2-(piperidin-1-yl)-4-heterocyclyl-thiazole-5-carboxylic acid derivatives against bacterial infections   

This application claims priority to U.S. Provisional Application No. 61/121,953, Attorney Docket No. 103596-1L, filed on Dec. 12, 2008; the entire contents of which is hereby expressly incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

BACKGROUND OF THE INVENTION

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may 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 regarded as having a broad spectrum of activity.

Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium.

The preferred clinically effective antibiotic for treatment of last resort of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β-lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M. catarrhalis.

Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.

Deoxyribonucleic acid (DNA) gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks in the DNA, catalyzing strand passage through the break and resealing the DNA. DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA. The enzyme consists of two subunits, encoded by gyrA and gyrB, forming an A2B2 tetrameric complex. The A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage. The B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.

Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).

DNA gyrase is a well-validated target of antibacterials, including the quinolones and the coumarins. The quinolones (e.g. ciprofloxacin) are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol. Rev. 61: 377-392). Members of this class of antibacterials also inhibit topoisomerase IV and as a result, the primary target of these compounds varies among species. Although the quinolones are successful antibacterials, resistance generated by mutations in the target (DNA gyrase and topoisomerase IV) is becoming an increasing problem in several organisms, including S. aureus and Streptococcus pneumoniae (Hooper, D. C., 2002, The Lancet Infectious Diseases 2: 530-538). In addition, quinolones, as a chemical class, suffer from toxic side effects, including arthropathy that prevents their use in children (Lipsky, B. A. and Baker, C. A., 1999, Clin. Infect. Dis. 28: 352-364). Furthermore, the potential for cardiotoxicity, as predicted by prolongation of the QTc interval, has been cited as a toxicity concern for quinolones.

There are several known natural product inhibitors of DNA gyrase that compete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson, D. M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins are natural products isolated from Streptomyces spp., examples of which 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 targets the GyrB subunit is the cyclothialidines, which are isolated from Streptomyces filipensis (Watanabe, J. et al 1994, J. Antibiot. 47: 32-36). Despite potent activity against DNA gyrase, cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).

Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomeraseIV are known in the art. For example, coumarin-containing compounds are described in patent application number WO 99/35155,5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879, and pyrazole compounds are described in patent application WO 01/52845 (U.S. Pat. No. 6,608,087). AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599 and WO2006/092608.

SUMMARY

We have discovered a new class of compounds that are useful for inhibiting DNA gyrase and/or topoisomerase IV. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.

According to the present invention there is provided a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is chloro or cyano;

R2 is hydrogen, chloro, or cyano;

R3 is halo, C1-4alkyl, C1-4alkoxy, or allyloxy;

R4 is hydrogen or C1-4alkyl;

Ring A is selected from formula (a), (b) or (b′):

wherein:

“*” is the point of attachment to the thiazolyl ring;

X is CH, CR6, or N;

R5 is H, a C1-4alkyl, or C1-4alkoxyC1-4alkyl;

R6, for each occurrence is independently selected from halo, —NR7R8, —OR8, and heterocycle wherein said heterocycle comprises at least one nitrogen ring member and is optionally substituted on one or more carbon atoms with one or more R9 and is optionally substituted on one or more ring nitrogens with R10;

R6 is hydrogen or R6;

R7 and R8 are each, independently, selected from the group consisting of hydrogen and a C1-6alkyl wherein said alkyl is optionally substituted with one or more independently selected from —OH, N,N-di(C1-4alkyl)amino, a C1-6alkoxy, a C1-6alkoxyC1-6alkoxy, and heterocycle, wherein said heterocycle is optionally substituted on one or more carbon atoms with one or more independently selected halo, C1-6alkyl, and C1-6alkoxy, and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a C1-4alkyl;

R9 is, for each occurrence, is independently selected from a C1-4alkyl, halo, hydroxy, C1-4alkoxy, amino, N—(C1-4alkyl)amino, and N,N-di(C1-4alkyl)amino;

R10, for each occurrence, is independently selected from a C1-4alkyl optionally substituted with N,N-di(C1-4alkyl)amino, —OH, heterocycle, and C3-6cycloalkyl, wherein the heterocycle may be optionally substituted with C1-4alkyl; and

n is 0, 1, 2, or 3.

In another aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is chloro or cyano;

R2 is hydrogen, chloro, or cyano;

R3 is halo, C1-4alkyl, C1-4alkoxy, or allyloxy;

R4 is hydrogen or C1-4alkyl;

Ring A is selected from formula (a) or (b):

wherein:

“*” is the point of attachment to the thiazolyl ring;

X is CH, CR6, or N;

R5 is H, a C1-4alkyl, or C1-4alkoxyC1-4alkyl;

R6, for each occurrence, is independently selected from halo, —NR7R8, and heterocycle wherein said heterocycle comprises at least one nitrogen ring member and is optionally substituted on one or more carbon atoms with one or more R9 and is optionally substituted on one or more ring nitrogens with R10;

R6′ is hydrogen or R6;

R7 and R8 are each, independently, selected from the group consisting of hydrogen and a C1-6alkyl wherein said alkyl is optionally substituted with one or more independently selected —OH, a C1-6alkoxy, a C1-6alkoxyC1-6alkoxy, and heterocycle, wherein said heterocycle is optionally substituted on one or more carbon atoms with one or more independently selected halo, C1-6alkyl, or C1-6alkoxy, and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a C1-4alkyl;

R9 is, for each occurrence, is independently selected from a C1-4alkyl, halo, hydroxy, C1-4alkoxy, amino, N—(C1-4alkyl)amino, and N,N-di(C1-4alkyl)amino;

R10, for each occurrence, is independently selected from a C1-4alkyl; and

n is 0, 1, 2, or 3.

In certain embodiments of formula (I), n is 1, 2, or 3.

In certain embodiments of formula (I), R6, for each occurrence, is independently selected from —NR7R8, and heterocycle wherein said heterocycle comprises at least one nitrogen ring member and is optionally substituted on one or more carbon atoms with one or more R9 and is optionally substituted on one or more ring nitrogens with R10; and R6′ is R6.

In certain embodiments of formula (I), —OR8 is selected from the group consisting of hydrogen and a —OC2-6alkyl wherein said alkyl moiety is optionally substituted with one or more independently selected from —OH, N,N-di(C1-4alkyl)amino, a C1-6alkoxy, a C1-6alkoxyC1-6alkoxy, and heterocycle, wherein said heterocycle is optionally substituted on one or more carbon atoms with one or more independently selected halo, C1-6alkyl, and C1-6alkoxy, and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a C1-4alkyl. In particular embodiments, —OR8 is ethoxy optionally substituted as described above.

In another embodiment, the invention provides pharmaceutical compositions comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In another embodiment, the invention provides a method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human. In one embodiment, the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection in a warm-blooded animal. In one embodiment, the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.

DETAILED DESCRIPTION

In this specification, the term “alkyl” includes both straight and branched chain hydrocarbon which are fully saturated. “C1-6” or “C1-4” before a group, such as an alkyl group or an alkoxy group, indicates the number of carbon atoms in the group. For example, a “C1-6alkyl” is an alkyl groups that has from 1 to 6 carbon atoms. Likewise, a “C1-4alkyl” is an alkyl group that has from 1 to 4 carbon atom. Examples of “C1-4alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, and t-butyl. References to individual alkyl groups such as propyl are specific for the straight chain version only unless otherwise specified. An analogous convention applies to other generic terms.

Where optional substituents are chosen from one or more groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH2-group can optionally be replaced by a —C(O)— and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). In one aspect of the invention a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a —CH2— group can optionally be replaced by a —C(O)— and a ring sulphur atom may be optionally oxidised to form the S-oxides. In a further aspect of the invention a “heterocyclyl” is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen. Examples of suitable values of the term “heterocyclyl” are piperazinyl, piperidinyl, morpholinyl, 2-oxo-pyrrolidinyl, 1,3-dioxanyl, and 2-oxo-1,3-oxazolidinyl, 2-oxo-imidazolidinyl. Further examples of suitable values for the term “heterocyclyl” include pyridinyl, pyrazinyl, imidazolyl, and 1,2,4-triazolyl.

An “alkoxy” is an alkyl group that is linked to another moiety via —O—. Examples of “C1-4alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

An “alkoxyalkyl” is an alkyl group which is substituted with an alkoxy group.

An “alkoxyalkoxy is an alkoxy group which is substituted with another alkoxy group, wherein the alkoxy groups may have the same or a different number of carbon atoms.

An “amino” group is —NH2. An “N—(C1-4alkyl)amino” is an amino group in which on hydrogen is replaced with a C1-4alkyl group. Examples of “N—(C1-4alkyl)amino” groups include methylamino and ethylamino. An “N,N-di(C1-4alkyl)amino” is an amino group in which both hydrogens are replaced with the same or a different C1-4alkyl group. Examples of “N,N-di(C1-4alkyl)amino” include N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino.

A compound of formula (I) may form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. In one aspect of the invention the pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be utilised whether pharmaceutically-acceptable or not.

Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DNA gyrase and/or topoisomerase IV and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names.

It will be appreciated by those skilled in the art that in addition to the two asymmetric carbons drawn in formula (I), compounds of formula (I) may contain additional asymmetrically substituted carbon(s) and sulphur atom(s), and accordingly may exist in, and be isolated in, as far as those additional asymmetrically substituted carbon(s) and sulphur atom(s) are concerned, optically-active and racemic forms at those positions. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, at any additional asymmetrically substituted carbon(s) and sulphur atom(s), which possesses properties useful in the inhibition of DNA gyrase and/or topoisomerase IV.

Optically-active forms may be prepared by procedures known in the art for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase.

Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic form, or mixtures thereof, which form possesses properties useful in the inhibition of DNA gyrase and/or topoisomerase IV

It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit DNA gyrase and/or topoisomerase IV.

By way of clarity, compounds of the invention included all isotopes of the atoms present in formula (I) and any of the examples or embodiments disclosed herein. For example, H (or hydrogen) represents any isotopic form of hydrogen including 1H, 2H (D), and 3H (T); C represents any isotopic form of carbon including 12C, 13C, and 14C; O represents any isotopic form of oxygen including 16O, 17O and 18O; N represents any isotopic form of nitrogen including 13N, 14N and 15N; P represents any isotopic form of phosphorous including 31P and 32P; S represents any isotopic form of sulfur including 32S and 35S; F represents any isotopic form of fluorine including 19F and 18F; Cl represents any isotopic form of chlorine including 35Cl, 37Cl and 36Cl; and the like. In a preferred embodiment, compounds represented by formula (I) comprises isotopes of the atoms therein in their naturally occurring abundance. However, in certain instances, it is desirable to enrich one or more atom in a particular isotope which would normally be present in less abundance. For example, 1H would normally be present in greater than 99.98% abundance; however, a compound of the invention can be enriched in 2H or 3H at one or more positions where H is present. In one embodiment, when a compound of the invention is enriched in a radioactive isotope, for example 3H and 14C, they may be useful in drug and/or substrate tissue distribution assays. It is to be understood that the invention encompasses all such isotopic forms which inhibit DNA gyrase and/or topoisomerase IV.

Another embodiment of the invention provides a compound selected from the group consisting of any one or more of the compounds described in the Examples section, or a salt, e.g., a pharmaceutically acceptable salt, thereof. Moreover, if such compound is represented as a salt, the present invention is intended to include free bases, free acids, or alternative salts of these particular compounds. Additional embodiments comprise compositions and medicaments containing the same (including the aforementioned free bases, free acids, or alternative salts), as well as processes for the preparation and use of such compounds, compositions and medicaments. Moreover, it should be noted that each of these compounds, and salts thereof, are also intended to be separate embodiments, and in this regard, each species listed in the Examples, and salt thereof, should be considered to be an individual embodiment.

Moreover, it should be understood that the present invention is intended to include any novel compound or pharmaceutical composition described herein.

There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter. For the avoidance of doubt each stated species represents a particular and independent aspect of this invention. Unless otherwise stated, variables in the particular embodiments described below are defined as for formula (I).

R1 is chloro.

R1 is cyano.

R2 is hydrogen.

R2 is chloro.

R2 is cyano.

R3 is halo.

R3 is fluoro.

R3 is C1-4alkyl.

R3 is methyl.

R3 is ethyl.

R3 is C1-4alkoxy.

R3 is methoxy.

R3 is ethoxy.

R3 is allyloxy.

R3 is methyl, ethoxy, or allyloxy.

R3 is methyl, methoxy, ethoxy, or allyloxy.

R4 is hydrogen.

R4 is methyl.

R4 is ethyl.

Ring A is represented by formula (a):

Ring A is represented by formula (a), and X is CR6′.

Ring A is represented by formula (a), and X is N.

Ring A is 1-(2-methoxyethyl)-1H-imidazol-2-yl.

Ring A is 1-methyl-1H-1,2,4-triazol-5-yl.

Ring A is selected from the group consisting of 1-(2-methoxyethyl)-1H-imidazol-2-yl or 1-methyl-1H-1,2,4-triazol-5-yl.

Ring A is formula (c):

R5 is hydrogen.

R5 is C1-4alkyl.

R5 is methyl.

R5 is C1-4alkoxyC1-4alkyl.

R5 is methoxyethyl.

Ring A is represented by formula (b):

Ring A is represented by formula (b) and X is CH or CR6.

Ring A is represented by formula (b) and X is N.

Ring A is 3-fluoropyridin-2-yl.

Ring A is pyrazin-2-yl

Ring A is selected from the group consisting of 3-fluoropyridin-2-yl or pyrazin-2-yl.

R6 is piperidino.

R6 is piperazinyl.

R6 is N-methylpiperazino.

R6 is morpholino.

R6 is piperidino, piperazinyl, N-methylpiperazino or morpholino.

R6 is 1-(1H-1,2,3-triazol-5-yl)methanamino.

R6 is 2-(2-oxo-pyrrolidino)ethylamino.

R6 is 2-methoxyethylamino.

R6 is 2-(4-fluoropiperidino)ethylamino.

R6 is 1-(1,3-dioxan-4-yl)-N-methylmethanamino.

R6 is N-(1-methoxymethyl-2-methoxyethyl)amino.

R6 is 2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino.

R6 is 2-(2-methoxyethoxy)-ethylamino.

R6 is 2-morpholinoethylamino.

R6 is 2-(2-oxo-imidazolidin-1-yl)ethylamino.

R6′ is hydrogen. P R6′ is R6.

Ring A is represented by formula (b), X is CH or CR6, and R6 is piperidino, piperazinyl, N-methylpiperazino or morpholino.

Ring A is represented by formula (b), X is N, and R6 is piperidino, piperazinyl, N-methylpiperazino or morpholino.

Ring A is represented by formula (b), X is CH or CR6, n is 1 and R6 is selected from 1-(1H-1,2,3-triazol-5-yl)methanamino, 2-(2-oxo-pyrrolidino)ethylamino, 2-methoxyethylamino, 2-(4-fluoropiperidino)ethylamino, 1-(1,3-dioxan-4-yl)-N-methylmethanamino, N-(1-methoxymethyl-2-methoxyethyl)amino, 2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino, 2-(2-methoxyethoxy)-ethylamino, 2-morpholinoethylamino, or 2-(2-oxo-imidazolidin-1-yl)ethylamino.

Ring A is represented by formula (b), n is 1 and R6 is selected from 1-(1H-1,2,3-triazol-5-yl)methanamino, 2-(2-oxo-pyrrolidino)ethylamino, 2-methoxyethylamino, 2-(4-fluoropiperidino)ethylamino, 1-(1,3-dioxan-4-yl)-N-methylmethanamino, N-(1-methoxymethyl-2-methoxyethyl)amino, 2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino, 2-(2-methoxyethoxy)-ethylamino, 4-[2-(diethylamino)ethyl]piperazin-1-yl, 2-(4-methylpiperazin-1-yl)ethylamino, 2-(dimethylamino)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-morpholinoethylamino, or 2-(2-oxo-imidazolidin-1-yl)ethylamino.

Ring A is represented by formula (d):

Ring A is represented by formula (e):

Ring A is selected from formula (d) or (e):

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R1 is chloro;

R2 is hydrogen, chloro or cyano;

R3 is methyl, ethoxy, or allyloxy;

R4 is hydrogen, methyl or ethyl;

Ring A is 1-(2-methoxyethyl)-1H-imidazol-2-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 3-fluoropyridin-2-yl or pyrazin-2-yl.

Therefore in a further aspect of the invention there is provided a compound of formula

(I) (as depicted above) wherein:

R1 is chloro;

R2 is hydrogen, chloro or cyano;

R3 is methyl, ethoxy, or allyloxy;

R4 is hydrogen, methyl or ethyl;

Ring A is formula (c):

wherein:

X is CH or N; and

R5 is H, a C1-4alkyl, or C1-4alkoxyC1-4alkyl.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R1 is chloro;

R2 is hydrogen, chloro or cyano;

R3 is methyl, ethoxy, or allyloxy;

R4 is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

X is CH or N; and

R6 is a halo.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R1 is chloro;

R2 is hydrogen, chloro or cyano;

R3 is methyl, methoxy, ethoxy, or allyloxy;

R4 is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R6 is —OR8 or —NR7R8;

R7 is hydrogen or a C1-4alkyl; and

R8 is selected from the group consisting of 1-(1H-1,2,3-triazol-5-yl)methyl, 2-(2-oxo-pyrrolidino)ethyl, 2-methoxyethyl, 2-(4-fluoropiperidino)ethyl, 1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(dimethylamino)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl, 2-(2-methoxyethoxy)-ethyl, 2-morpholinoethyl, or 2-(2-oxo-imidazolidin-1-yl)ethyl.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R1 is chloro;

R2 is hydrogen, chloro or cyano;

R3 is methyl, methoxy, ethoxy, or allyloxy;

R4 is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R6 is —NR7R8;

R7 is hydrogen or a C1-4alkyl; and