).

  Synthetic inhibitors targeting the DNA gyrase B subunit and topoisomerase IV are known in the art. For example, patent application number WO 99/35155 describes coumarin-containing compounds, patent application WO 02/060879 describes 5,6-bicyclic heteroaromatic compounds, and patent application WO 01/52845 (US Pat. No. 6,608). , 087) describes pyrazole compounds.

  We have discovered a new class of compounds that are useful for inhibiting DNA gyrase and topoisomerase IV.

SUMMARY OF THE INVENTION Therefore, the present invention provides a compound of formula (I):

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ⁴ and R ⁵ are independently selected from hydrogen or C _1-4 alkyl;
X is a direct bond, —CH ₂ —, —C (O) —, or S (O) _q — (where q is 1 or 2);
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl, or a pharmaceutically acceptable salt thereof.

  Also provided is the formula IA:

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ⁴ and R ⁵ are independently selected from hydrogen or C _1-4 alkyl;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl], or a pharmaceutically acceptable salt thereof.

  Also provided is the formula IB:

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ⁵ is hydrogen or C _1-4 alkyl;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl], or a pharmaceutically acceptable salt thereof.

  Also provided is the formula IC:

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl], or a pharmaceutically acceptable salt thereof.

  Also provided is Formula ID:

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl], or a pharmaceutically acceptable salt thereof.

The present invention also provides:
6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylate;
Methyl 2-chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} pyrimidine-4-carboxylate;
2- {4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxylate methyl 6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylic acid;
2-chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} pyrimidine-4-carboxylic acid;
2- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxylic acid;
2-Chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -N-methoxypyrimidine-4- Carboxamide; or 2- {4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5 Provided are compounds that are carboxamides, or pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical composition comprising a compound of formula I, IA, IB, IC, or ID, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of treating a bacterial infection in a warm-blooded animal such as a human in need of such treatment, the method comprising a compound of formula I, IA, IB, IC, or ID or a Administering to the animal an effective amount of a pharmaceutically acceptable salt.

  The invention also provides a method for inhibiting bacterial DNA gyrase in a warm-blooded animal such as a human in need of such treatment, said method comprising a compound of formula I, IA, IB, IC, or ID Administering to the animal an effective amount of a compound or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula I, IA, IB, IC, or ID and pharmaceutically acceptable salts thereof for use as a medicament.
The invention also provides the use of a compound of formula I, IA, IB, IC or ID or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in producing an antibacterial effect in a warm-blooded animal such as a human. To do.

  The invention also relates to the use of a compound of formula I, IA, IB, IC or ID or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of bacterial infections in warm-blooded animals such as humans. provide.

The present invention also provides that the compounds of formula (I) and pharmaceutically acceptable salts thereof can be prepared by the following methods (wherein the variables and variables are defined otherwise, As defined above):
Method a) Formula (II):

Wherein R ^a is cyano and R ^b is dimethylamino or diethylamino; or R ^a and R ^b are independently selected from C _1-4 alkylthio; or R ^a and R ^b are Together, forming 1,3-dithianyl or 1,3-dithiolanyl] to the compound of formula (I);
Method b) Formula (III):

A compound of formula (IV):

Reacting with a compound wherein D is a substitutable group;
Method c) For compounds of formula (I) wherein X is —C (O) —; a compound of formula (III) is represented by formula (V):

Reacting with a compound of
Method d) Formula (VI):

[Wherein L is a substitutable group] a compound of formula (VII):

Reacting with a compound of
Method e) Formula (VIII):

[Wherein M is an organometallic group] a compound of formula (IX):

Reacting with the compound wherein L is a displaceable group, and then if necessary:
i) converting a compound of formula (I) to another compound of formula (I);
ii) removing any protecting groups;
iii) producing a pharmaceutically acceptable salt.

D is a substitutable group. Suitable values for D include halo, such as chloro, bromo, and iodo, tosylate, and mesylate.
L is a substitutable group. Suitable values for L include halo, such as chloro and bromo, pentafluorophenoxy, and 2,5-oxopyrrolidin-1-yloxy.

  M is an organometallic group and suitable values for M include organic copper salts such as CuLi, organozinc, Zn, or Grignard reagents such as MgG (where G is halo, such as chloro). included}.

Detailed Description of the Invention As used herein, the term "alkyl" includes both straight and branched chain alkyl groups. For example, “C _1-4 alkyl” includes methyl, ethyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as propyl are specific to the linear version only. Similar conventions apply to other general groups.

  Where an optional substituent is selected from one or more groups, this definition includes all substituents selected from one of the specified groups, or substitutions selected from two or more of the specified groups It should be understood that the group is included.

“Heterocyclyl” contains 4-12 atoms, at least one of which is selected from nitrogen, sulfur, or oxygen, and unless otherwise specified, may be linked with carbon or nitrogen, saturated, partially saturated, Or an unsaturated monocyclic or bicyclic ring, wherein the —CH ₂ — group may be replaced by —C (O) —, and the ring nitrogen and / or ring sulfur atom is oxidized. N or S-oxide may be formed. In one aspect of the invention, “heterocyclyl” contains 5 or 6 atoms, at least one atom selected from nitrogen, sulfur, or oxygen, and is linked by carbon or nitrogen unless otherwise specified. A saturated, partially saturated or unsaturated monocyclic ring in which the —CH ₂ — group may be replaced by —C (O) — and the ring sulfur atom is oxidized. To form S-oxide. In a further aspect of the invention, a “heterocyclyl” is an unsaturated, carbon-linked, monocyclic ring in which at least one atom contains 5 or 6 atoms selected from nitrogen, sulfur or oxygen . Examples and preferred meanings of the term “heterocyclyl” include morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiol Morpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridalidinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, Pyridine-N-oxide and quinoline-N-oxide.

“Carbocyclyl” is a saturated, partially saturated or unsaturated mono- or bicyclic carbocycle containing from 3 to 12 atoms, wherein the —CH ₂ — group is —C (O) —. It may be replaced by. In particular, “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl, or 1-oxoindanyl. A particular example of “carbocyclyl” is phenyl.

An example of “C _1-4 alkanoyloxy” is acetoxy. Examples of “C _1-4 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n and t-butoxycarbonyl. Examples of “C _1-4 alkoxycarbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, n and t-butoxycarbonylamino. Examples of “C _1-4 alkoxy” include methoxy, ethoxy, and propoxy. Examples of “C _1-4 alkanoylamino” include formamide, acetamide, and propionylamino. Examples of “C _1-4 alkyl S (O) _a, where a is 0-2” include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, and ethylsulfonyl. Examples of “C _1-4 alkanoyl” include propionyl and acetyl. Examples of “N— (C _1-4 alkyl) amino” include methylamino and ethylamino. Examples of “N, N— (C _1-4 alkyl) ₂ amino” include diN-methylamino, di (N-ethyl) amino, and N-ethyl-N-methylamino. Examples of “C _2-4 alkenyl” are vinyl, allyl, and 1-propenyl. Examples of “C _2-4 alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of “N- (C _1-4 alkyl) sulfamoyl” are N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl. Examples of “N, N- (C _1-4 alkyl) ₂ sulfamoyl” are N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (ethyl) sulfamoyl. Examples of “N— (C _1-4 alkyl) carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N, N- _{(C 1-4 alkyl) 2} carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “N— (C _1-4 alkoxy) carbamoyl” are methoxyaminocarbonyl and isopropoxyaminocarbonyl. Examples of “N- (C _1-4 alkyl) -N- (C _1-4 alkoxy) carbamoyl” are N-methyl-N-methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl. Examples of “C _3-6 cycloalkyl” are cyclopropyl, cyclobutyl, cyclopropyl, and cyclohexyl. Examples of “N ′-(C _1-4 alkyl) ureido” are N′-methylureido and N′-isopropylureido. Examples of “N ′, N ′-(C _1-4 alkyl) ₂ ureido” are N ′, N′-dimethylureido and N′-methyl-N′-isopropylureido. Examples of “N ′-(C _1-4 alkyl) hydrazinocarbonyl” are N′-methylhydrazinocarbonyl and N′-isopropylhydrazinocarbonyl. Examples of “N ′, N ′-(C _1-4 alkyl) ₂ hydrazinocarbonyl” are N′N′-dimethylhydrazinocarbonyl and N′-methyl-N′-isopropylhydrazinocarbonyl. Examples of “C _1-4 alkylsulfonylamino” include methylsulfonylamino, isopropylsulfonylamino, and t-butylsulfonylamino. Examples of “C _1-4 alkylsulfonylaminocarbonyl” include methylsulfonylaminocarbonyl, isopropylsulfonylaminocarbonyl, and t-butylsulfonylaminocarbonyl. Examples of “C _1-4 alkylsulfonyl” include methylsulfonyl, isopropylsulfonyl, and t-butylsulfonyl.

  The compounds of formula (I) may form stable acidic or basic salts, in which case administration of the compound as a salt may be appropriate, and conventional methods as described below To produce a pharmaceutically acceptable salt.

  Suitable pharmaceutically acceptable salts include methanesulfonate, tosylate, α-glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate, and (less preferred) ) Acid addition salts such as hydrobromide are included. Also suitable are salts formed with phosphoric acid and sulfuric acid. In another aspect, suitable salts include alkali metal (eg, sodium or potassium) salts, alkaline earth metal (eg, calcium or magnesium) salts, organic amines (eg, triethylamine, morpholine, N-methylpiperidine, N— A basic salt such as ethyl piperidine, procaine, dibenzylamine, N, N-dibenzylethylamine, tris- (2-hydroxyethyl) amine, N-methyl d-glucamine, and amino acids such as lysine) salts. . Depending on the number of charged functional groups and the valence of the cation or anion, there may be more than one cation or anion. A preferred pharmaceutically acceptable salt is the sodium salt.

However, salts that are not very soluble in the selected solvent may be preferred to facilitate isolation of the salt during manufacture, whether pharmaceutically acceptable or not.
Within the present invention, a compound of formula (I) or a salt thereof may demonstrate the phenomenon of tautomerism, and the formulas within this specification may represent only one of the possible tautomeric forms. Please understand that. It should be understood that the present invention includes any tautomeric form that inhibits DNA gyrase and is not limited to any one tautomeric form utilized in the formula diagram. The formulas within this specification may represent only one of the possible tautomeric forms, and this specification includes all of the illustrated compounds, not just the forms that could be shown here graphically. It should be understood that possible tautomeric forms are included. The same applies to compound names.

  One skilled in the art may know that certain compounds of formula (I) contain asymmetrically substituted carbon and / or sulfur atoms and therefore exist in optically active and racemic forms and may be isolated. It will be understood. Some compounds manifest polymorphism. The present invention is understood to include any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of which the form possesses properties useful for inhibition of DNA gyrase. (E.g., by resolution by racemic recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, by enzymatic resolution, by bioconversion, or by chromatographic separation using a chiral stationary phase) And methods for quantifying the efficacy of DNA gyrase inhibition by standard tests described below are well known in the art.

  It is also to be understood that certain compounds of formula (I) and their salts may exist in unsolvated forms as well as solvated forms, such as hydrated forms. It should be understood that the invention includes all such solvated forms that inhibit DNA gyrase.

  The special and suitable meanings for certain substituents and groups mentioned in the present description continue below. Any of these definitions and embodiments disclosed above or below may be used as appropriate. For the avoidance of doubt, each species mentioned represents a special and independent aspect of the present invention.

R ¹ is selected from C _1-4 alkyl.
R ¹ is selected from methyl.
R ² is selected from halo.

R ² is selected from fluoro, chloro, or bromo.
R ² is selected from chloro or bromo.
R ³ is selected from hydrogen or halo.

R ³ is selected from hydrogen, fluoro, or chloro.
R ³ is selected from hydrogen or chloro.
R ² and R ³ are both selected from chloro.

R ⁴ and R ⁵ are both hydrogen.
X is a direct bond.
X is —CH ₂ —.

X is —C (O) —.
X is S (O) _q- (where q is 1 or 2).
Ring A is carbocyclyl.

Ring A is heterocyclyl; where the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ .
Ring A is heterocyclyl.

Ring A is pyridinyl, benzothiazolyl, quinolinyl, pyrimidinyl, or thiazolyl.
Ring A is pyrimidinyl or thiazolyl.

Ring A is pyrimidin-4-yl or thiazol-2-yl.
R ⁶ is a substituent on carbon and is selected from halo, carboxy, carbamoyl, N- (C _1-4 alkoxy) carbamoyl, or C _1-4 alkoxycarbonyl.

R ⁶ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, N- (methoxy) carbamoyl, or methoxycarbonyl.
m is 1 or 2; wherein the meanings of R ⁶ may be the same or different.

Thus, in a further aspect of the invention, a compound of formula (I) (illustrated above) [wherein:
R ¹ is selected from C _1-4 alkyl;
R ² is selected from halo;
R ³ is selected from hydrogen or halo;
R ⁴ and R ⁵ are both hydrogen;
X is a direct bond;
Ring A is heterocyclyl;
R ⁶ is a substituent on carbon and is selected from halo, carboxy, carbamoyl, N- (C _1-4 alkoxy) carbamoyl, or C _1-4 alkoxycarbonyl; and m is 1 or 2; Wherein the meanings of R ⁶ may be the same or different.], Or a pharmaceutically acceptable salt thereof.

Thus, in a further aspect of the invention, a compound of formula (I) (illustrated above) [wherein:
R ¹ is selected from methyl;
R ² is selected from chloro or bromo;
R ³ is selected from hydrogen or chloro;
R ⁴ and R ⁵ are both hydrogen;
X is a direct bond;
Ring A is pyrimidin-4-yl or thiazol-2-yl;
R ⁶ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, N- (methoxy) carbamoyl, or methoxycarbonyl;
m is 1 or 2, wherein the meanings of R ⁶ may be the same or different.], or a pharmaceutically acceptable salt thereof.

  In a further aspect of the invention the formula IA:

[Where:
R ¹ is selected from hydrogen, halo, or C _1-4 alkyl;
R ² is selected from hydrogen, halo, or C _1-4 alkyl;
R ³ is selected from hydrogen, halo, or C _1-4 alkyl;
R ⁴ and R ⁵ are independently selected from hydrogen or C _1-4 alkyl;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl].

  Also provided is the formula IB:

[Where:
R ¹ is selected from hydrogen, halo, or C _1-4 alkyl;
R ² is selected from hydrogen, halo, or C _1-4 alkyl;
R ³ is selected from hydrogen, halo, or C _1-4 alkyl;
R ⁵ is hydrogen or C _1-4 alkyl;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is selected from halo, carboxy, carbamoyl, N- (C _1-4 alkoxy) carbamoyl, or C _1-4 alkoxycarbonyl;
R ⁷ is C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _{1 -4} alkyl) ₂ carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and is selected from phenylsulfonyl; and m is 0-4; wherein the significance of R ⁶ is a compound also may be different] the same is there.

  Also provided is the formula IC:

[Where:
R ¹ is selected from hydrogen, halo, or C _1-4 alkyl;
R ² is selected from hydrogen, halo, or C _1-4 alkyl;
R ³ is selected from hydrogen, halo, or C _1-4 alkyl;
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, N- (methoxy) carbamoyl, or methoxycarbonyl;
R ⁷ is C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _{1 -4} alkyl) ₂ carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and is selected from phenylsulfonyl; and m is a compound of either 0 or 1].

  Also provided is Formula ID:

[Where:
R ¹ is selected from hydrogen, halo, or C _1-4 alkyl;
R ² is selected from hydrogen, halo, or C _1-4 alkyl;
R ³ is selected from hydrogen, halo, or C _1-4 alkyl;
Ring A is heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, N- (methoxy) carbamoyl, or methoxycarbonyl].

  Special compounds of the invention are those of the “Examples”, each of which provides a more independent aspect of the invention. In a further aspect, the present invention also includes any two or more compounds of the “Examples”.

In one aspect of the invention, a compound of formula (I) is provided, and in another aspect, a pharmaceutically acceptable salt of the compound of formula (I) is provided.
In another aspect of the invention, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Accordingly, the present invention also provides that the compounds of formula (I) and their pharmaceutically acceptable salts can be prepared by the following methods (wherein the variables and variables are otherwise stated). As defined above):
Method a) Formula (II):

Wherein R ^a is cyano and R ^b is dimethylamino or diethylamino; or R ^a and R ^b are independently selected from C _1-4 alkylthio; or R ^a and R ^b are Together, forming 1,3-dithianyl or 1,3-dithiolanyl] to the compound of formula (I);
Method b) Formula (III):

A compound of formula (IV):

Reacting with a compound wherein D is a substitutable group;
Method c) For compounds of formula (I) wherein X is —C (O) —; a compound of formula (III) is represented by formula (V):

Reacting with a compound of
Method d) Formula (VI):

[Wherein L is a substitutable group] a compound of formula (VII):

Reacting with a compound of
Method e) Formula (VIII):

[Wherein M is an organometallic group] a compound of formula (IX):

Reacting with the compound wherein L is a displaceable group, and then if necessary:
i) converting a compound of formula (I) to another compound of formula (I);
ii) removing any protecting groups;
iii) producing a pharmaceutically acceptable salt.

D is a substitutable group. Suitable values for D include halo, such as chloro, bromo, and iodo, tosylate, and mesylate.
L is a substitutable group. Suitable values for L include halo, such as chloro and bromo, pentafluorophenoxy, and 2,5-oxopyrrolidin-1-yloxy.

  M is an organometallic group and suitable values for M include organic copper salts, such as CuLi, or organozinc, Zn, or Grignard reagents, such as MgG (where G is halo, such as chloro) Is included}.

Specific reaction conditions for the above reaction are as follows.
Method a) A compound of formula (II) may be converted to a compound of formula (I):
(I) when R ^a is cyano and R ^b is dimethylamino or diethylamino; in the presence of a base such as sodium hydroxide in a suitable solvent such as aqueous methanol at room temperature.

(Ii) or when R ^a and R ^b are independently selected from C _1-4 alkylthio; or when R ^a and R ^b together form 1,3-dithianyl or 1,3-dithiolanyl; In the presence of reagents such as mercury, copper, or silver salts, such as Hg (ClO ₄ ) ₂ , CuCl ₂ , or AgNO ₃ / Ag ₂ O, in the presence of a suitable solvent such as methanol, acetone, or ethanol. At temperatures ranging from room temperature to reflux.

  Compounds of formula (II) may be prepared according to Scheme 1:

[Wherein Pg is a hydroxy protecting group as defined below; and D is a displaceable group as defined above].
Deprotection of hydroxy protecting groups is well known in the art. Examples of such deprotection are shown below.

  FGI represents functional group interconversion. In the above scheme, such conversion between hydroxy and D groups is well known in the art and is well within the ability of one skilled in the art.

Compounds of formula (IIa) and (IId) are known in the literature or they are prepared by standard methods known in the art.
Method b) Compounds of formula (III) and (IV) are heated in a suitable solvent such as DMF, N-methylpyrrolidinone, or dimethylacetamide in the presence of a base such as triethylamine or diisopropylethylamine under heating conditions or You may react under a wave reactive group.

  The compound of formula (III) is represented by Scheme 2:

[Wherein L is a substitutable group as defined above].
The compounds of formula (IIIa) and (IV) are commercially available compounds or they are known in the literature or they are prepared by standard methods known in the art.

  Method c) Compounds of formula (III) and (V) can be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art may be utilized as suitable coupling reagents or, for example, carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally dimethylaminopyridine or 4-pyrrolidinopyridine. Optionally in the presence of a catalyst such as triethylamine, pyridine, or 2,6-dialkyl-pyridine such as 2,6-lutidine or 2,6-ditert-butylpyridine Available below. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. This coupling reaction may conveniently be performed at a temperature in the range of -40 to 40 ° C.

The compounds of formula (V) are commercially available compounds or they are known in the literature or they are prepared by standard methods known in the art.
Method d) Compounds of formula (VI) and (VII) are prepared in a suitable solvent such as DCM or 1,2-dichloroethane, optionally in the presence of a Lewis acid, for example AlCl ₃ , at 0 ° C. to room temperature. You may react.

  Compounds of formula (VI) are represented by Scheme 3:

[Wherein R ^a OC (O) is an ester group].
Suitable values for R ^a include C _1-6 alkyl. Deprotection of the R ^a carboxy protecting group may be achieved under standard conditions (eg, with acid or base hydrolysis such as those shown below).

  FGI represents functional group interconversion. In the above scheme, such conversion between acid groups and —C (O) L groups is well known in the art and is well within the ability of one skilled in the art.

The compounds of formulas (VIa) and (VII) are commercially available compounds or they are known in the literature or they are prepared by standard methods known in the art.
Method e) Compounds of formula (VIII) and (IX) may be reacted in a suitable aprotic solvent such as THF or ether at temperatures ranging from -78 ° C to 0 ° C.

  Compounds of formula (VIII) may be prepared from compounds of formula (IIc) under standard conditions known in the art. For example, when M is an organic cuprous reagent, such a compound can be represented by Scheme 4:

Can be manufactured according to.
The compounds of formula (IX) are commercially available compounds or they are known in the literature or they are prepared by standard methods known in the art.

The production of pharmaceutically acceptable salts is within the ordinary skill of an organic chemist using standard techniques.
Some of the various ring substituents in the compounds of the present invention may be generated by conventional functional group modifications, even if introduced by standard aromatic substitution reactions prior to or immediately following the method described above. It will be understood that it is itself included in the method aspect of the present invention. Reagents used to introduce such ring substituents are commercially available or are made by methods known in the art.

  One compound of formula (I) may be converted to another compound of formula (I) by introduction of a substituent into the ring. Such reactions and modifications include, for example, introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, heterogeneity. Includes the formation of an aryl ring. The reagents and reaction conditions for such procedures are well known in the chemical art. Specific examples of aromatic substitution reactions include the introduction of alkoxides, the introduction of thiol groups, alcohol groups, and halogen groups following diazotization reactions. Examples of modifications include the oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.

  A skilled organic chemist uses and employs the above references and the accompanying examples therein, and the information contained in the examples herein, to obtain the necessary starting materials and products. You can get it. If not commercially available, the starting materials required for procedures such as those described above are standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or procedures or examples described above. May be made by procedures selected from techniques similar to those described in. Many of the starting materials for synthetic methods as described above are commercially available and / or commercially available compounds using methods widely reported in the scientific literature or reported in the scientific literature. It is noted that it can be made more. Readers can further refer to “Advanced Organic Chemistry 4th Edition” by Jerry March, John Willie & Sons Publishing (1992), for general guidance on reaction conditions and reagents.

  It will also be appreciated that in some reactions described herein it may be necessary / desirable to protect sensitive groups in the compound. The instances where protection is necessary or desirable are known to those skilled in the art, as are methods suitable for such protection. Conventional protecting groups may be used in accordance with standard methods (see T. M. Greene "Protective Groups in Organic Chemistry" (1991) for illustrations).

  Examples of suitable protecting groups for hydroxy groups are, for example, acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl, silyl groups such as trimethylsilyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium. Alternatively, a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by an aqueous acid solution; or an arylmethyl group, such as a benzyl group, is hydrogen in the presence of a catalyst, such as, for example, palladium on carbon. It may be removed by conversion.

  Suitable protecting groups for amino groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, Or an aroyl group such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group, or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed by treatment with a suitable acid such as, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and an aryl such as a benzyloxycarbonyl group. The methoxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid such as tris (trifluoroacetic acid) boron. An alternative protecting group suitable for primary amino groups is, for example, a phthaloyl group, which may be removed by treatment with alkylamines such as dimethylaminopropylamine or 2-hydroxyethylamine or with hydrazine.

  Suitable protecting groups for carboxy groups are, for example, esterification groups (for example methyl or ethyl groups, which may be removed by hydrolysis with a base such as sodium hydroxide) or for example t-butyl. A group (eg, may be removed by treatment with an acid, eg, an organic acid such as trifluoroacetic acid), or a benzyl group (eg, may be removed by hydrogenation over a catalyst such as palladium on carbon). is there.

Protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, and they may be removed during subsequent reaction steps or workups. May be.
Where an optically active form of a compound of the invention is sought, it is by performing one of the above procedures using an optically active starting material (eg, generated by asymmetric induction of a suitable reaction step), Or may be obtained by resolving racemic forms of the compounds or intermediates using standard procedures, or by chromatographic separation of diastereoisomers (if produced). Enzymatic techniques may be useful for the production of optically active compounds and / or intermediates.

  Similarly, when a pure regioisomer of a compound of the invention is sought, it can be done by performing one of the above procedures using the pure regioisomer as a starting material, or using standard procedures. It may be obtained by resolution of a mixture of regioisomers or intermediates.

Enzyme titer test method For compounds using an ammonium molybdate / malachite green based phosphate detection assay (Lanzetta, PA, LJ Alvarez, PS Reinach, and OA Candia, 1979, 100: 95-97) Inhibition of GyrB ATPase activity was tested. The assay was performed in a multiwell plate in 50 mM TRIS buffer (pH 7.5), 75 mM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1,4-dithio-DL-threitol, 200 nM bovine serum albumin, 16 μg / ml sheared salmon sperm DNA, 4 nM E. coli E. coli GyrA, 4 nM E. coli E. coli GyrB, 250 μM ATP, and the compound were run in a 100 μl reaction containing dimethyl sulfoxide. The reaction was quenched with 150 μl of ammonium molybdate / malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates were read at 625 nm in an absorbance plate reader and percent inhibition values were calculated using dimethyl sulfoxide (2%) containing reaction as 0% inhibition and novobiocin containing (2 μM) reaction as 100% inhibition control. . For compounds, 100 μl reaction was: 20 mM TRIS buffer (pH 8), 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1,4-dithio-DL-threitol, 0.005% Brij-35, 5 μg / ml sheared salmon sperm DNA, 10 nM E. coli E. coli GyrA, 10 nM E. coli. Inhibition of topoisomerase IV ATPase activity was tested as described above for GyrB, except that E. coli GyrB, 160 μM ATP, and the compound were included in dimethyl sulfoxide. Compound titers were based on IC ₅₀ measurements quantified from reactions performed in the presence of 10 different compound concentrations.

The example compounds generally have IC ₅₀ values of less than 20 μg / ml.

Bacterial susceptibility testing method Compounds were tested for antimicrobial activity by susceptibility testing in liquid media. Compounds were dissolved in dimethyl sulfoxide and tested in a sensitivity assay in 10-fold dilutions. The microorganism used in the assay was grown overnight on a suitable agar medium and then suspended in a liquid medium suitable for growth of the microorganism. This suspension was made 0.5 McFarland and further diluted 10-fold with the same liquid medium to prepare a final microbial suspension in 100 μL. Plates were incubated under appropriate conditions at 37 ° C. for 24 hours before reading. The minimum inhibitory concentration (MIC) was determined as the lowest drug concentration capable of inhibiting growth by 80% or more.

  Example 7 had a MIC of 1.0 μg / ml against Streptococcus pneumoniae (Streptococcus pneumoniae). Other examples are provided in the table below.

According to a further feature of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treatment by therapy of the human or animal body.
We have found that the compounds of the present invention inhibit bacterial DNA gyrase and hence their antibacterial effects are interesting.

  According to a further feature of the present invention, there is provided a method for producing an antimicrobial effect in a warm-blooded animal such as a human in need of such treatment, said method comprising a compound of the present invention or a pharmaceutically acceptable salt thereof Administering an effective amount of to the animal.

  According to a further feature of the present invention there is provided a method of inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human in need of such treatment, said method being as defined above Administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

  According to a further feature of the present invention there is provided a method of treating a bacterial infection in a warm-blooded animal such as a human in need of such treatment, said method comprising a compound of formula (I) as defined above or Administering an effective amount of the pharmaceutically acceptable salt to said animal.

A further feature of the present invention is a compound of formula (I) and pharmaceutically acceptable salts thereof for use as a medicament. Suitably, the medicament is an antibacterial agent.
According to a further aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in producing an antibacterial effect in a warm-blooded animal such as a human.

  According to a further aspect of the invention, in the manufacture of a medicament for use in the inhibition of bacterial DNA gyrase and / or topoisomerase IV of a compound of formula (I) or a pharmaceutically acceptable salt thereof in warm-blooded animals such as humans. Provide use.

  Thus, according to a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of bacterial infections in warm-blooded animals such as humans.

According to a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the production of antibacterial effects in warm-blooded animals such as humans.
According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the inhibition of bacterial DNA gyrase and / or topoisomerase IV in warm-blooded animals such as humans.

Thus, according to a further aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial infections in warm-blooded animals such as humans.
The compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter “the compound of the present invention” in this section relating to pharmaceutical compositions) is particularly useful for therapy (including prevention) of mammals including humans. For use in treating infections, it is usually formulated as a pharmaceutical composition according to standard pharmaceutical practice.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the invention, a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier, such as human Provided for use in producing antibacterial effects in warm-blooded animals.

  According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier, such as human Provided for use in the inhibition of bacterial DNA gyrase and / or topoisomerase IV in warm-blooded animals.

  According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier, such as human Provided for use in the treatment of bacterial infections in warm-blooded animals.

  The compositions of the present invention are intended for oral use (eg, as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) For topical use (eg, as a cream, ointment, gel, or aqueous or oily solution or suspension), for administration by inhalation (eg, as a fine powder or liquid aerosol), for administration by inhalation In a form suitable for parenteral administration (eg, as a sterile aqueous or oily solution administered intravenously, subcutaneously, intramuscularly, or as a suppository for rectal administration) (eg, as a finely divided powder) It may be.

  The compositions of the present invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, a composition intended for oral use may contain, for example, one or more colorants, sweeteners, fragrances and / or preservatives.

  Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; starch Binders such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulation may be uncoated, in order to change the disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and / or appearance, in any case, Conventional coating agents and procedures well known in the art are used.

  Compositions for oral use may be in the form of hard gelatin capsules with active ingredients mixed with inert solid diluents such as calcium carbonate, calcium phosphate or kaolin, such as water or peanut oil, liquid paraffin, or olive oil. It may be in the form of a soft gelatin capsule in which an active oil and an active ingredient are mixed.

  In general, aqueous suspensions are one or more suspensions such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; lecithin, or condensation products of fatty acids and alkylene oxides ( Moieties derived from fatty acids and hexitol, such as, for example, polyoxyethylene stearate) or condensation products of long chain fatty alcohols and ethylene oxide, such as heptadecaethyleneoxycetanol, or polyoxyethylene sorbitol monooleate Condensation products of esters and ethylene oxide, or condensation products of long-chain aliphatic alcohols and ethylene oxide, such as heptadecaethyleneoxycetanol or polyoxyethylenesorbitol Condensation products of partial esters and ethylene oxide derived from fatty acids and hexitol, such as nooleate, or condensation products of partial esters and ethylene oxide derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate The active ingredient is contained in the form of a fine powder together with a dispersing or wetting agent. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, fragrances, and / or sweeteners (such as Sugars, saccharin or aspartame).

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents such as those set forth above may be added to provide palatable oral preparations. The composition may be preserved by the addition of an antioxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring, and coloring agents may also be present.

  The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifiers are, for example, naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phosphatides such as soy, lecithin, esters or partial esters derived from fatty acids and anhydrous hexitol (eg sorbitan monoesters). Oleate), and condensation products of ethylene oxide and the partial ester, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening, flavoring and preserving agents.

  Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and / or coloring agent.

  The pharmaceutical composition may also be in the form of a sterile injectable aqueous or oleaginous suspension, which uses one or more suitable dispersing or wetting agents and suspending agents as indicated above. It may be formulated according to known procedures. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable non-toxic diluents or solvents, for example, solutions in 1,3-butanediol. It's okay.

  Compositions for administration by inhalation may be in the form of aerosols containing fine solids or conventional pressurized aerosols arranged to formulate the active ingredient as liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used, and the aerosol device is conveniently arranged to dispense a graduated amount of the active ingredient.

  For further information on the formulation, the reader is referred to Volume 5, Chapter 25.2 of Pergamon Press (1990), “Comprehensive Medicinal Chemistry” (Corwin Hansch; Editor-in-Chief).

  The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, formulations contemplated for oral administration to humans generally contain, for example, 0.5 mg to 2 g of active agent and can be used in a suitable and convenient amount that can vary from about 5 to about 98 weight percent of the total composition. In combination with other excipients. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on the route of administration and mode of administration, the reader is referred to Volume 5, Chapter 25.3 of Pergamon Press (1990), “Comprehensive Medicinal Chemistry” (Corwin Hansch; Editor-in-Chief).

  In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may include other clinically useful antibacterial agents (eg, macrolides, quinolones, β-laclams, or aminoglycosides) and / or other anti-infective agents (eg, , One or more known drugs selected from the antifungal drugs triazole or amphotericin) may be administered together (simultaneously, sequentially or separately). These may include carbapenem (eg, meropenem or imipenem) to expand therapeutic efficacy. The compounds of the present invention may contain bactericidal / permeabilized protein (BPI) products or efflux pump inhibitors to improve activity against gram-negative bacteria and bacteria resistant to antimicrobial agents. It may be administered together.

  As noted above, the size of the dose required for therapy or prophylactic treatment of a particular disease state will necessarily vary depending on the host being treated, the route of administration, and the severity of the disease being treated. To do. Preferably a daily dose in the range of 1-50 mg / kg is employed. However, this daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Thus, the optimal dosage can be determined by the medical practitioner who is treating the particular patient.

  In addition to its use in therapeutic medicines, the compounds of formula (I) and their pharmaceutically acceptable salts have been used in cats, dogs, rabbits, monkeys, rats, and mice as part of the search for new therapeutic agents. It is also useful as a pharmacological tool in developing and standardizing in vitro and in vivo test systems for evaluating the effects of inhibitors of DNA gyrase in such laboratory animals.

  In the other pharmaceutical compositions, methods, techniques, uses, and pharmaceutical manufacturing features described above, the specific embodiments instead of the compounds of the invention described herein also apply.

Examples The invention will now be illustrated by the following non-limiting examples. Here, unless otherwise stated:
(I) Temperature is given in degrees Celsius (° C.); various operations were performed at room temperature or ambient temperature, ie at a temperature in the range of 18-25 ° C .;
(Ii) The organic solution was dried over anhydrous magnesium sulfate; solvent evaporation was performed using a rotary evaporator under reduced pressure (600-4000 Pascal; 4.5-30 mmHg) at a bath temperature up to 60 ° C. ;
(Iii) In general, the progress of the reaction is followed by TLC and the reaction time is shown for illustration only;
(Iv) The final product showed satisfactory proton nuclear magnetic resonance (NMR) spectra and / or mass spectral data;
(V) Yields are given for illustration only and are not necessarily available through careful process development; if more material is needed, the production was repeated;
(Vi) Where indicated, the NMR data is in the form of a major diagnostic proton delta value, expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and unless otherwise indicated, Determined at 300 MHz using hydrogen dimethyl sulfoxide (DMSO-d ₆ ) as solvent;
(Vii) chemical symbols have their usual meanings; use SI units and symbols;
(Viii) Solvent ratios are given in volume / volume (v / v) terminology; and (ix) Mass spectra were operated with an electron energy of 70 eV in chemical ionization (CI) mode using a direct exposure probe; Here, the predetermined ionization was performed by electron impact (EI), fast atom bombardment (FAB), or electrospray (ESP); shows m / z values; generally reports only ions showing the original mass And unless otherwise stated, the mass ion cited is (M + H) ⁺ ;
(X) If the synthesis is described as being similar to the description in the previous example, the amount used is equivalent to the millimolar ratio relative to that used in the previous example;
(Xi) The following abbreviations were used;
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate THF tetrahydrofuran DMF N, N-dimethylformamide; and DMSO dimethyl sulfoxide

Example 1
6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylate 1- ( 4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-piperidin-4-ylethanone hydrobromide (intermediate 5,0.16 g, 0.44 mmol) and triethylamine (0.12 ml, To a stirred solution of 0.874 mmol) DMF (3 ml) was added methyl 2,6-dichloropyrimidine-4-carboxylate (0.12 g, 0.56 mmol). The solution was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine. This was dried and concentrated to a crude residue. The residue was purified by reverse phase HPLC to give the title compound (0.14 g). _{MS (ES): C 18 H} 20 BrClN 4 O 3 with respect to 455. ¹ H NMR: 1.18 (m, 2H); 1.72 (m, 2H); 2.15 (m, 1H); 2.16 (s, 3H); 2.62 (d, 2H); 3.05 (m, 2H); 3.84 (s, 3H); 4.25 (bs, 1H); 4.70 (bs, 1H); 7.07 (d, 1H); 7.31 (s, 1H); 12.01 (s, 1H).

Examples 2-3
The following examples were prepared by the procedure of Example 1 using the indicated starting material (SM).

Example 4
6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylic acid 6- {4 -[2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylate (Example 1; 11 g, 0.24 mmol) was dissolved in methanol (5 ml) and 2N lithium hydroxide (3 ml) was added. The resulting solution was stirred overnight at room temperature. The solvent was removed and the aqueous solution was acidified with 1N hydrochloric acid to precipitate the product, which was collected by filtration and purified by reverse phase HPLC. _{MS (ES): C 17 H} 18 BrClN 4 O 3 with respect to 442. ¹ H NMR: 1.18 (m, 2H); 1.73 (m, 2H); 2.15 (m, 1H); 2.16 (s, 3H); 2.62 (d, 2H); 3.00 (m, 2H); 4.25 (bs, 1H); 4.70 (bs, 1H); 7.07 (d, 1H); 7.27 (s, 1H); 12.00 (s, 1H).

Examples 5-6
The following examples were prepared by the procedure of Example 4 using the starting material (SM) shown.

Example 7
2-Chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -N-methoxypyrimidine-4- Carboxamide 2-chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} pyrimidine-4-carboxylic acid ( HATU was added to a solution of Example 5, 0.10 g, 0.23 mmol) and diisopropylethylamine in DMF (1.5 ml). The mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added methoxylamine hydrochloride (0.02 g, 0.23 mmol) and this was allowed to stir overnight. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine. This was dried and concentrated to give the crude product, which was purified by reverse phase HPLC. _{MS (ES): C 18 H} 20 Cl 3 N 5 O 3 with respect to 461. ¹ H NMR: 1.19 (m, 2H); 1.76 (m, 2H); 2.19 (m, 1H); 2.20 (s, 3H); 2.78 (d, 2H); 3.01 (m, 2H); 3.65 (s, 3H); 4.16 (bs, 1H); 4.62 (bs, 1H); 7.21 (s, 1H); 11.94 (s, 1H); 12.23 (s, 1H).

Example 8
2- {4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxamide 2- {4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxylic acid (Examples) 6; 0.07 g, 0.17 mmol) in DMF (1.5 ml) was added diisopropylethylamine (0.06 ml, 0.34 mmol) and HATU, and the mixture was stirred at room temperature for 30 minutes. Next, an ammonia solution (7N, 0.1 ml) was added to the reaction, and the mixture was stirred for 2 hours. This was diluted with water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine. This was dried and concentrated to give the crude product, which was purified by reverse phase HPLC. _{MS (ES): C 16 H} 18 Cl 2 N 4 O 2 S with respect to 401. ¹ H NMR: 1.28 (m, 2H); 1.76 (m, 2H); 2.15 (m, 1H); 2.20 (s, 3H); 2.79 (d, 2H); 3.06 (t, 2H); 3.89 (d, 2H); 7.13 (bs, 1H); 7.61 (bs, 1H); 7.75 (s, 1H); 12.23 (s, 1H).

Preparation of starting materials
Intermediate 1
To a stirred solution of N-methyl-N-[(5-methyl-1H-pyrrol-2-yl) methylene] methanaminium chloride oxalyl chloride (1.07 ml, 12.34 mmol) in 30 ml of dry dichloromethane was added DMF (1 0.06 ml, 13.69 mmol)) in dry dichloromethane (2 ml) was slowly added at 0 ° C. The resulting mixture was stirred at 0 ° C. for 20 minutes before 2-methylpyrrole (1 g, 12.34 mmol) in 2 ml dichloromethane was added dropwise. This was warmed to room temperature and stirred for 20 minutes. The solvent volume was then reduced to 50% and dry ether was added to precipitate the product. The precipitated product (1.7 g, reference: J. Org. Chem., 1988, 53, 6115) was collected under nitrogen. ¹ H NMR: 2.41 (s, 3H); 3.47 (s, 3H); 3.59 (s, 3H); 6.45 (d, 1H); 7.35 (d, 1H); 8.46 (s, 1H); 13.36 (s, 1H).

Intermediate 2
N-methyl-N-[(5-methyl-1H-pyrrol-2-yl) methylene] methanaminium chloride in ( dimethylamino) (5-methyl-1H-pyrrol-2-yl) acetonitrile acetonitrile (70 ml) Sodium cyanide (3.07 g, 62.73 mmol) was added to a mixture of the product (intermediate 1,1.72 g, 12.55 mmol) and stirred at room temperature overnight. The mixture was poured into water (350 ml) and the layers were separated. The aqueous layer was extracted 3 times with diethyl ether. The combined extracts were washed with water, brine and dried over potassium carbonate. The solvent was removed in vacuo to give a brown solid (1.3 g, reference: J. Org. Chem., 1988, 53, 6115). ¹ H NMR: 2.14 (s, 3H); 2.18 (s, 6H); 6.45 (d, 1H); 5.65 (s, 1H); 5.95 (s, 1H); 10.75 (s, 1H).

Intermediate 3
4- [2- (5-Methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidine-1-carboxylate benzyldiisopropylamine (1.25 ml, 7.36 mmol) to a dry THF (51 ml) solution A 1.6 M hexane solution of n-butyllithium (4.21 ml, 6.13 mmol) was added at -78 ° C. After 15 min, (dimethylamino) (5-methyl-1H-pyrrol-2-yl) acetonitrile (intermediate 2,0.5 g, 3.07 mol) in THF (6 ml) was added and the resulting solution was Stir at 78 ° C. for 2 hours. Next, 3 ml of THF solution of benzyl 4- (bromomethyl) piperidine-1-carboxylate (0.48 g, 1.53 mmol) was added thereto, and the mixture was stirred at −78 ° C. for 15 minutes and then at 0 ° C. for 20 minutes. . The reaction mixture was poured at 0 ° C. into a beaker containing an aqueous ammonium chloride solution (30 ml). The layers were separated and the aqueous phase was extracted with diethyl ether and the extract was washed with brine and dried over potassium carbonate. Removal of the solvent gave a brown oil. This oil was dissolved in methanol (30 ml), and 10 wt% aqueous sodium hydroxide solution (30 ml) was added. The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether. The extract was washed with brine and dried. The ether was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using hexane-ethyl acetate (3: 1 to 2: 1) as the eluting solvent. The product (0.12 g) was obtained as a light brown solid. _{MS (ES): C 20 H} 24 N 2 O 3 with respect to 341. ¹ H NMR: 1.08 (m, 2H); 1.60 (m, 2H); 1.98 (m, 1H); 2.20 (s, 3H); 2.58 (d, 2H); 2.77 (m, 2H); 3.95 (d, 2H); 5.08 (s, 2H); 5.90 (t, 1H); 6.88 (t, 1H); 7.35 (m, 5H); 11.54 (s, 1H).

Intermediate 4
4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidine-1-carboxylate 4- [2- (5-methyl-1H-pyrrole-2- Yl) -2-oxoethyl] piperidine-1-carboxylate (Intermediate 3, 0.15 g, 0.44 mmol) in dichloromethane (4 ml) at 0 ° C. with N-bromosuccinimide (0.08 g) at a time. In addition, it was stirred at that temperature. The reaction was quenched after 30 minutes with 1N sodium hydroxide solution (1.5 ml) and extracted with dichloromethane. The extract was washed with water and brine and dried. Removal of the solvent gave a light brown thick oil (0.17 g) that solidified in vacuo. MS _(ES): 421 against _{C 20 H 23 BrN 2 O 3} . ¹ H NMR: 1.11 (m, 2H); 1.58 (m, 2H); 1.97 (m, 1H); 2.16 (s, 3H); 2.59 (d, 2H); 2.79 (m, 2H); 3.95 (d, 2H); 5.04 (s, 2H); 7.06 (d, 1H); 7.34 (m, 5H); 11.99 (s, 1H).

Intermediate 5
1- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-piperidin-4-ylethanone hydrobromide 4- [2- (4-Bromo-5-methyl-1H -pyrrole- 2-yl) -2-oxoethyl] piperidine-1-carboxylate (intermediate 4, 0.17 g, 0.41 mmol) and 33% acetic acid hydrobromic acid solution (0.6 ml) were combined at room temperature. For 1 hour. The product was precipitated by addition of diethyl ether, which was collected by filtration under N _2. The product was washed several times with diethyl ether and dried. MS _(ES): 286 against _{C 12} H 17 BrN ₂ O.

Intermediate 6

Intermediate 7
4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidine-1-carboxylate 4- [2- (5-methyl-1H-pyrrole- 2-yl) -2-oxoethyl] piperidine-1-carboxylate (intermediate 3, 0.70 g, 2.05 mmol) in dichloromethane (9 ml) at 0 ° C. with N-chlorosuccinimide (0.55 g, 4 0.1 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 2-3 hours. An additional 0.16 g of N-chlorosuccinimide was added to the reaction and stirred for an additional 2 hours at room temperature. The reaction was then quenched with 1N sodium hydroxide solution and extracted with dichloromethane. The extract was washed with water and brine and dried. Removal of the solvent gave a light brown solid that was purified by flash chromatography on silica gel using hexane-ethyl acetate (3: 1 to 2: 1) as the eluting solvent. The product (0.31 g) was obtained as a white solid. _{MS (ES): C 20 H} 22 Cl 2 N 2 O 3 with respect to 408. ¹ H NMR: 1.14 (m, 2H); 1.64 (m, 2H); 2.01 (m, 1H); 2.20 (s, 3H); 2.76 (d, 2H); 2.80 (m, 2H); 3.96 (d, 2H); 5.05 (s, 2H); 7.35 (m, 5H); 12.22 (s, 1H).

Claims (13)

Formula (I):

[Where:
R ¹ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2), and C _3-6 cycloalkyl; wherein R ¹ is substituted on the carbon by one or more halo or cyclopropyl Well;
R ² is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (wherein a is 0-2) and C _3-6 cycloalkyl; wherein R ² is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ³ is hydrogen, nitro, hydroxy, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkyl S (O) _a (where a is 0-2) and C _3-6 cycloalkyl; wherein R ³ is on the carbon by one or more halo or C _3-6 cycloalkyl May be substituted;
R ⁴ and R ⁵ are independently selected from hydrogen or C _1-4 alkyl;
X is a direct bond, —CH ₂ —, —C (O) —, or S (O) _q — (where q is 1 or 2);
Ring A is carbocyclyl or heterocyclyl; wherein if the heterocyclyl contains a —NH— moiety, the nitrogen may be substituted with a group selected from R ⁷ ;
R ⁶ is a substituent on carbon and is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamide, hydra Gino carbonyl, N- hydroxyethanimidamide yl, amino (hydroxyimino) _{methyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1- 4} alkanoyloxy, N- _{(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1-4} alkyl) carbamoyl, N, N - _{(C 1-4 alkyl) 2} carbamoyl, N- _{(C 1-4} alkoxy) carba Yl, N '- _{(C 1-4} alkyl) _{ureido, N', N '- (} C 1-4 _{alkyl) 2} ureido, N- _{(C 1-4 alkyl)-N-(C 1-4} alkoxy) carbamoyl C _1-4 alkyl S (O) _a (where a is 0 to 2), C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) sulfamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl aminocarbonyl, N '- _{(C 1-4} alkyl) hydrazinocarbonyl, N', N ' - _{(C 1-4 alkyl) 2} hydrazinocarbonyl, carbocyclyl -R ⁸ -, or heterocyclyl -R ⁹ - from selected; wherein ^{R 6,} on carbon, is substituted by one or more ^{R 10} Even if well; if and said heterocyclyl here contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ^11;
m is 0-4; where the meanings of R ⁶ may be the same or different;
R ¹⁰ is halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1-4 alkanoyl, C 1-4} alkanoyloxy, _{N-(C 1-4} alkyl) amino, N, N- _{(C 1-4 alkyl) 2 amino, C 1-4} alkanoylamino, N- _{(C 1 -4} alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2 carbamoyl, C 1-4} alkyl S _{(O) a} (wherein a is 0 to _{2), C 1-4} alkoxycarbonyl, _{N-(C 1-4} alkyl) sulphamoyl, N, N- _{(C 1-4 alkyl) 2 sulphamoyl, C 1-4 alkylsulfonylamino, C 1-4} Alkoxycarbonyl amino, carbocyclyl ^{-R 12} -, or heterocyclyl ^{-R 13} - from selected; wherein ^{R 10} is on a carbon, one or more by ^{R 14} may be substituted; and said heterocyclyl here If it contains a —NH— moiety, the nitrogen may be substituted by a group selected from R ¹⁵ ;
R ⁷ , R ¹¹ , and R ¹⁵ are C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- _{(C 1-4 alkyl) 2} carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and are independently selected from phenylsulfonyl;
R ⁸ , R ⁹ , R ¹² , and R ¹³ are a direct bond, —O—, —N (R ¹⁶ ) —, —C (O) —, —N (R ¹⁷ ) C (O) —, —C (O) N (R ¹⁸ ) —, —S (O) _p —, —SO ₂ N (R ¹⁹ ) —, or —N (R ²⁰ ) SO ₂ — (wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are independently selected from hydrogen or C _1-4 alkyl, and p is 0-2);
R ¹⁴ is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyl Amino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethyl Carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N- Selected from dimethylsulfamoyl, N, N-diethylsulfamoyl, or N-methyl-N-ethylsulfamoyl], or a pharmaceutically acceptable salt thereof. Formula IA:

The compound of claim 1, wherein the compound is Formula IB:

The compound of Claims 1-2 which is a compound of these. Formula IC:

The compound of Claims 1-3 which is a compound of these. Formula ID:

The compound of Claims 1-4 which is a compound of these. 6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylate;
Methyl 2-chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} pyrimidine-4-carboxylate;
2- {4- [2- (3,4-Dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxylate methyl 6- {4- [2- (4-Bromo-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -2-chloropyrimidine-4-carboxylic acid;
2-chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} pyrimidine-4-carboxylic acid;
2- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5-carboxylic acid;
2-Chloro-6- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -N-methoxypyrimidine-4- Carboxamide; or 2- {4- [2- (3,4-dichloro-5-methyl-1H-pyrrol-2-yl) -2-oxoethyl] piperidin-1-yl} -1,3-thiazole-5 A compound which is a carboxamide, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound of claim 1-6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.   A method of treating a bacterial infection in a warm-blooded animal such as a human, comprising administering an effective amount of the compound of claim 1-6 or a pharmaceutically acceptable salt thereof to said animal in need of said treatment. Said method.   A method for inhibiting bacterial DNA gyrase in a warm-blooded animal such as a human, wherein an effective amount of a compound of claim 1-6 or a pharmaceutically acceptable salt thereof is applied to said animal in need of said treatment. Said method comprising administering.   7. The compound of claims 1-6 and pharmaceutically acceptable salts thereof for use as a medicament.   7. The compound of claim 1-6 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in producing an antibacterial effect in a warm-blooded animal such as a human.   7. A compound of claim 1-6 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of bacterial infections in warm-blooded animals such as humans. Process for preparing the compounds of claims 1-6 as follows (wherein the variables and variables are as defined above unless otherwise stated):
Method a) Formula (II):

Wherein R ^a is cyano and R ^b is dimethylamino or diethylamino; or R ^a and R ^b are independently selected from C _1-4 alkylthio; or R ^a and R ^b are taken together To form 1,3-dithianyl or 1,3-dithiolanyl] into a compound of formula (I);
Method b) Formula (III):

A compound of formula (IV):

Reacting with a compound wherein D is a substitutable group;
Method c) For compounds of formula (I) wherein X is —C (O) —; a compound of formula (III) is represented by formula (V):

Reacting with a compound of
Method d) Formula (VI):

[Wherein L is a substitutable group] a compound of formula (VII):

Reacting with a compound of
Method e) Formula (VIII):

[Wherein M is an organometallic group] a compound of formula (IX):

Reacting with the compound wherein L is a displaceable group, and then if necessary:
i) converting a compound of formula (I) to another compound of formula (I);
ii) removing any protecting groups;
iii) producing a pharmaceutically acceptable salt;
{D is a substitutable group. Suitable values for D include halo, such as chloro, bromo, and iodo, tosylate, and mesylate.
L is a substitutable group. Suitable values for L include halo, such as chloro and bromo, pentafluorophenoxy, and 2,5-oxopyrrolidin-1-yloxy.
M is an organometallic group and suitable values for M include organic copper salts, such as CuLi, or organozinc, Zn, or Grignard reagents, such as MgG (where G is halo, such as chloro) Is included}.