5-6-BICYCLIC HETEROAROMATIC COMPOUNDS WITH ANTIBACTERIAL ACTIVITY

Field of the Invention

The present invention relates to compounds which 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 Enter ococcus 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 A ₂ B ₂ 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 QT _C 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 Al. 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 topoisomerase IV 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 (US patent US6,608,087). AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599, WO2006/092608, WO2007/071965, WO2008/020227, WO2008/020222, WO2008/020229, and WO2008/068470.

Summary of the Invention

We have discovered a new class of compounds which 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):

- A -

(I)

R ¹ is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-6 cycloalkyl; wherein R ¹ may be optionally substituted on carbon by one or more R ⁵ ; R ² is selected from hydrogen or Ci_6alkyl; wherein said may be optionally substituted by one or more groups independently selected from halo, cyano, hydroxy, nitro and amino;

X ¹ is selected from =N- or =C(R ⁶ )-; X ² and X ³ are independently selected from (i) or (ii): (i) -N= or -C(R ⁷ )=;

(ii) -O-, -S-, -N(R ⁸ )- or -C(R ⁹ )(R ¹⁰ )-; wherein X ² and X ³ are not both selected from (i);

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹¹ ; R ³ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, 7V-(Ci-6alkyl)amino, λ/,N-(Ci-6alkyl)2amino, Ci.6alkanoylamino, λ/-(Ci-6alkyl)carbamoyl, λ/,λ/-(Ci _-6 alkyl) ₂ carbamoyl, λ/-(Ci. ₆ alkoxy)carbamoyl, λ/,λ/-(Ci. ₆ alkoxy) ₂ carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci-όalkoxycarbonylamino, jV,jV-(Ci-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl-R ¹² - or heterocyclyl-R ¹³ -; wherein R ³ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ independently of each other may be optionally substituted on carbon by one or more R ¹⁴ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁵ ;

R ⁴ is a substituent on carbon is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^alkyl, C2-6alkenyl, C ₂ - ₆ alkynyl, Ci_6alkoxy, λ/-(Ci. ₆ alkyl)amino, λ/,λ/-(Ci.6alkyl)2carbamoyl,

λ/-(Ci-6alkoxy)carbamoyl, λ/,λ/-(Ci-6alkoxy)2Carbamoyl, Ci.6alkylS(O) _a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci-όalkoxycarbonylamino, λ/-(Ci- ₆ alkyl)sulphamoyl, λ/,N-(Ci _-6 alkyl)2Sulphamoyl, d- _ό alkylsulphonylamino, carbocyclyl-R ¹⁶ - or heterocyclyl-R ¹⁷ -; wherein R ⁴ may be optionally substituted on carbon by one or more R ¹⁸ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁹ ; n is 0-4; wherein the values of R ⁴ may be the same or different;

R ⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C ₂ - ₆ alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, λ/-(Ci- ₆ alkyl)amino, Ci. ₆ alkanoylamino and C ₃ _ ₆ cycloalkyl;

R ⁸ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, Ci _-6 alkanoyl, Ci_6alkylsulphonyl, Ci_6alkoxycarbonyl, carbamoyl, TV-(C i-6alkyl)carbamoyl, λ/,λ/-(Ci. ₆ alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R ¹² , R ¹³ , R ¹⁶ and R ¹⁷ are independent selected from a direct bond, -O-, -N(R ²⁰ )-, -C(O)-, -N(R ²¹ )C(O)-, -C(O)N(R ²² )-, -S(O) ₈ -, -SO ₂ N(R ²³ )- or -N(R ²⁴ )SO ₂ -; wherein R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently selected from hydrogen or and s is 0-2; and

R ^π , R ¹⁵ and R ¹⁹ are independently selected from Ci_6alkyl, C ₃ _ ₆ cycloalkyl, Ci-6alkanoyl, Ci-όalkylsulphonyl, Ci-όalkoxycarbonyl, carbamoyl, λ/-(Ci- ₆ alkyl)carbamoyl, λ/,λ/-(Ci. ₆ alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; R ¹⁴ and R ¹⁸ are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-iV-ethylamino, acetylamino, λ/-methylcarbamoyl, iV-ethylcarbamoyl, λ/,λ/-dimethylcarbamoyl, 7V,7V-diethylcarbamoyl, 7V-methyl-7V-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, 7V-methylsulphamoyl, 7V-ethylsulphamoyl, λ/,λ/-dimethylsulphamoyl, λ/,λ/-diethylsulphamoyl or TV-methyl-TV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention there is provided a compound of formula (I'):

(I')

R ¹ , R ² , R ⁴ , X ¹ , X ² , X ³ , ring A and n are as defined in formula (I); R ³ is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^aUcyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, Ci_6alkanoyl, Ci_6alkanoyloxy, λ/-(Ci-6alkyl)amino, λ/,λ/-(Ci-6alkyl)2amino, λ/,λ/-(Ci. ₆ alkyl) ₂ carbamoyl, λ/-(Ci-6alkoxy)carbamoyl, 7V _> 7V-(Ci-6alkoxy)2Carbamoyl, Ci.6alkylS(0) _a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci-όalkoxycarbonylamino, λ/-(Ci-6alkyl)sulphamoyl, λ/,λ/-(Ci-6alkyl) ₂ sulphamoyl, d-όalkylsulphonylamino, carbocyclyl-R ¹² - or heterocyclyl-R ¹³ -; wherein R ³ may be optionally substituted on carbon by one or more R ¹⁴ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁵ ; wherein R ¹² , R ¹³ and R ¹⁵ are defined as for formula (I); and

R ¹⁴ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifiuoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dime thy lamino, diethylamino, 7V-methyl-7V-ethylamino, acetylamino, 7V-methylcarbamoyl, JV-ethylcarbamoyl, λζiV-dimethylcarbamoyl, 7V,7V-diethylcarbamoyl, TV-methyl-TV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, 7V-methylsulphamoyl, 7V-ethylsulphamoyl, 7V,7V-dimethylsulphamoyl, 7V,7V-diethylsulphamoyl, jV-methyl-jV-ethylsulphamoyl, and morpholinomethyl.

For the avoidance of doubt, when X ² is selected from -N= or -C(R ⁷ )=; the bond between the -C(X ² )- and the -C(Ring A)- in formula (I) or (I') is a double bond; when X ² is selected from -O-, -S-, -N(R ⁸ )- or -C(R ⁹ )(R ¹⁰ )-, the bond between -C(X ² )- and -C(Ring A)- in formula (I) or (I') is a single bond; when X ³ is selected from -N= or -C(R ⁷ )= the bond between -C(Ring A)- and -C(X ³ )- in formula (I) or (I') is a double bond; and when X ³ is selected -O-, -S-, -N(R ⁸ )- or -C(R ⁹ )(R ¹⁰ )-, the bond between -C(Ring A)- and -C(X ³ )- in formula (I) or (I') is a single bond.

Furthermore, X ² and X ³ are not both selected from (i) because the bond between -C(X ² )- and -C(Ring A)- and the bond between -C(Ring A)- and -C(X ³ )- in formula (I) or (V) cannot both be double bonds.

In addition, when X ² and X ³ are both selected from (ii) and the bond between -C(X ² )- and -C(Ring A)- and the bond between -C(Ring A)- and -C(X ³ )- in formula (I) or (I') are both single bonds the carbon attached to Ring A has an additional hydrogen on it. For example as shown:

In one embodiment, the compounds represented by formula (I) or (I') do not include the compounds in Table A.

In another embodiment, the invention provides pharmaceutical compositions comprising a compound represented by formula (I) or (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 (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 (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 (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 (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 (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 (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 (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 (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 (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 (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 of the Invention

In this specification the term alkyl includes both straight and branched chain alkyl groups. For example, includes methyl, ethyl, propyl, isopropyl and t-butyl. However references to individual alkyl groups such as propyl are specific for the straight chain version only. 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 -CH ₂ - 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 -CH ₂ - 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 and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,

3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 7V-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine -TV-oxide and quinoline-λ/-oxide. Further examples and suitable values of the term "heterocyclyl" are imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrazolyl, 1,2,4-triazolyl, pyridyl, benzothiazolyl, isoxazolyl, pyrazinyl, pyrimidinyl and thiazolyl.

A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH ₂ - group can optionally be replaced by a -C(O)-. Particularly "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 is acetoxy. Examples are methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Ci- ₄ alkoxycarbonylamino" are methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples are methoxy, ethoxy and propoxy.

Examples are formamido, acetamido and propionylamino. Examples of "Ci- ₄ alkylS(O)a wherein a is 0 to 2" are methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of are propionyl and acetyl. Examples of 'W-(d _-4 alkyl)amino" are methylamino and ethylamino. Examples of 'W,N-(C _1-4 alkyl) ₂ amino" are di-N-methylamino, di-(7V-ethyl)amino and jV-ethyl-jV-methylamino. Examples of "C2-4alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C ₂ - ₄ alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of

'W-(Ci. ₄ alkyl)sulphamoyl" are 7V-(methyl)sulphamoyl and 7V-(ethyl)sulphamoyl. Examples of "λ/,λ/-(Ci-4alkyl)2Sulphamoyl" are λ/,λ/-(dimethyl)sulphamoyl and λ/-(methyl)-λ/-(ethyl)sulphamoyl. Examples of are methylaminocarbonyl and ethylaminocarbonyl. Examples are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of 'W-(Ci- ₄ alkoxy)carbamoyl" are methoxyaminocarbonyl and isopropoxyaminocarbonyl. Examples of 'W-(Ci-4alkyl)-λ/-(Ci-4alkoxy)carbamoyl" are λ/-methyl-7V-methoxyaminocarbonyl and N-methyl-TV-ethoxyaminocarbonyl. Examples of 'W-(Ci. ₄ alkyl)ureido" are N'-methylureido and N'-isopropylureido. Examples of 'W,iV-(C _1-4 alkyl) ₂ ureido" are NW-dimethylureido and N'-methyl-N'-isopropylureido. Examples of 'W-(Ci- ₄ alkyl)hydrazinocarbonyl" are N'-methylhydrazinocarbonyl and

TV-isopropylhydrazinocarbonyl. Examples of W,N'-(Ci _-4 alkyl) ₂ hydrazinocarbonyl" are λW-dimethylhydrazinocarbonyl and 7V'-methyl-7V -isopropylhydrazinocarbonyl. Examples of "Ci _-4 alkylsulphonylamino" are methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino. Examples of "Ci^alkylsulphonylaminocarbonyl" are methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl. Examples are methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl. Examples of "Cs- _ό Cycloalkyl" are cyclopropyl and cyclohexyl.

The term "formula (I)", unless otherwise specified, refers to all embodiments of formula (I), including but not limited to formula (IA) and formula (IB). Likewise, the term "formula (I')", unless otherwise specified, refers to all embodiments of formula (I'), including but not limited to formula (IA), formula (IB), and formula (IC). The phrase "compounds of the invention," unless otherwise specified, refers to all embodiments of formula (I) and (I'). A compound of formula (I) or (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, 7V-methylpiperidine, 7V-ethylpiperidine, procaine, dibenzylamine, 7V,7V-dibenzylethylamine, tris-(2-hydroxyethyl)amine, TV-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 utilized whether pharmaceutically-acceptable or not.

Within the present invention it is to be understood that a compound of the formula (I) or (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

utilized 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 compounds of formula (I) or (I') may contain 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.

By way of clarity, compounds of the invention included all isotopes of the atoms present in formula (I) or (I') and any of the examples or embodiments disclosed herein. For example, H (or hydrogen) represents any isotopic form of hydrogen including ¹ H, ² H (D), and ³ H (T); C represents any isotopic form of carbon including ¹² C, ¹³ C, and ¹⁴ C; O represents any isotopic form of oxygen including ¹⁶ O, ¹⁷ O and ¹⁸ O; N represents any isotopic form of nitrogen including ¹³ N, ¹⁴ N and ¹⁵ N; P represents any isotopic form of phosphorous including ³¹ P and ³² P; S represents any isotopic form of sulfur including ³² S and ³⁵ S; F represents any isotopic form of fluorine including ¹⁹ F and ¹⁸ F; Cl represents any isotopic form of chlorine including ³⁵ Cl, ³⁷ Cl and ³⁶ Cl; and the like. In a preferred embodiment, compounds represented by formula (I) or (I') comprise isomers 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, ¹ H would normally be present in greater than 99.98% abundance; however, a

compound of the invention can be enriched in ² H or ³ H 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 ³ H and ¹⁴ C, 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.

It is also to be understood that certain compounds of the formula (I) or (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. 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.

R ¹ is Ci _-6 alkyl. R ¹ is ethyl.

R ² is hydrogen. X ¹ is =N-. X ¹ is =C(R ⁶ )-.

X ¹ is =C(R ⁶ )-; wherein R ⁶ is hydrogen. One of X ² and X ³ is selected from (i) and the other is selected from (ii):

(i) -N= or -C(R ⁷ )=; (ii) -O-, -S-, -N(R ⁸ )- or -C(R ⁹ )(R ¹⁰ )-. X ² is selected from (i) and X ³ is selected from (ii):

(i) -N= or -C(R ⁷ )=; (ii) -O-, -S-, -N(R ⁸ )- or -C(R ⁹ )(R ¹⁰ )-.

X ² is selected from (ii) and X ³ is selected from (i): (i) -N= or -C(R ⁷ )=; (ϋ) -O-, -S-, -N(R ⁸ )- or -C(R ⁹ XR ¹⁰ )-. X ² is -N=. X ² is -C(R ⁷ )=.

X ² is -O-. X ² is -S-. X ² is -N(R ⁸ )-.

X ² is -C(R ⁹ XR ¹⁰ )-.

X ³ is -N=.

X ³ is -C(R ⁷ )=.

X ³ is -O-.

X ³ is -S-.

X ³ is -N(R ⁸ )-.

X ³ is -N(R ⁸ )-; wherein R ⁸ is hydrogen or

X ³ is -N(R ⁸ )-; wherein R ⁸ is Ci _-6 alkyl;

X ³ is -N(R ⁸ )-; wherein R ⁸ is hydrogen or t-butoxycarbonyl. X ³ is -C(R ⁹ XR ¹⁰ )-.

X ² is -N= and X ³ is -NH-.

X ² is -N= and X ³ is -N(CH ₃ )-.

X ² is -N= and X ³ is -N[C(O)OC(CH ₃ ) ₃ ]-.

X ² is -N= and X ³ is -O-. X ² is -CH= and X ³ is -S-.

X ² is -CH= and X ³ is -N(CH ₃ )-.

X ¹ and X ² are both =N-; X ³ is -NR ⁸ -; and R ⁸ is hydrogen or a Ci _-6 alkyl.

X ¹ is -C(R ⁷ )=; X ² is =N-; X ³ is -NR ⁸ -; R ⁷ is hydrogen; and R ⁸ is hydrogen or a Ci- ₆ alkyl. X ¹ is -C(R ⁷ )=; X ² is =N-; X ³ is -O-; and R ⁷ is hydrogen.

X ¹ is =N-; X ² is =C(R ⁷ )-; X ³ is -S-; and R ⁷ is hydrogen.

Ring A is carbocyclyl.

Ring A is phenyl.

Ring A and (R ⁴ ) _n together are 4-cyanophenyl. Ring A and (R ⁴ ) _n together are 3-cyanophenyl.

Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹¹ .

Ring A is heterocyclyl.

Ring A is a pyridyl. Ring A is pyrid-3-yl.

Ring A is pyrid-4-yl.

Ring A is a thiazolyl.

Ring A is thiazol-2-yl.

Ring A and (R ⁴ ) _n together are 4-carboxy-thiazol-2-yl.

Ring A and (R ⁴ ) _n together are 4-carbamoyl-thiazol-2-yl.

Ring A and (R ⁴ ) _n together are 4-(7V-methyl-carbamoyl)-thiazol-2-yl.

Ring A and (R ⁴ ) _n together are 4-(ethoxycarbonyl)-thiazol-2-yl. Ring A is a triazolyl.

Ring A is l,2,4-triazol-3-yl.

R ³ is hydrogen.

R is a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R ¹⁴ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁵ .

R ³ is a piperazinyl.

R ³ is piperazin-1-yl.

R ³ is a morpholinyl.

R ³ is morpholin-4-yl. R ³ is a piperidinyl.

R ³ is piperidin-1-yl.

R ³ is pyridyl.

R ³ is pyrid-4-yl.

R ³ is benzothiazolyl. R ³ is benzothiazol-2-yl.

R ³ is a phenyl which may be optionally substituted on one or more carbon with one or more independently selected R ¹⁴ .

R ³ is phenyl.

R ³ is 3-methyl-phenyl. R ³ is 4-methyl-phenyl.

R ³ is 2-fiuoro-phenyl.

R ³ is hydrogen.

R ³ is a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R ¹⁴ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁵ .

R ³ is a piperazinyl.

R ³ is piperazin-1-yl.

R ³ is a morpholinyl.

R ³ is morpholin-4-yl.

R ³ is a piperidinyl.

R ³ is piperidin-1-yl.

R ³ is pyridyl. R ³ is pyrid-4-yl.

R ³ is benzothiazolyl.

R ³ is benzothiazol-2-yl.

R ³ is a phenyl which may be optionally substituted on one or more carbon with one or more independently selected R ¹⁴ . R ^3' is phenyl.

R ³ is 3-methyl-phenyl.

R ³ is 4-methyl-phenyl.

R ³ is 2-fluoro-phenyl.

R ³ is 4-(moropholinomethyl)-phenyl. R ⁴ is cyano.

R ⁴ is carboxy.

R ⁴ is carbamoyl.

R ⁴ is N-methyl-carbamoyl.

R ⁴ is N-ethyl-carbamoyl. R ⁴ is ethoxycarbonyl. n is 0. n is 1.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein: R ¹ is Ci- ₆ alkyl;

R ² is hydrogen;

X ¹ is =C(R ⁶ )-; wherein R ⁶ is hydrogen;

X ² is -N=;

X ³ is -N(R ⁸ )-; wherein R ⁸ is hydrogen or Ci_ ₆ alkoxycarbonyl; Ring A is pyridyl;

R ³ is hydrogen; n is 0; or a pharmaceutically acceptable salt thereof.

According to a further feature of the invention, there is provided a compound of formula (I) which is a compound of formula (IA):

(IA) wherein R ¹ , R ² , X ¹ , R ³ , R ⁸ , Ring A, R ⁴ and n are as described herein above; or a pharmaceutically acceptable salt thereof. In one embodiment of formula (IA), R ³ is H. In another embodiment, ring A is pyridyl. In another embodiment of formula (IA), R ³ is H and ring A and (R ⁴ ) _n together are pyrid-3-yl. In another embodiment of formula (IA), R ³ is piperazinyl and ring A together with (R ⁴ ) _n is 4-carboxy-thiazole-2-yl, 4-carbamoyl-thiazol-2- yl or 4-ethoxycarbonyl-thiazol-2-yl. In another embodiment of formula (IA), R ³ is morpholino and ring A together with (R ⁴ ) _n is 4-carboxy-thiazole-2-yl, 4-(N-methyl- carbamoyl)-thiazol-2-yl, or 4-ethoxycarbonyl-thiazol-2-yl. In another embodiment of formula (IA), R ⁸ is H or methyl. In another embodiment of formula (IA), R ³ is piperdinyl and ring A together with (R ⁴ ) _n is l,2,4-triazol-3-yl, 4-carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)- thiazol-2-yl, or 4-carbamoyl-thiazol-2-yl. In another embodiment of formula (IA), R ³ is phenyl, 3-methylphenyl, 4-methylphenyl, or 2-fluorophenyl and ring A together with (R ⁴ ) _n is l,2,4-triazol-3-yl, 4-carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)-thiazol-2-yl, or 4- ethoxycarbonyl-thiazol-2-yl.

According to a further feature of the invention, there is provided a compound of formula (I) which is a compound of formula (IB):

(IB)

R ¹ , R ² , X ¹ , R ³ , Ring A, R ⁴ and n are as described herein above; or a pharmaceutically acceptable salt thereof. In one embodiment of formula (IB), R ³ is H, and ring A together with (R ⁴ ) _n is pyrid-3yl, pyrid-4-yl, 3-cyano-phenyl, or 4-cyanophenyl.

According to a further feature of the invention, there is provided a compound of formula (I') which is a compound of formula (IC):

(IC) R ¹ , R ² , X ¹ , R ³ , Ring A, R ⁴ and n are as described herein above; or a pharmaceutically acceptable salt thereof. In one embodiment of formula (IC), R ³ is pyrid-4-yl and ring A together with (R ⁴ ) _n is 4-carboxy-thiazole-2-yl or 4-ethoxycarbonyl-thiazol-2-yl. In another embodiment of formula (IC), R ³ ' is benzothiazol-2-yl and ring A together with (R ⁴ ) _n is 4- carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)-thiazol-2-yl, or 4-ethoxycarbonyl-thiazol-2- yl. In another embodiment of formula (IC), R ³ ' is 4-(morpholinomethyl)-phenyl, and ring A together with (R ⁴ ) _n is 4-carboxy-thiazole-2-yl or 4-ethoxycarbonyl-thiazol-2-yl. In another embodiment of formula (IC), R ³ ' is phenyl and ring A together with (R ⁴ ) _n is 4- ethoxycarbonyl-thiazol-2-yl.

Particular compounds of the invention are the compounds of the Examples, each of which provides a further independent aspect of the invention. In further aspects, the present invention also comprises any two or more compounds of the Examples.

In one embodiment of the invention are provided compounds of formula (I) or (I'). In an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I) or (I').

In a further aspect the present invention provides a process for preparing a compound of formula (I) or (I') or a pharmaceutically-acceptable salt thereof.

Thus, the present invention also provides that the compounds of the formula (I) or (I') and pharmaceutically-acceptable salts thereof, can be prepared by a process as follows (wherein the variables are as defined above unless otherwise stated): Process a) reacting an amine of formula (II):

(H) with an acid of formula (III) or (HI'):

(HI) (in') or an activated derivative thereof;

Process b) reacting an acid of formula (IV):

(IV) or an activated derivative thereof; with an amine of formula (V) or (V'):

(V) (V')

Process c) for compounds of formula (I) or (I') wherein R ² is hydrogen; reacting an isocyanate of formula (VI): i ^O

R.

(VI) with an amine of formula (V) or (V');

Process d) reacting an isocyanate of formula (VII) or (VII'):

(VII) (VIP) with an amine of formula (II);

Process e) for compounds of formula (I) or (I') wherein the five membered ring of formula (I) or (I') is attached to a double bond of Ring A; reacting a compound of formula (VIII) or (VIII'):

(VIII) (VIII') with a compound of formula (IX):

(IX) wherein one of X ^a and X ^b is a displaceable group "L" and the other is an organometallic reagent "M";

Process f) for compounds of formula (I) or (I') wherein Ring A is a thiazole-2-yl; reacting a compound of formula (X) or (X'):

(X) (X') with a compound of formula (XI):

(XI) wherein X ^a is a displaceable group "L";

Process g) for compounds of formula (I) or (I') wherein Ring A is a l,2,4-triazol-3-yl; reacting a compound of formula (XII) or (XII'):

(XII) (XII') with hydrazine hydrate and a compound of formula (XIII):

(XIII)

Process h) for compounds of formula (I) or (I') wherein R ³ or R ³ has a double bond that is attached directly to the six membered fused ring system; reacting a compound of formula (I) or (Y) wherein R3 or R3', respectively, is hydrogen with a compound of formula (XIV) or (XIV):

. R25 _R 25

O O

_/ -R ²⁶

R ³ ' ^' O

(XIV) (XIV) wherein R ²⁵ and R ²⁶ are hydrogen or a C^aUcyl; or R ²⁵ and R ²⁶ together with -0-B-O- form a five or six membered ring; and thereafter if necessary: i) converting a compound of the formula (I) or (I') into another compound of the formula (I) or (F); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.

L is a displaceable group. Suitable values for L include chloro, bromo, tosyl and trifluoromethylsulphonyloxy.

M is an organometallic reagent, suitable values for M include organoboron and organotin reagents, in particular B(OR ^Z ) ₂ where R ^z is hydrogen or C^aUcyl for example B(OH) ₂ ; and Sn(R ^y ) ₃ where R ^y is Ci _-6 alkyl for example Sn(Bu) ₃ .

Specific reaction conditions for the above reactions are as follows. Process a) and Process b): Amines and acids may be coupled together in the presence of a

suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole (CDI) and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-α/Ay/-pyridines such as 2,6-lutidine or

2,6-di-fe/t-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40 ⁰ C.

Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of -40 to 40 ⁰ C. Compounds of formula (III) may be prepared according to the following scheme:

CDI (V) (III)

Scheme 1 Compounds of formula (III') may be prepared in a likewise manner.

Compounds of formula (V) may be prepared according to the following scheme:

Scheme 2

Wherein L' is CN, CHO, CO ₂ H or COCl. Compounds of formula (V) can be prepared in a likewise manner.

Compounds of formula (II), (IV), (Va) and (Vb) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

Process c) and Process d): Isocyanates and amines may be coupled together in a suitable solvent such as chloroform, dicholormethane, toluene, or 7V-methylpyrrolidine in the presence of base such as triethylamine and with the addition of heat.

Compounds of formula (VII) may be prepared according to the following scheme: formic acid (V) " (VII) heat

Scheme 3 Compounds of formula (VII') may be prepared in a likewise manner.

Compounds of formula (VI) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art. Process e) Compounds of formula (VIII) and (IX) may be reacted together by coupling chemistry utilizing an appropriate catalyst. Such reactions are well known in the art. For example, where M is an organoboron group, Pd(PPh ₃ ) ₄ and a suitable base such as sodium carbonate can be utilized. In the case where M is an organotin reagent, Pd(PPh ₃ ) ₄ can be utilized as the catalyst. The reactions take place in suitable solvents and may require thermal conditions.

Compounds of formula (VIII) may be prepared according to the following scheme:

Scheme 4 wherein Y is halo. Compounds of formula (VIIF) may be prepared in a likewise manner. Compounds of formula (Villa), (VIIIb) and (IX) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

Process β: Formation of a thiazole-2-yl ring A can be carried out by heating a compound of formula (X) or formula (X') with a compound of formula (XI) in a suitable polar solvent such as an alcohol.

Compounds of formula (X) or (X') can be prepared by reacting a compound of formula (XI) or (XI'), respectively, with ammonium sulphide in a suitable polar solvent such as an alcohol, typically, with the addition of heat.

Compounds of formula (XI) or (XI') wherein R ³ or R ³ is an amine, such as -NH ₂ , N- alkyl amine, N,N-dialkylamine or a non-aromatic heterocycle comprising at least one secondary nitrogen ring member can be prepared by heating a compound of formula (XIa) with an amine derivative represented by formula (XIb)

(XIa) (XIb) (Xl)

Scheme V

Wherein R and R are each independently hydrogen, a Ci_ ₆ alkyl, or R and R together with the nitrogen to which they are attached form a heterocycle.

Compounds of formula (XI) or (XI') wherein R ³ or R ³ is an aromatic carbocycle or heterocycle or a group which has a double bond linked the six membered fused ring system can be prepared by coupling a compound of formula (XIa) with a compound of formula (XIV) or (XIV) via a reaction analogous to that described in Process g).

A compound of formula (XIa) can be prepared by reacting 2-amino-6-chloro-9- methyl-9H-purine-8-carbonitrile (see J Chem Soc, Perkin Trans I, 1977, 1003 for preparation) with an isocyanate derivative in a manner analogous to that described for Process c).

Process g): Formation of a l,2,4-triazol-3-yl ring A can be carried out by heating a compound of formula (XI) or formula (XF) in the presence of hydrazine and a compound of formula (XIII). When the compound of formula (XIII) is formic acid it may be used as the solvent for the reaction.

Process h): Compounds of formula (I) or (I') in which R ³ or R ³ is hydrogen may be reacted with a compound of formula (XIV) or (XIV) by coupling chemistry utilizing an appropriate catalyst. Such reactions are well known in the art. For example, Pd(PPh ₃ ) ₄ and a suitable base such as sodium carbonate can be utilized. The reactions take place in suitable solvents and may require thermal conditions.

The formation of a pharmaceutically-acceptable salt is within the skill of an ordinary organic chemist using standard techniques.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or

generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. The reagents used to introduce such ring substituents are either commercially available or are made by processes known in the art. Introduction of substituents into a ring may convert one compound of the formula (I) or (I') into another compound of the formula (I) or (I'). Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings. The reagents and reaction conditions for such procedures are well known in the chemical art.

Particular examples of aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group. Examples of modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 4 ^th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).

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

A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example 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 for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or for example, an allyl group which may be removed, for example, by use of a palladium catalyst such as palladium acetate.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

Optically active forms of a compound of the invention may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure. Enzyme Potency Testing Methods Compounds may be tested for inhibition of GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97). Assays can be performed in multiwell plates in 100 μl reactions containing: 50 mM HEPES 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, 5 μg/ml sheared salmon sperm DNA, 2.5 nM E. coli GyrA, 2.5 nM E. coli GyrB, 250 μM ATP, and compound in dimethylsulfoxide. Reactions can be quenched with 150 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium mo lybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read in an absorbance plate reader at 650 nm and percent inhibition values may be calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and novobiocin-containing (2 μM) reactions as 100% inhibition controls. Compound potency can be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Inhibition of E. coli GyrA and/or GyrB can be assessed by observing percent inhibition at a given compound concentration.

Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the lOOμl reactions may contain the following: 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, 2.5 nM Streptococcus pneumoniae ParE, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Compound activity against S. pneumoniae can be assessed by observing percent inhibition at a given compound concentration. Inhibition of S. pneumoniae ParE can be assessed by observing percent inhibition at a given compound concentration.

Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the 30μl reactions contained the following: 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, 1.25 nM S. pneumoniae ParE, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Inhibition of S. pneumoniae ParE can be assessed by observing percent inhibition at a given compound concentration. Compounds in the following table were tested in an assay substantially similar to the assay described in this paragraph to determine percent inhibition of S. pneumoniae ParE at a compound concentration of 50 μM:

In general, compounds of the invention have IC50 values of <200μM in one or both assays described herein above. For example, Example 1 showed an IC50 of 20.2 μM against Streptococcus pneumoniae ParE. However, the compounds in Table A have IC50 values of >200 μM against Streptococcus pneumoniae ParE.

Bacterial Susceptibility Testing Methods

Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media. Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the

organism. The suspension can be a 0.5 McFarland and a further 1 in 10 dilution can be made into the same liquid medium to prepare the final organism suspension in 100 μL. Plates can be incubated under appropriate conditions at 37 ⁰ C for 24 hrs prior to reading. The Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more.

According to a further feature of the invention there is provided a compound of the formula (I) or (I'), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

We have found that compounds of the present invention inhibit bacterial DNA gyrase and / or topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention, the compounds of the invention inhibit bacterial DNA gyrase and are therefore of interest for their antibacterial effects. In one aspect of the invention, the compounds of the invention inhibit topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention, the compounds of the invention inhibit both DNA gyrase and topoisomerase IV and are therefore of interest for their antibacterial effects.

It is expected that the compounds of the present invention will be useful in treating bacterial infections. In one aspect of the invention "infection" or "bacterial infection" refers to a gynecological infection. In one aspect of the invention "infection" or "bacterial infection" refers to a respiratory tract infection (RTI). In one aspect of the invention "infection" or "bacterial infection" refers to a sexually transmitted disease. In one aspect of the invention "infection" or "bacterial infection" refers to a urinary tract infection. In one aspect of the invention "infection" or "bacterial infection" refers to acute exacerbation of chronic bronchitis (ACEB). In one aspect of the invention "infection" or "bacterial infection" refers to acute otitis media. In one aspect of the invention "infection" or "bacterial infection" refers to acute sinusitis. In one aspect of the invention "infection" or "bacterial infection" refers to an infection caused by drug resistant bacteria. In one aspect of the invention "infection" or "bacterial infection" refers to catheter-related sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to chancroid. In one aspect of the invention "infection" or "bacterial infection" refers to chlamydia. In one aspect of the invention

"infection" or "bacterial infection" refers to community-acquired pneumonia (CAP). In one aspect of the invention "infection" or "bacterial infection" refers to complicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to

uncomplicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to endocarditis. In one aspect of the invention "infection" or "bacterial infection" refers to febrile neutropenia. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal cervicitis. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal urethritis. In one aspect of the invention "infection" or "bacterial infection" refers to hospital-acquired pneumonia (HAP). In one aspect of the invention "infection" or "bacterial infection" refers to osteomyelitis. In one aspect of the invention "infection" or "bacterial infection" refers to sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to syphilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter junii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter Iwoffi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by B acteroides bivius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by B acteroides fragilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia urealyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium difficili. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecalis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection"

refers to an infection caused by Escherichia coli. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus par ainfiuenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter pylori. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella pneumophila. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella catarrhalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella morganii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by N ^' eisseria gonorrhoeae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Peptostreptococcus anaerobius . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus asaccharolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus prevotii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus mirabilis. In one aspect of the invention an

"infection" or "bacterial infection" refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quinolone-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhimurium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia marcescens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Staphylococcus saprophyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus agalactiae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enter ococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Vancomycin-Resistant Enterococcus faecalis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia

spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia spp.. In one aspect of the invention an "infection" or

"bacterial infection" refers to an infection caused by Gardnerella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Strep toccocus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused

by Ureaplasma spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by aerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by obligate anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by facultative anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-positive bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-negative bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram- variable bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by atypical respiratory pathogens.

According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof. According to a further feature of the invention there is provided a method for inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof as defined hereinbefore. According to a further feature of the invention there is provided a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof as defined hereinbefore.

According to a further feature of the invention there is provided a method of treating a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and /or syphilis in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to

said animal an effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof as defined hereinbefore.

A further feature of the present invention is a compound of formula (I) or (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 (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of an anti-bacterial effect in a warm-blooded animal such as a human being. According to a further aspect of the invention there is provided the use of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.

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

Thus according to a further aspect of the invention there is provided the use of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and / or syphilis in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in inhibition of

bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and / or syphilis in a warm-blooded animal such as a human being.

In order to use a compound of the formula (I) or (I') or a pharmaceutically-acceptable salt thereof, for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or (I') or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and/or syphilis in a warm-blooded animal, such as a human being.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as

ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant 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, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. 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 emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative 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, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or 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 metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

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, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from

about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. In one aspect of the invention a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

As noted above, one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a GyrB ATPase or topoisomerase IV ATPase enzyme. "Treating a subject with a disease caused by a bacterial infection" includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.

As used herein, the terms "preventing a bacterial infection" refer to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection. In a preferred embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.

As used herein, the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

In addition to its use in therapeutic medicine, compounds of formula (I) or (I') and their pharmaceutically acceptable salts are also useful as pharmacological tools in the

development and standardisation of in- vitro and in- vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase and / or topoisomerase IV in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other, pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and particular embodiments of the compounds of the invention described herein also apply.

Combinations

The compounds of the invention described herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofloxacin; β-lactams e.g. penicillins e.g. amoxicillin or piperacillin; cephalosporins e.g. ceftriaxone or ceftazidime; carbapenems, e.g. meropenem or imipenem etc; aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones; and/or ii) anti-infective agents for example, an antifungal triazole e.g. or amphotericin; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.

Therefore, in a further aspect of the invention there is provided a compound of the formula (I) or (I'), or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.

Examples

The invention is now illustrated but not limited by the following Examples in which

unless otherwise stated :-

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;

(ii) operations were generally carried out at ambient temperature, that is typically in the range 18-26 ⁰ C and without exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere;

(iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques; proton magnetic resonance spectra is quoted and was generally determined in DMSOd ₆ unless otherwise stated using a Bruker DRX-300 spectrometer operating at a field strength of 300 MHz. Chemical shifts are reported in parts per million downfield from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; AB or dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad;

(vi) fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1 lOOseries LC/MSD equipped with Sedex 75ELSD, run in atmospheric pressure chemical ionization mode and, where appropriate, either positive ion data or negative ion data were collected; mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ES); values for m/z are given; generally, only ions which indicate the parent mass are reported;

(vii) each intermediate was generally purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; (vii) the following abbreviations may be used: DMSO is dimethylsulfoxide; CDCI ₃ is deuterated chloroform;

MS is mass spectroscopy; EtOAc is ethyl acetate;

EDC is N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; HATU is 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanaminium; OAc is acetate; THF is tetrahydrofuran; MeOH is methanol; and TFA is trifluoroacetic acid; Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene; and

(viii) temperatures are quoted as ⁰ C.

Example 1

A/-Ethyl-A/*-(2-pyridin-3-yl-3H-imidazor4,5-olpyridin-5-v l)urea

tert-Butyl 5-(3-ethylureido)-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridine -3-carboxylate (Example 2; 4.5 mg, 0.01 mmol) was dissolved in a CH ₂ Cl ₂ (9 mL). TFA (1 mL, 0.01 mmol) was added in a single portion and the reaction was stirred at room temperature overnight, and was monitored by LC/MS. The solvent was removed and the residue was suspended in 4N HCl in dioxane. The solids were stirred for 2 hours, filtered and dried in vacuo. Isolation gave 2.4 mg of the title compound (hydrochloride salt) in 64% yield. LC/MS (ES ⁺ ) [(M+H) ⁺ ]: 283

Example 2 ferf-Butyl 5-(3-ethylureido)-2-(pyridin-3-yl)-3H-imidazor4,5-blpyridine -3-carboxylate

Reference: Abad, A., et al, Synthesis, 2005, 6, 915-924.

In a 1-neck glass round bottom flask purged with nitrogen, Pd(OAc) ₂ (48.9 mg, 0.07 mmol), and Xantphos (84 mg, 0.15 mmol) were combined and dissolved in dioxane (3 mL). The solution was degassed. tert-Butyl 5-chloro-2-pyridin-3-yl-3H-imidazo[4,5-ό]pyridine-3- carboxylate (Intermediate 3, 200 mg, 0.60 mmol), 1-ethylurea (53.3 mg, 0.60 mmol), potassium tert-butoxide (102 mg, 0.91 mmol) and water (16.33 mg, 0.91 mmol) were added successively to the flask. The reaction mixture was then heated to 100 ⁰ C and monitored by LC/MS. Analysis showed product and the de-protected starting material. The Boc-group is very unstable and falls off during the reaction. Consequently the reaction stops with about 30% product formed. The reaction was dilute with EtOAc and wash with water, then the organic layer was dried over Na ₂ SO ₄ , filter and concentrate. The concentrate was dissolved in DMSO and purify by Gilson HPLC. Isolation gave 4.5 mg of the title compound in 2% yield. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 383 for Ci ₉ H ₂₂ N ₆ O ₃ .

Example 3

N-Ethyl-N'-(2-pyridin-3-yl[1.31oxazolor5,4-blpyridin-5-yl)ur ea

To argon purged dioxane (50 mL) was added palladium acetate (40 mg, 0.2 mmol) and Xantphos (140 mg, 0.25 mmol) under nitrogen atmosphere and stirred for 1 h at room temperature. 5-Chloro-2-pyridin-3-yl-oxazolo[5,4-b]pyridine (Intermediate 11, 0.85 mmol) was added, followed by N-ethyl urea (0.18g, 2 mmol), potassium tert-butoxide (140 mg, 1.3 mmol), and nitrogen purged water (0.02g, 1.3 mmol). The reaction mixture was then refluxed at 100 ⁰ C for 14 h, then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3x10 mL). The combine extracts were washed with water (20 mL) and brine, then dried over anhydrous sodium sulphate and concentrated to a residue. The residue was subjected to column chromatography (silica, chloroform-methanol) to yield the title compound.

MS (ES): 284 (M+ 1) for Ci ₄ H ₁₃ N ₅ O ₂ 400 MHz, CDCl ₃ : δ 1.41 (t, J= 7.2 Hz, 3H), 3.49-3.54 (m, 2H), 6.96 (d, J = 8.5 Hz, IH), 7.50 (dd, J= 4.8, 7.9 Hz, IH), 8.01 (d, J= 8.5 Hz, IH), 8.49 (d, J= 8.0 Hz, IH), 8.74(br s, IH), 8.79 (d, J= 4.2 Hz, IH), 8.88 (s, IH), 9.46 (s, IH)

Examples 4-6

The following Examples were prepared by the procedure described in Example 3 from the starting materials (SM) indicated.

Example 7

2-r2-(3-Ethyl-ureido)-9-methyl-6-piperazin- 1 -yl-QH-purin-δ-yll-thiazole^-carboxylic acid ethyl ester

To a stirred solution of 4-[2-(3-ethyl-ureido)-9-methyl-8-thiocarbamoyl-9H-purin-6-yl ]- piperazine-1-carboxylic acid tert-butyl ester (Intermediate 16, 1.83 g, 3.95 mmol) in ethanol (20 mL), ethyl 3-bromo-2-oxopropanoate (0.774 mL, 5.92 mmol) was added and the mixture was heated to 100 ⁰ C for 18 h. The reaction mixture was cooled to room temperature and the resulting residue was washed with acetonitrile followed by diethylether. The solid that formed was collected by filtration and dried to afford 1.65 g (89%) of 2-[2-(3-ethyl-ureido)-9-methyl- 6-piperazin-l-yl-9H-purin-8-yl]-thiazole-4-carboxylic acid ethyl ester.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.17 (t, 3H), 1.36 (t, 3H), 3.26-3.50 (m, 8H), 4.116 (s, 3H), 4.336-4.389 (q, 4H), 8.69 (s, IH), 8.88 (t, IH), 9.265 (br s, IH).

Example 8 2-r2-(3-Ethyl-ureido)-9-methyl-6-piperazin- 1 -yl-9H-purin-8-yll-thiazole-4-carboxylic acid

To a stirred solution of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperazin-l-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid ethyl ester (Example 7, 0.75 g, 1.63 mmol) in methanol (10 mL), 2 M sodium hydroxide (10 mL) was added, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissovled in water and acidified to pH = 2 with 2N hydrochloric acid solution (10 mL). The solid obtained was filtered and then co-distilled with toluene (2 x 20 mL) to afford 0.65 g (92.3%) of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperazin- 1 -yl-9H-purin-8-yl]-thiazole-4- carboxylic acid.

¹ H NMR (400 MHz. DMSO-cϋ: δ 1.17 (t, 3H), 3.28-3.33 (m, 6H), 3.49 (q, 2H), 4.11 (s, 3H), 4.45 (br s, 2H), 8.62 (s, IH), 8.9 (t, IH), 9.26 (br s, IH), 9.7 (br s, IH).

Example 9

2-r2-(3-Ethyl-ureido)-9-methyl-6-piperazin- 1 -yl-gH-purin-δ-yll-thiazole^-carboxylic acid amide

In a sealed tube (20 mL), 2-[2-(3-Ethyl-ureido)-9-methyl-6-piperazin-l-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid ethyl ester (Example 7, 0.3 g, 0.653 mmol) was taken and 30% of aqueous ammonia (15 mL) was added. The reaction mixture was heated to 100 ⁰ C for 18 h, then cooled to room temperature. The solid that formed was collected by filtration and washed with acetonitrile (5 mL) and diethylether (5 mL), then dried under vacuum to afford 0.12 g (42.7%) of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperazin-l-yl-9H-purin-8-y l]-thiazole-4- carboxylic acid amide. 1H NMR (400 MHz. DMSO-d _fi ): δ 1.17 (t, 3H), 3.72 (t, 4H), 3.26 (q, 2H), 4.11 (s, 3H), 4.20 (br s, 4H), 7.74 (s, IH), 7.90 (s, IH), 8.36 (s, IH), 9.03 (t, IH), 9.08 (s, IH).

Example 10

2-r2-(3-Ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin- 8-yll-thiazole-4-carboxylic acid ethyl ester

To a stirred solution of 2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purine-8- carbothioic acid amide (Intermediate 18, 1.4 g, 3.85 mmol) in ethanol (20 mL) was added ethyl 3-bromo-2-oxopropanoate (0.725 mL, 5.78 mmol). The reaction mixture was heated to 100 ⁰ C for 15 h. After completion of the reaction, the reaction mixture was concentrated to

dryness, and the residue was taken up in water (10 mL) and stirred for 20 min. The solid obtained was filtered and washed with diethyl ether and finally co-distilled with toluene (2 x 25 mL) to afford 1.6 g, (96%) of 2-[2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin- 8-yl]-thiazole-4-carboxylic acid ethyl ester as pale-yellow solid. 1H NMR (400 MHz. CDCl ₁ ): δ 1.16 (t, 3H), δ 1.34 (t, 3H), δ 3.26 (q, 2H), δ 3.76 (t, 4H), δ 4.09 (s, 3H), δ 4.21 (bs, 4H), δ 4.35 (q, 2H), δ 8.65 (s, IH), δ 8.95 (bs, IH), δ 9.21 (bs, IH). Mass (APCI. +ve scan): m/z 461 (M+H) for Ci ₉ H ₂₄ N ₈ O ₄ S.

Example 11 2-r2-(3-Ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin-8-y ll-thiazole-4-carboxylic acid

To a stirred solution of 2-[2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid ethyl ester (Example 10, 0.25 g, 0.541 mmol) in methanol (15 mL) was added 2 N sodium hydroxide solution (6 mL), and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was taken up in water (10 mL) and was extracted with ethyl acetate (2 x 20 mL). The aqueous layer was acidified to pH 2, and the solid precipitate formed. The solid was filtered and washed with diethyl ether and finally co-distilled with toluene (2 x 20 mL) to afford 1.2 g, (51%) of 2-[2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin-8- yl]-thiazole-4-carboxylic acid as pale brown solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.16 (t, 3H), δ 3.28 (q, 2H), δ 3.77 (t, 3H), δ 4.09 (s, 3H), δ 4.21 (bs, 4H), δ 8.58 (s, IH), δ 9.01 (bs, IH), δ 9.25 (bs, IH). Mass (APCI. +ve scan): m/z 433 (M+H) for. Ci ₇ H ₂₀ N ₈ O ₄ S.

Example 12

2-r2-(3-Ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin- 8-yll-thiazole-4-carboxylic acid methyl amide

To a stirred solution of 2-[2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid (Example 11, 0.2 g, 0.464 mmol) in dry dimethyl formamide (5 mL) was added N-methyl morpholine (0.153 mL, 1.392 mmol), and the mixture was cooled to 0 ⁰ C. HOBt (0.142 g, 0.928 mmol) was added to the reaction mixture, followed by methyl amine (2 M solution in THF) (0.225 mL, 0.464 mmol), and the mixture was stirred for 10 min. EDCHCl (0.177 g, 0.928 mmol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The organic layer was washed with 2N hydrochloric acid (1 x 30 mL), followed by a bicarbonate wash (1 x 30 mL). The organic layer was then dried over anhydrous sodium sulfate, then concentrated to give a yellow solid which was triturated with acetonitrile and filtered to afford 0.06 g, (29.1%) of 2- [2-(3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl] -thiazole-4-carboxylic acid methyl amide as yellow solid.

Example 13 l-Ethyl-3-r9-methyl-6-(piperidin-l-vπ-8-(4H-1.2.4-triazol-3 -vπ-9H-purin-2-yl1urea

H H \ H

Hydrazine hydrate (61 mg, 1.22 mM) was added to a stirred solution of l-[8-cyano-9-methyl- 6-(piperidin-l-yl)-9H-purin-2-yl]-3-ethylurea (Intermediate 20, 200 mg, 0.609 mmol) in formic acid (5 mL). The mixture was heated to reflux for 24 h, then cooled to room temperature and concentrated under reduced pressure. Isopropyl alcohol (5 mL) was added to the resulting residue, and the solid was collected by filtration then purified by preparative HPLC to afford 30 mg (13.3%) of l-ethyl-3-[9-methyl-6-(piperidin-l-yl)-8-(4H-l,2,4-triazol- 3-yl)-9H-purin-2-yl]urea.

¹ H NMR (400 MHz. DMSO-cϋ: δ 1.16 (t, 3H), 1.69 (dd, 6H), 3.26 (q, 2H), 3.97 (s, 3H), 4.20 (br s, 3H), 8.56 (s, IH), 8.94 (s, IH), 9.11 (t, IH).

Example 14 l-Ethyl-3-r9-methyl-6-phenyl-8-(4H-1.2.4-triazol-3-vn-9H-pur in-2-yllurea

Hydrazine hydrate (93.45 mg, 1.869 mmol) was added to a stirred solution of l-(8-cyano-9- methyl-6-phenyl-9H-purin-2-yl)-3-ethylurea (Intermediate 21, 300 mg, 0.934 mmol) and formic acid (10 mL) at room temperature. The resulting mixture was refluxed overnight, then cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue and a solid was collected by filtration, then purified by preparative HPLC to afford 40 mg (11.7%) of l-ethyl-3-[9-methyl-6-phenyl-8-(4H-l,2,4-triazol-3-yl)-9H-pu rin-2-yl]urea. ¹ H NMR (400 MHz, DMSO-d _fi ): δ 1.23 (t, 3H), 3.31 (q, 3H), 4.11 (s, 3H), 7.63 (d, 3H), 8.78 (d, 2H), 9.14 (s, IH), 9.72 (s, IH).

Examples 15-17

The following Examples were prepared by the procedure described in Example 14 from the starting materials (SM) indicated.

Example 18

Ethyl 2-(2-r(ethylcarbamoyl)aminol-9-methyl-6-(3-methylphenyl)-9H- purin-8-vU-l,3- thiazole-4-carboxylate

To a stirred solution of 2-[(ethylcarbamoyl)amino]-9-methyl-6-(3-methylphenyl)-9H-pur ine-8- carbothioamide (Intermediate 25, 0.57 g, 1.54447 mmol) in ethanol (20 mL), ethyl 3-bromo-2- oxopropanoate (1.16 mL, 9.324 mmol) was added, and the mixture was heated to 100 ⁰ C for 45 h. After the completion of the reaction, the reaction mixture was concentrated to dryness.

Diethylether (10 mL) was added, and the residue was triturated. The solid obtained was filtered and dried under vacuum to afford 610 mg of crude product (60% in HPLC). The crude product was further purified by preparative HPLC to give 255 mg (35.5%) of product ethyl 2-{2- [(ethylcarbamoyl)amino]-9-methyl-6-(3-methylphenyl)-9H-purin -8-yl}-l,3-thiazole-4- carboxylate as yellow solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.24 (t, 3H), 1.36 (t, 3H), 2.45 (s, 3H), 3.33 (q, 2H), 4.19 (s, 3H), 4.39 (q, 2H), 7.52 (m, 2H), 8.47 (s, IH), 8.57 (d, IH), 8.78 (s, IH), 9.10 (t, IH), 9.83 (s, IH).

Example 19

2-{2-r(Ethylcarbamoyl)aminol-9-methyl-6-(3-methylphenyl)- 9H-purin-8-vU-N-methyl-l,3- thiazole-4-carboxamide

In a sealed tube (20 mL), 2-[2-(3-ethyl-ureido)-9-methyl-6-m-tolyl-9H-purin-8-yl]-thia zole-4- carboxylic acid ethyl ester (Example 18, 106 mg, 0.2279 mmol) was taken and methyl amine (15 mL) was added. The reaction mixture was heated to 105 ⁰ C for 24 h, then cooled to room temperature, and filtered. The solid obtained was washed with ethylacetate (5 mL) and methanol (5 mL) respectively, then dried to afford 26 mg (24%) of 2-[2-(3-ethyl-ureido)-9- methyl-6-m-tolyl-9H-purin-8-yl]-thiazole-4-carboxylic acid methyl amide as yellow solid. ¹ H NMR (400 MHz. DMSO-dή): δ 1.25 (t, 3H), 2.50 (s, 3H), 2.87 (d, 3H), 3.30 (q, 2H), 4.25 (s, 3H), 7.54 (m, 2H), 8.58 (m, 3H), 9.11 (br s, IH), 9.77 (br s, IH).

Example 20

2-r2-(3-Ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-pur in-8-yll-thiazole-4-carboxylic acid ethyl ester

To a stirred solution of 2-(3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purine-8- carbothioic acid amide (Intermediate 26, 0.1 g, 0.268 mmol) in ethanol (5 mL), ethyl 3- bromo-2-oxopropanoate (0.05 mL, 0.402 mmol) was added, and the mixture was heated to 100 ⁰ C for 18 h. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was triturated with diethylether to give a solid, which was filtered and dried under vacuum to afford 0.098 g (61.9%) of 2-[2-(3-ethyl-ureido)-6-(2-fiuoro-phenyl)-9- methyl-9H-purin-8-yl]-thiazole-4-carboxylic acid ethyl ester as solid. 1H NMR (400 MHz. DMSOd _n ): δ 1.162 (t, 3H), δ 1.35 (t, 3H), δ 3.286 (q, 2H), δ 4.195 (s, 3H), δ 4.38 (q, 2H), δ 7.49 (m, 2H), δ 7.68 (m, IH), δ 8.27 (t, IH), δ 8.77 (s, IH), δ 9.21 (t, IH), δ 9.21 (t, IH), δ 9.85 (s, IH).

Example 21

2-r2-(3-Ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-pur in-8-yll-thiazole-4-carboxylic acid

To a stirred solution of 2-[2-(3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purin- 8-yl]- thiazole-4-carboxylic acid ethyl ester (Example 20, 0.098 g, 0.208 mmol) in methanol (5 mL) was added 2N sodium hydroxide solution (2 mL). The resulting mixture was stirred at room temperature for 2 h, then concentrated to dryness. The residue was dissolved in water and acidified to pH = 2 with 2N hydrochloric acid solution to get solid, which was filtered and washed with acetonitrile, methanol and diethylether to afford 0.025 g, (28.4%) of 2-[2- (3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purin-8-yl] -thiazole-4-carboxylic acid as solid.

¹ H NMR (400 MHz. DMSO-dή): δ 1.14 (t, 3H), δ 3.27 (q, 2H), δ 4.195 (s, 3H), δ 7.49 (m, 2H), δ 7.65 (m, IH), δ 8.27 (t, IH), δ 8.70 (s, IH), δ 9.225 (t, IH), δ 9.84 (s, IH), δ 13.4 (bs, IH).

Example 22

2-r2-(3-Ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-pur in-8-yll-thiazole-4-carboxylic acid methyl amide

To a stirred solution of 2-[2-(3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purin- 8-yl]- thiazole-4-carboxylic acid (Example 21, 0.2 g, 0.454 mM) in dry dimethyl formamide (5 mL), N-methyl morpholine (0.15 mL, 1.36 mM) was added, and the reaction mixture was cooled to 0 ⁰ C. HOBt (0.14 g, 0.909 mM) was added, and the mixture was stirred for 10 min. EDCHCl (0.173 g, 0.909 mM) was then added, and the mixture was stirred for 20 min, followed by methyl amine (2M solution in THF) (0.231 mL, 0.454 mM). The reaction mixture was stirred for 18 h, then diluted with water (20 mL) and ethyl acetate (50 mL) and the layers were separated. The organic layer was washed with 2N hydrochloric acid (1 x 25 mL), sodium bicarbonate solution (1 x 25 mL) and brine (1 x 25 mL), respectively. The organic layer was dried and concentrated to give a crude product which was triturated with acetonitrile (5 mL) to give a solid. The solid was collected by filtration, then dried under vacuum to afford 2-[2-(3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purin- 8-yl]-thiazole- 4-carboxylic acid methyl amide as solid. 1H NMR (400 MHz. DMSOd _n ): δ 1.16 (t, 3H), δ 2.87 (d,3H), δ 3.27 (q, 2H), δ 4.24 (s, 3H), δ 7.5 (m, 2H), δ 7.67 (m, IH), δ 8.27 (t, IH), δ 8.49 (s, IH), δ 9.22 (t, IH), δ 9.80 (t, IH).

Example 23

2-r2-(3-Ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin- 8-yll-thiazole-4-carboxylic acid ethyl ester

To a stirred solution of 2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purine-8-car bothioic acid amide (Intermediate 28, 1.079 g, 3.85 mmol) in ethanol (20 mL) was added 3-bromo-2- oxopropanoate (0.554 mL, 4.42 mmol). The reaction mixture was heated to 100 ⁰ C for 18 h, then concentrated to dryness. Diethyl ether was added to the residue and it was triturated to

give a solid which was collected by filtration and dried under vacuum to afford 1.3 g, (96.4%) of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin-8-y l]-thiazole-4-carboxylic acid ethyl ester as solid.

¹ H NMR (400 MHz. DMSO-dή): δ 1.16 (t, 3H), δ 1.34 (t, 3H), δ 1.64-1.69 (m, 6H), δ 3.26 (q, 2H, δ 4.075 (s, 3H), δ 4.364 (q, 2H), δ 4.20 (bs, 2H), δ 4.32 (bs, 2H), δ 8.65 (s, IH), δ 8.88 (s, IH), δ 9.25 (s, IH).

Example 24 2-r2-(3-Ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin-8-y ll-thiazole-4-carboxylic acid

To a stirred solution of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid ethyl ester (Example 23, 0.6 g, 1.31 mmol) in methanol (10 mL) was added 2 N sodium hydroxide solution (7 mL), and the mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was dissolved in water and the solution was acidified with 2N hydrochloric acid causing a solid to precipitate out. The solid was collected by filtration, then co-distilled with toluene (2 x 20 mL) to afford 0.498 g, (88.9%) of 2-[2-(3-ethyl-ureido)-9- methyl-6-piperidin-l-yl-9H-purin-8-yl]-thiazole-4-carboxylic acid as solid. 1H NMR (400 MHz. DMSO-dή): δ 1.16 (t, 3H), δ 1.65-1.694 (m, 6H), δ 3.269 (q, 2H), δ 4.077 (s, 3H), δ 4.25 (bs, 4H), δ 8.568 (s, IH), δ 8.94 (s, IH), δ 9.28 (s, IH).

Example 25

2-r2-(3-Ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin- 8-yll-thiazole-4-carboxylic acid

amide

In a sealed tube 2-[2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin-8-y l]-thiazole-4- carboxylic acid ethyl ester (Example 23, 0.3 g, 0.652 mmol) was taken and 30% aqueous ammonia (15 mL) was added. The mixture was heated to 100 ⁰ C for 20 h, then the solid that formed was collected by filtration. The solid was washed with acetonitrile and diethyl ether respectively, then dried under vacuum to afford 0.05 g (17.9%) 2-[2-(3-ethyl-ureido)-9- methyl-6-piperidin-l-yl-9H-purin-8-yl]-thiazole-4-carboxylic acid amide solid. 1H NMR (400 MHz. DMSO-d _fi ): δ 1.15 (t, 3H), 1.62-1.67 (m, 6H), 3.26 (q, 2H), 4.09 (s, 3H), 4.1 (bs, 4H), 7.72 (bs, IH), 7.89 (bs, IH), 8.34 (s, IH), 9.04 (bs, 2H)

Example 26

2-r2-(3-Ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin- 8-yll-thiazole-4-carboxylic acid methyl amide

To a stirred solution of 2-[2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purin-8-y l]- thiazole-4-carboxylic acid (Example 24, 0.2 g, 0.464 mmol) in dry dimethyl formamide (5 mL) was added N-methyl morpholine (0.153 mL, 1.392 mmol). The mixture was cooled to 0 ⁰ C and HOBt (0.142 g, 0.928 mmol) was added, followed by methyl amine (2 M solution in THF) (0.225 mL, 0.464 mmol) and then EDCHCl (0.177 g, 0.928 mmol). The mixture was stirred overnight at room temperature, then diluted with ethyl acetate (100 mL) and water (20 mL) then extracted. The organic layer was washed with 2N hydrochloric acid (2 x 25 mL) and bicarbonate wash (50 mL) respectively. The organic layer was dried over anhydrous sodium sulfate then concentrated to a residue which was triturated with acetonitrile. The solid was collected by filtration to afford 0.115 g, (56.31%) of 2-[2-(3-ethyl-ureido)-9-methyl-6- piperidin-l-yl-9H-purin-8-yl]-thiazole-4-carboxylic acid methyl amide as pale yellow solid.

¹ H NMR (400 MHz. DMSO-cϋ: δ 1.17 (t, 3H), δ 1.62-1.69 (m, 6H), δ 2.85 (d, 3H), δ 3.29 (q, 2H, δ 4.12 (s, 3H), δ 4.24 (bs, 4H), δ 8.34 (s, IH), δ 8.41 (s, IH), δ 9.06 (s, IH).

Example 27 Ethyl 2-(2-(3-ethylureido)-4-(pyridin-4-yl)thienor2,3-dlpyrimidin- 6-yl)thiazole-4-carboxylate

2-(3-Ethylureido)-4-(pyridin-4-yl)thieno[2,3-d]pyrimidine-6- carboxamide (Intermediate 41 , 140 mg, 0.41 mmol) was dissolved in THF (5 mL). Lawesson's reagent (165 mg, 0.41 mmol) was added in a single portion and the resulting suspension was heated to reflux. The reaction was about 50% complete after 12 h of heating, so more Lawesson's reagent was added (0.5 mmol). After completion of the reaction, it was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and then brine, then concentrated to dryness by rotary evaporation. The residue was azeotropically dried with toluene (x2). Then the residue was suspended in toluene (50 mL) and ethyl 3-bromo-2-oxopropanoate (0.057 mL, 0.41 mmol) was added. The reaction mixture was heated to reflux. The reaction was complete (as determined by LC/MS) in 2 h, then cooled to room temperature, wash with water and brine. The organic layer was dry over Na2SOφ filtered and concentrated. The concentrate was purified by silica gel flash column chromatography (gradient 95:5 CH ₂ Cl ₂ /methanol) to give 165 mg of the title compound (90% purity by LC/MS).

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 455 for C ₂₀ Hi ₈ N ₆ O ₃ S ₂ .

Examples 28-30 The following Examples were prepared by the procedure described in Example 27 from the starting materials (SM) indicated.

Example 31

2-(2-(3-Ethylureido)-4-(pyridin-4-yl)thienor2.3-dlpyrimid in-6-yl)thiazole-4-carboxylic acid:

Ethyl 2-(2-(3-ethylureido)-4-(pyridin-4-yl)thieno[2,3-d]pyrimidin- 6-yl)thiazole-4-carboxylate (Example 27, 165 mg, 0.36 mmol) was dissolved in a mixture of THF (3 mL), EtOH (3 mL) and 1 N LiOH (1.5 mL, 1.50 mmol). The solution was stirred at room temperature for 8 h. The pH was adjusted to 1 with 1 M HCl. Water was added to precipitate the product. The solids were filtered and washed with water, then dissolved in minimal DMSO and purified by Gilson HPLC (reverse phase). Isolation gave 7.9 mg of the title compound. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 427 for Ci ₈ Hi ₄ N ₆ O ₃ S ₂ . ¹ H NMR (300 MHz, d ₆ -DMSO): 1.09 (t, 3H), 3.22 (m, 2H), 7.92 (m, 2H), 8.15 (s, IH), 8.53 (s, IH), 8.78 (t, IH), 8.81 (m, 2H), 10.12 (s, IH).

Examples 32-34

The following Examples were prepared by the procedure described in Example 31 from the starting materials (SM) indicated.

Example 35

2-(4-(Benzo[dlthiazol-2-vπ-2-(3-ethylureido)thienor2,3-d lpyrimidin-6-yl)-N-methylthiazole- 4-carboxamide:

2-(4-(Benzo[d]thiazol-2-yl)-2-(3-ethylureido)thieno[2,3-d ]pyrimidin-6-yl)thiazole-4- carboxylic acid (Example 33, 85 mg, 0.18 mmol) and HATU (80 mg, 0.21 mmol) were dissolved in DMF (3 mL) and DIEA (0.092 niL, 0.53 mmol). The solution was stirred for 5 min, then methyl amine (0.097 mL, 0.19 mmol) was added in a single portion. After 1 h the reaction was complete, and the DMF was removed by rotary evaporation. The product was precipitated from solution using IM HCl. The solids were collected, washed with water, dried, and dissolved in minimal DMSO, then purified by Gilson HPLC (reverse phase). Isolation gave 22 mg of the title compound.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 496 for C ₂ IHi ₇ N ₇ O ₂ S ₃ . ¹ H NMR (300 MHz, d ₆ -DMSO): 1.27 (t, 3H), 2.84 (d, 3H), 3.37 (m, 2H), 7.66 (m, 2H), 8.32 (m, 2H), 8.43 (s, IH), 8.44 (m, IH), 8.64 (t, IH), 8.82 (s, IH), 10.29 (s, IH).

Examples 36-59

The compounds in Table A were made by methods analogous to the methods described herein above using the appropriate starting materials:

Table A

Preparation of Starting Materials

Intermediate 1

6-Chloropyridine-2,3-diamine

In a 2-neck, 250 mL glass round bottom flask 6-chloro-3-nitropyridin-2-amine (J Med. Chem., 2000, 43, 3053-3066, 5 g, 28.81 mmol) and tin (II) chloride dihydrate (32.5 g, 144.04 mmol) were combined and suspended in EtOAc (90 mL) and (10 mL).

The reaction slurry was heated to 6O ⁰ C for 1 hour. Sodium borohydride (0.544 g, 14.40 mmol) was added in a single portion, and the reaction was heated for an additional 12 hours. The progress of the reaction was monitored by LC/MS. When the reaction was complete, the solvent was removed by rotary evaporation. The solid was dissolved in EtOAc and water. The mixture was neutralized with K ₂ CO ₃ while cooling the mixture in an ice bath. The tin salts precipitated from solution and were removed by filtering the mixture though a pad of Celite. The aqueous and organic phases were then separated, and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to 3.2 grams (77% yield) of a light green solid which was used with no further purification. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 144, 146 for C ₅ H ₆ ClN ₃ . ¹ R NMR (300 MHz, d ₄ -MeOD): 6.47 (d, IH), 6.85 (d, IH).

Intermediate 2

5-Chloro-2-pyridin-3-yl-3H-imidazor4,5-όlpyridine

6-Chloropyridine-2,3-diamine (Intermediate 1, 2.4 g, 16.72 mmol) was dissolved in MeOH (20 mL). Nicotinaldehyde (1.584 mL, 16.72 mmol) was added in a single portion and the reaction was heated to 6O ⁰ C. Upon reacting, the solution turned red, and LC/MS showed that the condensation product ([M+H] ⁺ : 233, 235 for C ₁₁ H ₉ CIN4) had formed. The reflux condenser was removed, and the saturated product was aromatized by heating the solution in the presence of air for 4 days. Upon cooling and concentrating a precipitate formed. Ethyl ether (10 mL) was added, then the solids were collected by filtration, washed with ether and dried in vacuo to give 857 mg of the title compound in a 22% yield. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 231, 233 for CnH ₇ ClN ₄ . ¹ H NMR (300 MHz, d ₆ -DMSO): 7.33 (d, IH), 7.60 (dd, IH), 8.12 (broad singlet, IH), 8.50 (m, IH), 8.72 (dd, IH), 9.36 (dd, IH), 13.66 (d, IH).

Intermediate 3 ferz-Butyl 5-chloro-2-pyridin-3-yl-3/7-imidazor4,5-61pyridine-3-carboxv late

5-Chloro-2-pyridin-3-yl-3H-imidazo[4,5-ό]pyridine (Intermediate 2, 638 mg, 2.77 mmol) and di-tert-butyl dicarbonate (664 mg, 3.04 mmol) were combined and dissolved in THF (10 mL). Triethylamine (0.463 mL, 3.32 mmol) was added in a single portion along with a few crystals of DMAP. The reaction was then heated to 65 ⁰ C for while monitoring by LC/MS. After one hour, the reaction mixture was concentrated to an oil, the diluted with EtOAc and wash with sat. NH ₄ Cl (x2). The organic layer was dry over Na ₂ SO ₄ , filter and concentrate to a brown solid to give 867 mg of the title compound in a 95% yield which was used with no further purification. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 331, 333 for Ci ₆ Hi ₅ ClN ₄ O ₂ . ¹ U NMR (300 MHz, CDCl ₃ ): 1.5 (s, 9H), 7.43 (d, IH), 7.52 (m, IH), 8.11 (d, IH), 8.30 (d, IH), 8.77 (d, IH), 8.94 (s, IH).

Intermediate 4 6-Chloro-3-nitro-pyridin-2-ylamine

A solution of 2,6-dichloro-3-nitro pyridine (5 g, 26 mmol) in ethanol (50 mL) at 0 ⁰ C was purged with ammonia gas for 3 h, then allowed to stir overnight at room temperature. The reaction mixture was diluted with water (100 mL), and the precipitate that formed was filtered and washed with water (50 mL), followed by hexane (50 mL) and dried to obtain 6-chloro-3- nitro-pyridin-2-ylamine in 88% yield (4 g, 23 mmol). MS(ES): 174 (M+l) for C ₅ H ₄ ClN ₃ O ₂ 1R NMR (MeOD, 400 MHz) δ: 6.71 (d, J= 8.6 Hz, IH), 8.39 (d, J= 8.6 Hz, IH).

Intermediate 5 6-Chloro-3-nitropyridin-2(l//)-one

To ice cold concentrated sulphuric acid was added 6-chloro-3 -nitro-pyridin-2-ylamine (Intermediate 4, 5 g, 28 mmol), and the reaction mixture was stirred for 10 min at 0 ⁰ C. A solution OfNaNO ₂ (4 g, 58 mmol in 30 mL of water) was added slowly over a period of 10 min maintaining the temperature at 0 ⁰ C, then the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured onto ice cold water (150 mL), the precipitate that formed was collected by filtration, washed with cold water (2x50 mL) and dried under vacuum to provide 6-chloro-3-nitropyridin-2(lf/)-one in 80% yield (4 g, 23 mmol) as yellow color solid. MS (ES): 172.9 (M-I) for C ₅ H ₃ ClN ₂ O ₃ .

¹ H-NMR (DMSO-d _6, 400 MHz): δ 7.06 (d, J= 8.3 Hz, IH), 8.40-8.43 (m, IH).

Intermediate 6

3-Aminopyridin-2(l//)-one hydrochloride

To a stirred solution of 6-chloro-3-nitropyridin-2(lH)-one (Intermediate 5, 3.5 g, 20 mmol) in ethyl acetate (50 mL) was added SnCl ₂ .H ₂ O(32 g, 142 mmol) in portions over a period of 15 min at room temperature, then the mixture was re fluxed at 80 ⁰ C for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and

neutralized with solid NaHCO ₃ (50 g). The mixture was filtered and the solids were washed with ethyl acetate (2 x 50 mL). The filtrate was concentrated to remove ethyl acetate under vacuum and the residue was taken in ice cold dioxane (20 mL). 4N HCl in dioxane (10 mL) was added and the mixture was concentrated to give desired product in 95%yield (3.5 g, 19 mmol).

MS (ES): 143.2 (M-I) for C ₅ H ₅ ClN ₂ O

¹ H-NMR (CDCl ₃ , 300 MHz): δ 4.20 (br s, 2H), 6.20 (d, J= 7.6 Hz, IH), 6.59 (d, J= 7.6 Hz,

IH).

Intermediate 7

N-(6-Chloro-2-hvdroxy-pyridin-3-vD-nicotinamide

To a solution of 3-aminopyridin-2(lH)-one hydrochloride (Intermediate 6, 250 mg, 1.38 mmol) in pyridine (5 mL) was added nicotinoyl chloride (1.6 mmol) slowly over a period of 10 min while maintaining the solution at 0 ⁰ C. The reaction mixture was stirred at room temperature overnight, then poured on to ice cold water (20 mL). The precipitate was collected by filtration, washed with water (5 mL) and dried. Recrystallized with ethanol (5 mL) provide the title compound. MS (ES): 250.0 (M+ 1) for C ₁₁ H ₈ ClN ₃ O ₂ 300 MHz, CDCl ₃ : δ 6.40 (d, IH), 7.40-7.50 (m, IH), 8.20(br s, IH), 8.50 (d, IH), 8.80(br s, IH), 8.90 (br s, IH), 9.20 (br s, IH).

Intermediates 8-10

The following Intermediates were prepared by the procedure described in Intermediate 7 from the starting materials (SM) indicated.

Intermediate 11

5-Chloro-2-pyridin-3-yl-oxazolor5,4-blpyridine

POCl ₃ was added to N-(6-Chloro-2-hydroxy-pyridin-3-yl)-nicotinamide (Intermediate 7, 28 mmol) slowly at room temperature and then refiuxed at 110 ⁰ C for 6 h. The reaction mixture was cooled to room temperature and POCl ₃ was removed under vacuum. The residue was poured onto ice water (5 mL), and the precipitate that formed was filtered, washed with water and dried to give the corresponding compound.

300 MHz, CDCl ₃ : δ 7.43 (d, IH), 7.50-7.60 (m, IH), 8.05 (d, IH), 8.50 (d, IH), 8.80 (d, IH), 9.49 (s, IH).

Intermediates 12-14

The following Intermediates were prepared by the procedure described in Intermediate 11 from the starting materials (SM) indicated.

Intermediate 15

4-r8-Cvano-2-(3-ethyl-ureido)-9-methyl-9H-purin-6-yll-pip erazine-l-carboxylic acid tert- butyl ester

To a stirred solution of l-(6-chloro-8-cyano-9-methyl-9H-purin-2-yl)-3-ethylurea (Intermediate 19, 1.6 g, 5.73 mmol) in ethanol (25 mL), N-Boc piperazine (1.59 mL, 8.6

mmol) was added and the mixture was heated to 100 ⁰ C for 18 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was treated with acetonitrile (5 mL). The solid that formed was collected by filtration and vacuum dried to afford 2.3 g (83.35%) of 4-[8-cyano-2-(3-ethyl-ureido)-9-methyl-9H-purin- 6-yl]-piperazine-l-carboxylic acid tert-butyl ester.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.15 (t, 3H), 1.43 (s, 9H), 3.05 (t, 2H), 3.227 (t, 2H), 3.48-

3.63 (m, 4H), 3.78 (s, 3H), 4.45 (br s, 2H), 8.83 (t, IH), 9.27 (t, IH).

Intermediate 16

4-r2-(3-Ethyl-ureido)-9-methyl-8-thiocarbamoyl-9H-purin-6 -yll-piperazine-l-carboxylic acid tert-butyl ester

To a stirred solution of 4-[8-cyano-2-(3-ethyl-ureido)-9-methyl-9H-purin-6-yl]-pipera zine-l- carboxylic acid tert-butyl ester (Intermediate 15, 1.8 g, 4.19 mmol) in ethanol (20 mL), 40% ammonium sulphide (1.07 mL, 6.29 mmol) was added and heated to 100 ⁰ C for 18 h. The reaction mixture was cooled to room temperature and the resulting residue was treated with diethylether. The solid that formed was collected by filtration and dried under vacuum to afford 1.83 g (95.3%) of 4-[2-(3-ethyl-ureido)-9-methyl-8-thiocarbamoyl-9H-purin-6-yl ]- piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz. DMSOd _n ): δ 1.16 (t, 3H), 1.437 (s, 9H), 3.076 (t, 2H), 3.239 (m, 2H), 3.48-3.64 (m, 4H), 4.004 (s, 3H), 4.45 (br s, 2H), 8.94 (br t, IH), 9.1 (br s, IH), 9.8 (br s, IH), 10.04 (br s, IH).

Intermediate 17 l-(8-Cvano-9-methyl-6-morpholin-4-yl-9H-purin-2-vπ-3-ethyl- urea

To a stirred solution of l-(6-Chloro-8-cyano-9-methyl-9H-purin-2-yl)-3-ethyl-urea (Intermediate 19, 1.53 g, 5.48 mmol) in ethanol (25 mL), morpholine (0.73 mL, 8.225 mol) was added and heated to reflux for 15 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was treated with water (10 mL) and stirred for 30 min. The solid obtained was filtered and dried under vacuum to afford 1.3 g (72%) of l-(8-Cyano-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-3-ethyl- urea as off-white solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.13 (t, 3H), δ 3.24 (q, 2H), δ 3.71 (m, 4H), δ 3.76 (s, 3H), δ 4.36 (bs, 4H), δ 8.84 (t, IH), δ 9.27 (s, IH).

Intermediate 18

2-(3-Ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purine-8- carbothioic acid amide

To a stirred solution of l-(8-cyano-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-3-ethyl- urea

(Intermediate 17, 1.38 g, 3.93 mmol) in ethanol (20 mL) was added ammonium sulphide (1.0 mL, 5.9 mmol). The reaction mixture was heated to 100 ⁰ C for 15 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, then triturated with diethyl ether to give solid compound which was filtered and dried to afford 1.4 g (92%) of 2- (3-ethyl-ureido)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbo thioic acid amide as yellow solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.15 (t, 3H), δ 3.25 (q, 2H), δ 3.72 (m, 4H), δ 3.99 (s, 3H), δ 4.21 (bs, 4H), δ 8.95 (s, IH), δ 9.11 (s, IH), δ 9.79 (s, IH), δ 10.05 (s, IH). Mass (APCI. +ve scan): m/z 365 (M+H) for Ci ₄ H ₂₀ N ₈ O ₂ S.

Intermediate 19 l-fό-Chloro-δ-cvano^-methyl^H-purin^-viyS-ethylurea

A mixture of 2-amino-6-chloro-9-methyl-9H-purine-8-carbonitrile (J Chem Soc, Perkin Trans I, 1977, 1003, 10.0 g, 48.076 mmol), ethyl isocyanate (34.14 g, 480.85 mmol) and dibutyl tin diacetate (1.69 g, 4.814 mM) in a 1:1 mixture of toluene (100 mL) and tetrahydrofuran (100 mL) was heated in an autoclave at 100 ⁰ C for 20 h. After the completion of the reaction, the reaction mixture was cooled to room temperature; water (100 mL) was added and the mixture was stirred for 10 min. The layers were separated and organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. Diethyl ether was added to the crude product and the precipitated solid was filtered and dried to yield 12.0 g (52%) of l-(6-chloro-8-cyano-9-methyl-9H-purin-2-yl)-3- ethylurea. 1H NMR (400 MHz. DMSO-d _fi ): δ 1.19 (t, 3H), 3.32 (q, 2H), 3.91 (s, 3H), 8.42 (t, IH), 10.30 (s, IH).

Intermediate 20

1 -r8-Cvano-9-methyl-6-(piperidin- 1 -vD-9H-purin-2-yl ^" |-3-ethvlurea

To a stirred solution of l-(6-chloro-8-cyano-9-methyl-9H-purin-2-yl)-3-ethylurea

(Intermediate 19, 1.2 g, 4.3 mmol) in ethanol (20 mL) was added piperidine (0.638 mL, 6.45 mmol). The reaction mixture was heated to 100 ⁰ C for 18 h, then cooled to room temperature and concentrated under reduced pressure. Water (10 mL) was added to the residue and the mixture was stirred for 20 min. The suspension was filtered to afford 1.05 g (75%) of l-[8- cyano-9-methyl-6-(piperidin-l-yl)-9H-purin-2-yl]-3-ethylurea as solid.

¹ H NMR (400 MHz. DMSO-cϋ: δ 1.14 (t, 3H), δ 1.60-1.67 (m, 6H), δ 3.23 (q, 2H), δ 3.762 (s, 3H), δ 3.88 (brs, 2H), δ 4.42 (brs, 2H), δ 8.91 (s, IH).

Intermediate 21 l-(8-Cvano-9-methyl-6-phenyl-9H-purin-2-ylV3-ethylurea

Argon gas was purged through a mixture of l-(6-chloro-8-cyano-9-methyl-9H-purin-2-yl)-3- ethyl-urea (Intermediate 19, 100 mg, 0.3577 mmol) in toluene (5 mL) for 15 min, then palladium acetate (6.97 mg, 0.0311 mmol), tri-o-tolylphosphine (24 mg, 0.0789 mmol), potassium phosphate (151.6 mg, 0.715 mmol) were added. The reaction mixture was again purged with argon gas for 10 min and phenylboronic acid (86.5 mg, 0.7148 mmol) was added and the mixture was heated to 80 ⁰ C for 6 h. The reaction mixture was cooled to room temperature, then passed through a celite bed. The filtrate was concentrated under reduced pressure to obtain a residue which was stirred in diethyl ether for 10-20 min. The solid which formed was collected by filtration and dried to afford 70 mg (60%) of l-(8-cyano-9-methyl-6- phenyl-9H-purin-2-yl)-3-ethylurea.

¹ H NMR f400 MHz. CDCl ₁ ): δ 1.26 (t, 3H), 3.42 (q, 2H), 3.96 (s, 3H), 7.57 (s, IH), 7.60 (dd, 3H), 8.62 (m, 2H), 9.01 (br s, IH).

Intermediates 22-24

The following Intermediates were prepared by the procedure described in Intermediate 21 from the starting materials (SM) indicated.

Intermediate 25

2-r(Ethylcarbamoyl)aminol-9-methyl-6-(3-methylphenyl)-9H- purine-8-carbothioamide

To a stirred solution of l-[8-cyano-9-methyl-6-(3-methylphenyl)-9H-purin-2-yl]-3-ethy lurea (Intermediate 22, 0.2 g, 0.597 mmol) in ethanol (10 mL) 40% ammonium sulfide (0.152 mL, 0.8955 mol) was added and the reaction mixture was heated to 100 ⁰ C for 38 h. After the completion of the reaction, the reaction mixture was concentrated to dryness. Water (20 mL) was added to the residue added, the mixture was stirred for 10 min. The water was decanted and diethylether (20 mL) was added. A solid formed which was collected by filtration and dried under vacuum to afford 0.17 g (79%) of 2-[(ethylcarbamoyl)amino]-9-methyl-6-(3- methylphenyl)-9H-purine-8-carbothioamide as yellow solid. 1H NMR (400 MHz. DMSOd _n ): δ 1.23 (t, 3H), 2.45 (s, 3H), 3.32 (q, 2H), 4.00 (s, 3H), 7.48 (m, 2H), 8.47 (s, IH), 8.62 (d, IH), 9.10 (t, IH), 9.82 (br s, IH), 10.18 (br s, IH), 10.54 (br s, IH).

Intermediate 26 2-(3-Ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H-purine-8- carbothioic acid amide

In a sealed tube (20 mL), l-[8-cyano-6-(2-fluoro-phenyl)-9-methyl-9H-purin-2-yl]-3-eth yl- urea (Intermediate 24, 0.1 g, 0.295 mmol) was taken and ethanol (5 mL) was added. To the above reaction mixture 40% ammonium sulphide (0.075 mL, 0.443 mmol) was added. The reaction mixture was heated to 100 ⁰ C for 3 h. After the completion of the reaction, the reaction mixture was concentrated to dryness, and water (10 mL) was added to the residue. The mixture was stirred for 10 min and a solid formed which was filtered and dried under vacuum to afford 0.06 g (54.5%) of 2-(3-ethyl-ureido)-6-(2-fluoro-phenyl)-9-methyl-9H- purine-8-carbothioic acid amide.

¹ H NMR (400 MHz. DMSO-cϋ: δ 1.15 (t, 3H), δ 3.27 (q, 2H), δ 3.97 (s, 3H), δ 7.45 (m, 2H), δ 7.65 (m, IH), δ 8.36 (t, IH), δ 9.226 (t, IH), δ 9.78 (s, IH), δ 10.058 (s, IH), 10.47 (s, IH).

Intermediate 27 l-(8-Cvano-9-methyl-6-piperidin-l-yl-9H-purin-2-yl)-3-ethyl- urea

Piperidine (0.638 mL, 6.45 mmol) was added to a stirred solution of l-(6-chloro-8-cyano-9- methyl-9H-purin-2-yl)-3-ethyl-urea (Intermediate 19, 1.2 g, 4.3 mmol) in ethanol (20 mL).

The reaction mixture was heated to 100 ⁰ C for 18 h. After completion of the reaction, the reaction mixture was concentrated to dryness. Water (10 mL) was added to the residue and the suspension that formed was stirred for 20 min. The suspension was filtered and the solid was co-distilled with toluene (2 x 20 mL) to afford 1.05 g (75%) of l-(8-cyano-9-methyl-6- piperidin-l-yl-9H-purin-2-yl)-3 -ethyl-urea as solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.14 (t, 3H), δ 1.60-1.67 (m, 6H), δ 3.23 (q, 2H), δ 3.762 (s, 3H), δ 3.88 (bs, 2H), δ 4.42 (bs, 2H), δ 8.91 (s, IH).

Intermediate 28

2-(3-Ethyl-ureido)-9-methyl-6-piperidin- 1 -yl-9H-purine-8-carbothioic acid amide

To a stirred solution of l-(8-cyano-9-methyl-6-piperidin-l-yl-9H-purin-2-yl)-3-ethyl- urea (Intermediate 27, 1.05 g, 2.08 mmol) in ethanol (20 mL) was added ammonium sulphide (0.533 mL, 3.13 mmol) and the mixture was heated to 100 ⁰ C for 18 h. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was triturated with diethyl ether to give a solid compound which was collected by filtration and dried under

vacuum to afford 1.079 g (86%) of 2-(3-ethyl-ureido)-9-methyl-6-piperidin-l-yl-9H-purine-8- carbothioic acid amide as pale-brown solid.

¹ H NMR (400 MHz. DMSO-d _fi ): δ 1.15 (t, 3H), δ 1.60-1.67 (m, 6H), δ 3.23 (q, 2H), δ 3.971 (s, 3H), δ 4.29 (bs, 4H), δ 9.01 (bs, 2H), δ 9.73 (s, IH), δ 10.03 (s, IH).

Intermediate 29

2-Amino-4,6-dichloropyrimidine-5-carbaldehvde

Phosphorus oxychloride (93 mL, 1020.54 mmol) was cooled to 5 ⁰ C using an ice bath. Dry DMF (35 mL) was added slowly with stirring over 30 min to the phosphorus oxychloride. A white precipitate formed during the addition. The reaction mixture was gently warmed (45 ⁰ C) to dissolve the precipitate and produce a clear solution to which was added 2- aminopyrimidine-4,6-diol (24.2 g, 190.40 mmol) in small portions over 1 h, then the mixture was heated at 8O ⁰ C. The reaction mixture turned a dark red-brown color. After 12 hours, the reaction mixture was cooled to room temperature and excess POCl^ was removed by rotary evaporation. The oily residue was poured over ice. The mixture became homogeneous and was allowed to stir at room temperature overnight to hydrolyze the Vilsmeier adduct. A yellow solid precipitated from solution and was collected by filtration, washed with water and dried under vacuum. The solid precipitate was recrystallized from hot EtOAc. Isolation gave

27.7 grams of the title compound. Reference: Bell, L., et ah, J. Heterocyclic Cheni., 1983,

20, 41.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 192, 194 for C ₅ H ₃ ClN ₃ O. ¹ H NMR (300 MHz, d ₆ -DMSO): 8.51 (s,

2H), 10.06 (s, IH).

Intermediate 30

Ethyl 2-(2-amino-6-chloro-5-formylpyrimidin-4-ylthio)acetate

To a stirred suspension of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (Intermediate 29, 10.66 g, 55.52 mmol) in ethanol (100 mL), triethylamine (8.51 mL, 61.07 mmol) and ethyl 2- mercaptoacetate (6.12 mL, 55.52 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The precipitate was collected by filtration and washed with water, then recrystallized from 2-propanol, and dried in vacuo to afford 12.6 grams of the title compound. Reference: Tumkevicius, S. et al., J. Heterocyclic Chem., 2006, 43, 1629-33. LC/MS (ES ⁺ )[(M+H) ⁺ ]: 276, 278 for C ₉ Hi ₀ ClN ₃ O ₃ S. ¹ R NMR (300 MHz, d ₆ -DMSO): 1.19 (t, 3H), 3.98 (s, 2H), 4.10 (q, 2H), 7.95 (s, IH), 8.25 (s, IH), 10.08 (s, IH).

Intermediate 31

Ethyl 2-amino-4-chlorothieno[2,3-dlpyrimidine-6-carboxylate

A suspension of ethyl 2-(2-amino-6-chloro-5-formylpyrimidin-4-ylthio)acetate (Intermediate

30, 12.6 g, 45.70 mmol) in ethanol (100 mL) and triethylamine (12.74 mL, 91.40 mmol) was refiuxed for 20 h. The solution became homogeneous upon heating, but a solid began to precipitate out of solution after a few hours. The reaction mixture was cooled to room temperature, and the solids were collected by filtration, washed with water, methanol and dried in vacuo to afford 8.21 grams of the title compound. Reference: Tumkevicius, S. et al,

J. Heterocyclic Chem., 2006, 43, 1629-33.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 258, 260 for C ₉ H ₈ ClN ₃ O ₂ S. ¹ H NMR (300 MHz, d ₆ -DMSO): 1.31

(t, 3H), 4.31 (s, 2H), 7.70 (br s, 2H), 7.79 (s, IH).

Intermediate 32

Ethyl 2-amino-4-(pyridin-4-yl)thienoF2,3-d1pyrimidine-6-carboxvlat e

In a microwave reaction vessel, ethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (Intermediate 31, 1 g, 3.88 mmol), pyridin-4-ylboronic acid (0.636 g, 4.66 mmol) and sodium carbonate (0.494 g, 4.66 mmol) were combined and suspended in a 4:1 mixture of dioxane and water. Pd(PPh ₃ ) ₄ (0.224 g, 0.19 mmol) was added in a single portion. The vessel was sealed and heated to 15O ⁰ C in the microwave for 30 min. The reaction mixture was diluted with water and methanol, then filtered through a pad of Celite to remove the palladium salts. The filtrate was concentrated by rotary evaporation, and the residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SOφ filtered and concentrated to a residue which was purified by silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford 30 mg of the title compound. Reference: WO 2005/021552; PCT/GB2004/00364; pg 20.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 301 for Ci ₄ Hi ₂ N ₄ O ₂ S. ¹ R NMR (300 MHz, d ₆ -DMSO): 1.31 (t, 3H), 4.31 (s, 2H), 7.70 (br s, 2H), 7.79 (s, IH).

Intermediates 33-35

The following Intermediates were prepared by the procedure described in Intermediate 32 from the starting materials (SM) indicated.

Intermediate 36

Methyl 2-amino-4-(4-(morpholinomethyl)phenyl)thienor2,3-dlpyrimidin e-6-carboxylate

Ethyl 2-amino-4-(4-formylphenyl)thieno[2,3-d]pyrimidine-6-carboxyl ate (Intermediate 35, 550 mg, 1.68 mmol) and morpholine (732 mg, 8.40 mmol) were combined and suspended in

methanol (20 niL). The mixture was heated to reflux for 2.5 h, then cooled to room temperature and sodium borohydride (0.192 mL, 5.04 mmol) was added in a single portion. The mixture was allowed to stirred for 10 min, then it was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SOφ filtered and concentrated by rotary evaporation. The concentrate was purified by silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford 150 mg of the title compound. Reference: WO 2005/021552; PCT/GB2004/00364; pg 23.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 385 for Ci ₉ H ₂₀ N ₄ O ₃ S. ¹ H NMR (300 MHz, d ₆ -DMSO): 2.40 (m, 4H), 3.57 (m, 6H), 3.85 (s, 3H), 7.37 (br s, 2H), 7.52 (d, 2H), 7.82 (d, 2H), 7.92 (s, IH).

Intermediate 37

Ethyl 2-(3-ethylureido)-4-(pyridin-4-yl)thienor2.3-d1pyrimidine-6- carboxylate

In a microwave reaction vessel, ethyl 2-amino-4-(pyridin-4-yl)thieno[2,3-d]pyrimidine-6- carboxylate (Intermediate 32, 300 mg, 1.00 mmol), ethyl isocyanate (0.785 mL, 9.99 mmol) and dibutyltin diacetate (2.68 μL, 9.99 μmol) were combined and suspended in a 1:1 mixture of THF and toluene. The vessel was sealed and heated to 14O ⁰ C in the microwave for 60 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na2SOφ filter and concentrate, then purified by flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

LC/MS (ES ⁺ )[(M+H) ⁺ ]: 372 for Ci ₇ Hi ₇ N ₅ O ₃ S. ¹ R NMR (300 MHz, d ₆ -DMSO): 1.15 (t, 3H), 1.32 (t, 3H), 3.28 (m, 2H), 4.35 (q, 2H), 7.90 (d, 2H), 8.10 (s, IH), 8.81 (t, IH), 8.86 (d, 2H), 10.27 (s, IH).

Intermediates 38-40

The following Intermediates were prepared by the procedure described in Intermediate 37 from the starting materials (SM) indicated.

Intermediate 41

2-(3-Ethylureido)-4-(pyridin-4-yl)thienor2,3-d1pyrimidine -6-carboxamide

In a sealed microwave vessel, ethyl 2-(3-ethylureido)-4-(pyridin-4-yl)thieno[2,3- d]pyrimidine-6-carboxylate (Intermediate 37, 222 mg, 0.60 mmol) was suspended in 7N ammonia in methanol (5 mL, 35.00 mmol) and heated to 100 ⁰ C for 90 min. The vessel was cooled to room temperature and the solids were collected by filtration, washed with cold methanol and dried to afford 197 mg of the title compound (95% pure). LC/MS (ES ⁺ )[(M+H) ⁺ ]: 343 for Ci ₅ Hi ₄ N ₆ O ₂ S. ¹ R NMR (300 MHz, d ₆ -DMSO): 1.15 (t, 3H), 3.34 (m, 2H), 7.78 (m, IH), 7.90 (m, 2H), 8.27 (m, IH), 8.37 (m, IH), 8.87 (m, 3H), 10.14 (s, IH).

Intermediates 42-44

The following Intermediates were prepared by the procedure described in Intermediate 41 from the starting materials (SM) indicated.