HETEROCYCLIC COMPOUNDS, IN PARTICULAR 2-OXO-4,4,5,5,6,6,7,7-OCTAHYDROBENZOXAZOLE DERIVATIVES, AND THEIR USE AS ANTIBACTERIAL COMPOUNDS

This invention relates to antibacterial drug compounds containing a bicyclic core, typically a bicycle in which one of the rings is an oxazolidinone. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the compounds in treating bacterial infections and in methods of treating bacterial infections. The invention is also directed to antibacterial drug compounds which are capable of treating bacterial infections which are currently hard to treat with existing drug compounds. Such infections are frequently referred to as resistant strains.

The increasing occurrence of bacterial resistance to antibiotics is viewed by many as being one of the most serious threats to human health. Multidrug resistance has become common among some pathogens, for example Staphylococcus aureus, Streptococcus pneumoniae, Clostridium difficile and Pseudomonas aeruginosa. Of these, Staphylococcus aureus, a Gram-positive bacterium, is a major concern due to its potency and its capacity to adapt to environmental conditions. Methicillin-resistant Staphylococcus aureus (MRSA) is probably the most well-known group of resistant strains and has reached pandemic proportions. Of particular concern is the increasing incidence of 'community acquired' infections, i.e. those occurring in subjects with no prior hospital exposure.

While less widespread, antibiotic resistant Gram-negative strains, such as either Escherichia coli NDM-1 (New Delhi metallo^-lactamase 1) or Klebsiella pneumoniae NDM- 1 , are also very difficult to treat. Frequently only expensive antibiotics such as vancomycin and colistin are effective against these strains.

The fluoroquinolone antibacterial family are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram-negative bacterial infections, but are also used for the treatment of Gram-positive strains. One problem with existing fluoroquinolones can be the negative side effects that may sometimes occur as a result of their use. In general, the common side-effects are mild to moderate but, on occasion, more serious adverse effects occur. Some of the serious side effects that occur, and which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include central nervous system (CNS) toxicity and cardiotoxicity. In cases of acute overdose there may be renal failure and seizure. In addition, an increasing number of strains of MRSA are also resistant to fluoroquinolone antibiotics, in addition to β-lactam antibiotics such as methicillin. Gonorrhoea is a human sexually-transmitted infection (STI) caused by the Gram-negative bacterium Neisseria gonorrhoeae, a species of the genus Neisseria that also includes the pathogen N. meningitidis, which is one of the aetiological agents of meningitis. Untreated infection can result in a range of clinical complications including urethritis, dysuria, epididymitis, pelvic inflammatory disease, cervicitis, endometritis and even infertility and ectopic pregnancy. In rare cases, gonorrhoea can also spread to the blood to cause disseminated gonococcal infection that can manifest as arthritis, endocarditis or meningitis. Human immunodeficiency virus (HIV) is more readily-transmitted in individuals co-infected with gonorrhoea. Throughout the twentieth and twenty-first centuries gonorrhoea has been treated with a range of antibiotics. The sulphonamides were the first antibiotics used for the treatment of gonorrhoea, followed by penicillin, tetracycline and spectinomycin. In each case the development of resistance to these drugs by N. gonorrhoeae led to their use being discontinued. The fluoroquinolone antibiotics ciprofloxacin and ofloxacin were also historically recommended for the treatment of gonorrhoea. However, by 2007, fluoroquinolone resistance rates had reached 15% of gonococcal isolates and their use was abandoned. Current treatment recommendations comprise the cephalosporin antibiotics cefixime or ceftriaxone in combination with azithromycin or doxycycline. Resistance to cefixime and ceftriaxone has emerged in recent years. The CDC estimates that approximately 246,000 of the 820,000 gonococcal infections per year in the United States are drug-resistant (Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention).

Another disease in which the development of resistance and multidrug resistance is of particular concern is tuberculosis (TB). From the 17 ^th century to the early-20 ^th century TB was one of the most common causes of death. The development of effective treatments and vaccinations during the mid-20 ^th century led to a sharp reduction in the number of deaths arising from the disease. TB is usually caused by Mycobacterium tuberculosis. Mycobacteria are aerobic bacteria and, as a result, tuberculosis infections most often develop in the lungs (pulmonary tuberculosis), although this is not always the case. Mycobacteria lack an outer cell membrane and as such they are often classified as Gram- positive bacteria, although they are in many ways atypical. They have a unique cell wall which provides protection against harsh conditions (e.g. acidic, oxidative) but also provides natural protection against many antibiotics. Other antibiotics, such as beta-lactams, are inactive against TB due to the intrinsic lack of activity of the compounds in the mycobacteria. Thus, a drug molecule may have excellent activity against other bacterial strains but no activity against wild-type TB. A number of TB-specific antibiotics have been developed, such as isoniazid, rifampicin, pyrazinamide and ethambutol and these are typically used in combination. Unfortunately, there is now increasing incidence of multidrug- resistant TB (MDR-TB). MDR-TB is the term typically used to refer to TB that has developed resistance to isoniazid and rifampicin. MDR-TB can also be resistant to fluoroquinolones and also to the so-called 'second-line' injectable anti-TB drugs: kanamycin, capreomycin and amikacin. Where a strain of TB is resistant to isoniazid and rifampicin as well as one fluoroquinolone and one of the injectable anti-TB drugs, it is known as extensively drug resistant (XDR-TB). MDR-TB and XDR-TB are often found in those who have been previously treated for TB, but these forms of TB are just as infectious as wild-type TB and the incidence of MDR-TB and XDR-TB around the world is increasing. According to a 2013 World Health Organisation report, infections arising from XDR-TB had at that time been identified in 84 different countries. There have even been some reports of strains of TB which were resistant to all drugs tested against them (so-called 'totally drug resistant tuberculosis', TDR-TB). The 'second-line' anti-TB drugs and other antibiotics typically used to treat resistant infections can have unfavourable side effects.

Bacterial resistance is also becoming a problem in the treatment of animals. Antibiotics find widespread use in industrial farming, e.g. to prevent mastitis in dairy cattle, where they are often used prophylactically. Such widespread prophylactic use has led to the build-up of resistance in certain bacterial strains that are particularly relevant to animal health.

In spite of the numerous different antibiotics known in the art for a variety of different infections, there continues to be a need for antibiotics that can provide an effective treatment in a reliable manner. In addition, there remains a need for antibiotic drugs that can avoid or reduce the side-effects associated with known antibiotics.

It is an aim of certain embodiments of this invention to provide new antibiotics. In particular, it is an aim of certain embodiments of this invention to provide antibiotics that are active against resistant strains of Gram-positive and/or Gram-negative bacteria. It is an aim of certain embodiments of this invention to provide compounds that have activity that is comparable to those of existing antibiotics, and ideally which is better. It is an aim of certain embodiments of this invention to provide such activity against wild-type strains at the same time as providing activity against one or more resistant strains. It is an aim of certain embodiments of this invention to provide compounds that exhibit a smaller decrease in activity against resistant strains compared to wild-type strains than prior art compounds do. It may be that certain compounds of the invention are less active than prior art compounds but there is a benefit associated with having a more consistent activity against a range of strains.

It is an aim of certain embodiments of this invention to provide antibiotics that exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.

It is an aim of certain embodiments of this invention to provide treatment of bacterial infections that is effective in a selective manner at a chosen site of interest. Another aim of certain embodiments of this invention is to provide antibiotics having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide antibiotics in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of the above aims. Compounds of the Invention

In a first aspect, the invention provides a compound of formula (I), or a pharmaceutically reof:

I)

wherein is a double bond or a single bond;

Y ¹ is independently selected from NR ⁴ , O and S;

Y ² is independently selected from O and S;

Y ³ is independently selected from O and S;

Y ⁴ is (CH ₂ ) _m ;

Y ⁵ is (CH ₂ ) _P ;

R ¹ is independently selected from -L ¹ -Ar ¹ -Ar ² and

Ar ¹ and Ar ² are each independently selected from a phenyl or monocyclic heteroaryl group; -L ¹ - is -Ci-C3-alkylene-;

X ¹ is independently selected from N and CR ⁵ and X ² is independently selected from N and CR ⁶ ; or

X ¹ and X ² together form a 5-membered heteroaryl ring;

-L ² - is -C2-C3-alkylene-;

Ring B is independently selected from: phenyl, monocyclic 6-membered heteroaryl and pyridinone, optionally substituted with a single -Y ⁶ -R ⁷ group; wherein Y ⁶ is absent or is independently selected from NR ⁸ , O and S; where Ring B is a pyridinone ring, the nitrogen of the Ring B pyridinone may be attached to the proximal end of a -Ci-C3-alkylene- group that is attached at its distal end to the group -L ² -

R ² is independently at each occurrence selected from: halo, nitro, cyano, NR ⁹ R ¹⁰ , NR ⁹ S(0) ₂ R ⁹ , NR ⁹ CONR ⁹ R ⁹ , NR ⁹ C(0)R ⁹ , NR ⁹ C0 ₂ R ⁹ , OR ⁹ , SR ⁹ , SOR ⁹ , SO3R ⁹ , SO2R ⁹ , S0 ₂ NR ⁹ R ⁹ , CO2R ⁹ , C(0)R ⁹ , CONR ⁹ R ⁹ , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, Ci-C ₄ - haloalkyl and 0-Ci-C ₄ -haloalkyl;

R ³ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aryl or heteroaryl;

or R ³ is -L ³ -phenyl; wherein -L ³ - is selected from -CR ¹¹ =CR ¹¹ - and -C ₄ -cycloalkyl-;

R ⁴ is independently selected from: H, Ci-C ₄ -alkyl, C(0)-Ci-C ₄ -alkyl, and Ci-C3-alkylene-R ¹² ; wherein R ¹² is independently selected from phenyl or monocyclic heteroaryl;

or wherein R ⁴ and either -L ¹ - or -L ² - and the nitrogen to which they are attached together form a 4- to 7- membered heterocycloalkyl ring;

R ⁵ and R ⁶ are each independently selected from H, halo, cyano, Ci-C ₄ -alkyl and 0-Ci-C ₄ - alkyl;

R ⁷ is independently selected from: H, Ci-C ₄ -alkyl, C2-C ₄ -alkenyl, C2-C ₄ -alkynyl, Ci-C ₄ - haloalkyl, C3-Cs-cycloalkyl, ₄ -7-heterocycloalkyl, phenyl, monocyclic heteroaryl and C1-C3- alkylene-R ^7a ; wherein R ^7a is independently selected from C3-Cs-cycloalkyl, ₄ . ₇ - heterocycloalkyl, phenyl and monocyclic heteroaryl;

R ⁸ is independently selected from: H and Ci-C ₄ -alkyl;

or R ⁷ and R ⁸ together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl ring; R ⁹ is independently at each occurrence selected from: H and Ci-C4-alkyl;

R ¹⁰ is independently selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, S(0)2-CrC4-alkyl and

C(0)-Ci-C ₄ -alkyl;

R ¹¹ is independently at each occurrence selected from H and Ci-C4-alkyl;

a is an integer from 0 to 4;

n is an integer selected from 0, 1 and 2;

m and p are each an integer selected from: 0 and 1 ;

wherein any of the aforementioned alkyl, alkylene, alkenyl, alkynyl, haloalkyi, cycloalkyi, carbocyclic, heterocyclic, heterocycloalkyi, aryl, phenyl and heteroaryl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NR ^a , =NOR ^a , halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a , SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, Ci-C ₄ -haloalkyl and 0-Ci-C ₄ -haloalkyl ; wherein R ^a is independently at each occurrence selected from H, Ci-C4-alkyl.

For the absence of doubt, where ring B is substituted with a single -Y ⁶ -R ⁷ group it may also be substituted with further substituents as described above, i.e. further substituents selected from selected from oxo, =NR ^a , =NOR ^a , halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a R ^a OR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl.

I pound of formula (I) is a compound of formula (II):

)

wherein , R\ R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , n and a are as defined above for formula (I).

In certain embodiments, the compound of formula (I) is a compound of formula (III):

wherein R ¹ , R ² , R ³ , R ⁴ , Y ² , Y ³ , Y ⁵ , n and a are as defined above for formula (I).

In certain embodiments, the compound of formula (I) is a compound of formula (IV):

wherein R ¹ , R ² , R ³ , R ⁴ , Y ² and a are as defined above for formula (I).

In certain embodiments, the compound of formula (I) is a compound of formula

wherein , R ¹ , R R ²² , R R ³³ , v Y ⁱ¹ , Y ² , Y ⁵ and a are as defined above for formula (I). pound of formula (I) is a compound of formula (VI):

wherein R ¹ , R ² , R ⁴ and a are as defined above for formula (I) and wherein Y ² is independently selected from O and S; V ¹ , V ² and V ³ are each independently selected from: N and CR ¹³ ; with the proviso that no more than two of V ¹ , V ² and V ³ are N; and wherein the ring A is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring; and R ¹³ is independently at each occurrence selected from H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl. rmula (I) is a compound of formula (VII):

wherein Ar ¹ , Ar ² , R ² , R ⁴ , L ¹ , Y ² and a are as defined above for formula (I) and wherein V ¹ , V ² and V ³ and ring A are as described above for formula (VI). ula (I) is a compound of formula (VIII):

I)

wherein R ² , R ⁴ , L ² , Y ² , X ¹ , X ² Ring B and a are as defined above for formula (I) and wherein V ¹ , V ² and V ³ and ring A are as described above for formula (VI).

In certain embodiments, the compound of formula (I) is a compound of formula (IX):

wherein R ² , R ⁴ , L ² , Y ² , Ring B and a are as defined above for formula (I) and wherein V ¹ , V ² and V ³ and ring A are as described above for formula (VI) and wherein ring C is a 5- membered heteroaryl ring.

In certain embodiments, the compound of formula (I) is a compound of formula (X):

wherein R ¹ , R ² , R ³ , R ⁴ and a are as defined above for formula (I). For the absence of doubt the hashed and solid wedges in formula (X) are intended to depict the relative stereochemistry of the indicated bonds and not the absolute stereochemistry, i.e. the compound may be in the form of a single enantiomer or in the form of a racemate. In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry depicted in formula (X). In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry the opposite to that depicted in formula (X).

In certain embodiments, the compound of formula (I) is a compound of formula (XI):

wherein R ¹ , R ² , R ³ , R ⁴ and a are as defined above for formula (I). For the absence of doubt the hashed and solid wedges in formula (XI) are intended to depict the relative stereochemistry of the indicated bonds and not the absolute stereochemistry, i.e. the compound may be in the form of a single enantiomer or in the form of a racemate. In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry depicted in formula (XI). In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry the opposite to that depicted in formula (XI).

In certain embodiments, the compound of formula (I) is a compound of formula (XII):

wherein R ¹ , R ² , R ³ , R ⁴ and a are as defined above for formula (I). For the absence of doubt the hashed and solid wedges in formula (XII) are intended to depict the relative stereochemistry of the indicated bonds and not the absolute stereochemistry, i.e. the compound may be in the form of a single enantiomer or in the form of a racemate. In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry depicted in formula (XII). In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry the opposite to that depicted in formula (XII).

In certain embodiments, the compound of formula (I) is a compound of formula (XIII):

wherein R ¹ , R ² , R ³ , R ⁴ and a are as defined above for formula (I). For the absence of doubt the hashed and solid wedges in formula (XIII) are intended to depict the relative stereochemistry of the indicated bonds and not the absolute stereochemistry, i.e. the compound may be in the form of a single enantiomer or in the form of a racemate. In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry depicted in formula (XIII). In certain embodiments, the compound is in a substantially enantiomerically pure form (i.e. greater than 95%) and has the absolute stereochemistry the opposite to that depicted in formula (XIII).

The following statements apply to compounds of any of formulae (I) to (XIII). These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described in one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this invention in this specification. may be a double bond. Typically, however, - - — js a single bond.

Where is a single bond, it may be that the groups Y ⁴ and Y ⁵ are orientated cis to each other. Alternatively, it may be that the groups Y ⁴ and Y ⁵ are orientated trans to each other. Where is a single bond, it may be that the groups Y ¹ R ¹ and Y ⁴ are orientated cis to each other. Alternatively, it may be that the groups Y ¹ R ¹ and Y ⁴ are orientated trans to each other. In certain embodiments, Y ⁴ and Y ⁵ are orientated cis to each other and Y ¹ R ¹ and Y ⁴ are orientated trans to each other. In certain embodiments, Y ⁴ and Y ⁵ are orientated trans to each other and Y ¹ R ¹ and Y ⁴ are orientated trans to each other. Where is a single bond and m is 0, it may be that the groups NR ³ and Y ⁵ are orientated cis to each other. Alternatively, it may be that the groups NR ³ and Y ⁵ are orientated trans to each other. Thus, where is a single bond and m is 0, it may be that the groups Y ¹ R ¹ and

NR ³ are orientated cis to each other. Alternatively, it may be that the groups Y ¹ R ¹ and NR ³ are orientated trans to each other. In certain embodiments, NR ³ and Y ⁵ are orientated cis to each other and Y ¹ R ¹ and NR ³ are orientated trans to each other. In certain embodiments, Y ⁴ and Y ⁵ are orientated trans to each other and Y ¹ R ¹ and Y ⁴ are orientated trans to each other. Where is a single bond and p is 0, it may be that the groups Y ⁴ and Y ² are orientated cis to each other. Alternatively, it may be that the groups Y ⁴ and Y ² are orientated trans to each other. In certain embodiments, Y ⁴ and Y ² are orientated cis to each other and Y ¹ R ¹ and Y ⁴ are orientated trans to each other. In certain embodiments, Y ⁴ and Y ² are orientated trans to each other and Y ¹ R ¹ and Y ⁴ are orientated trans to each other. Where is a single bond and m and p are both 0, it may be that the groups

NR ³ and Y ² are orientated cis to each other. Alternatively, it may be that the groups NR ³ and Y ² are orientated trans to each other. In certain embodiments, NR ³ and Y ² are orientated cis to each other and Y ¹ R ¹ and NR ³ are orientated trans to each other. In certain embodiments, NR ³ and Y ² are orientated trans to each other and Y ¹ R ¹ and NR ³ are orientated trans to each other. In certain embodiments, it has been observed that a trans relationship between Y ⁴ or NR ³ on the one hand and Y ⁵ or Y ² on the other is associated with higher potencies against certain bacterial strains.

Y ¹ may be O or S. Y ¹ is preferably NR ⁴ .

R ⁴ may be independently selected from: H, Ci-C4-alkyl, C(0)-Ci-C4-alkyl, and C1-C3- alkylene-R ¹² R ⁴ may be Ci-C ₃ -alkylene-R ¹² . R ⁴ may be CH ₂ R ¹² . R ⁴ may be CH ₂ CH ₂ R ¹² . R ¹² may be phenyl, e.g. unsubstituted phenyl. R ¹² may be a monocyclic heteroaryl group. Thus, R ¹² may be a 6-membered heteroaryl ring, e.g. pyridine. Alternatively, R ¹² may be a 5-membered heteroaryl ring. R ⁴ may be Ci-C4-alkyl, e.g. Ci-C4-alkyl substituted with an OH or NH2 group. R ⁴ may be unsubstituted Ci-C4-alkyl, e.g. unsubstituted Ci-C2-alkyl. R ⁴ may be H. Thus, R ⁴ may be selected from H and Ci-C4-alkyl, e.g. R ⁴ may be selected from H and unsubstituted Ci-C ₂ -alkyl. R ⁴ may be C(0)-Ci-C ₄ -alkyl.

Y ² may be S. Preferably, however, Y ² is O.

Y ³ may be S. Preferably, however, Y ³ is O. m may be 1. m may be 0. p may be 1. p may be 0. Preferably, the sum of m and p is 0 or 1. Thus, m and p may both be 0. ¹ may be:

Throughout this specification, the group may be referred to as R ^1a . Thus,

R ¹ may be -L ² -R ^1a .

-L ² - may be -C2-C3-alkylene-. -L ² . may be -C2-alkylene-. -L ² . may be -C3-alkylene-. -L ² - may be substituted with 1 or 2 groups selected from =0, methyl, CH2OH, C02R ^a , and C02NR ^a R ^a . Where -L ² - is a C3-alkylene, it may be that the central atom is substituted, e.g. with an ORa group. It may be that -L ² - is CH2CH(OH)CH2-. It may be, however, that -L ² - is unsubstituted alkylene. Thus, -L ² - may be -CH2CH2-. It may be that -L ² - is CH2CH2CH2-.

It may be that -L ² - and R ⁴ together with the nitrogen to which they are attached form a 4- to 7- membered heterocyclic ring. Thus, it may be that -L ² - and R ⁴ together with the nitrogen to which they are attached form a 4- to 5- membered heterocyclic ring. -L ² - and R ⁴ together with the nitrogen to which they are attached may form a pyrrolidine or azetidine ring. 1 may be N. Thus, R ^1a may have the structure:

Alternatively, X ¹ may be CR ⁵ . Thus, R ^1a may have the structure:

² may be N. Thus, R ^1a may have the structure:

Alternatively, X ² may be CR ⁶ . Thus, R ^1a may have the structure:

It may be that X ¹ is N and X ² is CR ⁶ . Thus, R ^1a may have the structure:

It may be that X ¹ is N and X ² is N. Thus, R ^1a may have the structure:

It may be that X ¹ is CR ⁵ and X ² is N. Thus, R ^1a may have the structure:

It may be that X ¹ is CR ⁵ and X ² is CR ⁶ . Thus, R ^1a may have the structure: It may be that R ⁵ and R ⁶ are each independently selected from H, halo, cyano, Ci-C4-alkyl and 0-Ci-C4-alkyl; or R ⁵ and R ⁶ together with the carbons to which they are attached together form a 5-membered heteroaryl ring. Compounds in which R ⁵ and R ⁶ together with the carbons to which they are attached together form a 5-membered heteroaryl ring are examples of compounds in which X ¹ and X ² together form a 5-membered heteroaryl group.

It may be that R ⁵ is independently selected from H or Ci-C4-alkyl. It may be that R ⁵ is H. It may be that R ⁶ is independently selected from H or Ci-C4-alkyl. It may be that R ⁶ is H.

It may be that R ⁵ and R ⁶ are each independently selected from: H, halo, cyano, Ci-C4-alkyl and 0-Ci-C4-alkyl. It may be that R ⁵ and R ⁶ are each independently selected from H, C1-C4- alkyl and 0-Ci-C4-alkyl or that R ⁵ and R ⁶ , together with the carbons to which they are attached together form a 5-membered heteroaryl ring. It may be that R ⁵ and R ⁶ are each independently at each occurrence selected from H or Ci-C4-alkyl. It may be that R ⁵ and R ⁶ are at each occurrence H.

Alternatively, it may be that R ⁵ and R ⁶ , together with the carbons to which they are attached together form a 5-membered heteroaryl ring. Exemplary heteroaryl rings include oxazole, thiazole, isoxazole, isothiazole, pyrazole, imidazole, triazole, pyrole, thiophene, furan and oxadiazole. For the absence of doubt, the double bond depicted in the structure above between X ¹ and X ² may be delocalised into the heteroaromatic ring. 1 ^a may have the structure:

wherein Z ⁴ and Z ⁵ are each independently selected from C and N; Z ¹ , Z ² and Z ³ are each independently selected from O, S, N, S(O), NR ^a and CR ¹⁴ ; wherein the ring formed by Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ contains two endocyclic double bonds and with the further proviso that at least one of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is O, S, N or NR ^a ; and wherein R ¹⁴ is independently selected from H, Ci-C ₄ -alkyl, CR ^a ROR ^a , CR ^a R ^a NR ^a R ^a , C0 ₂ R ^a and CONR ^a R ^a . In certain examples, the heteroaryl ring may be a ring selected from oxazole, thiazole, thiazole. Thus, R ^1a may have the structure:

wherein one of Z Z ² and Z ³ is N, one of Z Z ² and Z ³ is CR ¹⁴ and the final one of Z Z ² and Z ³ is selected from O and S; provided that the ring comprising Z Z ² and Z ³ contains two endocyclic double bonds; and wherein R ¹⁴ is independently selected from H, C1-C4- alkyl, CR ^a ROR ^a , CR ^a R ^a NR ^a R ^a , C0 ₂ R ^a and CONR ^a R ^a . 1 ^a may have the structure:

Z ² is independently selected from O and S. Z ² may be O. Z ²

Ring B may be selected from a phenyl ring or a 6-membered heteroaryl ring. Thus, Ring B may be a phenyl ring. Ring B may be a pyridine ring or a pyrimidine ring.

R ^1a may have the structure:

wherein x is 0 or 1 ; y is an integer from 0 to 2; Z ⁶ and Z ⁷ are each independently selected from carbon or nitrogen; and R ¹⁵ is independently selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C4-alkyl, C ₂ -C4-alkenyl, C ₂ -C4-alkynyl and Ci-C4-haloalkyl. ^{1 a} may have the structure:

wherein one of Z Z ² and Z ³ is N, one of Z Z ² and Z ³ is CR ¹⁴ and the final one of Z Z ² and Z ³ is selected from O and S; provided that the ring comprising Z Z ² and Z ³ contains two endocyclic double bonds.

Likewise, R ^{1 a} may have the structure:

wherein Z ² is independently selected from O and S. Z ² may be O. Z ² may be S. x may be 0. Thus it may be that there is no Y ⁶ -R ⁷ group on R ¹ .

Alternatively, x may 1 ^a may have the structure:

R ^{1 a} may have the structure: Z ² and Z ³ is N, one of Z ¹ , Z ² and Z ³ is CR ¹⁴ and the final one of Z ¹ , Z ² and Z ³ is selected from O and S; provided that the ring comprising Z Z ² and Z ³ contains two endocyclic double bonds.

Likewise, R ^{1 a} may have the structure:

dependently selected from O and S. Z ² may be O. Z ²

an integer from 0 to 2; Z ⁶ , Z ⁷ and Z ⁸ are each independently selected from carbon or nitrogen; providing that no more than 2 of Z ⁶ , Z ⁷ and Z ⁸ are nitrogen; and R ¹⁵ is independently selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , CrC ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl. y may be 0. Z ⁶ may be nitrogen. Alternatively, Z ⁶ may be carbon. Z ⁷ may be nitrogen. Alternatively, Z ⁷ may be carbon. It may be that Z ⁶ and Z ⁷ are each carbon. It may be that Z ⁶ and Z ⁷ are each nitrogen. It may be that Z ⁶ is nitrogen and Z ⁷ is carbon.

Z ⁸ may be carbon. Z ⁸ may be nitrogen.

R ¹⁴ may be selected from H and Ci-C4-alkyl. In certain particular embodiments, R ¹⁴ is H.

If present, R ¹⁵ may at each occurrence be selected from halo and Ci-C4-alkyl.

It may be that Y ⁶ is independently selected from NR ⁸ , O and S. Y ⁶ is preferably O.

It may be that R ⁷ and R ⁸ together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl ring. It may be that R ⁷ and R ⁸ together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring, e.g. a piperidine, morpholine or piperazine ring.

Preferably, however, R ⁷ is independently selected from: H, Ci-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-haloalkyl, C3-Cs-cycloalkyl, 4-7-heterocycloalkyl, phenyl, monocyclic heteroaryl and Ci-C3-alkylene-R ^7a ; wherein R ^7a is independently selected from C3-C8- cycloalkyl, 4-7-heterocycloalkyl, phenyl and monocyclic heteroaryl. R ⁷ is independently selected from: Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, C3-Cs-cycloalkyl, 4- 7-heterocycloalkyl, phenyl, monocyclic heteroaryl and Ci-C3-alkylene-R ^7a ; wherein R ^7a is independently selected from C3-Cs-cycloalkyl, 4-7-heterocycloalkyl, phenyl and monocyclic heteroaryl. R ⁷ may be independently selected from: Ci-C4-alkyl, phenyl and monocyclic heteroaryl.

R ⁷ may be alkyl. R ⁷ may be Ci-C4-alkyl. R ⁷ may be Ci-C4-haloalkyl. Alternatively, R ⁷ may be selected from phenyl and monocyclic heteroaryl. R ⁷ may be phenyl. R ⁷ may be unsubstituted phenyl or R ⁷ may be substituted. R ⁷ may be monocyclic heteroaryl, e.g. a 6- membered heteroaryl group. Thus, R ⁷ may be pyridyl, e.g. unsubstituted pyridyl. R ⁷ may be 3-pyridyl, e.g. unsubstituted 3-pyridyl. R ⁷ may be C3-Cs-cycloalkyl, e.g. cyclohexyl. R ⁷ may be 4-7-heterocycloalkyl, e.g. piperidine or tetrahydropyran or azetidine.

It may be that Y ⁶ is O and R ⁷ is independently selected from: Ci-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-haloalkyl, C3-Cs-cycloalkyl, 4-7-heterocycloalkyl, phenyl, monocyclic heteroaryl and Ci-C3-alkylene-R ^7a ; wherein R ^7a is independently selected from C3-C8- cycloalkyl, 4-7-heterocycloalkyl, phenyl and monocyclic heteroaryl.

Exemplary R ^1a groups include:

21

. in these embodiments, -L ² - is typically an ethylene group. -L ² - may also be a propylene group.

It may be that R ¹ is -L ¹ -Ar ¹ -Ar ² ; wherein Ar ¹ is independently selected from a phenyl or monocyclic heteroaryl group; and wherein Ar ² is a monocyclic heteroaryl group.

-L ¹ - may be -Ci-C2-alkylene-. -L ¹ . may be -Ci-alkylene-. -L ¹ . may be -C2-alkylene-. -L ¹ - may be substituted with 1 or 2 groups selected from =0, methyl, CH2OH, C02R ^a , and C02NR ^a R ^a . It may be, however, that -L ¹ - is unsubstituted alkylene. Thus, -L ¹ - may be - CH ₂ -.

It may be that -L ¹ - and R ⁴ together with the nitrogen to which they are attached form a 4- to 7- membered heterocyclic ring. Thus, it may be that -L ¹ - and R ⁴ together with the nitrogen to which they are attached form a 4- to 5- membered heterocyclic ring. -L ¹ - and R ⁴ together with the nitrogen to which they are attached may form a pyrrolidine or azetidine ring.

It may be that at least one of Ar ¹ and Ar ² is a monocyclic heteroaryl group, e.g. a 6- membered monocyclic heteroaryl group, e.g. a pyridine. It may be that a single one of Ar ¹ and Ar ² is a monocyclic heteroaryl group, e.g. a 6-membered monocyclic heteroaryl group , e.g. a pyridine. It may be that a single one of Ar ¹ and Ar ² is phenyl, e.g. substituted phenyl.

It may be that Ar ¹ is a phenyl group, e.g. a substituted phenyl group and Ar ² is a 6- membered heteroaryl group, e.g. pyridine. It may be that Ar ¹ is a 6-membered heteroaryl group, e.g. pyridine, and Ar ² is a phenyl group.

Ar ¹ may be a monocyclic heteroaryl group, e.g. a 6-membered monocyclic heteroaryl group. Ar ¹ may be pyridine. Ar ¹ may be a phenyl group. Ar ¹ may be unsubstituted. Ar ¹ may be substituted, e.g. Ar ¹ may be substituted with a single hydroxyl group.

Thus, Ar ¹ may have the structure: wherein z is an integer from 0 to 4; and R ¹⁶ is independently selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , -C4-alkyl, C ₂ -C4-alkenyl, C ₂ -C4-alkynyl and C1-C4 haloalkyl. Ar ¹ may have the structure:

Ar ² may be a monocyclic heteroaryl group, Ar ² may be 6-membered heteroaryl group, e.g. a pyridyl group. 2 may have the structure:

wherein w is an integer from 0 to 4; and R ¹⁷ is independently selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci- -alkyl, C ₂ -C4-alkenyl, C ₂ -C4-alkynyl and Ci-C4-haloalkyl. Ar ¹ may have the structure:

Exemplary examples of Ar ¹ -Ar ² include:

In these embodiments, L ¹ is typically a methylene group.

R ² may be independently at each occurrence selected from: CO2R ⁹ , C(0)R ⁹ , CONR ⁹ R ⁹ , Ci- C ₄ -alkyl, C2-C ₄ -alkenyl, C2-C ₄ -alkynyl and Ci-C ₄ -haloalkyl. a may be 0. n may be 0. Alternatively, n may be 1.

It may be that R ³ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aryl or heteroaryl.

Thus, R ³ may take the form:

wherein V ¹ , V ² and V ³ are each independently selected from: N and CR ¹³ ; with the proviso that no more than two of V ¹ , V ² and V ³ are N; and wherein the ring A is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyi or heterocycloalkyi ring; and wherein R ¹³ is independently at each occurrence selected from H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C2-C ₄ -alkynyl and Ci-C ₄ -haloalkyl.

Preferably, R ³ takes the form:

wherein V ⁴ and V ⁵ are each independently selected from O, S and NR ^a ; R ¹⁸ is independently at each occurrence selected from: H, fluoro, cyano, C02R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl; or any two R ¹⁸ groups which are attached to the same carbon together form a group selected from: =0, =NR ^a and =NOR ^a ; and b is an integer selected from 1 and 2. For the absence of doubt, V ¹ , V ² , V ³ , V ⁴ , V ⁵ , R ¹⁸ and b are selected such that the number of substituent groups (as defined above in relation to formula (I)) off the R ³ bicycle does not exceed 5.

It may be that V ¹ , V ² and V ³ are each independently selected from: N and CH; with the proviso that no more than two of V ¹ , V ² and V ³ are N. It may be that a single one of V ¹ , V ² and V ³ is N. Preferably, V ³ is CR ¹³ (e.g. CH). Thus, it may be that V ¹ is N and V ² is CR ¹³ (e.g. CH). Alternatively, it may be that V ² is N and V ¹ is CR ¹³ (e.g. CH). In a further alternative, it may be that V ¹ and V ² are each N.

R ¹⁸ may be independently at each occurrence selected from: H, fluoro, cyano, C02R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl; or any two R ¹⁸ groups which are attached to the same carbon together form a group selected from: =0, =NR ^a and =NOR ^a . Preferably R ¹⁸ is independently at each occurrence selected from H, F, Ci-C ₄ -alkyl or Ci-C ₄ -haloalkyl; or any two R ¹⁸ groups which are attached to the same carbon together form a =0 group. Preferably R ¹⁸ is independently at each occurrence selected from: H, Ci-C ₄ -alkyl or Ci-C ₄ -haloalkyl; or any two R ¹⁸ groups which are attached to the same carbon together form a =0 group.

In a preferred embodiment, V ⁴ is O. Thus, it may be that both V ⁴ and V ⁵ are O. It may be that V ⁴ is O and V ⁵ is S. It may be that V ⁴ is O and V ⁵ is NR ^a (e.g. NH).

V ⁴ can also be S. Thus, it may be that V ⁴ is S and V ⁵ is NR ^a (e.g. NH).

It may be that V ⁵ is NR ^a (e.g. NH). In this case it is preferable that the -CR ¹⁸ R ¹⁸ - group attached to said V ⁵ is C=0. b may be 1. Preferably, b is 2.

In a specific embodiment, V ⁴ is O, V ⁵ is O, b is 2 and R ¹⁸ is at each occurrence H. In another specific embodiment, V ⁴ is O, V ⁵ is S, b is 2 and R ¹⁸ is at each occurrence H. In yet another specific embodiment, V ⁴ is O, V ⁵ is NH, b is 2, the -CR ¹⁸ R ¹⁸ - group attached to V ⁵ is C=0 and the -CR ¹⁸ R ¹⁸ - group attached to V ⁴ is CH ₂ .

R ³ ma take the form:

V ¹ , V ² and V ³ are each independently selected from: N and CR ¹³ ; with the proviso that no more than two of V ¹ , V ² and V ³ are N; V ⁴ and V ⁵ are each independently selected from O, S and NR ^a ; wherein R ¹³ is independently at each occurrence selected from H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ - haloalkyl; and R ¹⁸ is independently at each occurrence selected from: H, fluoro, cyano, C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl.

R ³ may take the form:

V ¹ is are each independently selected from: N and CR ¹³ ; V ⁴ is independently selected from O and S; wherein R ¹³ is independently at each occurrence selected from H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a R ^a OR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ - haloalkyl; and R ¹⁸ is independently at each occurrence selected from: H, fluoro, cyano, C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl.

Exemplary R ³ groups include:

R ³ may be -L ³ -phenyl.

R ³ may take the form: , wherein R ¹⁹ is independently at each occurrence selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a R ^a OR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and C1-C4- haloalkyl; and u is an integer from 0 to 5.

R ¹¹ may at each occurrence be H.

may take the form wherein R ¹⁹ is independently at each occurrence selected from halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ - haloalkyl; R ²⁰ is independently at each occurrence selected from oxo, fluoro, cyano, C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl; u is an integer from 0 to 5; and v is an integer from 0 to 4; R ²⁰ may be selected from: fluoro, cyano, C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ - alkenyl, C2-C ₄ -alkynyl and Ci-C ₄ -haloalkyl. v may be 0.

R ¹⁹ may be independently at each occurrence selected from Ci-C ₄ -alkyl, halo, nitro and cyano. u may be an integer from 1 to 5, e.g. from 1 to 3.

R ³ may also take the form

, wherein V ⁶ is independently selected from N and CR ¹³ (e.g. CH);

V ⁷ is independently selected from NR ^a , S and O; and R ²¹ is independently at each occurrence selected from: H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , NR ^a C(0)R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a C(0)R ^a , CONR ^a R ^a , CrC ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, Ci-C ₄ -haloalkyl, and CR ^a R ^a NR ^a R ^a . R ²¹ may be independently at each occurrence selected from H, F, CN, OR ^a , nitro, Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl. For the absence of doubt, V ⁶ , V ⁷ and R ²¹ are selected such that the number of substituent groups (as defined es not exceed 5.

exemplary R ³ group is The compound may be any one or more compound(s) selected from those prepared in Examples 1 to 107 and tested in Example 108 or a pharmaceutically acceptable salt or N- oxide thereof.

The compound may be as described in any of the following numbered clauses: la (I), or a pharmaceutically acceptable salt or N-oxide thereof:

(I)

wherein is a double bond or a single bond;

Y ¹ is independently selected from NR ⁴ , O and S;

Y ² is independently selected from O and S;

Y ³ is independently selected from O and S;

Y ⁴ is (CH ₂ ) _m ;

Y ⁵ is (CH ₂ ) _P ;

1 is independently selected from -L ¹ -Ar ¹ -Ar ² and

Ar ¹ is independently selected from a phenyl or monocyclic heteroaryl group;

Ar ² is a monocyclic heteroaryl group;

-L ¹ - is -Ci-C3-alkylene-;

X ¹ is independently selected from N and CR ⁵ and X ² is independently selected from N and CR ⁶ ; or

X ¹ and X ² together form a 5-membered heteroaryl ring;

-L ² - is -C2-C3-alkylene-;

Ring B is independently selected from: phenyl, monocyclic 6-membered heteroaryl and pyridinone, optionally substituted with a single -Y ⁶ -R ⁷ group; Y ⁶ is independently selected from NR ⁸ , O and S; where Ring B is a pyridinone ring, the nitrogen of the Ring B pyridinone may be attached to the proximal end of a -Ci-C3-alkylene- group that is attached at its distal end to the group -L ² -

R ² is independently at each occurrence selected from: halo, nitro, cyano, NR ⁹ R ¹⁰ , NR ⁹ S(0) ₂ R ⁹ , NR ⁹ CONR ⁹ R ⁹ , NR ⁹ C(0)R ⁹ , NR ⁹ C0 ₂ R ⁹ , OR ⁹ , SR ⁹ , SOR ⁹ , S0 ₃ R ⁹ , S0 ₂ R ⁹ , S0 ₂ N R ⁹ R ⁹ , CO2R ⁹ , C(0)R ⁹ , CON R ⁹ R ⁹ , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ - haloalkyl;

R ³ is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aryl or heteroaryl;

or R ³ is -L ³ -phenyl; wherein -L ³ - is selected from -CR ^{1 1} =CR ^{1 1} - and -C ₄ -cycloalkyl-;

R ⁴ is independently selected from: H, Ci-C ₄ -alkyl and Ci-C3-alkylene-R ¹² ; wherein R ¹² is independently selected from phenyl or monocyclic heteroaryl;

or wherein R ⁴ and either -L ¹ - or -L ² - and the nitrogen to which they are attached together form a 4- to 7- membered heterocycloalkyi ring;

R ⁵ and R ⁶ are each independently selected from H, halo, cyano, Ci-C ₄ -alkyl and 0-Ci-C ₄ - alkyl;

R ⁷ is independently selected from: H, Ci-C ₄ -alkyl, C3-Cs-cycloalkyl, ₄ -7-heterocycloalkyl, phenyl and monocyclic heteroaryl;

R ⁸ is independently selected from: H and Ci-C ₄ -alkyl;

or R ⁷ and R ⁸ together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyi ring;

R ⁹ is independently at each occurrence selected from: H and Ci-C ₄ -alkyl;

R ¹⁰ is independently selected from: H, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, S(0)2-CrC ₄ -alkyl and

C(0)-CrC ₄ -alkyl;

R ^{1 1} is independently at each occurrence selected from H and Ci-C ₄ -alkyl;

a is an integer from 0 to 4;

n is an integer selected from 0, 1 and 2;

m and p are each an integer selected from: 0 and 1 ;

wherein any of the aforementioned alkyl, alkylene, alkenyl, alkynyl, haloalkyl, cycloalkyl, carbocyclic, heterocyclic, heterocycloalkyi, aryl, phenyl and heteroaryl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =N R ^a , =NOR ^a , halo, nitro, cyano, N R ^a R ^a , N R ^a S(0) ₂ R ^a , N R ^a C(0)R ^a , N R ^a CON R ^a R ^a , N R ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ N R ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CON R ^a R ^a , CR ^a R ^a N R ^a R ^a , CR ^a R ^a OR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl; wherein R ^a is independently at each occurrence selected from H, Ci-C ₄ -alkyl.

2. A compound of clause 1 , wherein the compound of formula (I) is a compound of formula (X):

3. A compound of clause 1 , wherein the compound of formula (I) is a compound of formula (XI):

R ³

/

I . (R ² ),

(XI).

4. A compound of any preceding clause, wherein a is 0. of any preceding clause, wherein R ¹ is:

6. A compound of clause 5, wherein -L ² . is -C2-alkylene-

7. A compound of clause 5 or clause 6, wherein X ¹ is CR ⁵ and X ² is CR ⁶ .

8. A compound of any one of clauses 5 to 7, wherein R ⁵ and R ⁶ , together with the carbons to which they are attached together form a 5-membered heteroaryl ring.

9. A compound of clause 8, wherein the heteroaryl ring is a ring selected from oxazole, thiazole, isoxazole and isothiazole.

10. A compound of any one of clauses 5 to 9, wherein Ring B is a phenyl ring. 1 1. A compound of any one of clauses 5 to 9, wherein Ring B is a pyridine ring or a pyrimidine ring.

12. A compound of any one of clauses 1 to 4, wherein R ¹ is -L ¹ -Ar ¹ -Ar ² ; wherein Ar ¹ is independently selected from a phenyl or monocyclic heteroaryl group; and wherein Ar ² is a monocyclic heteroaryl group.

13. A compound of clause 12, wherein -L ¹ . is -Ci-alkylene-.

14. A compound of clause 13, wherein Ar ¹ is a phenyl group.

15. A compound of clause 13 or clause 14, wherein Ar ² is a 6-membered heteroaryl group.

16. A compound of any preceding clause, wherein R ³ takes the form:

wherein V ¹ , V ² and V ³ are each independently selected from: N and CR ¹³ ; with the proviso that no more than two of V ¹ , V ² and V ³ are N; and wherein the ring A is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyi or heterocycloalkyi ring; and wherein R ¹³ is independently at each occurrence selected from H, halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , CR ^a R ^a NR ^a R ^a , CR ^a ROR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl.

17. A compound of any preceding clause, wherein R ⁴ is selected from H and Ci-C ₄ -alkyl

Detailed Description

Throughout this specification, the term 'compound of the invention' is intended to refer to a compound of any one of formulae (I) to (XI) or a pharmaceutically acceptable salt or N- oxide thereof. Where the compound of the invention is an N-oxide, it will typically be a pyridine N-oxide, i.e. where the compound of the invention comprises a pyridine ring (which may form part of a bicyclic or tricyclic ring system), the nitrogen of that pyridine may be N ⁺ -0 ^" . Alternatively, it may be that the compound of the invention is not an N-oxide.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Specifically, the oxime groups present in certain compounds of the invention may be present as the E-oxime, as the Z- oxime or as a mixture of both in any proportion. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Where structurally isomeric forms of a compound are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety.

Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).

It follows that a single compound may exhibit more than one type of isomerism.

The term C _m -C _n refers to a group with m to n carbon atoms.

The term "alkyl" refers to a monovalent linear or branched hydrocarbon chain. For example, Ci-C6-alkyl may refer to methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, sec-butyl, tert- butyl, n-pentyl and n-hexyl. An alkyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, OR ^a or NHR ^a .

The term "alkylene" refers to a bivalent linear hydrocarbon chain. For example, -C1-C3- alkyl may refer to methylene, ethylene or propylene. An alkylene group may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be methyl or ethyl.

The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom.

The term "alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. An alkenyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, OR ^a or NHR ^a .

The term "alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, "C2-C6-alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. An alkynyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, OR ^a or NHR ^a .

The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, "C3-C6-cycloalkyl" may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. A cycloalkyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, OR ^a or NHR ^a .

The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane.

The term "heteroaromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane, the ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring or ring system are selected from O, S and N). The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. For example, the "aryl" may be phenyl and naphthyl. An aryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each aryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR ^a or NHR ^a .

Aryl groups may have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements. Aryl groups comprise aromatic rings, i.e. rings which satisfy the Huckel rule. Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups. Equally, aryl groups may include non-aromatic carbocyclic portions. An aromatic ring is a phenyl ring.

The term "heteroaryl" may refer to any aromatic (i.e. a ring system containing (4n + 2) ττ- electrons or n- electrons in the ττ-system) 5-10 membered ring system comprising from 1 to

4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O,

5 and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine. Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones. The heteroaryl system itself may be substituted with other groups. A heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR ^a or NHR ^a . Heteroaryl groups may mean a 5- or 6-membered heteroaryl group. They may therefore comprise a 5- or 6- membered heteroaromatic ring, i.e. a 5- or 6- membered ring which satisfies the Huckel rule and comprises a heteroatom. Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is includes 1-4 heteroatoms selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring includes 1-2 nitrogen atoms. Specifically, heteroaryl groups and heteroaromatic rings may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine.

The term " _y -z-rnembered heterocycloalkyl" may refer to a monocyclic or bicyclic saturated or partially saturated group having from y to z atoms in the ring system and comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 8 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine. Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms. A heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, OR ^a or NHR ^a .

An 'endocyclic' double bond is one where both of the atoms between which the double bond is formed are in the ring or ring system in which the atoms are situated.

A carbocyclic group consists of one or more rings which are entirely formed from carbon atoms. A carbocylic group can be a mono- or bicyclic cycloalkyl group, or it can comprise at least one phenyl ring.

A heterocyclic group consists of one or more rings wherein the ring system includes at least one heteroatom. A heterocyclic group comprises at least one heteroaryl or heterocycloalkyl rings. A heterocycloalkyl ring may be a saturated ring comprising at least one heteroatom selected from O, S and N. Where a ring system is described as being a x-membered bicyclic group, that is intended to mean that the skeleton of the bicyclic ring system is formed from x atoms (i.e. the total number of atoms across the two rings of the bicycle is x).

Aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , NR ^a C(0)R ^a , OR ^a ; SR ^a , SOR ^a , S0 ₃ R ^a , S0 ₂ R ^a , S0 ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ - alkynyl, Ci-C ₄ -haloalkyl and CR ^a R ^a NR ^a R ^a ; wherein R ^a is independently at each occurrence selected from H, Ci-C ₄ -alkyl and Ci-C ₄ -haloalkyl.

The present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ l and ¹²⁵ l, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ 0, ¹⁷ 0 and ¹⁸ 0, phosphorus, such as ³² P, and sulphur, such as ³⁵ S.

Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ 0 and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

Uses, methods of treatment and pharmaceutical formulations

Each of the compounds of the present invention may be used as a medicament. Thus, in another aspect of the invention, there is provided a compound as defined above for the treatment of bacterial infections.

The compounds and formulations of the present invention may be used in the treatment of a wide range of bacterial infections. In some embodiments, the compounds can be used to treat bacterial infections caused by one or more resistant strains of bacteria e.g. a strain which is resistant to at least one approved antibiotic drug. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-positive bacteria e.g. a strain which is resistant to at least one approved antibiotic drug. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-negative bacteria, e.g. a strain which is resistant to at least one approved antibiotic drug.

The compounds and formulations of the invention may be used to treat infections caused by bacteria which are in the form of a biofilm.

The term 'resistant strains' is intended to mean strains of bacteria which have shown resistance to one or more known antibacterial drug. For example, it may refer to strains which are resistant to methicillin, strains that are resistant to one or more other β-lactam antibiotics, strains that are resistant to one or more fluoroquinolones and/or strains that are resistant to one or more other antibiotics (i.e. antibiotics other than β-lactams and fluoroquinolones). A resistant strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for the parent (susceptible) strain.

The term 'approved drug' is intended to mean that the drug is one which had been approved by the US FDA or the EMA prior to 1 February 2016. The bacterial strain (e.g. the MRSA strain or E. coli strain) may be resistant to one or more fluoroquinolone antibiotics, e.g. one or more antibiotics selected from levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.

The compounds of the invention may be particularly effective at treating infections caused by Gram-positive bacteria. The compounds of the invention may be particularly effective at treating infections caused by Gram-positive bacteria which are resistant to one or more fluoroquinolone antibiotics.

The compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria. The compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria which are resistant to one or more fluoroquinolone antibiotics.

The compounds of the invention may be particularly effective at treating infections caused by aerobic bacteria, e.g. S. aureus. The compounds of the invention may be particularly effective at treating infections caused by anaerobic bacteria, e.g. a Clostridium spp. such as Clostridium difficile.

The compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc). In a specific embodiment, the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram-positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and formulations may be used to treat category A and/or category B pathogens as defined by the US government on 1 ^st Jan 2014.

The bacterial infection may be caused by a strain selected from: Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp. Like Neisseria spp., Haemophilus spp., Legionella spp., Pasteurella spp., Bordetella spp., Brucella spp., Francisella spp. and Moraxella spp. are fastidious Gram-negative organisms. A fastidious bacterium is one having a complex nutritional requirement, i.e. one which will only grow when specific nutrients are included in the culture medium. As an example Neisseria gonorrhoeae requires, amongst other supplements, iron, several amino acids, cofactors and vitamins in order to grow. Members of the fastidious Gram-negative bacteria group often share common antibiotic susceptibility profiles. Pathogenic Neisseria species include Neisseria gonorrhoeae (the pathogen responsible for gonorrhoea) and Neisseria meningitidis (one of the pathogens responsible for bacterial meningitis). Infections which can be treated by the compounds and methods of the invention include gonorrhoea. Infections which can be treated include secondary infections which can arise from lack of treatment of a primary Neisseria gonorrhoeae infection. Exemplary secondary infections include urethritis, dysuria, epididymitis, pelvic inflammatory disease, cervicitis and endometritis and also systemic gonococcal infections (e.g. those manifesting as arthritis, endocarditis or meningitis). The gonorrhoea infection may be one caused by a strain of Neisseria gonorrhoeae which is resistant to at least one known antibacterial drug, e.g. at least one β-lactam drug. The gonorrhoea infection may be one caused by a strain of Neisseria gonorrhoeae which is resistant to at least one approved drug. The at least one drug may be an antibiotic drug, e.g. one that is approved for use in treating one of the fastidious Gram-negative species mentioned in this specification. It may be approved for use in treating gonorrhoea. The approved drug may be a β-lactam drug. Further infections which can be treated by the compounds and methods of the invention include bacterial meningitis and Neisseria meningitidis infections of other parts of the human or animal body.

The compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by resistant strains of mycobacteria. Thus, for example, they can be used to treat TB or leprosy. Thus, it may be that the mycobacterial infection is caused by M. tuberculosis. It may also be that the mycobacterial infection is caused by a mycobacterium selected from: M. avium complex, M. abscessus, M. leprae, M. bovis, M. kansasii, M. chelonae, M. africanum, M. canetti and M. microti. The compounds may be used to treat resistant strains of TB, e.g. MDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin), XDR-TB (i.e. TB infections caused by strains which are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR-TB (i.e. TB infections caused by strains which have proved resistant to every drug tested against it with the exception of a compound of the invention). The mycobacterium is caused by a mycobacterial strain which is resistant to at least one approved antimycobacterial compound. The at least one approved antimycobacterial compound may be selected from: rifampicin, isoniazid, kanamycin, capreomycin, amikacin and a fluoroquinolone. The at least one approved antimycobacterial compound may be selected from: rifampicin, moxifloxacin, isoniazid, ciprofloxacin and levofloxacin. The compounds of the invention may be used to treat non-replicating TB.

The compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic infections and/or viral infections.

The compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.

The compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

The compounds of the invention may be administered in combination with other active compounds (e.g. antifungal compounds, oncology compounds) and, in particular, with other antibacterial compounds. The compound of the invention and the other active (e.g. the other antibacterial compound) may be administered in different pharmaceutical formulations either simultaneously or sequentially with the other active. Alternatively, the compound of the invention and the other active (e.g. the other antibacterial compound) may form part of the same pharmaceutical formulation.

Examples of other bacterial compounds which could be administered with the compounds of the invention are penems, carbapenems, fluoroquinolones, β-lactams, vancomycin, erythromycin or any other known antibiotic drug molecule.

Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition. The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an aerosol or by nebulisation).

If administered topically, high-dosages of the compounds of the invention can be administered. Thus, a compound with an in vitro MIC of, for example, 16-64 μg/mL may still provide an effective treatment against certain bacterial infections.

For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.

For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution. The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

In another aspect the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient. The formulation may further comprise one or more other antibiotics, e.g. one or more fluoroquinolone antibiotics. Illustrative fluoroquinolone antibiotics include levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.

In another aspect of the invention is provided a method of treating a bacterial infection, the method comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.

Medical uses

The compounds of the present invention can be used in the treatment of the human body.

The compounds of the invention may be for use in treating human bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus). The compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tuberculosis, tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, abdominal infection, bacteraemia, septicaemia, sexually transmitted bacterial infection (e.g. gonorrhoea, Chlamydia), bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, Helicobacter pylori, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.

The compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside for example a chemotherapeutic agent used in the treatment of cancer.

In yet another aspect of the invention is provided a compound for use in the preparation of a medicament. The medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.

In an aspect of the invention is provided a compound of the invention for medical use. The compound may be used in the treatment of any of the diseases, infections and indications mentioned in this specification.

Veterinary uses

They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. The livestock may be mammal (excluding humans) e.g. cows, pigs, goats, sheep, llamas, alpacas, camels and rabbits. The livestock may be birds (e.g. chickens, turkeys, ducks, geese etc.). Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc. The veterinary use may be to treat wild populations of animals in order to prevent the spread of disease to humans or to commercial animals. In this case, the animals may be rats, badgers, deer, foxes, wolves, mice, kangaroos and monkeys and other apes.

In an aspect of the invention is provided a compound of the invention for veterinary use. The compound may be used in the treatment of any of the animal diseases and infections and indications mentioned in this specification. In another aspect the present invention provides a veterinary formulation comprising a compound of the invention and a veterinarily acceptable excipient.

The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice. The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

As an alternative, when treating animals the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.

Certain compounds of the invention are of particular use in the treatment of mastitis. In this regard, a particularly preferred method of administration is by injection into the udder of a subject (e.g. a cow, a goat, a pig or sheep).

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Synthesis

The skilled man will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.

Throughout this specification these abbreviations have the following meanings:

ACN - Acetonitrile CDI - Carbonyl diimidazole BOC - te/f-Butyl carbonate dba ~ Dibenzylideneacetone

DCM - Dichloromethane DMF - A/,A/-Dimethylformamide

DMSO - Dimethylsulfoxide I PA - / ^' so-Propyl alcohol

NMP - /V-Methylpyrolidinone PMB - para-Methoxybenzyl

TFA - Trifluoroacetic acid THF- Tetrahydrofuran

DMA - N,N-Dimethylacetamide

EDCI - N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

Certain compounds of the invention can be made according to the following general schemes. Certain compounds of the invention can be made according to or analogously to the methods described in Examples 1 to 107.

Certain compounds of the invention in which Y ¹ is NH can be made by Scheme A:-

(3)

Scheme A

Amine (1) can be converted to (3) via reductive amination with aldehyde (2). The reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1 ,2- dichloroethane, at a temperature from room temperature to 80°C. In certain examples, 4A sieves can be added to the reaction mixture.

Certain compounds of the invention in which Y ¹ is O can be made by Scheme B:-

Scheme B

Alcohol (4) can be converted to (6) via alkylation with (5), where LG represents a leaving group, such as a halide. The reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.

Following Scheme B, but using thiol (7), compound (8) (a subset of compounds of the invention in which Y ¹ is S) can be prepared.

(7) (8)

Following Scheme A but using aldehyde (9), compound (10) (a subset of compounds of the invention in which Y ¹ is NH) can be prepared.

Following Scheme B but using alkylating agent (1 1), compound (12) (a subset of compounds of the invention in which Y ¹ is O) can be prepared.

(11) (12)

Following Scheme B but using thiol (7) and alkylating agent (1 1) compound (13) (a subset of compounds of the invention in which Y ¹ is S) can be prepared.

(13)

Certain compounds of the invention can be made by Scheme C:-

Scheme C

Reductive amination of (3) (prepared as described in Scheme A) with aldehyde (14) or (15) can afford (16) (a subset of compounds of the invention in which Y ¹ is NR ⁴ ) The reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1 ,2- dichloroethane or DCM, at a temperature from room temperature to 80°C. In certain examples, 4A sieves can be added to the reaction mixture.

Following Scheme C, but using amine (10), compound (17) (a subset of compounds of formula (II)) can be prepared.

Following Scheme A, but using amine (18), compound (19) (a subset of compounds of formula (IV)) can be prepared.

Following Scheme A, but using aldehyde (9) and amine (18), compound (20) (a subset of compounds of formula (IV)) can be prepared.

(20)

Following Scheme C, amine (19) and amine (20) can be converted to compounds (21) and (22) representing a subset of compounds of formula (IV).

Following Scheme A, but using aldehyde (9) and amine (23), compound (24) (a subset of compounds of formula (VII)) can be prepared.

Following Scheme A, but using amine (23), compound (25) (a subset of compounds of formula (VIII)) can be prepared.

Following Scheme C, amine (24) and amine (25) can be converted to compounds (26) and (27) representing subsets of compounds of formula (VI).

Following Scheme A, but using aldehyde (28) and amine (23), compound (29) (a subset of compounds of formula (VII)) can be prepared.

(28) (29)

Certain compounds of formula (VIII) can be made by Scheme D:-

Reaction of pyridone (30) with commercially available bromo acetals (31) can generate pyridone acetals (32). The alkylation reaction can be carried out in the presence of a base, such as CS2CO3, in a solvent, such as dry NMP, at a temperature from 50-100°C. Hydrolysis of pyridone acetals (32) to give the requisite aldehydes (33) can be effected using a strong acid, such as concentrated HCI, in a solvent, such as ACN, at room temperature. Aldehydes (33) can be converted to pyridones (35) (a subset of compounds of formula (VIII)) via reductive amination with amine (34). The reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1 ,2-dichloroethane, at a temperature from room temperature to 80°C. In certain examples, 4A sieves can be added to the reaction mixture.

Amine (34) can be made by Scheme E:

(34)

Scheme E

Reaction of protected amine (36), where P represents a standard nitrogen protecting group, such as BOC, with a carbonylating reagent, such as CDI, in a solvent, such as dioxane or ACN, at a temperature from 80-100°C can generate (37). Addition of a base, such as K2CO3, is optional. Cross coupling reaction of (37), with (38), where X=Br or CI, can generate protected amine (39). The cross coupling reaction can be copper catalysed, using for example Cul, in the presence of a diamine, such as 1 ,2-diaminocyclohexane or N,N- dimethyl-1 ,2-ethanediamine, in the presence of a base, such as K2CO3, in a solvent, such as dioxane or toluene, at a temperature from 70-1 10°C. The cross coupling reaction can be palladium catalysed, using for example, Pd2(dba)3 or Pd(OAc)2 in the presence of a phosphine, such as Xantphos or P(t-Bu)3 or X-Phos, in the presence of a base, such as t- BuONa or CS2CO3, in a solvent, such as dioxane or toluene, at a temperature from 80- 120°C. The nitrogen protecting group in (39) can be deprotected to give the free amine (34) under standard conditions. Where the nitrogen protecting group is BOC the deprotection can be achieved by the action of TFA in DCM at room temperature.

Following Scheme C, but using amine (35), compound (40) (a subset of compounds of formula (VIII)) can be prepared.

Following Scheme D, but using tricyclic pyridone (41), amine (42) (a subset of compounds of formula (IX)) can be prepared.

Experimental

Analytical Methods

NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A), a Bruker AVIII 400 Nanobay using a 5 mm BBFQ with z-gradients (Method B), a Bruker AV1 Avance using a 5mm QNP probe (Method C), a Bruker AV1 Avance using a ¹ H/ ¹³ C Dual probe (Method D) or a Bruker ASCEND 400 MHz spectrometer (Method E). MS was carried out on either a Waters ZQ MS (Method A and B), an Agilent Technologies 1200 series (Method C and D) using H ₂ 0 and ACN (0.1 % formic acid - acidic pH; 0.1 % ammonia - basic pH) - wavelengths were 254 and 210 nM, or a Shimadzu LCMS-2020 (Method E) using H2O and MeOH (0.1 % formic acid - acidic pH; 0.1 % ammonia - basic pH) - wavelengths were 254 and 210 nM.

Method A

Column: YMC-Triart C18, 5 μηι, 50 x 2 mm. Flow rate: 0.8 mL/min. Injection volume 5 μΙ_.

Method B

Column: YMC-Triart C18, 5 μηι, 50 x 2 mm. Flow rate: 0.8 mL/min. Injection volume 5-10

Method C

Column: Poroshell 120, 2.7 μηι, 50 x 2.1 mm. Flow rate: 0.8 mL/min. Injection volume 5-10

Time

H ₂ 0 (%) ACN (%)

(min)

0.0 90 10

0.5 90 10

4.0 20 80 5.0 20 80

5.1 90 10

6.0 90 10

Method D

Column: Poroshell 120, 2.7 μηι, 50 x 2.1 mm. Flow rate: 0.8 mL/min. Injection volume 5-10

Method E

Column: Atlantis T3, 3 μηι, 3.0 x 75 mm. Flow rate: 0.8 mL/min. Injection volume 1-10

Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) Waters 2767 Sample Manager (Method B) using H ₂ 0 and ACN (0.1-% formic acid pH; 0.1% ammonia - basic pH).

Method A

Column: XBridge™ prep C18, 5 μηι OBD 19 x 100 mm. Flow rate: 20 mL/min. Method B

Column: XBridge™ prep C18, 5 μηι OBD 19 x 100 mm. Flow rate: 20 mL/min. Example 1 :- 1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

a) te/f-butyl N-[(3aR, 6R, 7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 a

Step 1 : tert-butyl N-[(1 R,3R,4R)-4-azido-3-hydroxycyclohexyl]carbamate

To a 500 mL round bottom flask at 25 °C was added tert-butyl N-[(1 R,3R,6S)-7- oxabicyclo[4.1.0]heptan-3-yl]carbamate (WO 201 1 146953 A1) (20.0 g, 93.7 mmol) and MeOH (200 mL) to form a solution. Lithium perchlorate (49.8 g, 468 mmol) was added at 25 °C and the mixture heated to 50 °C for 16 h. The reaction was allowed to cool to 25 °C and sodium azide (9.14 g, 140 mmol) added. The mixture was heated at 50 °C for 16 h and TLC (petroleum ether/EtOAc = 1/1 , Rf = 0.43) showed the reaction was complete. Aqueous NaHCC>3 (500 mL) was added and the mixture extracted with EtOAc (500 mL). The organic layer was washed with H2O (300 mL x 2) and concentrated. The crude material was purified by column chromatography (Si02, 100-200 mesh, petroleum ether/EtOAc = 20/1 to 5/1) to give tert-butyl N-[(1 R,3R,4R)-4-azido-3-hydroxycyclohexyl]carbamate (1 .40 g, 5.0% yield) as white solid. ¹ H NMR (Method A) (CDCI3): δ ppm 4.51 (br, 1 H), 3.47-3.52 (m, 2H), 3.17-3.23 (m, 1 H), 2.54 (d, J = 3.2 Hz, 1 H), 2.28 (d, J = 10.4 Hz, 1 H), 2.07-2.04 (m, 1 H), 1 .43 (s, 9H), 1 .17-1 .29 (m, 2H)

Step 2: tert-butyl N-[(1 R,3R,4R)-4-amino-3-hydroxycyclohexyl]carbamate tert-butyl N-[(1 R,3R,4R)-4-azido-3-hydroxycyclohexyl]carbamate (4.40 g, 17.1 mmol) was added to a 50 mL round bottom flask and THF (24.0 mL) added. Triphenylphospine (9.01 g, 34.3 mmol,) and H2O (4.00 mL) were added and the mixture stirred for 16 h at 25 °C. TLC (petroleum ether/EtOAc = 1/1 , Rf = 0.00) showed the reaction was complete. The mixture was directly concentrated and purified by column chromatography (Si02, 100-200 mesh, DCM/MeOH = 1/0 to 10/1) to give tert-butyl N-[(1 R,3R,4R)-4-amino-3- hydroxycyclohexyl]carbamate (3.60 g, 91 % yield) as white solid. TLC (DCM/MeOH = 5/1 , R _f = 0.32). ¹ H NMR (Method C) (CDCI3): δ ppm 4.45 (br. s, 1 H), 3.57 (br. s, 1 H), 3.27-3.17 (m, 1 H), 2.45-2.37(m, 1 H), 2.34-2.37 (m, 1 H), 2.06 - 1.97 (m, 1 H), 1.93 - 1.84 (m, 1 H), 1.84- 1.59 (m, 2H), 1.47 (s, 9H), 1.28 - 1.11 (m, 3H).

Step 3: te/f-butyl N-[(3aR, 6R, 7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 a

To a mixture of tert-butyl N-[(1 R,3R,4R)-4-amino-3-hydroxycyclohexyl]carbamate (20 g, 86.84 mmol) and triethylamine (36.3 ml_, 260.5 mmol) in THF (350 ml_) was added portionwise triphosgene (10.31 g, 34.7 mmol) - the reaction exothermed, liberating gas. The mixture was stirred at 25°C for 24 h then quenched with aqueous HCI (1.0 N, 100 ml_), extracted with DCM (150 ml_), dried over MgS0 ₄ and the solvent evaporated to afford a yellow solid. This was triturated with DCM/EtOAc (1 : 1) to afford a solid which was filtered and dried to give tert-butyl N-[(3aR,6R,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6- yl]carbamate 1 a (16.5 g, 64.38 mmol, 74.1 % yield) as a white solid. ¹ H NMR (Method C) (CDCI3): δ ppm 5.42 (s 1 H), 4.53 (d, J = 8.5 Hz, 1 H), 3.89 (ddd, J = 12.0, 10.8, 3.5 Hz, 1 H), 3.81-3.59 (m, 1 H), 3.45-3.26 (m, 1 H), 2.57 (dt, J = 10.8, 3.6 Hz, 1 H), 2.19-2.10 (m,

1 H), 2.10 - 2.06 (m, 1 H), 1.65-1.47 (m, 2H), 1.44 (s, 9H), 1.25 (qd, J = 12.8, 4.1 Hz, 1 H). b) fe/f-butyl N-[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 b

A mixture of te/f-butyl N-[(3aR, 6R, 7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 a (0.3 g, 1.17 mmol), 6-bromo-4-[(4-methoxyphenyl)methyl]-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-3-one (prepared as described in WO2014108832) (0.53 g, 1.52 mmol), K ₂ C0 ₃ (320 mg, 2.34 mmol), trans-1 ,2-diaminocyclohexane (27 mg, 0.23 mmol) and Cul (45 mg, 0.23 mmol) in dioxane (25 ml_) was heated at reflux for 18 h under N2. The mixture was cooled to room temperature, poured into H2O and extracted with EtOAc (200 ml_). The organic layer was washed with brine, dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by silica gel chromatography using DCM/EtOAc, 2: 1 to 1 : 1 , v/v to give tert-butyl N-[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 b (400 mg, 65%). TLC: R _f = 0.4 (silica gel, DCM/EtOAc = 2 : 1 , v/v). LC-MS (Method D) 525.2 [M+H] ⁺ ; RT 5.03 min. c) (3aR,6R7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c

To a solution of te/f-butyl N-[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 b (0.40 g, 0.76 mmol) in DCM (10 mL) at room temperature was added TFA (3 mL) and the mixture was stirred for 2 h, then concentrated under reduced pressure. The residue was adjusted to pH 8-9 with saturated aqueous Na2CC>3, then partitioned between brine and DCM. The organic phase was dried over Na2S0 ₄ , filtered and concentrated to give

(3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo -2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (380 mg), which was used without further purification. TLC: R _f = 0.3 (silica gel, DCM/MeOH = 10 : 1 , v/v). LC-MS (Method D) 425.1 [M+H] ⁺ ; RT 2.77 min. d) 1-({[(3aR,6R, 7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3, 2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-7-methoxy-1 ,2- dihydro-1 ,8-napthyridin-2-one 1 d

To a solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (380 mg, 0.90 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)acetaldehyde (prepared as described in WO2008009700) (200 mg, 0.91 mmol) in DCM (40 mL) was added NaBH(OAc) ₃ (570 mg, 2.69 mmol) and the mixture was stirred at room temperature for 17 h. The mixture was adjusted to pH 8-9 with saturated aqueous Na2C03 and extracted with DCM (100 mL). The organic layer was washed with brine, dried (Na2S0 ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography using 2% MeOH in DCM to give 1- ({[(3aR,6R, 7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3, 2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-7-methoxy-1 ,2-dihydro-1 ,8- napthyridin-2-one 1 d (100 mg, 17%). TLC: R _f = 0.3 (silica gel, DCM/MeOH = 10: 1 , v/v). LC-MS (Method D) 627.2 [M+H] ⁺ ; RT 3.38 min. e) 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 1 To a solution of 1-({[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-7-methoxy-1 ,2-dihydro- 1 ,8-napthyridin-2-one 1d (100 mg, 0.16 mmol) in DCM (20 mL) was added TFA (3 mL) followed by CF3SO3H (1 mL) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH and the mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 mL). The organic extract was washed with brine, dried (Na2S0 ₄ ), filtered and concentrated under reduced pressure. The residue was purified by chromatography to give 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2- dihydro-1 ,8-naphthyridin-2-one 1 (60 mg, 74%). TLC: R _f = 0.4 (silica gel, DCM/MeOH = 20 : 1 , v/v). LC-MS (Method D) 507.2 [M+H] ⁺ ; RT 2.75 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 11.2 (br s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.51 (d, J = 9.2 Hz, 1 H), 4.62 (s, 2H), 4.45 (m, 2H), 4.04 (m, 1 H), 4.00 (s, 3H), 3.74 (m, 1 H), 2.90-2.73 (m, 4H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.49 (m, 1 H), 1.34-1.16 (m, 3H).

Example 2:- (3aR,6RJaR)-6-r(2-{2-methoxy-7-oxo-7H,8H-pyridor2,3-dlpyrimi din-8- yl)ethyl)amino1-3-(3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6 -yl)-octahvdro-1 ,3- benzoxazol-2-one

2 a) 8-(2,2-diethoxyethyl)-2-methoxy-7H,8H-pyrido[2,3-d]pyrimidin -7-one 2a

K2CO3 (143 mg, 1.04 mmol) was added to a suspension of 2-methoxy-7H,8H-pyrido[2,3- d]pyrimidin-7-one (prepared as described in J. Med. Chem., 54(22), 7834-7847; 201 1) (100 mg, 0.56 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 h.

Bromoacetaldehyde diethyl acetal (0.09 mL, 0.62 mmol) was added and the mixture heated at 103°C for 4 h. The reaction mixture was allowed to cool to room temperature then diluted with H2O and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with saturated brine (3 mL), dried over anhydrous MgSCU, filtered, and concentrated to afford a brown residue of 8-(2,2-diethoxyethyl)-2-methoxy-7H,8H-pyrido[2,3-d]pyrimidin -7- one 2a (91 mg, 55%) which was used without further purification.

(b) 2-(2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl)acetald ehyde 2b

A solution of TFA (6 mL, 1.02 mmol) in H ₂ 0 (1.5 mL) was added to 8-(2,2-diethoxyethyl)-2- methoxy-7H,8H-pyrido[2,3-d]pyrimidin-7-one 2a (300 mg, 1.02 mmol) and the reaction mixture stirred at room temperature for 3 h. The reaction was basified with saturated aqueous NaHCOs to pH 8. The mixture was extracted with DCM (20 mL) and IPA/DCM (1 :3, 4 x 20 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSCU, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography eluting with 100 % EtOAc to afford a white solid of 2-(2- methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl)acetaldehyde 2b (173 mg, 77%). LC-MS (Method A) 220.4 [M+H] ⁺ ; RT 1.39 min.

c) (3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one 2c

A solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (228 mg, 0.54 mmol) and 2-(2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl)acetald ehyde 2b (59 mg, 0.27 mmol) in DCM (2 mL) was stirred at room temperature over molecular sieves (4A) for 2 h.

NaBH(OAc)3 (170 mg, 0.80 mmol) was added and the reaction stirred for 17 h. Further 2-(2- methoxy-7-oxo-pyrido[2,3-d]pyrimidin-8-yl)acetaldehyde 2b (20 mg) was added and the reaction stirred for 2 h then quenched with saturated aqueous NaHCOs. The resulting mixture was passed through a SPE phase separator and the DCM filtrate concentrated under reduced pressure and purified by chromatography using 0-20% DCM/MeOH.

Concentration of the clean fractions gave a white solid of (3aR,6R,7aR)-6-[(2-{2-methoxy-7- oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl}ethyl)amino]-3-{4-[(4- methoxyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 2c (116 mg, 69%). LC-MS (Method A) 628.1 [M+H] ⁺ ; RT 1.95 min. d) (3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8- yl}ethyl)amino]-3-(3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol- 2-one 2

To a stirred solution of (3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin- 8-yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-octahydro-1 ,3-benzoxazol-2-one 2c (116 mg, 0.18 mmol) in DCM (20 mL), was added TFA (3.6 mL, 47 mmol) and CF3SO3H (1.2 mL, 13.56 mmol). Stirring was continued for 1 h at room temperature then MeOH (1 mL) added. Saturated aqueous Na2CC>3 was added adjusting the pH between 8-9. The mixture was extracted with DCM (2 x 25 mL) and 10% MeOH/DCM (2 x 25 mL) and the combined DCM extracts were passed through a SPE phase separator. Concentration gave a residue which was purified by chromatography using 0-20% DCM/MeOH to give a solid of (3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H- pyrido[2,3-d]pyrimidin-8-yl}ethyl)amino]-3-(3-oxo-2H,3H,4H-p yrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-2-one 2 (37 mg, 39%). LC-MS (Method B) 508.2 [M+H] ⁺ ; RT 4.93 min. ¹ H NMR (Method D) (DMSO-d6): δ ppm 11.24 (s, 1 H), 8.92 (s, 1 H), 7.95 (d, J = 9.4 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 8.5 Hz, 1 H), 6.57 (d, J = 9.5 Hz, 1 H), 4.63 (s, 2H), 4.34 (t, J = 6.7 Hz, 2H), 4.06 (m, 1 H), 4.03 (s, 3H), 3.74 (m, 1 H), 2.86 (m, 2H), 2.76 (m, 2H), 2.45 (m, 1 H), 1.98 (d, J = 13.3 Hz, 1 H), 1.46 (q, J = 11.1 Hz, 1 H), 1.27 (m, 2H).

Example 3:- 1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)ethyl)-7-(3-aminopropoxy)-1 ,2- dihydroquinolin-2-one

3 a) benzyl N-{3-[(2-oxo-1 ,2-dihydroquinolin-7-yl)oxy]propyl}carbamate 3a To a suspension of 7-hydroxy-1 H-quinolin-2-one (2.10 g, 13.0 mmol) and CS2CO3 (6.37 g, 19.6 mmol) in anhydrous DMF (40 mL) was added a solution of benzyl N-(3- bromopropyl)carbamate (3.55 g, 13.0 mmol) in anhydrous DMF (10 mL) and the resulting mixture heated to 90°C . After 2 h the reaction was diluted with EtOAc (100 mL) and H ₂ 0 (50 mL). A precipitate formed in the organic phase. The organic and aqueous phases were separated and the organic phase filtered to remove the precipitate. The resulting filtrate was concentrated to give a brown residue and combined with the initial precipitate using DCM. Concentration of the DCM solution gave a residue which on trituration with EtOAc gave a precipitate. The precipitate was filtered and dried to give a yellow solid of benzyl N- {3-[(2-oxo-1 ,2-dihydroquinolin-7-yl)oxy]propyl}carbamate 3a (2.5 g, 54%) which was used without further purification. LC-MS (Method A) 353.5 [M+H] ⁺ ; RT 2.42 min. b) benzyl N-(3-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3b

A solution of benzyl N-{3-[(2-oxo-1 ,2-dihydroquinolin-7-yl)oxy]propyl}carbamate 3a (654 mg, 1.86 mmol) in anhydrous DMF (150mL) was heated to 50°C for 15 min. The reaction was cooled to 40°C and CS2CO3 (907 mg, 2.78 mmol) added followed by bromoacetaldehyde diethyl acetal (279 μί, 1.86 mmol). The mixture was heated to 70°C for 21.5 h and further bromoacetaldehyde diethyl acetal (279 μί, 1.86 mmol) added. After 65.5 h the reaction was allowed to cool and then concentrated down. The resulting crude was diluted with EtOAc (100 mL) and saturated aqueous NaHCC>3 (30 mL). The aqueous phase was separated and extracted using EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgS0 ₄ , filtered and concentrated. The resulting crude was purified by chromatography using 0 to 10% DCM/EtOAc to give a colourless oil of benzyl N-(3-{[1-(2,2- diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3b (520 mg, 64%). c) benzyl N-(3-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3c

To a solution of benzyl N-(3-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}propyl)carbamate 3b (400 mg, 0.91 mmol) in THF (20 mL) was added HCI (2.0 M, 15 mL) and the resulting mixture heated to 50°C. After 2 h the reaction was allowed to cool to room temperature. EtOAc (20 mL) was added and the aqueous phase was separated and extracted using EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over MgS0 ₄ , filtered, and concentrated. The resulting residue was purified by chromatography using 0 to 10% DCM/MeOH to give a yellow solid of benzyl N-(3-{[2- oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3c (155 mg, 43%). LC-MS (Method A) 395.5 [M+H] ⁺ ; RT 2.50 min. d) benzyl N-(3-{[1-(2-{[(3aR.6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}propyl)carbamate 3d

Benzyl N-(3-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3c (67 mg, 0.17 mmol) and (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (144, 0.34 mmol) were dissolved in THF (3 mL) and heated to 70°C for 2 h then cooled. NaBH(OAc)3 (108 mg, 0.51 mmol) was added and the reaction stirred for 30 min. Excess volatiles were removed and the residue mixed with DCM (10 mL) and saturated aqueous NaHCC>3 (10 mL). The organic layer was separated and the aqueous phase further extracted with DCM. The organics extracts were combined, washed with saturated brine then passed through an SPE phase separator. The DCM filtrate was concentrated down to give a yellow residue. Purification by column chromatography using DCM/MeOH gave a white solid of benzyl N- (3-{[1-(2-{[(3aR.6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-ox o-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}propyl)carbamate 3d (95 mg, 70%). LC-MS (Method A) 803.8

[M+H] ⁺ ; RT 3.21 min. e) 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(3-aminopropoxy)-1 ,2-dihydroquinolin-2-one 3

To a solution of benzyl N-(3-{[1-(2-{[(3aR.6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)- 2-OXO-1 , 2-dihydroquinolin-7-yl]oxy}propyl)carbamate 3d (95 mg, 0.1 1 mmol) in DCM (2 mL) was added TFA (3 mL) and CF3SO3H (1 mL). Stirring was continued at room temperature for 1 h, then saturated aqueous Na2C03 was added adjusting the pH to 8. The solution was extracted with DCM (3 x 20 mL), organics extracts were combined and passed through a SPE phase separator. The filtrate was concentrated to afford a dark yellow solid. The solid was purified by chromatography (Biotage 10g KP-Si cartridge, 0-20% DCM/MeOH, then 0- 20% DCM/(2M NH ₃ in MeOH) affording a white solid of 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(3- aminopropoxy)-1 ,2-dihydroquinolin-2-one 3 (14 mg, 22%). LC-MS (Method A) 549.6

[M+H] ⁺ ; RT 2.23 min. ¹ H NMR (Method C) (CDCb): δ ppm 7.57 (d, J = 9.4 Hz, 1 H), 7.45 (d, J = 8.7 Hz, 1 H), 7.27 (m, 2H), 6.92 (d, J = 2.3 Hz, 1 H), 6.83 (dd, J = 8.6, 2.2 Hz, 1 H), 6.50 (d, J = 9.4 Hz, 1 H), 4.56 (d, 2H), 4.50-4.39 (m, 1 H), 4.32 (m, 1 H), 4.18 (m, 2H), 3.96 (m, 1 H), 3.81 (m, 1 H), 3.15-3.00 (m, 3H), 3.00-2.96 (m, 2H), 2.91 (m, 2H), 2.68 (m, 1 H), 2.61- 2.56 (m, 1 H), 2.22-2.13 (m, 1 H), 2.02 (m, 1 H), 1.69-1.57 (m, 1 H), 1.45-1.32 (m, 1 H).

Example 4:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-2H,3H,4H-pyridor3,2-bin,41oxazin-6- ylV octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2- one

4

(a) te/f-butyl N-[(3aS,6S,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4a

To a suspension of te/f-butyl N-[(1S,3R,4S)-4-amino-3-hydroxy-cyclohexyl]carbamate (prepared from tert-butyl N-[(1S,3S,4S)-4-amino-3-hydroxycyclohexyl]carbamate following the methods described in Example 25a-d) (0.50 g, 2.17 mmol) in dioxane (30 ml_) at 60°C was added CDI (0.52 g, 3.26 mmol) and the mixture was heated at 60°C for 4.5 h. After cooling to room temperature, 5% aqueous Na2COs (5 ml_) was added and the mixture extracted with EtOAc. The organic layer was washed with brine, dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by chromatography using 30% DCM/EtOAc to give a solid te/f-butyl N-[(3aS,6S,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4a (0.30 g). TLC: R _f = 0.73 (MeOH/DCM = 1 : 10, v/v). ¹ H-NMR (Method E) (CDCb) <5 ppm: 5.41 (s, 1 H), 4.70 (m, 1 H), 4.45 (m, 1 H), 3.66-3.60 (m, 2H), 2.44 (m, 1 H), 2.02 (m, 2H), 1.60- 1.51 (m, 1 H), 1.44 (s, 9H), 1.18-1.25 (m, 2H).

(b) terf-butyl N-[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4b A mixture of te/f-butyl N-[(3aS,6S,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4a (0.20 g, 0.78 mmol), 6-bromo-4-[(4-methoxyphenyl)methyl]-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-3-one (prepared as described in WO2014108832) (0.27 g, 0.77 mmol), K ₂ C0 ₃ (210 mg, 1.56 mmol), trans-1 ,2-diaminocyclohexane (18 mg, 0.16 mmol) and Cul (30 mg, 0.16 mmol) in dioxane (30 ml_) was heated at reflux for 18 h under N2. The mixture was cooled to room temperature, poured into H2O and exacted with EtOAc (200 ml_). The organic layer was washed with brine, dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by chromatography using 20% EtOAc in petroleum ether then 40% EtOAc in DCM to give a solid of te/f-butyl N-[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]- 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6- yl]carbamate 4b (300 mg, 73%). TLC: R _f = 0.2 (silica gel, DCM/EtOAc = 4 : 1 , v/v). LC-MS (Method D) 525.2 [M+H] ⁺ ; RT 5.00 min.

(c) (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c

To a solution of fe/f-butyl N-[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4b (0.16 g, 0.30 mmol) in DCM (1.5 ml_) was added TFA (2 ml_) and the mixture was stirred at room temperature for 30 min then concentrated under reduced pressure. The residue was adjusted to pH 8-9 with saturated aqueous Na2CC>3, then partitioned between brine and DCM. The organic phase was dried over Na2S0 ₄ , filtered and concentrated to give a yellow solid of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (130 mg, 52%) which was used without further purification. TLC: R _f = 0.3 (silica gel, DCM/MeOH = 15 : 1 , v/v). LC-MS (Method D) 425.2 [M+H] ⁺ ; RT 2.87 min.

(d) 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl-7-methoxy-1 ,2-dihydro- 1 ,8-naphthyridin-2-one 4d

To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (130 mg, 0.31 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)acetaldehyde (prepared as described in WO2008009700) (70 mg, 0.32 mmol) in DCM (25 mL) was added NaBH(OAc) ₃ (325 mg, 1.50 mmol) and the mixture was stirred for 22 h. The mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 ml_). The organic layer was washed with brine, dried (NaaSCU), filtered and concentrated. The residue was purified by chromatography using 2% MeOH in DCM to give a solid of 1-(2-{[(3aS,6S,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 4d (100 mg, 50%). TLC: R _f = 0.4 (silica gel, DCM/MeOH = 20: 1 , v/v). LC-MS (Method D) 627.3 [M+H] ⁺ ; RT 3.49 min.

(e) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 4

To a solution of 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl-7-methoxy- 1 ,2-dihydro-1 ,8-naphthyridin-2-one 4d (100 mg, 0.16 mmol) in DCM (15 ml_) was added TFA (1.2 ml_) followed by CF3SO3H (0.4 ml_) and the mixture was stirred for 1 h. The reaction was quenched with MeOH and the mixture adjusted to pH 8-9 with saturated aqueous Na2C03 and extracted with DCM (100 ml_). The organic layer was washed with brine, dried (Na2S04), filtered and concentrated. The residue was purified by

chromatography (DCM/MeOH, 50: 1 to 20: 1 , v/v) to give a solid of 1-(2-{[(3aS,6S,7aR)-2- oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 4 (50 mg, 62%). TLC: R _f = 0.4 (silica gel, DCM/MeOH = 20 : 1 , v/v). LC-MS (Method D) 505.2 [M-H] ^" ; RT 2.77 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 1 1.2 (br s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 9.6 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.52 (d, J = 9.2 Hz, 1 H), 4.89-4.75 (m, 1 H), 4.61 (s, 2H), 4.59-4.43 (m, 3H), 4.01 (s, 3H), 3.14- 2.89 (m, 3H), 2.44-2.29 (m, 1 H), 1.93-1.81 (m, 1 H), 1.80-1.64 (m, 1 H), 1.32-1.16 (m, 3H).

Example 5:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(3-aminopropoxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one

a) 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a

To a solution of 7-chloro-1 ,2-dihydro-1 ,8-naphthyridin-2-one (1.80 g, 10.0 mmol) and bromoacetaldehyde diethyl acetal (4.92 g, 25.0 mmol) in DMF (25 ml_) was added CS2CO3 (4.90 g, 15.0 mmol) and the mixture heated at 70°C under N2 overnight. The mixture was diluted with H2O (200 ml_), extracted with EtOAc (100 ml_ x 3) and the combined organic extracts were washed with H2O (200 ml_ x 2), brine (100 ml_) and concentrated under reduced pressure. The residue was purified by chromatography (EtOAc/petroleum ether, 1 :5 to 1 :2, v/v) to afford a white solid of 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8- naphthyridin-2-one 5a (1.80 g, 61 %). TLC: R _f = 0.45 (silica gel, petroleum ether/EtOAc = 2 : 1 , v/v). ¹ H NMR (Method E) (CDC ): δ ppm 7.78 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 9.6 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 6.72 (d, J = 9.6 Hz, 1 H), 5.10 (t, J = 5.6 Hz, 1 H), 4.67 (d, J = 5.6 Hz, 2H), 3.79 (m, 2H), 3.54 (m, 2H), 1.1 1 (t, J = 7.2 Hz, 6H). b) te/f-butyl N-(3-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5b

To a solution of 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a (595 mg, 2.0 mmol) and te/f-butyl N-(3-hydroxypropyl)carbamate (1.05 g, 6.0 mmol) in DMF (15 ml_) was added a solution of f-BuOK (784 mg, 7.0 mmol) in dry THF (25 ml_) and the mixture was stirred at room temperature overnight. The mixture was diluted with H2O (100 ml_), extracted with EtOAc (100 ml_ x 3) and the combined organic extracts were washed with H2O (100 ml_ x 2), brine (100 ml_) and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/EtOAc, 3:1 , v/v) to give a colourless oil of te/f-butyl N-(3-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5b (540 mg). TLC: Rf =0.30 (silica gel, petroleum ether/EtOAc = 2 : 1 , v/v) ¹ H NMR (Method E) (DMSO-d6): δ ppm 8.04 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 9.4 Hz, 1 H), 6.89 (m, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 6.50 (d, J = 9.4 Hz, 1 H), 5.03 (t, J = 5.7 Hz, 1 H), 4.48 (d, J = 5.7 Hz, 2H), 4.38 (m, 2H), 3.65 (m, 2H), 3.37 (m, 2H), 3.09 (m, 2H), 1.90 (m, 2H), 1.36 (s, 9H), 0.98 (t, J = 7.0 Hz, 6H). c) ferf-butyl N-(3-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5c

To a solution of te/f-butyl N-(3-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5b (540 mg, 1.24 mmol) in THF (10 mL) was added 1 M HCI (6.0 mL, 6.0 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was adjusted to pH 8-9 with a saturated aqueous NaHCC solution and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with H2O (50 mL), brine (50 mL), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/EtOAc, 5: 1 to 1 : 1 , v/v) to give a white solid of te/f-butyl N-(3-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5c (250 mg, 56%). TLC: Rf = 0.14 (silica gel, petroleum

ether/EtOAc = 2 : 1 , v/v). LC-MS (Method C) 362.3 [M+H] ⁺ , RT 3.38 min. ¹ H-NMR (Method E) (CDC ) <5 ppm: 9.65 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 9.4 Hz, 1 H), 6.63 (d, J = 9.6 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.20 (s, 2H), 4.32 (t, J = 6.2 Hz, 2H), 3.29 (m, 2H), 1.95 (m, 2H), 1.43 (s, 9H). d) terf-butyl N-(3-{[8-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8- dihydro-1 ,8-naphthyridin-2-yl]oxy}propyl)carbamate 5d

A mixture of te/f-butyl N-(3-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}propyl)carbamate 5c (110 mg, 0.30 mmol) and (3aS,6S,7aR)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 4c (130 mg, 0.30 mmol) in DCM (20 mL) was stirred at room temperature for 30 min. NaBH(OAc)3 (254 mg, 1.20 mmol) was then added and stirring was continued overnight. The mixture was diluted with a saturated aqueous NaHCC solution and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 50: 1 to 20: 1 , v/v) to give a white foam of terf-butyl N-(3-{[8-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8- dihydro-1 ,8-naphthyridin-2-yl]oxy}propyl)carbamate 5d (140 mg, 60%). TLC: Rf = 0.35 (silica gel, DCM/MeOH = 20 : 1 , v/v). LC-MS (Method C) 770.4 [M+H] ⁺ , RT 3.81 min. e) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(3-aminopropoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5

To a solution of te/f-butyl N-(3-{[8-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)- 7-0X0-7, 8-dihydro-1 ,8-naphthyridin-2-yl]oxy}propyl)carbamate 5d (140 mg, 0.18 mmol) in DCM (10 mL) was added TFA (2.0 mL) and the mixture stirred at room temperature for 4 h. CF3SO3H (1.0 mL) was then added and stirring continued for a further 1 h. The mixture was adjusted to pH 8-9 with a saturated aqueous K2CO3 solution (40 mL) and then extracted with DCM/IPA (3: 1 , 20 mL x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH/NH3.H ₂ 0, 100: 10:2, v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(3-aminopropoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5 (72 mg, 72%). TLC: R _f = 0.25 (silica gel, DCM/MeOH = 10 : 1+1 drop N H3.H2O, v/v). LC-MS (Method C) 550.2 [M+H] ⁺ , RT 1.80 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm: 8.07 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 9.4 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.51 (d, J = 9.4 Hz, 1 H), 4.77 (m, 1 H), 4.61 (s, 2H), 4.55-4.39 (m, 5H), 2.96 (t, J = 7.3 Hz, 2H), 2.89 (m, 2H), 2.76 (m, 1 H), 2.45 (m, 1 H), 2.31 (m, 1 H), 2.10 (m, 2H), 1.80 (m, 1 H), 1.58 (m, 1 H), 1.27 (m, 1 H), 1.06 (m, 1 H).

Example 6:- 1 -(2-f r(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri ,41oxazin-6- yl)-octahydro-1 ,3-benzoxazol-6-vnamino)ethyl)-7-(2-hvdroxyethoxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one

a) 1-(2,2-diethoxyethyl)-7-(2-hydroxyethoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 6a

7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a (592 mg, 2 mmol) and CS2CO3 (978 mg, 3 mmol) were suspended in ethylene glycol (5 mL) and the mixture was heated at 100°C in the microwave for 1 h. The mixture was diluted with H2O (30 mL), extracted with EtOAc (30 mL x 3) and the combined organic extracts were washed with H2O (50 mL x 2), brine (50 mL), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure to give a yellow solid of 1-(2,2-diethoxyethyl)-7-(2-hydroxyethoxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one 6a (574 mg, 89%) which was used without further purification. TLC: Rf = 0.33 (silica gel, petroleum ether/EtOAc = 1 : 1 , v/v). LC-MS (Method C) 277.1 [M-OEt] ⁺ , RT 2.76 min. b) 2-[7-(2-hydroxyethoxy)-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 6b

To a solution of 1-(2,2-diethoxyethyl)-7-(2-hydroxyethoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2- one 6a (574 mg, 1.8 mmol) in dioxane (6 mL) was added 3 M HCI (6 mL, 18 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 8-9 with a saturated aqueous NaHCC>3 solution and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with H2O (30 mL), brine (30 mL), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography using petroleum ether/EtOAc, 5: 1 to 1 : 1 , v/v to give a pale yellow oil of 2-[7-(2- hydroxyethoxy)-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 6b (240 mg). TLC: Rf = 0.20 (silica gel, petroleum ether/EtOAc = 1 : 1 , v/v). LC-MS (Method D) 249.1 [M+H] ⁺ , RT 2.17 min. c) 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-hydroxyethgoxy)- 1 ,2-dihydro-1 ,8-naphthyridin-2-one 6c

A mixture of 2-[7-(2-hydroxyethoxy)-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 6b (1 14 mg, 0.46 mmol), (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (200 mg, 0.47 mmol) and AcOH (55 mg, 0.92 mmol) in DCM (10 mL) was stirred at room temperature for 10 min. NaBH(OAc)3 (488 mg, 2.3 mmol) was added and stirring continued for 17 h. The mixture was diluted with a saturated aqueous NaHC03 solution and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography using DCM/MeOH, 40: 1 to 20: 1 , v/v to give a white solid of 1 -(2- {[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H -pyrido[3,2-b][1 ,4]oxazin-6- yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-hydroxyethgoxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one 6c (260 mg, 86%). TLC: R _f = 0.44 (silica gel, DCM/MeOH = 15 : 1 , v/v). LC-MS (Method C) 657.3 [M+H] ⁺ , RT 2.86 min. d) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-hydroxyethoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 6

To a solution of 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2- hydroxyethgoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 6c (260 mg, 0.39 mmol) in TFA (5.0 mL) at 0°C was added CF3SO3H (0.5 mL) and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was adjusted to pH 8-9 with a saturated aqueous K2CO3 solution (40 mL) and then extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure The residue was purified by preparative-TLC (DCM/MeOH, 10: 1 , v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-hydroxyethoxy)-1 ,2- dihydro-1 ,8-naphthyridin-2-one 6 (61 mg, 29%). TLC: R _f = 0.50 (silica gel, DCM/MeOH = 10 : 1 , v/v). LC-MS (Method D) 537.2 [M+H] ⁺ , RT 2.46 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm: 1 1.2 (br s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 9.6 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.49 (d, J = 9.6 Hz, 1 H), 4.89 (br s, 1 H), 4.76 (m, 1 H), 4.61 (s, 2H), 4.42 (m, 5H), 3.77 (m, 2H), 2.89 (m, 2H), 2.76 (m, 1 H), 2.45 (m, 1 H), 2.29 (m, 1 H), 1.79 (m, 1 H), 1.56 (m, 1 H), 1.26 (m, 2H), 1.04 (m, 1 H).

Example 7:-1 -(2-f r(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri ,41oxazin-6-ylV octahvdro-1 ,3-benzoxazol-6-yl1(2-hvdroxyethyl)amino)ethyl)-7-methoxy-1 ,2-dihvdro- 1 ,8-naphthyridin-2-one

7 a) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]({2-[(fe/f-butyldimethylsilyl)oxy]ethyl}) amino}ethyl)-7-methoxy- dihydro-1 ,8-naphthyridin-2-one 7a

To a solution of 1-(2-{[(3aS,6S,7aR)-2-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 4 (150 mg, 0.30 mmol) and 2-[te/f-butyl(dimethyl)silyl]oxyacetaldehyde (164 mg, 0.94 mmol) in DCM (60 mL) was added NaBH(OAc)3 (400 mg, 1.89 mmol) and the mixture was stirred at room temperature for 17 h. A saturated aqueous NaHCC>3 solution was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography using DCM/EtOAc, 5: 1 to 3: 1 , v/v to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b]

[1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]({2-[(te/f- butyldimethylsilyl)oxy]ethyl})amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 7a (140 mg, 71 %). TLC: R _f = 0.59 (silica gel, DCM/ MeOH = 15: 1 , v/v). LC-MS (Method D) 665.2 [M+H] ⁺ , RT 4.59 min. b) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl](2-hydroxyethyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin- 2-one 7

A mixture of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]({2-[(fe/f-butyldimethylsilyl)oxy]ethyl}) amino}ethyl)-7- methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 7a (140 mg, 0.21 mmol) and cone. HCI (1 mL) in THF/H2O (25 mL/3 mL) was stirred at room temperature for 3 h. The mixture was adjusted to pH 8-9 with a saturated aqueous Na2CC>3 solution and extracted with DCM (20 ml_ x 3). The combined organic extracts were washed with H2O, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure The residue was purified by

chromatography using DCM/MeOH, 40: 1 to 10: 1 , v/v to give a white solid of 1 -(2- {[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl](2-hydroxyethyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2- one 7 (50 mg, 43%). TLC: R _f = 0.24 (silica gel, DCM/MeOH = 10: 1 , v/v). LC-MS (Method D) 551.2 [M+H] ⁺ , RT 2.77 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 1 1.2 (br s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 9.6 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 6.50 (d, J = 9.6 Hz, 1 H), 4.78 br (s, 1 H), 4.61 (s, 2H), 4.49-4.33 (m, 4H), 4.00 (s, 3H), 3.38 (m, 2H), 2.83 (m, 1 H), 2.74 (m, 2H), 2.65 (m, 2H), 2.10 (m, 1 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.31-1.16 (m, 3H).

Example 8:- 4-f r8-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri , 41oxazin-

6-yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)ethyl)-7-oxo-7,8-dihvdro-1 ,8-naphthyridin-

2-yl1oxy)benzene-1 -sulphonamide

8 a) 4-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}benzene-1- sulfonamide 8a

A solution of 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a (547 mg, 1.54 mmol) and K2CO3 (425 mg, 3.08 mmol) in DMF (10 ml_) was stirred for 30 min. 4- hydroxybenzene-1 -sulfonamide (400 mg, 2.31 mmol) was added and the stirred mixture was heated to 90 °C for 17 h. The mixture was concentrated under reduced pressure and the residue was mixed with DCM and saturated aqueous NaHCC then passed through a SPE phase separator. The organic phase was concentrated under reduced pressure and purified by chromatography (DCM/MeOH, 100: 1 to 10: 1 , v/v) to give a pale yellow solid of 4-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}benzene-1- sulfonamide 8a (322 mg, 0.74 mmol). LC-MS (Method A) 388.5 [M-OEt] ⁺ ; RT 2.31 min. b) 4-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}benzene-1 -sulfonamide

8b

To a solution of 4-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}benzene-1 -sulfonamide 8a (322 mg, 0.74 mmol) in THF (10 mL) was added HCI (2.0 M, 7.43 mL) and the mixture heated to 50 °C for 2 h. The reaction was mixed with saturated aqueous NaHCC>3 and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine, dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified via chromatography (DCM/MeOH, 100: 1 to 10: 1 , v/v) to give a cream solid of 4-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}benzene-1- sulfonamide 8b (89.4 mg, 33.4%). LC-MS (Method A) 360.4 [M+H] ⁺ ; RT 1.71 min. c) 4-{[8-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo -2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro-1 ,8- naphthyridin-2-yl]oxy}benzene-1 -sulfonamide 8c

A mixture of 4-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}benzene-1- sulfonamide 8b (50 mg, 0.14 mmol) and (3aR,6R,7aR)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 1 c (1 18 mg, 0.28 mmol) in THF (2 mL) was heated at 70 °C for 2h. The reaction mixture was allowed to cool and NaBH(OAc)3 (88.4 mg, 0.42 mmol) added. After 1.5 h further NaBH(OAc)3 (88.4 mg, 0.42 mmol) was added and stirring continued at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure, saturated aqueous NaHCC added and the crude products extracted with DCM (3 x 30 mL). The combined organics were filtered through a SPE phase separator, concentrated under reduced pressure then purified by chromatography (DCM/MeOH, 10: 1 , v/v) to give an off white solid, which was further purified via chromatography using a Biotage KPNH cartridge 11 g (DCM/MeOH, 1 : 100 to 2: 1 , v.v) to give a white solid of 4-{[8-(2- {[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H -pyrido[3,2-b][1 ,4]oxazin-6- yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}benzene-1 -sulfonamide 8c (50 mg, 70%). LC-MS (Method A) 768.9 [M+H] ⁺ ; RT 2.70 min. d) 4-{[8-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b ][1,4]oxazin-6-yl}- octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro -1,8-naphthyridin-2- yl]oxy}benzene-1-sulphonamide 8

To a solution of 4-{[8-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo -2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-2-oxo-octahydro-1,3-benzoxazo l-6-yl]amino}ethyl)-7-oxo-7,8- dihydro-1,8-naphthyridin-2-yl]oxy}benzene-1 -sulfonamide 8c (31 mg, 0.04 mmol) in DCM (1.2 mL) was added TFA (2.0 mL) then CF3SO3H (0.34 mL). After 10 min the mixture was adjusted to pH 8-9 with saturated aqueous K2CO3(40 mL) and extracted with DCM (3 x 30 mL). The combined organics were filtered through an SPE phase separator and

concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 100:1 to 2:1 followed by DCM/2M NH ₃ in MeOH, v/v) to give a white solid of 4-{[8-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b ][1,4]oxazin-6-yl}-octahydro- 1,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro-1,8-napht hyridin-2-yl]oxy}benzene-1- sulphonamide 8 (9.8 mg, 26%). LC-MS (Method B) 648.5 [M+H] ⁺ ; RT 6.24 min. ¹ H NMR (Method C) (CDCI3): δ ppm: 8.11- 8.05 (m, 2H), 7.86 (d, J= 8.3 Hz, 1H), 7.54 (d, J= 9.5 Hz, 1 H), 7.40 - 7.35 (m, 2H), 7.25 (d, J = 1.3 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1 H), 6.59 (d, J = 9.5 Hz, 1 H), 4.56 (d, J = 3.7 Hz, 2H), 4.29 - 4.22 (m, 2H), 3.87 (td, J= 11.7, 3.4 Hz, 1 H), 3.76 (m, 1H), 2.81 (m, 2H), 2.73 (td, J= 11.7, 10.9, 6.2 Hz, 1H), 2.60 (d, J= 11.7 Hz, 1H), 2.41 (d, J= 10.9 Hz, 1H), 1.86 (d, J= 12.8 Hz, 1H), 1.46 (dd, J= 11.3, 11.3 Hz, 1H), 1.30- 1.20 (m, 2H), 1.19-1.08 (m, 1H).

Example 9:- 1-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-yl1amino)ethyl)-7-(2-aminoeth oxy)-1,2-dihvdroquinolin- -one

9

a) 7-(prop-2-en-1-yloxy)-1,2-dihydroquinolin-2-one 9a A mixture of 7-hydroxy-1 ,2-dihydroquinolin-2-one (4.0 g, 24.82 mmol), K ₂ C0 ₃ (5.15 g, 37.23 mmol) and allyl bromide (2.6 mL, 29.78 mmol) in acetone (40 mL) was heated at 60°C for 16 h. After cooling to room temperature the mixture was filtered and the solid collected was washed with acetone (2 x 15 mL). The filtrates were combined and the solvent removed in vacuo. The resulting residual solid was triturated with MeOH to furnish 7-(prop- 2-en-1-yloxy)-1 ,2-dihydroquinolin-2-one 9a (3.7 g, 74 % yield) as a white solid.

LC-MS (Method A) 202.4 [M+H]+; RT 2.14 min b) 2-[2-oxo-7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-1-yl]acetaldehyde 9b

To a mixture of 7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-2-one 9a (28.5 g, 141.64 mmol) and Cs ₂ C0 ₃ (55.4 g, 167.97 mmol) in NMP (230 mL) was added 2-bromo-1 , 1- diethoxyethane (23.44 mL, 155.8 mmol) and the suspension heated at 100°C for 16 h. On cooling H2O (500 mL) was added and the mixture was extracted with EtOAc (3 x 350 mL). The combined organics were washed with H2O and brine, dried (MgS0 ₄ ) and concentrated in vacuo. The residue was taken up in THF (150 mL) and HCI (2M, 150 mL) and heated to 55°C for 2 h. On cooling the reaction mixture was extracted with EtOAc (200 mL x 3) and the combined organics were washed with H2O and brine, dried (MgS04) and concentrated in vacuo. The resulting residue was triturated with petroleum ether then Et20 and dried to give 2-[2-oxo-7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-1-yl]acetaldehyde 9b (10.4 g, 30 % yield). c) 1-(2,2-diethoxyethyl)-7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-2-one 9c

lA mixture of 2-[2-oxo-7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-1-yl]acetaldehyde 9b (100 mg, 0.41 mmol), 4-methylbenzene-1 -sulfonic acid (10 mg, 0.05 mmol), EtOH (1 mL) in Toluene (30 mL) was stirred at reflux for 7 h under azeotropic conditions. The reaction was allowed to cool and Na2C03 (1 M, 20 mL) added. The mixture was extracted with EtOAc (2 x 30 mL) and the combined extracts were washed with water, brine and dried over Na2S0 ₄ . The filtrate was concentrated under reduced pressure and purified by chromatography using 30% EtOAc in petroleum ether to give a yellow solid of 1-(2,2-diethoxyethyl)-7-(prop- 2-en-1-yloxy)-1 ,2-dihydroquinolin-2-one 9c, (60 mg, 46%). TLC: R _f = 0.54 (silica gel, DCM/MeOH =15: 1 , v/v). LC-MS (Method C) 318.2 [M+H] ⁺ ; RT 3.96 min. d) 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d

A mixture of 1-(2,2-diethoxyethyl)-7-(prop-2-en-1-yloxy)-1 ,2-dihydroquinolin-2-one 9c (60 mg, 0.19 mmol), Pd(PPh ₃ ) ₄ (21.8 mg, 0.02 mmol) and K2CO3 in EtOH (10 mL) was stirred at room temperature for 17 h. The mixture was adjusted to pH 7.0 - 7.5 with saturated aqueous NaHCC>3 and extracted with EtOAc (20 ml_ x 3). The combined extracts were washed with water, brine, dried over Na2S0 ₄ and concentrated under reduced pressure. The residue was purified by preparative-TLC (DCM/MeOH, 15: 1 , v/v) to give a white solid of 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d, (55 mg, 81 %). TLC: R _f = 0.33 (silica gel, DCM/MeOH =15: 1 , v/v). LC-MS (Method C) 278.3 [M+H] ⁺ ; RT 2.80 min. e) te/f-butyl N-(2-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9e

To a stirring suspension of 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d (45 mg, 0.16 mmol) and K ₂ C0 ₃ in DMF (10 ml_) was added te/f-butyl N-(2- bromoethyl)carbamate (73 mg, 0.32 mmol). The mixture was heated to 85 °C for 4 h then allowed to cool. Water was added and the mixture extracted with EtOAc (3 x 30 ml_). The combined extracts were washed with water (30 ml_), brine (30 ml_), dried over Na2S0 ₄ and concentrated under reduced pressure. The residue was purified using chromatography (DCM:MeOH 15: 1 to 10:1) to give a yellow oil of terf-butyl N-(2-{[1-(2,2-diethoxyethyl)-2- oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9e (55 mg, 81 %) TLC: Rf = 0.52 (silica gel, DCM/MeOH =15: 1 , v/v). LC-MS (Method C) 375.2 [M+OEt] ⁺ ; RT 3.96 min. f) te/f-butyl N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9f To a solution of te/f-butyl N-(2-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)carbamate 9e (55 mg, 0.13 mmol) in THF (20 mL) was added HCI (1.0 M, 1.3 mL) and heated to 35 °C for 20 h. Saturated aqueous NaHCOswas added and the mixture extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified using chromatography (petroleum ether/EtOAc, 5: 1-1 : 1 , v/v) to give a yellow oil of te/f-butyl N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9f (55 mg, 81 %) TLC: R _f = 0.34 (silica gel, EtOAc/petroleum ether = 1 :2, v/v). LC-MS (Method C) 347.4

[M+H] ⁺ ; RT 3.26 min. g) terf-butyl N-(2-{[1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}ethyl)carbamate 9g

To a mixture of te/f-butyl N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)carbamate 9f (33 mg, 0.09 mmol) and (3aS,6S,7aR)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,^ benzoxazol-2-one 4c (41 mg, 0.09 mmol) in DCM (15 mL) was added NaBH(OAc) ₃ and stirred at room temperature for 4 h. Saturated aqueous NaHCC>3 was added and extracted with EtOAc (3 x 20 mL). The combined organics were washed with water, brine, dried over Na2S0 ₄ , and concentrated under reduced pressure. The residue was purified by preparative-TLC (DCM/MeOH, 10: 1 , v/v) to give a white solid of te/f-butyl N-(2-{[1-(2- {[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H -pyrido[3,2-b][1 ,4]oxazin-6- yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)carbamate 9g (50 mg, 70%), which was used directly in the next step without further purification. TLC: R _f = 0.52 (silica gel, DCM/MeOH = 20: 1 , v/v). h) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydroquinolin-2-one

To a solution of te/f-butyl N-(2-{[1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-

2- OXO-1 , 2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9g (50 mg, 0.07 mmol) in DCM (10 mL) was added TFA (2.0 mL, 26.1 mmol) and stirred at room temperature for 3 h. CF3SO3H (1.0 mL, 1 1.3 mmol) was then added and stirring continued for a further 1 h. The resulting mixture was adjusted to pH 8-9 with saturated aqueous K2CO3 (40 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water, brine, dried over Na2S0 ₄ and concentrated under reduced pressure. The residue was purified by

preparative-TLC (DCM/MeOH, 10: 1 , v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-

3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydroquinolin-2-one (55 mg, 81 %). TLC: Rf = 0.31 (silica gel, DCM/MeOH =8:1 , v/v). LC-MS (Method C) 535.5 [M+H] ⁺ ; RT 1.91 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 7.81 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.05 (br s, 1 H), 6.90 (d, J = 9.6 Hz, 1 H), 6.41 (d, J = 9.6 Hz, 1 H), 4.76 (m, 1 H), 4.61 (s, 2H), 4,47 (m, 1 H), 4.26 (m, 2H), 4.09 (m, 2H), 2.96 (m, 2H), 2.79 (m, 2H), 2.71 (m, 1 H), 2.45 (m, 1 H), 2.25 (m, 1 H), 1.80 (m, 1 H), 1.55 (m, 1 H), 1.26 (m, 1 H), 1.00 (m, 1 H).

Example 10:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdrc-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one

10

a) ferf-butyl N-(2-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10a

To a solution of 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a (500 mg, 1.7 mmol) and te/f-butyl N-(2-hydroxyethyl)carbamate (815 mg, 5.1 mmol) in DMF (15 mL) was added a solution of f-BuOK (1 M in THF, 5.1 mL, 5.1 mmol ) dropwise and the mixture was stirred at room temperature for 17 h. The resulting mixture was diluted with water (100 mL), extracted with EtOAc (3 x 100 mL) and the combined extracts were washed with water (2 x 100 mL), brine (100 mL) and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether: EtOAc, 3: 1 , v/v) to give a colourless oil of te/f-butyl N-(2-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10a (430 mg, 60%). TLC: R _f =0.58 (silica gel, PE: EtOAc = 1 :1 , v/v). ¹ H NMR (Method E) (DMSO-d6): δ ppm 8.03 (d, J= 8.4 Hz, 1 H), 7.85 (d, J= 9.5 Hz, 1 H), 7.01 (t, J= 5.8 Hz, 1 H), 6.69 (d, J= 8.4 Hz, 1 H), 6.49 (d, J= 9.4 Hz, 1 H), 5.00 (t, J = 5.1 Hz, 1 H), 4.47 (d, J = 5.57 Hz, 2H), 4,36 (t, J = 5.8 Hz, 2H), 3.63 (m, 2H), 3.44-3.37 (m, 4H), 1.36 (s, 9H), 0.97 (t, J = 7.0 Hz, 6H). b) te/f-butyl N-(2-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10b

To a solution of te/f-butyl N-(2-{[8-(2,2-diethoxyethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10a (430 mg, 1.02 mmol) in THF was added aqueous HCI (1.0 M, 5.1 mL, 5.1 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was adjusted to pH 8-9 with saturated aqueous NaHCOs and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over Na2S0 ₄ and concentrated under reduced pressure. . The residue was purified by chromatography (Petroleum ether : EtOAc, 5: 1 to 1 : 1 , v/v) to give a white solid of te/f-butyl N-(2-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2-yl]oxy}ethyl)carbamate 10b (174 mg, 50%). TLC: R _f = 0.25 (silica gel, Petroleum ether/EtOAc =1 : 1 , v/v). ¹ H NMR (Method E) (DMSO-d6): δ ppm 9.69 (s, 1 H), 8.09 (d, J= 8.5 Hz, 1 H), 7.94 (d, J = 9.5 Hz, 1 H), 7.00 (t, J = 5.8 Hz, 1 H), 6.71 (d, J= 8.4 Hz, 1 H), 6.55 (d, J= 9.4 Hz, 1 H), 5.24 (s, 2H), 4.27 (t, J = 5.9 Hz, 2H), 3.28 (m, 2H), 1.36 (s, 9H). c) terf-butyl N-(2-{[8-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8- dihydro-1 ,8-naphthyridin-2-yl]oxy}ethyl)carbamate 10c

A mixture of te/f-butyl N-(2-{[7-oxo-8-(2-oxoethyl)-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10b (174 mg, 0.50 mmol) and (3aS,6S,7aR)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 4c (212 mg, 0,50 mmol) in DCE (15 ml_) was prepared. NaBH(OAc)3 (424 mg, 2 mmol) was added and stirred at room temperature for 4h. The resulting mixture was diluted with saturated aqueous NaHCC and extracted with EtOAc (3 x 20 ml_). The combined extracts were washed with water (50 ml_), brine (50 ml_), dried over Na2S0 ₄ and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 50: 1 to 20: 1 , v/v) to give a white foam of terf-butyl N-(2-{[8-(2-{[(3aS,6S,7aR)- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-2-oxo- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridin-2- yl]oxy}ethyl)carbamate 10c (140 mg, 37%). TLC: R _f = 0.35 (silica gel, DCM/MeOH = 20: 1 , v/v). LC-MS (Method C) 756.3 [M+H] ⁺ ; RT 4.13 min. d) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 10 To a solution te/f-butyl N-(2-{[8-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)- 7-0X0-7, 8-dihydro-1 ,8-naphthyridin-2-yl]oxy}ethyl)carbamate 10c (140 mg, 0.18 mmol) in DCM (10 ml_) was added TFA (2.0 ml_, 26.1 mmol) and the mixture was stirred at room temperature for 3 h. CF3SO3H (1.0 ml_, 1 1.3 mmol) was then added and stirring was continued for a further 1 h. The resulting mixture was adjusted to pH 8-9 with saturated aqueous K ₂ CO ₃ (40 ml_) and extracted with DCM/IPA (3: 1 , 3 x 20 ml_). The combined organic extracts were washed with water, brine, dried over Na2S0 ₄ , filtered and

concentrated under pressure. The residue was purified by preparative-TLC

(DCM/MeOH/NH ₃ .H ₂ 0, 100: 10:2, v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)- 7-(2-aminoethoxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 10 (30 mg, 31 %). TLC: R _f = 0.25 (silica gel, DCM/MeOH =10: 1 drop of NH ₃ , v/v). LC-MS (Method C) 536.5 [M+H] ⁺ ; RT 1.72 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 8.12 (d, J = 8.5 Hz, 1 H), 7.92 (d, J= 9.5 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 6.54 (d, J= 9.4 Hz, 1 H), 4.84 (m, 1 H), 4.73 (m, 2H), 4.61 (m, 4H), 4.51 (m, 1 H), 3.26 (m, 2H), 3.08 (m, 3H), 2. 45 (m, 2H), 1.89 (m, 2H), 1.33 (m, 2H).

Example 11 :- (3aS,6S,7aR)-6-r(2-{7-methoxy-4-oxo-4H,5H-H ,21oxazolor3,4-c1quinolin-

5-yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri ,41oxazin-6-yl)-octahydro-1 ,3- benzoxazol-2-one

11

a) 5-(2-hydroxyethyl)-7-methoxy-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one 11 a

A mixture of 7-methoxy-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one (preparation described in PCT 2016024096) (1.1 g, 5.1 mmol, 1 eq), 1 ,2-dibromoethane (5.2 g, 27.7 mmol, 5.4 eq) and Cs ₂ C0 ₃ (8.5 g, 26.1 mmol, 5.1 eq) in NMP (80 mL) was heated at 45°C for 4 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc, 3: 1 to 1 : 1 , v/v) to give 5-(2-hydroxyethyl)-7-methoxy-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one 11 a (700 mg, 54%) as a grey solid. TLC: R _f = 0.27 (silica gel, EtOAc/Petroleum ether = 1 : 1 , v/v). LC- MS (Method C) 261.1 [M+H] ⁺ ; RT 1.72 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 9.92 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 6.95 (dd, J = 8.4, 2.0 Hz, 1 H), 4.96 (t, J = 6.0 Hz, 1 H), 4.33 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.71 (dt, J = 6.0, 6.4 Hz, 2H). ¹³ C NMR (Method E) (DMSO-d6): δ ppm 160.6, 156.4, 154.9, 150.9, 138.8, 127.4, 1 17.3, 109.9, 106.5, 102.9, 58.3, 56.0, 44.7. b) 2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}acetaldehyde 11 b

A mixture of 5-(2-hydroxyethyl)-7-methoxy-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-4-one 11 a (150 mg, 0.38 mmol, 1 eq) and PCC (800 mg, 3.7 mmol, 9.7 eq) in DCM (20 mL) was stirred at room temperature for 6 h. The mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure to afford 2-{7-methoxy-4-oxo-4H,5H- [1 ,2]oxazolo[3,4-c]quinolin-5-yl}acetaldehyde 11 b (80 mg) as a grey solid, which was used directly in the next step without further purification. TLC: Rf=0.5 (silica gel, EtOAc/petroleum ether, 1 : 1 , v/v). LC-MS (Method C) 259.0 [M+H] ⁺ ; RT 3.16 min. c) (3aS,6S,7aR)-6-[(2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one 11 c

To a mixture of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (30 mg, 0.17 mmol) and 2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}acetaldehyde 11 b (50 mg, 0.12 mmol) in DCM (20 ml_) was added NaBH(OAc) ₃ (150 mg, 0.71 mmol) and stirred at room temperature for 20 h. The resulting mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3 solution and extracted with DCM. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via chromatography (DCM/EtOAc, 2: 1 to 1 : 1 , v/v) to give a white solid of (3aS,6S,7aR)-6- [(2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5-yl}ethyl)amino]-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 11 c (40 mg, 52%) TLC: R _f = 0.31 (silica gel, DCM/EtOAc =1 : 1 , v/v). LC- MS (Method C) 667.2 [M+H] ⁺ ; RT 3.92 min. d) (3aS,6S,7aR)-6-[(2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5- yl}ethyl)amino]-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol- 2-one 11

To a solution of (3aS,6S,7aR)-6-[(2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4-c]quinolin-5- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one 11 c (40 mg, 0.06 mmol) in DCM was added TFA (1.5 mL, 19.6 mmol) and CF3SO3H (0.7 mL, 7.9 mmol) and stirred at room temperature for 1 h. The resulting mixture was diluted with MeOH (1.5 mL), the pH adjusted to pH 8-9 with saturated aqueous Na2C03 solution and extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 15: 1 , v/v) to give a pale yellow solid of (3aS,6S,7aR)-6-[(2-{7-methoxy-4-oxo-4H,5H-[1 ,2]oxazolo[3,4- c]quinolin-5-yl}ethyl)amino]-3-{3-oxo-2H,3H,4H-pyrido[3,2-b] [1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 11. TLC: R _f = 0.28 (silica gel, DCM/MeOH =15: 1 , v/v). LC-MS (Method B) 547.2 [M+H] ⁺ ; RT 3.04 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 1 1.20 (s, 1 H), 9.95 (s, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 7.00 (dd, J = 8.8, 2.4 Hz, 1 H), 4.77 (dt, J = 6.7, 3.2 Hz, 1 H), 4.61 (m, 2H), 4.48 (d, J = 9.4 Hz, 1 H), 4.33 (m, 2H), 3.89 (s, 3H), 2.89 (m, 2H), 2.77 (m, 1 H), 2.29 (m, 1 H), 1.81 (m, 1 H), 1.57 (m, 1 H), 1.26 (m, 2H), 1.03 (m, 1 H), 0.85 (m, 1 H).

Example 12:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one

12

a) 1-(2,2-diethoxyethyl)-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12a

To a solution of 7-chloro-1-(2,2-diethoxyethyl)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 5a (360 mg, 1.22 mmol) and pyridin-3-ol (174 mg, 1.83 mmol) in DMF (10 mL) was added CS2CO3 (800 mg, 2.45 mmol) and the mixture was heated to 70 °C under a nitrogen atmosphere for 17 h. The mixture was diluted with water (100 mL), extracted with EtOAc (3 x 30mL) and the combined organics extracts were washed with water (2 x 100 mL), brine (50 mL) and concentrated under reduced pressure to give a colourless oil of 1-(2,2-diethoxyethyl)-7- (pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12a (430 mg, 100%). TLC: R _f = 0.30 (silica gel, petroleum ether/EtOAc = 2: 1 , v/v). LC-MS (Method C) 310.10 [M+OEt] ⁺ ; RT 3.29 min. b) 2-[2-oxo-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 12b

To a solution of 1-(2,2-diethoxyethyl)-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12a (430 mg, 1.22 mmol) in THF (20 mL) was added HCI (2.0 M, 12.2 mL, 24.4 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 8-9 with saturated aqueous NaHCC and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (50 ml_), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (Petroleum ether: EtOAc, 5: 1 to 1 : 1 , v/v) to give a waxy solid of 2-[2-oxo-7-(pyridin-3-yloxy)- 1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 12b (240 mg, 70%). TLC: R _f = 0.14 (silica gel, Petroleum ether/EtOAc = 2: 1 , v/v). LC-MS (Method C) 282.1 [M+H] ⁺ ; RT 2.46 min. ¹ H NMR (Method E) (CDC ): δ ppm 9.40 (s, 1 H), 8.54 (br s, 2H), 7.92 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 9.5 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.40 (br s, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.66 (d, J = 9.5 Hz, 1 H), 4.94 (s, 2H). c) 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(pyridin-3-yloxy)- 1 ,2-dihydro-1 ,8-naphthyridin-2-one 12c

A mixture of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (100 mg, 0.23 mmol) and

2- [2-oxo-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-1-yl]acetaldehyde 12b (66 mg, 0.23 mmol) in DCE (15 ml_) was stirred at room temperature for 30 min. NaBH(OAc)3 (150 mg, 0.71 mmol) was added and the reaction stirred at room temperature for 17 h. The mixture was diluted with DCM (30 ml_) and washed with water, brine, dried Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified via chromatography (DCM/MeOH, 50: 1 to 20: 1 , v/v) to give a white foam of 1-(2-{[(3aS,6S,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12c (140 mg, 88%). TLC: R _f = 0.35 (silica gel, DCM/MeOH = 20: 1 , v/v). LC-MS (Method C) 690.3 [M+H] ⁺ ; RT 3.22 min. d) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(pyridin-3-yloxy)-1 ,2-dihydro-1 ,8- naphthyridin-2-one 12

To a solution of 1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(pyridin-

3- yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12c (140 mg, 0.20 mmol) in DCM (10 mL) was added TFA (1.5 mL, 19.6 mmol) and CF3SO3H (0.7 mL, 7.9 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (40 mL) and the pH was adjusted to pH 8-9 with saturated aqueous Na2C03 solution and extracted with DCM (20 ml_ x 3). The combined organic layer was washed with brine, dried on Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 100: 1 to 10: 1 , v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3- oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7- (pyridin-3-yloxy)-1 ,2-dihydro-1 ,8-naphthyridin-2-one 12 (30mg, 30%). TLC: R _f = 0.25 (silica gel, DCM/MeOH =10: 1 , v/v). LC-MS (Method C) 570.2 [M+H] ⁺ ; RT 2.37 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm: 11.2 (s, 1 H), 8.58 (s, 1 H), 8.51 (d, J = 3.2 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 7.93 (d, J = 9.6 Hz, 1 H), 7.80 (m, 1 H), 7.53 (m, 2H), 7.41 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 9.6 Hz, 1 H), 6.56 (d, J = 9.6 Hz, 1 H), 4.73 (m, 1 H), 4.62 (s, 2H), 4.45 (m, 1 H), 4.05 (m, 2H), 2.56 (m, 2H), 2.42 (m, 1 H), 2.15 (m, 1 H), 1.62 (m, 1 H), 1.42 (m, 1 H), 1.23 (m, 2H), 0.88 (m, 1 H).

Example 13:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1(2-aminoethyl)amino)ethyl)-7-methoxy-1 ,2-dihvdro- -naphthyridin-2-one

13

a) terf-butyl N-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]amino}ethyl)carbamate 13a

A solution of 1-(2-{[(3aS,6S,7aR)-2-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 4 (100 mg, 0.20 mmol) and te/f-butyl N-(2-oxoethyl)carbamate (200 mg, 0.46 mmol) in DCM (10 ml_) was added NaBH(OAc)3 (488 mg, 2.3 mmol) and the mixture was stirred at room

temperature for 17 h. The resulting mixture was diluted with saturated aqueous NaHCC solution and extracted with EtOAc (3 x 20ml_). The combined organic extracts were washed with water, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/EtOAc, 5: 1 to 3: 1 , v/v) to give a white solid of terf-butyl N-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]amino}ethyl)carbamate 13a (100 mg, 78%). TLC: R _f = 0.59 (silica gel, DCM/MeOH =15: 1 , v/v). LC-MS (Method C) 630.3 [M+H] ⁺ ; RT 3.57 min. b) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one 13

To a solution of terf-butyl N-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8- naphthyridin-1-yl)ethyl]amino}ethyl)carbamate 13a (140 mg, 0.21 mmol) in DCM (30 mL) at 0 °C was added TFA (5 mL) and the mixture allowed to warm to room temperature and stirred for 5 h. The mixture was adjusted to pH 8-9 with saturated aqueous K2CO3 solution (40 mL) and extracted with DCM (30 mL x 3). The combined organic extracts were washed with water, brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 25: 1 to 10: 1 , v/v) to give a white solid of 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one 13 (50 mg, 59%). TLC: R _f = 0.24 (silica gel, DCM/MeOH =8: 1 , v/v). LC- MS (Method C) 550.2 [M+H] ⁺ ; RT 3.05 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 8.05 (d, J = 8.8 Hz, 1 H), 7.86 (d, J = 9.2 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 6.50 (d, J = 9.2 Hz, 1 H), 4.79 (m, 1 H), 4.61 (s, 2H), 4.41 (m, 3H), 4.00 (s, 3H), 2.85 (m, 1 H), 2.73 (m, 2H), 2.55 (m, 3H), 2.48 (m, 1 H), 2.1 1 (m, 1 H), 1.77 (m, 1 H), 1.61 (m, 1 H), 1.33-1.23 (m, 3H).

Example 14:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)ethyl)-2-oxo-1 ,2-dihydroquinoline-7- carbonitrile

14 a) (3aS,6S,7aR)-6-amino-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 14a

To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (200 mg, 0.20 mmol) in DCM (40 mL) was added TFA (1.5 mL, 19.6 mmol) and CF3SO3H (0.7 mL, 7.9 mmol). The mixture was stirred at room temperature for 1.5 h, diluted with MeOH (1.5 mL) and the pH adjusted to pH 8-9 with saturated aqueous Na2CC>3 solution. The organic phase was separated and the aqueous layer was extracted with DCM/IPA (4: 1). The organic phase was concentrated under reduced pressure and the residue purified by chromatography (DCM/MeOH, 100: 1 to 10: 1 , v/v) to give a white solid of (3aS,6S,7aR)-6-amino-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 14a (140 mg, 97%). LC-MS (Method A) 305.6 [M+H] ⁺ ; RT 1.45 min. b) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 14

A mixture of (3aS,6S,7aR)-6-amino-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-2-one 14a (70 mg, 0.23 mmol) and 2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinoline-7-carbonitrile (49 mg, 0.23 mmol) (J. Med. Chem (2014) 57 (1 1), 4889- 4905) in MeOH (2 mL) was stirred at room temperature for 2 h over molecular sieves (4A). NaBH(OAc)3 (146 mg, 0.69 mmol) was added and stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCC>3, the resulting mixture passed through a SPE phase separator and the organic filtrate collected and concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-100%

EtOAc/petroleum ether and 0-20% MeOH/DCM to give a yellow solid of 1-(2- {[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 14 (30 mg, 26.2%) LC-MS (Method B) 501.4 [M+H] ⁺ ; RT 5.64 min. ¹ H NMR (Method D) (DMSO-d6): 11.19 (s, 1H), 8.18 (d, J= 1.3 Hz, 1H), 8.00 (d, J= 9.5 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.65 (dd, J = 8.0, 1.3 Hz, 1H), 7.50 (d, J= 8.7 Hz, 1H), 7.40 (d, J= 8.7 Hz, 1H), 6.78 (d, J= 9.5 Hz, 1H), 4.75 (dt, J= 6.3, 3.2 Hz, 1H), 4.60 (d, J= 1.0 Hz, 2H), 4.46 (dt, J= 9.5, 6.3 Hz, 1H), 4.30 (t, J = 7.4 Hz, 2H), 2.85 - 2.74 (m, 2H), 2.68 (dd, J = 20.0, 9.8 Hz, 1 H), 2.24 (m, 1 H), 2.12 - 1.95 (m, 1H), 1.76 (d, J= 12.8 Hz, 2H), 1.51 (ddd, J= 15.0, 11.1, 4.2 Hz, 1H), 1.32- 1.21 (m, 1H), 1.02-0.92 (m, 1H).

Example 15:- 8-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-yl1amino)ethyl)-7-oxo-7,8-dih vdro-1,8-naphthyridine-2- carbonitrile

15 a) 8-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dihydro-1 ,8-naphthyridine-2-carbonitrile 15

A mixture of (3aS,6S,7aR)-6-amino-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxa zin-6-yl}- octahydro-1,3-benzoxazol-2-one 14a (70 mg, 0.23 mmol) and 7-oxo-8-(2-oxoethyl)-1,8- naphthyridine-2-carbonitrile (49 mg, 0.23 mmol) (Eur. Pat. Appl. (2008) EP1992628A1 20081119) in DCM (2 ml_) was stirred at room temperature for 2 h. NaBH(OAc) ₃ (146 mg, 0.69 mmol) was added and stirred at room temperature for 2 h. The mixture was diluted with NaHCC>3, passed through an SPE phase separator and the organic extracts collected and concentrated under reduced pressure. The residue was purified via silica gel chromatography using 50-100% EtOAc/petroleum ether and 0-20% MeOH/DCM to give an off white solid of 8-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6- yl}-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7-oxo-7,8-dih ydro-1,8-naphthyridine-2- carbonitrile 15 (2.6 mg, 2.2%) LC-MS (Method B) 502.4 [M+H] ⁺ ; RT 5.38 min. ¹ H NMR (Method C) (DMSO-d6) δ 11.19 (s, 1H), 8.42 (d, J= 7.7 Hz, 1H), 8.06 (d, J= 9.6 Hz, 1H), 7.92 (d, J =7.7 Hz, 1H), 7.52 (d, J= 8.7 Hz, 1H), 7.41 (d, J= 8.7 Hz, 1H), 6.88 (d, J= 9.6 Hz, 1 H), 4.77 (s, 1 H), 4.62 (d, J = 1.9 Hz, 1 H), 4.55 - 4.32 (m, 2H), 2.65 (p, J = 1.9 Hz, 1 H), 2.55 (p, J = 1.9 Hz, 3H), 1.80 (m, 1 H), 1.54 (m, 2H), 1.41 - 1.18 (m, 2H), 1.00 (s, 1 H), 0.88 (d, J = 6.8 Hz, 1 H).

Example 16:- 1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin- 6-yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

16

a) 2: 1 mixture of 2-bromo-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4- b] [1 ,4]oxazin-7-one and 2-chloro-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4- b][1 ,4]oxazin-7-one 16a

To a solution of a 2: 1 mixture of 2-bromo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one and 2- chloro-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one (preparation described in PCT int.

application 201 1 141848)(4.3 g, 20.6 mmol) in DMF under N ₂ conditions, was added 1- (chloromethyl)-4-methoxybenzene (3.57 g, 22.7 mmol) and K2CO3 (5.69 g, 41.2 mmol). The mixture was stirred at room temperature for 5 h. Water was added slowly whilst stirring was continued. The resulting precipitate was collected via filtration, washed with water and dried to give a white solid of a 2: 1 mixture of 2-bromo-8-[(4-methoxyphenyl)methyl]- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one and 2-chloro-8-[(4-methoxyphenyl)methyl]- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one 16a (4.3 g, 64%). TLC: R _f = 0.78 (silica gel, Petroleum ether/EtOAc = 4: 1 , v/v). LC-MS (Method C) 306.1 [M+H] ⁺ and 350.1 [M+H] ⁺ ; RT 4.24 min. ¹ H NMR (Method E) (CDC ): δ ppm: 8.09 (s, 0.33H), 8.04 (s, 0.66H), 7.48 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.20/5.19 (2 x s, 2H total), 4.76 (s, 2H), 3.79 (s, 3H). b) te/f-butyl N-[(3aS,6S,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8 H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 16b To a solution of te/f-butyl N-[(3aS,6S,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 4a (256 mg, 1.0 mmol) in toluene (10 mL) was added a 2: 1 mixture of 2-bromo-8-[(4- methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one and 2-chloro-8-[(4- methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-7-one 16a (330mg, 1.0 mmol), trans-1 ,2-diaminocyclhexane (48 mg, 0.4 mmol), K ₂ C0 ₃ (280mg, 2.00 mmol) and Cul (160 mg, 0.8 mmol) under N2 conditions. The mixture was heated to reflux and stirred for 17 h. The mixture was allowed to cool to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (30% EtOAc in DCM) to give a colourless oil of te/f-butyl N-[(3aS,6S,7aR)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]carbamate 16b (210 mg, 40 %). TLC: R _f = 0.39 (silica gel, Petroleum ether/EtOAc = 2: 1 , v/v). LC-MS (Method C) 526.3 [M+H] ⁺ ; RT 4.02 min. c) (3aS,6S,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 16c

To a solution of te/f-butyl N-[(3aS,6S,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 16b (210 mg, 0.40 mmol) in DCM (4 mL), TFA (2 mL, 26.1 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was adjusted to pH 8-9 with saturated aqueous NaHCC>3 and extracted with EtOAc (3 x 20 mL). The combined organics were washed with water (30 mL), brine (30 mL), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 15: 1 to 10: 1 , v/v) to give a white solid of (3aS,6S,7aR)-6-amino-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3- benzoxazol-2-one 16c (83 mg, 49%). TLC: R _f = 0.20 (silica gel, DCM/MeOH = 10:1 , v/v). LC-MS (Method C) 426.2 [M+H] ⁺ ; RT 2.61 min. d) 1-(2-{[(3aS,6S,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2- dihydro-1 ,8-naphthyridin-2-one 16d

A mixture of (3aS,6S,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H- pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 16c (83 mg, 0.19 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)acetaldehyde (41 mg, 0.19 mmol) (prepared as described in WO2008009700) in DCM (2 mL) was stirred at room temperature for 10 min. NaBH(OAc)3 (212 mg, 1.0 mmol) was added and the mixture stirred at room temperature for 17 h. Saturated aqueous NaHCC>3 was added and the mixture extracted with EtOAc (3 x 20 mL). The combined organics were washed with water, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure to give 1-(2-{[(3aS,6S,7aR)-3- {8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1 ,4]oxazin-2-yl}-2-oxo- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 16d (65 mg, 52%). TLC: R _f = 0.49 (silica gel, DCM/MeOH = 10: 1 , v/v). LC-MS (Method C) 628.3 [M+H] ⁺ ; RT 3.09 min. e) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one

dihydrochloride 16

To a stirring solution of 1-(2-{[(3aS,6S,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 16d (65 mg, 0.10 mmol) in TFA (4.0 mL, 52.2 mmol) at 0 °C, was added CF3SO3H (0.40 mL, 4.52 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC

(DCM/MeOH, 10: 1 , v/v) and converted to the dihydrochloride salt to give a white solid of 1- (2-{[(3aS,6S,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 16 (15 mg, 28%). TLC: R _f = 0.39 (silica gel, DCM/MeOH =10: 1 , v/v). LC-MS (Method C) 508.2 [M+H] ⁺ ; RT 2.41 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 1 1.75 (br s, 1 H), 9.47 (br s, 1 H), 8.21 (s, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.92 (d, J = 9.2 Hz, 1 H), 7.29 (br s, 2H), 6.77 (d, J = 8.4 Hz, 1 H), 6.54 (d, J = 9.2 Hz, 1 H), 4.84 (m, 1 H), 4.71 (m, 4H), 4.49 (m, 1 H), 4.04 (s, 3H), 2.00 (m, 4H), 1.39-1.49 (m, 3H), 1.10 (m, 1 H), 0.88 (m, 1 H).

Example 17:- (3aS,6S,7aR)-6-r(2-{2-methoxy-7-oxo-7H,8H-pyridor2,3-cnpyrim idin-8- yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6 -yl)-octahvdro-1 ,3- benzoxazol-2-one MeO

17 a) (3aS,6S7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimi din-8- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]ox yl}-octahydro-1 ,3-benzoxazol-2-one 17a

A mixture of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (91 mg, 0.21 mmol) and 2- (2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl)acetaldeh yde 2b (49 mg, 0.12 mmol) in DCM (1.5 mL) was stirred at room temperature for 2 h. NaBH(OAc)3 (75 mg, 0.36 mmol) was added and the mixture stirred at room temperature for 2 h. The mixture was basified with saturated aqueous NaHCC>3 and the resulting mixture was passed through a SPE phase separator. The organic phase was washed with brine, dried over MgS0 ₄ , filtered and concentrated under reduced pressure to give (3aS,6S,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H- pyrido[2,3-d]pyrimidin-8-yl}ethyl)amino]-3-{4-[(4-methoxyphe nyl)methyl]-3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 17a (31 mg, 41 %). LC-MS (Method A) 628.4 [M+H] ⁺ ; RT 2.13 min. b) (3aS,6S,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8-yl}ethyl)amino]-3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 17

To a solution of (3aS,6S,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one 17a (31 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.93 mL, 12.2 mmol) and CF3SO3H (0.31 mL, 3.46 mmol). After 2 h the mixture was quenched with MeOH (1.5 mL) and the pH adjusted to pH 8-9 with saturated aqueous Na2CC>3. The mixture was diluted with DCM and passed through a SPE phase separator. The organic filtrate was collected, washed with brine, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (0-10% MeOH in DCM) to give an off white solid of (3aS,6S,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H- pyrido[2,3-d]pyrimidin-8-yl}ethyl)amino]-3-{3-oxo-2H,3H,4H-p yrido[3,2-b][1,4]oxazi octahydro-1,3-benzoxazol-2-one 17 (15.9 mg, 63%). LC-MS (Method B) 508.5 [M+H] ⁺ ; RT 2.13 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm δ 11.19 (s, 1H), 8.90 (s, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.51 (d, J= 8.7 Hz, 1H), 7.40 (d, J= 8.7 Hz, 1H), 6.55 (d, J= 9.5 Hz, 1H), 4.74 (dt, J= 6.3, 3.1 Hz, 1H), 4.58 (s, 2H), 4.45 (dt, J= 9.5, 6.3 Hz, 1H), 4.38-4.29 (m, 2H), 4.00 (s, 3H), 2.90-2.76 (m, 2H), 2.70 (dt, J= 11.1, 6.3 Hz, 1H), 2.30-2.19 (m, 1H), 1.77 (d, J= 12.9 Hz, 1H), 1.50 (ddd, J= 15.1, 11.1, 4.2 Hz, 1H), 1.39-1.15 (m, 2H), 1.04 (m, 1H), 0.85 (m, 1H).

Example 18:- 6-r3-(fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin, 41oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-yl1amino)methyl)-2-hvdroxyphe nyllpyridine-2- carbonitrile

18

a) 2-(benzyloxy)-3-bromobenzaldehyde 18a

To a solution of 3-bromo-2-hydroxybenzaldehyde (6.03 g, 30.0 mmol) and triethylamine (12.4 ml_, 89.1 mmol) in DCM (100 ml_) was added (bromomethyl)benzene (6.63 g, 39.0 mmol) dropwise and the mixture stirred at room temperature for 17 h. The mixture was diluted with DCM (100 ml_), washed with water (200 ml_ x 2), brine (100 ml_) and concentrated under reduced pressure. The residue was purified via chromatography (0-5% EtOAc in petroleum ether) to give a white solid of 2-(benzyloxy)-3-bromobenzaldehyde 18a (6.0g, 70%). TLC: R _f = 0.60 (silica gel, petroleum ether/EtOAc = 20:1, v/v). ¹ H NMR (Method E) (CDC ): δ ppm 10.1 (d, J = 0.63 Hz, 1H), 7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.44 (m, 2H), 7.42-7.37 (m, 3H), 7.15 (m, 1H), 5.14 (s, 2H). b) 6-[2-(benzyloxy)-3-formylphenyl]pyridine-2-carbonitrile 18b To a solution of 2-(benzyloxy)-3-bromobenzaldehyde 18a (6.00 g, 20.6 mmol) and bis(pinacolato)diboron (6.10g and 24.0 mmol) in dioxane (60 mL), was added KOAc (6.00 g, 61.2 mmol) and Pd(PP i3) ₄ (700 mg, 0.0 mmol). The mixture was heated at reflux for 3 h. The mixture was cooled to room temperature and 6-chloropyridine-2-carbonitrile (2.20 g, 16.0 mmol), K ₂ C0 ₃ (8.18 g, 60 mmol), Pd(PPh ₃ )4 (700 mg, 6.0 mmol) and water (20 mL) were added and the mixture heated to reflux for 17 h. The solvent was removed under reduced pressure and the resulting residue was diluted with water (100 mL) and then extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/EtOAc, 10: 1 to 5: 1 , v/v) to give a pale yellow solid of 6-[2-(benzyloxy)-3-formylphenyl]pyridine-2-carbonitrile 18b (1.60 g, 33%). TLC: R _f = 0.20 (silica gel, petroleum ether/EtOAc = 10: 1 , v/v). ¹ H NMR (Method E) (CDC ): δ ppm 10.30 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 7.96 (d, J = 7.7 Hz, 1 H), 7.84 (t, J = 7.8 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.70 Hz, 1 H), 7.30 (m, 3H), 7.09 (d, J = 6.9 Hz, 2H), 4.75 (s, 2H). c) 6-(3-formyl-2-hydroxyphenyl)pyridine-2-carbonitrile 18c

To a solution of 6-[2-(benzyloxy)-3-formylphenyl]pyridine-2-carbonitrile 18b (1.6 g, 5.10 mmol) in EtOH (230 mL) was added palladium on carbon (10%, 160 mg, 0.15 mmol) and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/EtOAc, 5: 1 to 3: 1 , v/v) to give a yellow solid of 6-(3-formyl-2-hydroxyphenyl)pyridine-2-carbonitrile 18c (800 mg, 70%). TLC: R _f = 0.7 (silica gel, petroleum ether/EtOAc = 10: 1 , v/v). LC-MS (Method D) 225.1 [M+H] ⁺ ; RT 4.31 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 12.6 (s, 1 H), 10.30 (s, 1 H), 8.45 (dd, J = 8.3, 0.8 Hz, 1 H), 8.28-8.21 (m, 2H), 8.09 (dd, J = 7.6, 0.8 Hz, 1 H), 7.90 (dd, J = 7.6, 1.7 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H). d) 6-[3-({[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-2- hydroxyphenyl]pyridine-2-carbonitrile 18d

A mixture of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (220 mg, 0.53 mmol) and 6-(3-formyl-2-hydroxyphenyl)pyridine-2-carbonitrile 18c (1 19 mg, 0.53 mmol) in DCE (20 mL) was stirred at room temperature for 0.5 h. NaBH(OAc)3 (450 mg, 2.12 mmol) was added and stirred at room temperature for 17 h. The mixture was diluted with DCM (30 mL), washed with water, brine and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 50:1 to 20:1, v/v) to give a yellow solid of 6-[3- ({[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1,4]oxazin- 6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}methyl)-2-hy droxyphenyl]pyridine-2- carbonitrile 18d (320 mg, 95%). TLC: R _f = 0.38 (silica gel, DCM/MeOH =20:1, v/v). LC-MS (Method D) 633.2 [M+H] ⁺ ; RT 3.79 min. ¹ H NMR (Method E) (CDCb): δ ppm 8.18 (d, J= 8.4 Hz, 1H), 7.95 (t, J= 8.0 Hz, 1H), 7.74 (m, 2H), 7.64 (d, J= 7.5 Hz, 1H), 7.33-7.24 (m, 2H), 7.19 (d, J= 8.5 Hz, 2H), 6.93 (t, J =7.7 Hz, 1H), 6.82 (d, J= 8.6 Hz, 2H), 5.24 (d, J= 14.7 Hz, 1H), 5.12 (d, J= 14.7 Hz, 1H), 4.71 (s, 2H), 4.40 (m, 1H), 3.98 (s, 2H), 3.76 (s, 3H), 2.85 (m, 1H), 2.54 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65 (m, 1H).1.33-1.09 (m, 3H). e) 6-[3-({[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}methyl)-2-hydroxyphenyl]pyridine-2- carbonitrile 18

To a solution of 6-[3-({[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-2-oxo-octahydro-1,3-benzoxazo l-6-yl]amino}methyl)-2- hydroxyphenyl]pyridine-2-carbonitrile 18d (320 mg, 0.50 mmol) in DCM (3 mL) was added TFA (2.0 mL, 26.1 mmol) and CF3SO3H (1.0 mL, 11.3 mmol). The resulting mixture was stirred at room temperature for 1 h. Water (40 mL) was added and the pH adjusted to pH 8- 9 with saturated aqueous Na2C03 and extracted with DCM (20 mL x 3). The combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH, 100:1 to 10:1, v/v) to give a white solid of 6-[3-({[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-6-yl ]amino}methyl)-2- hydroxyphenyl]pyridine-2-carbonitrile 18 (180 mg, 70%). TLC: Rf = 0.40 (silica gel,

DCM/MeOH = 10:1, v/v). LC-MS (Method C) 513.2 [M+H] ⁺ ; RT2.79 min. ¹ H NMR (Method E) (CDCb): δ ppm 8.18 (d, J= 8.4 Hz, 1H), 7.95 (t, J= 8.0 Hz, 1H), 7.79-7.72 (m, 2H) 7.64 (d, J= 7.5 Hz, 1H), 7.29 (m, 2H), 6.93 (t, J= 7.7 Hz, 1H), 4.73 (m, 1H), 4.62 (m, 2H), 4.54 (m, 1H), 3.98 (s, 2H), 2.89 (m, 1H), 2.59-2.48 (m, 2H), 2.00 (m, 1H), 1.66 (m, 1H), 1.42 (m, 1H), 1.22 (m, 1H).

Example 19:-

1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1(2-aminoethyl)amino)ethyl)-2-oxo-1 ,2-dihvdroquinoline-7-carbonit rile

a) tert- butyl

N-(2-{[(3aR,6R7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H^yrido[3,2-b][1 ,4]oxa zin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)et hyl]amino}ethyl)carbamate 19a

A solution of

1 -(2-{[(3aR,6R7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 60a (180 mg, 0.29 mmol) and te/f-butyl N-(2-oxoethyl)carbamate (189 mg, 1.18 mmol) in DCM (5 mL) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (307 mg, 1.45 mmol) was added and stirred for 17 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 (10 mL), extracted with DCM (2 x 25 mL), passed through an SPE phase separator and the organic portion concentrated under reduced pressure to give te/f-butyl

N-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxa zin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)et hyl]amino}ethyl)carbamate 19a (230 mg, 104%) which was used without further purification. LC-MS (Method A) 764.3 [M+H] ⁺ ; RT 3.32 min. b)

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 19 To a stirring solution of te/f-butyl

N-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxa zin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)et hyl]amino}ethyl)carbamate 19a (230 mg, 0.30 mmol) in DCM (20 mL) was added TFA (0.15 ml_) followed by CF3SO3H (0.08 mL). The reaction was stirred at room temperature for 90 min then quenched with MeOH (10 mL) and basified to pH 9 with saturated Na2CC>3. The resulting mixture was diluted with 20 mL DCM, passed through an SPE phase separator and the organic portion was concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-20% MeOH in DCM to give

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b] [1,4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-2-oxo-1,2-dihydro quinoline-7-carbonitrile 19 (7 mg, 4%). LC-MS (Method B) 544.3 [M+H] ⁺ ; RT 5.68 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.15 (s, 1H), 8.12 (d, J= 9.5 Hz, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.77 (dd, J= 7.9, 1.3 Hz, 1H), 7.48 (d, J= 8.6 Hz, 1H), 7.23 (d, J= 8.6 Hz, 1H), 6.90 (d, J= 9.5 Hz, 1H), 4.68 (s, 2H), 4.45-4.39 (m, 2H), 4.05 (td, J= 11.5, 3.4 Hz, 1H), 3.75 (td, J= 11.1, 3.3 Hz, 1H), 3.01- 2.91 (m, 1H), 2.89-2.77 (m, 6H), 2.27 (m, 1H), 1.82 (m, 1H), 1.66 (q, J= 11.3 Hz, 1H), 1.47- 1.27 (m, 3H).

Example 20:- 1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-yl1amino)ethyl)-7-hvdroxy-1,2 -dihvdroquinolin-2-one

20

a) 2-(7-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde 20a

To a solution of 1-(2,2-diethoxyethyl)-7-hydroxy-1,2-dihydroquinolin-2-one 9d (1 g, 4 mmol) in THF (10 mL) was added aqueous HCI (2.0 M, 10 mL). The mixture was heated at reflux for 1 h then allowed to cool. Excess THF was removed under reduced pressure and the resultant yellow precipitate was filtered, washed with water and dried in vacuo to afford 2- (7-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde 20a (848 mg, 104%). ¹ H NMR (Method C) (DMSO-d6): δ ppm: 10.27 (s, 1H), 9.63 (s, 1H), 7.84 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1 H), 6.76 (dd, J = 8.5, 2.1 Hz, 1 H), 6.65 (s, 1 H), 6.39 (d, J = 9.3 Hz, 1 H), 5.14 (s, 2H). b) 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-hydroxy-1 ,2- dihydroquinolin-2-one 20b

2-(7-hydroxy-2-oxo-1 ,2-dihydroquinolin-1-yl)acetaldehyde 20a (146 mg, 0.72 mmol) and (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (305 mg, 0.72 mmol) were dissolved in DCM (8 ml_) . Molecular sieves (4A) were added and the mixture stirred at room temperature for 10 min followed by the addition of NaBH(OAc)3 (457 mg, 2.16 mmol). After 3 h, 2-(7-hydroxy-2-oxo-1 ,2-dihydroquinolin-1-yl)acetaldehyde 20a (50 mg, 0.25 mmol) and NaBH(OAc)3 (152 mg, 0.72 mmol) were added and stirring continued for 17 h. The reaction was quenched with saturated aqueous NaHCC and the mixture passed through a SPE phase separator. The DCM fraction was evaporated and the residue purified by

chromatography eluting with 0-100 % EtOAc in petroleumether followed by 0-20% MeOH in EtOAc to afford 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-hydroxy-

1.2- dihydroquinolin-2-one 20b (161 mgs, 36.6%) as a white solid. LC-MS (Method A) 612.1 [M+H] ⁺ ; RT 2.34 min. c) 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

1.3- benzoxazol-6-yl]amino}ethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 20

TFA (0.3 ml_, 3.92 mmol) and CF3SO3H (0.08 ml_, 0.85 mmol) were added to a stirred solution of 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-hydroxy-1 ,2- dihydroquinolin-2-one 20b (60 mg, 0.1 mmol) in DCM (15 ml_) at room temperature. After 1 h the reaction was diluted with MeOH (5 ml_) and DCM (10 ml_). Saturated aqueous Na2C03was added adjusting the pH to 8 and the mixture was passed through a SPE phase separator. The aqueous phase was further extracted with 5:1 DCM/MeOH (2 x 30 ml_) and the combined organic extracts evaporated. The residue was purified by chromatography (0- 20% MeOH in DCM) to afford 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-hydroxy-1 ,2- dihydroquinolin-2-one 20 (27 mg, 50%) as a white solid. LC-MS (Method B) 492.1 [M+H] ⁺ ; RT5.06 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.22 (s, 1H), 10.24 (s, 1H), 7.76 (d, J = 9.4 Hz, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 6.90 (d, J= 2.2 Hz, 1H), 6.73 (dd, J= 8.5, 2.1 Hz, 1H), 6.34 (d, J= 9.3 Hz, 1H), 4.62 (s, 2H), 4.19 (m, 2H), 4.05 (td, J= 11.8, 3.3 Hz, 1H), 3.76 (td, J= 11.2, 3.3 Hz, 1H), 2.79 (m, 3H), 2.52 - 2.45 (m, 3H), 1.49 (m, 1H), 1.32 - 1.17 (m, 2H).

Example 21 :-

1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-yl1amino)ethyl)-7-methoxy-1,2-dihvdroquinox alin-2-one

a)

1- (2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7- methoxy-1,2-dihydroquinoxalin-

2- one 21a

A solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-2-on e 1c (136 mg, 0.32 mmol) and 2-(7-methoxy-2-oxo-1,2-dihydroquinoxalin-1-yl)acetaldehyde (prepared as described in WO2013080156A1) (70 mg, 0.32 mmol) in DCM (10 ml_)was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (340 mg, 1.60 mmol) was added and stirred for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHCC (5 ml_) and passed through an SPE phase separator. The organic phase was concentrated under reduced pressure to give

1- (2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7- methoxy-1,2-dihydroquinoxalin-

2- one 21a (160 mg, 79%) which was used without further purification. LCMS (Method A) 627.3 [M+H] ⁺ ; RT 2.24 min. b)

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-2-one 21

To a stirring solution of

1- (2-{[(3aR,6R7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H, 4H-pyrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7- methoxy-1,2-dihydroquinoxalin-

2- one 21a (160 mg, 0.26 mmol) in DCM (30 ml_) was added TFA (0.6 ml_) followed by CF3SO3H (0.15 mL). The reaction was stirred at room temperature for 90 min then quenched with MeOH (5 mL), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1,2-dihydroquinoxalin -2-one 21 (31.9 mg, 25%). LC-MS (Method B) 507.2 [M+H] ⁺ ; RT 5.18 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.21 (s, 1H), 8.05 (s, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.09 (d, J= 2.5 Hz, 1H), 7.01 (dd, J= 8.9, 2.5 Hz, 1H), 4.61 (s, 2H), 4.26 (t, J = 7.0 Hz, 2H), 4.03 (td, J= 11.8, 3.4 Hz, 1H), 3.92 (s, 3H), 3.74 (td, J= 11.1, 3.3 Hz, 1H), 2.87-2.84 (m, 2H), 2.80-2.63 (m, 2H), 2.4 (m, 1H), 2.13 (br. s, 1H), 1.96 (m, 1H), 1.45 (q, J = 11.1 Hz, 1H), 1.36-1.26 (m, 1H), 1.25-1.15 (m, 1H).

Example 22:-

1-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-yl1amino)ethyl)-6J-difluoro-1,2-dihvdroquin oxalin-2-one

a)

1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}et hyl)-6,7-difluoro-1,2-dihydroqu inoxalin-2-one 22a To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (133 mg, 0.31 mmol) and 2-(6,7-difluoro-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (prepared as described in WO2008009700 A1 20080124) (70 mg, 0.31 mmol) in DCM (15 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (331 mg, 1.56 mmol) was added and stirred for 17 h. The molecular sieves were filtered through Celite and washed with DCM/MeOH. The filtrate was basified to pH 8-9 with saturated aqueous NaHCC and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin -2-one 22a (120 mg, 61 %) which was used without further purification. LC-MS (Method A) 633.1 [M+H] ⁺ ; RT 2.24 min. b) 1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 22

To a stirring solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin -2-one 22a (120 mg, 0.19 mmol) in DCM (20 ml_) was added TFA (0.6 ml_) followed by CF3SO3H (0.15 ml_). The reaction was stirred at room temperature for 90 min then quenched with MeOH (5 ml_), diluted with DCM (10 ml_), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 22 (24.4 mg, 25%). LC-MS (Method B) 513.1 [M+H] ⁺ ; RT 5.20 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.17 (s, 1 H), 8.25 (s, 1 H), 7.98-7.89 (m, 2H), 7.50 (d, J = 8.8 Hz, 1 H), 7.4 (d, J = 8.6 Hz, 1 H), 4.75-4.72 (m, 1 H), 4.60 (s, 2H), 4.47-4.43 (m, 1 H), 4.25-4.18 (m, 2H), 2.84-2.81 (m, 2H), 2.70-2.62 (m, 1 H), 2.43 (m, 1 H), 2.24-2.17 (m, 1 H), 1.98 (br. s, 1 H), 1.76-1.71 (m, 1 H), 1.52-1.45 (m, 1 H), 1.31-1.20 (m, 1 H), 0.98-0.90 (m, 1 H). Example 23:- 1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)ethyl)-7-(2-aminoethoxy)-1 ,2-dihvdroquinolin-

2-one

23

a) N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}ethyl)carbamate 23a te/f-Butyl N-(2-hydroxyethyl)carbamate (0.03 mL, 0.16 mmol), triphenylphosphine (42.9 mg, 0.16 mmol) and DIAD (0.04 mL, 0.21 mmol) were added to a stirred solution of 1 -(2- {[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H -pyrido[3,2-b][1 ,4]oxazin-6- yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 20b (100 mg, 0.16 mmol) in DCM (3 mL) at room temperature. The reaction was stirred for 3 h and purified directly by chromatography eluting with 0-100 % EtOAc in petroleum ether followed by 0-20% MeOH in EtOAc to afford N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 23a (46 mg, 37%) as an off white solid. LC-MS (Method A) 755.2 [M+H] ⁺ ; RT 2.98 min. b) 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydroquinolin-2-one 23

TFA (0.2 mL, 2.61 mmol) and CF3SO3H (0.05 mL, 0.57 mmol) were added to a stirred solution of N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}ethyl)carbamate 23a (46 mg, 0.06 mmol) in DCM (15 mL). After 1 h the reaction was diluted with MeOH (250 ml_) and loaded onto an ion exchange cartridge (10g Isolute SCX-2).The column was flushed with MeOH and DCM followed by methanolic ammonia solution (1.5 M, 50 ml_). The ammoniacal fraction was evaporated and the residue purified by chromatography (1 1g Biotage KP-NH cartridge) eluting with 0-100% EtOAc in petroleum ether followed by 0-10% MeOH in EtOAc to give 1-(2-{[(3aR,6R,7aR)- 2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-(2-aminoethoxy)-1 ,2-dihydroquinolin-2-one 23 (2.7 mg, 8.3%). LC-MS (Method B) 535.1 [M+H] ⁺ ; RT 4.09 min. NMR (Method C) (DMSO-d6): δ ppm: 7.79 (d, J = 9.6 Hz, 1 H), 7.61 (d, J = 8.7 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 7.01 (s, 1 H), 6.88 (d, J = 10.2 Hz, 1 H), 6.39 (d, J = 9.5 Hz, 1 H), 4.59 (s, 2H), 4.22 (t, J = 7.5 Hz, 2H), 4.02-3.92 (m, 4H), 3.72 (t, J = 1 1.1 Hz, 1 H), 2.91 (m, 2H), 2.82-2.64 (m, 5H), 1.97 (m, 2H), 1.54 - 1.40 (m, 2H).

Example 24:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 3-benzoxazol-6-vnamino)ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-2-one

24

a)

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroqui noxalin-2-one 24a

To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (136 mg, 0.32 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (prepared as described in WO2013080156 A1 20130606) (70 mg, 0.32 mmol) in DCM (10 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (340 mg, 1.60 mmol) was added and stirred for 4 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 (5 mL) and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 - (2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-

2- one 24a (175 mg, 88%) which was used without further purification. LC-MS (Method A) 627.3 [M+H] ⁺ ; RT 2.18 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-2-one 24

To a stirring solution of

1 - (2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-

2- one 24a (175 mg, 0.28 mmol) in DCM (30 mL) was added TFA (0.6 mL) followed by CF3SO3H (0.15 mL). The reaction was stirred at room temperature for 2.5 h, then quenched with MeOH (5 mL), basified to pH 8-9 with saturated Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and resulting residue purified via silica gel chromatography using 0-20% MeOH in DCM to give 1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydroquinoxalin-2-one 24 (57.2 mg, 41 %). LC-MS (Method B) 507.1 [M+H] ⁺ ; RT 5.20 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.18 (s, 1 H), 8.04 (s, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.09 (d, J = 2.5 Hz, 1 H), 7.00 (dd, J = 8.8, 2.5 Hz, 1 H), 4.76-4.73 (m, 1 H), 4.60 (s, 2H), 4.48-4.44 (m, 1 H), 4.29-4.19 (m, 2H), 3.92 (s, 3H), 2.86-2.81 (m, 2H), 2.71-2.66 (m, 1 H), 2.43 (m, 1 H), 2.26-2.23 (m, 1 H), 1.78-1.75 (m, 1 H), 1.97-2.12 (br s, 1 H), 1.54-1.48 (m, 1 H), 1.29-1.22 (m, 1 H), 1.02-0.92 (m, 1 H).

Example 25:-

1 -(2-fr(3aR,6R,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8 naphthyridin-2-one

a) benzyl N-[(1 R,2R,4R)-4-{[(fe/f-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25a

To a suspension of te/f-butyl N-[(1 R,3R,4R)-4-amino-3-hydroxy-cyclohexyl]carbamate (2.00 g, 8.68 mmol, (may be prepared according to the methods described in Example 1 a, steps 1 to 2)) in DCM (120 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (2.38 g, 9.55 mmol) and allowed to stir at 25°C for 20 hours. The reaction mixture was evaporated and the residue purified via column chromatography eluting with 0-10% MeOH in DCM to afford benzyl N-[(1 R,2R,4R)-4-{[(fe/f-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25a (1.97 g, 62%) as a white solid. LC-MS (Method A) 387.6 [M+Na] ⁺ ; RT 2.52 min. b) (1S,2R,5R)-2-{[(benzyloxy)carbonyl]amino}-5-{[(fe/f-butoxy)c arbonyl]amino}cyclohexyl 4-nitrobenzoate 25b

To a solution of benzyl

N-[(1 R,2R,4R)-4-{[(fe/f-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25a (1.97 g, 5.40 mmol) in anhydrous THF (60 mL) was added triphenylphosphine (1.56 g, 5.94 mmol) and 4-nitrobenzoic acid (0.99 g, 5.94 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (1.17 mL, 5.94 mmol) at 25°C. The reaction mixture was allowed to stir for 3 hours. The reaction mixture was evaporated to dryness, dissolved in EtOAc (200 mL), washed with water (100 mL), brine (100 mL) and dried over MgSCU. The crude product was purified via column chromatograph eluting with 0- 50% EtOAc in pet-ether to afford (1 S,2R,5R)-2-{[(benzyloxy)carbonyl]amino}-5-{[(fe/f-butoxy)car bonyl]amino}cyclohexyl 4-nitrobenzoate 25b (2.14 g, 77%) as a white solid. LC-MS (Method A) 512.3 [M-H]-; RT 3.45 min. c) benzyl N-[(1 R,2S,4R)-4-{[(tert-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25c

To a solution of

(1 S,2R,5R)-2-{[(benzyloxy)carbonyl]amino}-5-{[(fe/f-butoxy)car bonyl]amino}cyclohexyl 4-nitrobenzoate 25b (2.09 g, 4.07 mmol) in anhydrous THF (60 mL) was added 1 M lithium hydroxide solution (7.33 mL, 7.33 mmol) and the reaction was allowed to stir at 25°C for 3 hours. The reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL) and dried over MgSCU to afford benzyl

N-[(1 R,2S,4R)-4-{[(fe/f-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25c (1.42 g, 95%) as a cream solid. LC-MS (Method A) 387.1 [M+Na] ⁺ ; RT 2.69 min. d) te/f-butyl N-[(1 R,3S,4R)-4-amino-3-hydroxycyclohexyl]carbamate 25d To a solution of benzyl

N-[(1 R,2S,4R)-4-{[(fe/f-butoxy)carbonyl]amino}-2-hydroxycyclohexy l]carbamate 25c (1.36 g, 3.73 mmol) in ethanol (100 mL) was added 10% Pd/C paste (100 mg, 0.94 mmol) and the reaction mixture was allowed to stir for 20 hours at 25°C under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite, washed with ethanol (100 mL) and the filtrate evaporated to dryness to afford te/f-butyl

N-[(1 R,3S,4R)-4-amino-3-hydroxycyclohexyl]carbamate 25d (0.85 g, 99%) as a cream solid. e) te/f-butyl N-[(3aR,6R,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25e

To a mixture of te/f-butyl N-[(1 R,3S,4R)-4-amino-3-hydroxycyclohexyl]carbamate 25d (850 mg, 3.69 mmol) and triethylamine (1.54 mL, 1 1.07 mmol) in anhydrous THF (50 mL) was added triphosgene (438.15 mg, 1.48 mmol) and the mixture was allowed to stir at 25°C for 24 hours. The reaction temperature was increased to 60°C and heated for a further 5 hours. The reaction mixture was evaporated to dryness, taken up into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (50 mL) and dried over MgSCU to give a crude solid. The solid was triturated with diethyl ether and filtered to afford te/f-butyl

N-[(3aR,6R,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25e (177 mg, 19%) as a cream solid. f) terf-butyl

N-[(3aR,6R7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H ^yrido[3,2-b][1 ,4]oxazin 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25f

To a mixture of te/f-butyl N-[(3aR,6R,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25 e (177 mg, 0.69 mmol) , 6-bromo-4-[(4-methoxyphenyl)methyl]-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-3-one (prepared as described in WO2014108832) (313.49 mg, 0.90 mmol), potassium carbonate (190.89 mg, 1.38 mmol) in anhydrous 1 ,4-dioxane (25 ml_) under nitrogen was added copper(l) iodide (26.31 mg, 0.14 mmol) and then (±)-trans-1 ,2- diaminocyclohexane (3.28 uL, 0.03 mmol) a few minutes later. The reaction mixture was heated at 1 10°C for 4 days. The reaction mixture was diluted with water (50 ml_) and extracted with EtOAc (2 x 75 ml_). The combined organics were washed with brine (50 ml_) and dried over MgS0 ₄ . The crude was purified via column chromatography eluting with 0- 100% EtOAc in pet-ether followed by 0-50% EtOAc in DCM to afford te/f-butyl

N-[(3aR,6R,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25 f (163 mg, 45%) as a white solid. LC-MS (Method A) 525.2 [M+H] ⁺ ; RT 3.22 min.

9)

(3aR,6R,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1 ,4]o xazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 25g

To a solution of te/f-butyl

N-[(3aR,6R,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 25f (147 mg, 0.28 mmol) in DCM (25ml_) was added trifluoroacetic acid (2.0 ml_, 26.12 mmol) and the reaction mixture was allowed to stir at 25°C for 3 hours. The reaction mixture was carefully quenched with sat. sodium carbonate solution (25 ml_), diluted with DCM (50 ml_) and the layers separated. The aqueous layer was extracted with DCM (50 ml_) and the combined organics washed with brine (30 ml_) then dried over MgS0 ₄ to afford

(3aR,6R,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1 ,4]o xazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 25g (103 mg, 87%) as a beige solid. LC-MS (Method A) 425.1 [M+H] ⁺ ; RT 1.99 min. h)

1 -(2-{[(3aR _I 6R _I 7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H _I 4H-pyrido[3 _I 2-b][1 _I 4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napht hyridin-2-one 25h

To a mixture of

(3aR,6R7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]o xazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 25g (89 mg, 0.21 mmol) and 2-(7-methoxy-2- oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)acetaldehyde (prepared as described in

WO2008009700) (45.76 mg, 0.21 mmol) in DCM (10 mL) (with some molecular sieves) was added a few drops of acetic acid and allowed to stir at 25°C for 24 hours. To the reaction mixture was added sodium triacetoxyborohydride (133.32 mg, 0.63 mmol) and allowed to stir for a further 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with sat sodium carbonate solution (30 mL). The aqueous layer was extracted with DCM (2 x 50 mL), the combined organics washed with brine (50 mL) and dried over MgS0 ₄ to afford crude

1 -(2-{[(3aR,6R,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napht hyridin-2-one 25h (95 mg, 0.15 mmol, 72%) as a beige solid. LC-MS (Method A) 627.2 [M+H] ⁺ ; RT 2.88 min. i)

1 -(2-{[(3aR,6R,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 25

To a solution of

1 -(2-{[(3aR,6R,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napht hyridin-2-one 25 h (95 mg, 0.15 mmol) in DCM (10 mL) under nitrogen at 25°C was added trifluoroacetic acid (174 uL, 2.27 mmol) followed by trifluoromethanesulfonic acid (67 uL, 0.76 mmol). The reaction mixture was allowed to stir for 1 hour and then diluted with MeOH (1 mL) followed by the careful addition of sat. sodium carbonate solution (30 mL). The mixture was diluted with DCM (50 mL), the layers separated and the aqueous extracted with DCM (2 x 50 mL). The combined organics were washed with brine (30 mL) and dried over Na2S0 ₄ to give a crude solid. The crude was purified by column chromatography eluting with 0-20% MeOH in DCM to afford 1 -(2-{[(3aR,6R,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 25 (44 mg, 57%) as a white solid. LC-MS (Method A) 507.1 [M+H] ⁺ ; RT 2.29 min.

1 H NMR (Method C) (DMSO-d6): δ ppm 1 1.2 (br s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 9.6 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.52 (d, J = 9.2 Hz, 1 H), 4.85-4.75 (m, 1 H), 4.60 (s, 2H), 4.53-4.41 (m, 3H), 4.00 (s, 3H), 3.00-2.70 (m, 3H), 2.40-2.29 (m, 1 H), 1.83-1.75 (m, 1 H), 1.60-1.50 (m, 1 H), 1.32-1.22 (m, 2H), 1.05-0.95 (m, 1 H).

Example 26:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vnamino)ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2-one

a)

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydroquino xalin-2-one 26a

To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (144 mg, 0.34 mmol) and 2-(7-fluoro-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (prepared as described in W02008009700 A1 20080124) (70 mg, 0.34 mmol) in DCM (15 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (340 mg, 1.60 mmol) was added and stirred for 17 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2- one 26a (195 mg, 93%) which was used without further purification. LC-MS (Method A) 615.2 [M+H] ⁺ ; RT 2.23 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2-one 26

To a stirring solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2- one 26a (195 mg, 0.32 mmol) ) in DCM (30 ml_) and MeOH (5 ml_) was added TFA (0.85 ml_) followed by CF3SO3H (0.2 ml_). The reaction was stirred at room temperature for 45 min then quenched with MeOH (5 ml_), diluted with DCM (10 ml_), basified to pH 8-9 with saturated Na2C03 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2-one 26 (43 mg, 28%). LC-MS (Method B) 495.1 [M+H] ⁺ ; RT 4.94 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.18 (s, 1 H), 8.19 (s, 1 H), 7.88 (dd, J = 8.9, 6.1 Hz, 1 H), 7.62 (dd, J = 1 1.2, 2.6 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 7.24 (td, J = 8.5, 2.6 Hz, 1 H), 4.75-4.73 (m, 1 H), 4.60 (s, 2H), 4.48-4.44 (m, 1 H), 4.29-4.16 (m, 2H), 2.83 (br s, 2H), 2.24-2.21 (m, 1 H), 2.01 (m, 1 H), 1.75 (m, 1 H), 1.50 (m, 1 H), 1.25 (m, 2H), 0.96 (m, 1 H).

Example 27:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vnamino)ethyl)-7-methyl-1 ,2-dihydroquinoxalin-2-one

27

a) 7-bromo-1-(2,2-diethoxyethyl)-1 ,2-dihydroquinoxalin-2-one 27a 7-bromo-1 ,2-dihydroquinoxalin-2-one (12.1 g, 53.77 mmol), 2-bromo-1 , 1-diethoxyethane (7.6 mL, 50.74 mmol) and CsCOs (19.3 g, 59.15mmol) were added to DMF (100 mL) and heated at 90°C for 17 h. H2O (200 mL) was added to the cooled mixture and extracted with diethyl ether (2 x 200 mL, mL). The combined organic extracts were dried over MgS0 ₄ , concentrated under reduced pressure and purified by silica gel chromatography using 50 - 60 % Et20 in petroleum ether. The orange residue was mixed with 50% Et20 in heptane and the precipitate filtered to give 7-bromo-1-(2,2-diethoxyethyl)-1 ,2-dihydroquinoxalin-2- one (5.9 g, 17.3 mmol, 32% yield) as a yellow solid. LC-MS (Method A) 341 , 343 [M+H] ⁺ ; RT 3.13 min.

b) 1 -(2,2-diethoxyethyl)-7-methyl-1 ,2-dihydroquinoxalin-2-one 27b

A mixture of 7-bromo-1-(2,2-diethoxyethyl)-1 ,2-dihydroquinoxalin-2-one 27a (2.0 g, 5.86 mmol), CsCOs (5.72 g, 17.6 mmol), XPhos-Pd-G2 (230 mg, 0.29 mmol) and

trimethylboroxine (2.21 g, 17.59 mmol) in dioxane (50 mL) and water (4 mL) was stirred at 100 °C for 17 h. The reaction was allowed to cool, diluted with water (70 mL) and extracted with Et20 (2 x 70 mL). The combined organic extracts were dried over MgS04,

concentrated under reduced pressure and purified by silica gel chromatography using 10- 50% Et20 in heptane to afford 1-(2,2-diethoxyethyl)-7-methyl-quinoxalin-2-one 27a (1.28 g, 4.54 mmol, 77%) as a yellow gum. ¹ H NMR (Method C) (CDC ): δ ppm 8.23 (s, 1 H), 7.72 (d, J = 1.5 Hz, 1 H), 7.46 (s, 1 H), 7.14 (d, J = 1.5 Hz, 1 H), 4.82 (t, J = 1.2 HZ, 2H), 4.35 (d, J = 7.2 HZ, 1 H), 3.8 - 3.73 (m, 2H), 3.55 - 3.47 (m, 2H), 2.49 (s, 3H), 1.14 -1.09 (t, J = 1.5 HZ, 6H). c) 2-(7-methyl-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde 27c

1 - (2,2-diethoxyethyl)-7-methyl-1 ,2-dihydroquinoxalin-2-one 27b (1.28 g, 4.63 mmol) was added to a mixture of aqueous HCI (3 N, 20 mL) and THF (20 mL) and heated at reflux for 17 h. After cooling, H2O (100 mL) was added and the mixture extracted with EtOAc (2 x 75 ml). The combined organic extracts were dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford an orange solid. The solid was purified by silica gel chromatography using 10-50% Et20 in petroleum ether to afford

2- (7-methyl-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde 27c (0.75 g, 80%) as an orange solid. LC-MS (Method A) 203.1 [M+H] ⁺ ; RT 1.65 min. ¹ H NMR (Method C) (CDCb): δ ppm 9.71 (s, 1 H), 8.21 (s, 1 H), 7.74 (d, J = 1.5 Hz, 1 H), 7.34 (s, 1 H), 7.22 (d, J = 1.5 Hz, 1 H), 5.26 (s, 2H), 2.43 (s, 3H). d)

1 - (2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H, 4H^yrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methyl-1 ,2-dihydroquinoxalin-2- one 27d

A solution of 6-[(3R, 6S)-6-amino-2-oxo-3a,4,5,6,7,7a-hexahydro-1 ,3-benzoxazol-3-yl]-4H- pyrido[3,2-b][1 ,4]oxazin-3-one 4c (105 mg, 0.25 mmol) and

2- (7-methyl-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde 27c (50 mg, 0.25 mmol) in DCM (10 ml_) was stirred over molecular sieves (3A) for 2 h. NaBH(OAc)3 (262 mg, 1.25 mmol) was added and stirring continued for 2 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a

re1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methyl-1 ,2-dihydroquinoxalin -2-one 27d (176 mg, 1 17%) which was used without further purification. LC-MS (Method A) 611.2 [M+H] ⁺ ; RT 2.24 min. e)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methyl-1 ,2-dihydroquinoxalin-2-one 27

To a stirring solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methyl-1 ,2-dihydroquinoxalin-2- one 27e (176 mg, 0.29 mmol) in DCM (30 ml_) was added TFA (0.78 ml_) followed by CF3SO3H (0.18 ml_). The reaction was stirred at room temperature for 45 min, diluted with MeOH (8 ml_) followed by DCM (20 ml_), basified to pH 8-9 with saturated aqueous

Na2C03 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methyl-1 ,2-dihydroquinoxalin-2-one 27 (55 mg, 39%). LC- MS (Method B) 491.1 [M+H] ⁺ ; RT 5.07 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.18 (s, 1 H), 8.15 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.50 (s, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 7.21 (dd, J = 8.1 , 1.6 Hz, 1 H), 4.76-4.74 (m, 1 H), 4.64-4.58 (m, 2H), 4.49- 4.44 (m, 1 H), 4.27-4.24 (m, 2H), 2.84 (m, 2H), 2.70 (m, 1 H), 3.52 (m, 1 H), 2.54 (s, 3H), 2.27-2.20 (m, 1 H), 1.94-2.06 (br. s, 1 H), 1.77 (m, 1 H), 1.56-1.46 (m, 1 H), 1.33-1.22 (m, 1 H), 1.03-0.91 (m, 1 H).

Example 28:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5 naphthyridin-2-one

a)

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5-n aphthyridin-2-one 28a

A solution of 6-[(3R, 6S)-6-amino-2-oxo-3a,4,5,6,7,7a-hexahydro-1 ,3-benzoxazol-3-yl]-4H- pyrido[3,2-b][1 ,4]oxazin-3-one 4c (144 mg, 0.34 mmol) and

2-(7-fluoro-2-oxo-1 ,2-dihydro-1 ,5-naphthyridin-1 -yl)acetaldehyde (prepared as described in W02012108376 A1 20120816) (70 mg, 0.34 mmol) in DCM (20 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (287 mg, 1.36 mmol) was added and stirred for 2 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure to give

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5-naphthyr idin-2-one 28a (250 mg, 120%) which was used without further purification. LC-MS (Method A) 615.1 [M+H] ⁺ ; RT 2.24 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5-naphthyridin-2-one 28

To a stirring solution of

1 -(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H^yrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5-naphthyr idin-2-one 28a (250 mg, 0.41 mmol) in DCM (30 mL) was added TFA (1.10 mL) followed by CF3SO3H (0.25 mL). The reaction was stirred at room temperature for 1 h then quenched with MeOH (5 mL), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give 1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-fluoro-1 ,2-dihydro-1 ,5-naphthyridin-2-one 28 (89.7 mg, 45%). LC-MS (Method B) 495.1 [M+H] ⁺ ; RT 4.81 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.17 (s, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.12 (dd, J = 1 1.3, 2.5 Hz, 1 H), 7.95 (d, J = 9.5 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 9.8 Hz, 1 H), 4.75- 4.72 (m, 1 H), 4.60 (s, 2H), 4.47-4.43 (m, 1 H), 4.28-4.28 (m, 2H), 2.83-2.74 (m, 2H), 2.71- 2.61 (m, 1 H), 2.43 (m, 1 H), 2.26-2.17 (m, 1 H), 1.99 (br. s, 1 H), 1.74 (m, 1 H), 1.52-1.46 (m, 1 H), 1.31-1.20 (m, 1 H), 1.01-0.88 (m, 1 H).

Example 29:-

1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- -benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8 naphthyridin-2-one

a) te/f-butyl N-[(3aS,6S,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29a

To a suspension of te/f-butyl N-[(1S,3S,4S)-4-amino-3-hydroxycyclohexyl]carbamate (prepared from tert-butyl N-[(1S,3S,6R)-7-oxabicyclo[4.1.0]heptan-3-yl]carbamate using the methods described in example 1 a, steps 1 to 2) (500 mg, 2.17 mmol) in THF (5 mL) was added triethylamine (0.91 mL, 6.510 mmol) followed by careful addition of triphosgene (258 mg, 0.87 mmol) and the mixture was stirred at room temperature for 24 h. The reaction temperature was increased to 60 ^° C and stirred for a further 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was suspended in water and extracted with EtOAc (100 mL). The organic extracts were washed with brine, dried over MgSCU, filtered and concentrated under reduced pressure to give te/f-butyl

N-[(3aS,6S,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29a (493 mg, 75 %) as a white solid. ¹ H NMR (Method C) (DMSO-d6): δ ppm 7.59 (s, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 3.77 (td, J = 11.8, 3.5 Hz, 1 H), 3.49 (m, 1 H), 3.13 (td, J = 1 1.3, 3.5 Hz, 1 H), 2.18 (m, 1 H), 1.82 (m, 2H), 1.54 (q, J = 1 1.3 Hz, 1 H), 1.37 (s, 9H), 1.27 (m, 1 H). b) terf-butyl N-[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29b

To a mixture of te/f-butyl N-[(3aS,6S,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1 ,3- benzoxazol-6-yl]carbamate 29a (490 mg, 1.91 mmol), 6-bromo-4-[(4- methoxyphenyl)methyl]pyrido[3,2-b][1 ,4]oxazin-3-one (prepared as described in

WO2014108832) (868 mg, 2.49 mmol), K ₂ C0 ₃ (528 mg, 3.82 mmol) in anhydrous 1 ,4- Dioxane (45 mL) under nitrogen was added Cul (73 mg, 0.38 mmol) followed by trans-1 ,2- diaminocyclohexane (3.3 μί, 0.03 mmol) a few minutes later. The mixture was heated to 1 10 ^° C for 18 h under N ₂ . Another batch of Cul (73 mg, 0.38 mmol) and trans-1 ,2- diaminocyclohexane (3.3 μί, 0.03 mmol) was added and the mixture stirred at 1 10 ^° C for a further 50 h. The reaction was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with brine, dried over MgSCU, filtered and concentrated. The residue was purified by chromatography (Biotage 100 g KP-Si cartridge) using 0-100 % EtOAc in DCM to give te/f-butyl

N-[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29b (759 mg, 75 %) as a brown solid. LC-MS (Method A) 525.2 [M+H] ⁺ ; RT 3.23 min. ¹ H NMR (Method C) (CDC ): δ ppm 7.30 (m, 2H), 7.17 (m, 2H), 6.82 (m, 2H), 5.18 (m, 2H), 4.72 (s, 2H), 4.53 (m, 1 H), 3.94 (td, J = 1 1.5, 3.3 Hz, 1 H), 3.77 (s, 3H), 3.69 (td, J = 1 1.0, 3.3 Hz, 1 H), 2.63 (m, 1 H), 2.26 (m, 1 H), 2.03 (m, 1 H), 1.61 (q, J = 1 1.5 Hz, 1 H), 1.46 (s, 9H), 1.25 (m, 2H). c) (3aS,6S,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c To solution of te/f-butyl

N-[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29b (720 mg, 1.37 mmol) in DCM (25 ml_) was added TFA (2 ml_, 26.10 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3, then partitioned between brine and DCM. The organic phase was dried over MgS0 ₄ , filtered and concentrated to give

(3aS,6S,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (438 mg, 75 %), which was used without further purification. LC-MS (Method A) 425.2 [M+H] ⁺ ; RT 2.47 min. d) 1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydr

0- 1 ,8-naphthyridin-2-one 29d

To a solution of

(3aS,6S,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (210 mg, 0.49 mmol) and

2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1 -yl)acetaldehyde (108 mg, 0.49 mmol, prepared as described in WO2008009700) in DCM (20 ml_) was added a few drops of AcOH and the mixture stirred at room temperature for 18 h. NaBH(OAc)3 (314 mg, 1.48 mmol) was added and the reaction mixture stirred at room temperature for 30 min. The mixture was adjusted to pH 8-9 with saturated Na2C03 and extracted with DCM (150 ml_). The organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated to give

1 - (2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napht hyridin-2-one 29d, (298 mg, 96 %), which was used without further purification. LC-MS (Method A) 627.2 [M+H] ⁺ ; RT 2.90 min. e) 8-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-methoxy-7,8-dihydroquinoli n-7-one 29 To a solution of

1 -(2-{[(3aS,6S7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H^yrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napht hyridin-2-one 29d (290 mg, 0.46 mmol) in DCM (30 mL) was added TFA (531 μΙ_, 6.94 mmol) followed by CF3SO3H (204 μΙ_, 2.31 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH (1 mL) and the mixture was adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 mL). The organic extract was washed with brine, dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 10 g KP-Si cartridge) using 0-50 % MeOH in DCM to give

8-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-2-methoxy-7,8-dihydroquinolin-7 -one 29 (32 mg, 13 %) as an off-white solid. LC-MS (Method A) 507.1 [M+H] ⁺ ; RT 2.34 min. ¹ H NMR (Method C) (CDCI3): δ ppm 8.25 (s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 9.4 Hz, 1 H), 7.29 (d, J = 1.9 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1 H), 6.56 (d, J = 9.4 Hz, 1 H), 4.65 (t, J = 6.6 Hz, 2H), 4.59 (s, 2H), 4.04 (s, 3H), 3.95 (m, 1 H), 3.77 (td, J = 10.9, 3.4 Hz, 1 H), 3.15 (t, J = 6.6 Hz, 2H), 2.91 (m, 1 H), 2.63 (m, 2H), 2.13 (m, 1 H), 1.5 (q, J = 11.4, 1 H), 1.37 (m, 2H).

Example 30:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5 -naphthyridin-2-one

a)

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 , 5-naphthyridin-2-one 30a

A solution of 6-[(3R, 6S)-6-amino-2-oxo-3a,4,5,6,7,7a-hexahydro-1 ,3-benzoxazol-3-yl]-4H- pyrido[3,2-b][1 ,4]oxazin-3-one 4c (1 17 mg, 0.28 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,5-naphthyridin-1 -yl)acetaldehyde (prepared as described in WO201 1 148962A1) (60 mg, 0.28 mmol) in DCM (20 ml_) was stirred at room temperature over molecular sieves (3A) for 2 h. NaBH(OAc)3 (233 mg, 1.10 mmol) was added and stirred for 3 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-napht hyridin-2-one 30a (160 mg, 93%) which was used without further purification. LC-MS (Method A) 627.2 [M+H] ⁺ ; RT 2.23 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 30

To a stirring solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-napht hyridin-2-one 30a (160 mg, 0.26 mmol) in DCM (20 ml_) was added TFA (0.90 ml_) followed by CF3SO3H (0.20 ml_). The reaction was stirred at room temperature for 1 h then quenched with MeOH (5 ml_), diluted with DCM (10 ml), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 30 (83 mg, 51 %). LC-MS (Method B) 507.1 [M+H] ⁺ ; RT 4.70 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.18 (s, 1 H), 8.28 (d, J = 2.3 Hz, 1 H), 7.87 (d, J = 9.6 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.49 (s, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 6.66 (d, J = 9.7 Hz, 1 H), 4.76 (m, 1 H), 4.64-4.57 (m, 2H), 4.50-4.42 (m, 1 H), 4.32-4.25 (m, 2H), 3.98 (s, 3H), 2.81 (m, 2H), 2.69 (m, 1 H), 2.43 (m, 1 H), 2.24 (m, 1 H), 2.02 (br. s, 1 H), 1.76 (m, 1 H), 1.58-1.45 (m, 1 H), 1.32-1.19 (m, 1 H), 1.03-0.90 (m, 1 H). Example 31 :-

4-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino)ethyl)-3-oxo-3,4-dihvdroquinoxaline -6-carbonitrile

a)

4-(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxal ine-6-carbonitrile 31 a

A solution of 6-[(3R, 6S)-6-amino-2-oxo-3a,4,5,6,7,7a-hexahydro-1 ,3-benzoxazol-3-yl]-4H- pyrido[3,2-b][1 ,4]oxazin-3-one 4c (100 mg, 0.23 mmol) and

3- oxo-4-(2-oxoethyl)-3,4-dihydroquinoxaline-6-carbonitrile (prepared as described in WO 2006137485 A1 20061228) (50 mg, 0.23 mmol) in DCM (20 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (233 mg, 1.10 mmol) was added and stirred for 3 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure to give

4- (2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline -6-c arbonitrile 31 a (140 mg, 96%) which was used without further purification. LC-MS (Method A) 622.2 [M+H] ⁺ ; RT 2.29 min. b)

4-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline -6-carbonitrile 31

To a stirring solution of

4-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline -6-c arbonitrile 31 a (140 mg, 0.23 mmol) in DCM (14 ml_) was added TFA (0.60 ml_) followed by CF3SO3H (0.14 mL). The reaction was stirred at room temperature for 1 h then quenched with MeOH (5 mL), diluted with DCM (10 ml), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

4-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline-6- carbonitrile 31 (34 mg, 30%). LC-MS (Method B) 502.1 [M+H] ⁺ ; RT 5.10 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.17 (s, 1 H), 8.38 (s, 1 H), 8.28 (d, J = 1.3 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.77 (dd, J = 8.3, 1.6 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 4.75-4.73 (m, 1 H), 4.60 (m, 2H), 4.48-4.42 (m, 1 H), 4.28-4.25 (m, 2H), 2.84 (m, 2H), 2.62 (m, 1 H), 2.44 (m, 1 H), 2.22 (m, 1 H), 2.00 (m, 1 H), 1.74 (m, 1 H), 1.49 (m, 1 H), 1.25 (m, 1 H), 0.95 (m, 1 H).

Example 32:- 1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)ethyl)-7-r2-(dimethylamino)ethoxy1- 1 ,2- dih droquinolin-2-one

32

a) 1-(2,2-diethoxyethyl)-7-[2-(dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32a

Triphenylphosphine (179 mg, 0.68 mmol) and 2-(dimethylamino)ethan-1-ol (0.07 mL, 0.68 mmol) were added to a stirred solution of 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2- dihydroquinolin-2-one 9c (170 mg, 0.68 mmol) in DCM (2 mL) and cooled in an ice bath for 30 min. DIAD (0.17 mL, 0.89 mmol) was added and the mixture allowed to reach ambient temperature. After 17 h the mixture was purified by chromatography eluting with 0-100% EtOAc in petroleum ether and 0-10% MeOH in EtOAc to afford 1-(2,2-diethoxyethyl)-7-[2- (dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32a (61 mg, 28.5%). TLC: R _f = 0.31 (silica gel, MeOH/DCM = 1 : 9, v/v). LC-MS (Method A) 349.1 [M+H] ⁺ ; RT 1.48 min. b) 2-{7-[2-(dimethylamino)ethoxy]-2-oxo-1 ,2-dihydroquinolin-1-yl}acetaldehyde 32b

A solution of 1-(2,2-diethoxyethyl)-7-[2-(dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32a (105 mg, 0.30 mmol) in THF (1 ml_) and aqueous HCI (2M, 1 ml_) was stirred for 17 h at room temperature. The mixture was basified to pH 8 with saturated aqueous NaHCC>3. MeOH/DCM (1 :4, 50 ml_) was added and the mixture passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a brown oil of 2-{7-[2-(dimethylamino)ethoxy]-2-oxo-1 ,2-dihydroquinolin-1-yl}acetaldehyde 32b (90 mg, 108%). LC-MS (Method A) 275.11 [M+H] ⁺ ; RT 1.13 min. c) 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-[2- (dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32c

A solution of 2-{7-[2-(dimethylamino)ethoxy]-2-oxo-1 ,2-dihydroquinolin-1-yl}acetaldehyde 32b (90 mg, 0.33 mmol) in DCM (9 ml_) was stirred over molecular sieves (4A) at room temperature. After 15 min (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (133.5 mg, 0.31 mmol) and NaBH(OAc)3 (209 mg, 0.98 mmol) were added and the reaction stirred for 5 h. Saturated aqueous NaHC03 (5 ml_) was added and the mixture passed through an SPE phase separator. The organic phase was evaporated and the residue purified by chromatography eluting with 0-20% MeOH in DCM to give 1-(2-{[(3aR,6R,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-[2-(dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32c (75 mg, 34.8%) as a white solid. LC-MS (Method A) 683.3 [M+H] ⁺ ; RT 1.76 min. d) 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

1 ,3-benzoxazol-6-yl]amino}ethyl)-7-[2-(dimethylamino)ethoxy]- 1 ,2-dihydroquinolin-2-one 32

TFA (0.4 mL, 5.22 mmol) and CF3SO3H (0.1 mL, 1.13 mmol) were added to a stirred solution of 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-[2- (dimethylamino)ethoxy]-1 ,2-dihydroquinolin-2-one 32c (75 mg, 0.1 1 mmol) in DCM (15 mL) at room temperature. After 1h the reaction was diluted with MeOH (5 mL) and DCM (10 mL). Saturated aqueous NaaCC was added, adjusting the pH to 8, and the mixture was passed through an SPE phase separator. The aqueous phase was further extracted with DCM/MeOH (4:1, 2 x 30 mL) and the combined organics evaporated and the residue purified by chromatography eluting with 0-20% MeOH in DCM to give 1-(2-{[(3aR,6R,7aR)- 2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octah ydro-1,3-benzoxazol-6- yl]amino}ethyl)-7-[2-(dimethylamino)ethoxy]-1,2-dihydroquino lin-2-one 32 (20 mg, 29%). LC-MS (Method B) 563.2 [M+H] ⁺ ; RT 4.18 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.27 (s, 1H), 7.83 (d, J= 9.4 Hz, 1H), 7.64 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 8.7 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 7.06 (d, J= 2.3 Hz, 1H), 6.92 (dd, J= 8.5, 2.1 Hz, 1H), 6.43 (d, J = 9.3 Hz, 1H), 4.62 (s, 2H), 4.30 (t, J= 7.4 Hz, 2H), 4.23 (t, J =5.1 Hz, 2H), 4.05 (td, J= 11.7, 3.3 Hz, 1 H), 3.76 (dt, J= 11.0, 5.5 Hz, 1 H), 2.87 (m, 3H), 2.80 - 2.67 (m, 3H), 2.47 (m, 1 H), 2.28 (s, 6H), 2.02 (m, 1H), 1.53 (q, J= 11.2 Hz, 1H), 1.40-1.21 (m, 2H).

Example 33:-

(3aR,6RJaR)-6-r(2-{2-methoxy-7-oxo-7H,8H-pyridor2,3-dlpyr imidin-8-yl)ethyl)amin -{7-oxo-6H,7H,8H-pyrimidor5,4-biri,41oxazin-2-yl)-octahydro- 1,3-benzoxazol-2-one

33

a) tert- butyl

N-[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8 H-pyrimido[5,4-b][1,4]oxazi n-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 33a

To a stirring solution of te/f-butyl N-[(3aR, 6R, 7aR)-2-oxo-octahydro-1,3-benzoxazol-6- yl]carbamate 1a (1g, 3.90 mmol) in toluene (30 mL) under N2 conditions, was added a 2:1 mixture of 2-bromo-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4-b] [1 ,4]oxazin-7- one and 2-chloro-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4-b ][1 ,4]oxazin-7-one 16a (1.36 g, 3.90 mmol), trans-1,2-diaminocyclohexane (0.2 mL, 1.60 mmol), K2CO3 (1.078 g, 7.80 mmol) and Cul (594 mg, 3.12 mmol). The reaction was heated to reflux and stirred for 17 h. The reaction was allowed to cool to room temperature, and then filtered, washed with EtOAc (10 mL) and the filtrate concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-100% EtOAc in DCM to give te/f-butyl N-[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8 H-pyrimido[5,4-b][1 ,4]oxazi n-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 33a (614 mg, 30%). LC-MS

(Method A) 526.2 [M+H] ⁺ ; RT 3.03 min. b)

(3aR,6R,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H-pyrimido[5, 4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b

To a stirring solution of te/f-butyl

N-[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8 H-pyrimido[5,4-b][1 ,4]oxazi n-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 33a (614 mg, 1.17 mmol) in DCM (15 mL) was added TFA (4.8 mL) and the reaction stirred for 1 h. The volatiles were removed under reduced pressure, and the residue basified to pH 9 with saturated aqueous Na2CC>3, and partitioned between DCM (20 mL) and brine (3 mL). This was passed through an SPE phase separator and the organic portion concentrated under reduced pressure to give

(3aR,6R,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H-pyrimido[5,4-b][1 ,4 ]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b (400 mg, 80%) which was used without further purification. LC-MS (Method A) 426.1 [M+H] ⁺ ; RT 1.55 min. c)

(3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8-yl}ethyl)amino] -3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-octahydro -1 ,3-benzoxazol-2-one 33c

A solution of

(3aR,6R,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H-pyrimido[5,4-b][1 ,4 ]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b (78 mg, 0.18 mmol) and 2-(2-methoxy-7- oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl)acetaldehyde 2b (40 mg, 0.18 mmol) in DCM (15 mL) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (174 mg, 0.82 mmol) was added and stirring continued for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHC03 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a crude residue containing

(3aR,6R7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimi din-8-yl}ethyl)amino]-3-{8-[( 4-methoxyphenyl)methyl]-7-oxo-6H7H,8H^yrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-b enzoxazol-2-one 33c (127 mg, 1 10%) which was used without further purification. LC-MS (Method A) 629.2 [M+H] ⁺ ; RT 2.02 min. d)

(3aR,6R7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimi din-8-yl}ethyl)amino] -3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33

To a stirring solution of

(3aR,6R7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimi din-8-yl}ethyl)amino]-3-{8-[( 4-methoxyphenyl)methyl]-7-oxo-6H7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-b enzoxazol-2-one 33c (127 mg, 0.20 mmol) in DCM (15 mL) was added TFA (1 mL) followed by CF3SO3H (0.20 mL). The reaction was stirred at room temperature for 17 h then diluted with MeOH (5 mL) and DCM (10 ml), basified to pH 8-9 with saturated Na ₂ C0 ₃ and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

(3aR,6R,7aR)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8-yl}ethyl)amino]-3-{7-o xo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33 (22 mg, 22%). LC-MS (Method A) 509.1 [M+H] ⁺ ; RT 1.38 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.91 (s, 1 H), 8.25 (s, 1 H), 7.94 (d, J = 9.5 Hz, 1 H), 6.56 (d, J = 9.5 Hz, 1 H), 5.77 (s, 1 H), 4.75 (m, 2H), 4.33 (m, 2H), 4.10-4.03 (m, 1 H), 4.02 (s, 3H), 3.78 (td, J = 1 1.1 , 3.3 Hz, 1 H), 2.88-2.77 (m, 3H), 2.46-2.37 (m, 2H), 2.00-1.94 (m, 1 H), 1.46 (q, J = 1 1.1 Hz, 1 H), 1.37-1.27 (m, 1 H), 1.25-1.18 (m, 1 H).

Example 34:-

1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vnamino)ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one

a) 1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 34a

To a solution of

(3aS,6S7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H^yrido[3,2-b][1 ,4]ox azin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (230 mg, 0.54 mmol) and

2-(6,7-difluoro-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (121 mg, 0.54 mmol, prepared as described in WO2008009700A1) in DCM (20 ml_) was added a few drops of AcOH and the mixture stirred at room temperature for 20 h. NaBH(OAc)3 (344 mg, 1.63 mmol) was added and the reaction mixture stirred at room temperature for 30 min. The mixture was adjusted to pH 8-9 with saturated Na2CC>3 and extracted with DCM (100 ml_). The organic layer was washed with brine, dried over MgSCU, filtered and concentrated to give 1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 34a, (290 mg, 84 %), which was used without further purification. LC-MS (Method A) 633.1 [M+H] ⁺ ; RT 3.01 min. b) 1 -(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2

To a solution of

1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 34a (280 mg, 0.44 mmol) in DCM (25 ml_) was added TFA (508 μΙ_, 6.64 mmol) followed by CF3SO3H (196 μΙ_, 2.21 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH (1 ml_), adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 mL). The organic extract was washed with brine, dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 10 g KP-Si cartridge) using 0-50 % MeOH in DCM to give

1 -(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 34 (1 17 mg, 49 %) as a yellow solid. LC-MS (Method A) 513.1 [M+H] ⁺ ; RT 2.29 min. ¹ H NMR (Method C) (DMSO): δ ppm 1 1.28 (br s, 1 H), 8.32 (s, 1 H), 8.00 (m, 2H), 7.47 (d, J = 8.5 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 4.68 (s, 2H), 4.27 (t, J = 6.9 Hz, 2H), 4.09 (td, J = 1 1.7, 3.3 Hz, 1 H), 3.79 (td, J = 1 1.2, 3.3 Hz, 1 H), 2.90 (m, 2H), 2.81 (m, 2H), 2.46 (m, 1 H), 2.17 (br s, 1 H), 2.00 (m, 1 H), 1.49 (q, J = 1 1.2 Hz, 1 H), 1.37 (m, 1 H), 1.24 (m, 1 H).

Example 35:- (3aS,6S,7aR)-6-r(2-{6-methoxy-3-oxo-3H,4H-pyridor2,3-blpyraz in-4- yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6 -yl)-octahydro-1 ,3- benzoxazol-2-one

a) (3aS,6S,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-2-one 35a

To a solution of 2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyrazin-4-yl}acetaldeh yde (129 mg, 0.59 mmol) (prepared as described in EP2022793A1) in DCM (5 mL) over 4 A molecular sieves was added (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (250 mg, 0.59 mmol) and the reaction stirred at room temperature for 2h. Sodium triacetoxyborohydride (560 mg, 2.65 mmol) was added and the mixture was left to stir at room temperature for 1.5 h. The reaction was diluted with saturated aqueous NaHCOs and extracted with DCM (20 mL). The organic extracts were dried over MgS0 ₄ , filtered and concentrated under reduced pressure to give (3aS,6S,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octah 1 ,3-benzoxazol-2-one (60 mg, 36%) as a brown solid. LC-MS (Method A) 628.3 [M+H] ⁺ ; RT 1.83 min b) (3aS,6S,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 35

To a solution of (3aS,6S,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one (60 mg, 0.10 mmol) in DCM (5 mL) was added TFA (2 mL) and CF3SO3H (0.2 mL) dropwise and the reaction mixture was left to stir at room temperature for 1 h. The reaction was quenched with MeOH (5 mL) and the mixture evaporated. The residue was neutralised with saturated aqueous NaHCC>3 (50 mL), and extracted with DCM (25 mL). The organic extracts were washed with H2O, brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in EtOAc) to give an orange solid. The solid was dissolved in DCM (2 mL), triturated with diethyl ether (10 mL) and the precipitate filtered and dried to give (3aS,6S,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4- yl}ethyl)amino]-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol- 2-one (40 mg, 16 %) as a white solid. LC-MS (Method A) 508.1 [M+H] ⁺ ; RT 2.22 min. ¹ H NMR (Method C) (CDCI3) δ ppm: 8.17 (s, 1 H), 8.03 (d, J = 8.5, 1 H), 7.76 (d, J = 8.5, 1 H), 7.28 (d, J = 8.5, 1 H), 6.75 (d, J = 8.5, 1 H), 4.69 (m, 1 H), 4.62 (s, 2H), 4.58 (t, J = 6.5, 2H), 4.50 (m, 1 H), 4.04 (s, 3H), 3.1 1 (t, J = 6.5, 2H), 2.89 (m, 1 H), 2.47-2.42 (m, 2H), 1.88 (m, 1 H), 1.54 (ddd, J = 15.0, 11.0, 4.0, 1 H), 1.39 (m, 1 H), 1.1 1 (m, 1 H)

Example 36:- methyl 1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2- blH ,41oxazin-6-yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-2-oxo-1 ,2- dihydroquinoline-7-carboxylate

36

a) methyl 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinoline-7-carboxylate 36a

A solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c and methyl 2-oxo-1-(2- oxoethyl)-1 ,2-dihydroquinoline-7-carboxylate (prepared from 7-bromo-1 ,2-dihydroquinolin-2- one using similar methods to those described in EP 1.900732A1 p98) in DCM (8 ml_) was stirred over molecular sieves (4A) at room temperature. After 20 min, NaBH(OAc)3 (205 mg, 0.97 mmol) was added and the reaction stirred for 1 h. The reaction was quenched with saturated aqueous Na2CC>3 (8 ml_) and the mixture passed through an SPE phase separator. The organic phase was concentrated under reduced pressure and purified by chromatography eluting with 0-12% MeOH in DCM to give methyl 1-(2-{[(3aR,6R,7aR)-3-{4- [(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carboxylate 36a (1 14 mg, 61 %) (Method A) 654.2 [M+H] ⁺ ; RT 2.82 min. b) methyl 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carboxylate 36

TFA (0.5 ml_, 6.53 mmol) and CF3SO3H (0.1 ml_, 1.13 mmol) were added to a stirred solution of 1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinoline-7-carboxylate 36a (1 10 mg, 0.17 mmol) in DCM (10 ml_) at room temperature. After 1 h the reaction was diluted with MeOH (5 ml_) and DCM (5 ml_). Saturated aqueous NaaCC was added, adjusting the pH to 9, and the mixture was passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give methyl 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline- 7-carboxylate 36 (76 mg, 84.7%) as a pale green solid. (Method B) 534.2 [M+H] ⁺ ; RT 5.47 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.24 (s, 1 H), 8.13 (s, 1 H), 8.02 (d, J = 9.5 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.81 (dd, J = 8.0, 1.4 Hz, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.18 (d, J = 8.5 Hz, 1 H), 6.77 (d, J = 9.5 Hz, 1 H), 4.63 (s, 2H), 4.33 (t, J = 6.9 Hz, 2H), 4.06 (td, J = 1 1.7, 3.2 Hz, 1 H), 3.93 (s, 3H), 3.77 - 3.70 (m, 2H), 2.89-2.75 (m, 4H), 2.05 - 1.97 (m, 1 H), 1.53 - 1.43 (m, 1 H), 1.42 - 1.30 (m, 1 H), 1.24-1.18 (m, 2H).

Example 37:-

1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin-2-ylVoctahvdr o-1 ,3-benzoxazol-6-vnamino)ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile

37

a)

1 -(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7 H,8H-pyrimido[5,4-b ][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinol ine-7-carbonitrile 37a

A solution of

(3aR,6R,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H-pyrimido[5,4-b][1 ,4 ]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b (80 mg, 0.19 mmol) and 2-oxo-1-(2- oxoethyl)quinolone-7-carbonitrile (40 mg, 0.19 mmol) (J. Med. Chem (2014) 57 (1 1), 4889- 4905) in DCM (8 mL) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (180 mg, 0.85 mmol) was added and stirred for 3 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a crude residue containing

1 -(2-{[(3aR,6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H ,8H-pyrimido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-c arbonitrile 37a (197 mg, 168%) which was used without further purification. LC-MS (Method A) 622.2 [M+H] ⁺ ; RT 2.34 min. b)

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octah ydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 37

To a stirring solution of

1 -(2-{[(3aR,6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H ,8H-pyrirnido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-c arbonitrile 37a (197 mg, 0.32 mmol) in DCM (15 mL) was added TFA (1.26 mL) followed by CF3SO3H (0.30 mL). The reaction was stirred at room temperature for 17 h then diluted with MeOH (5 mL) and DCM (10 mL), basified to pH 8-9 with saturated aqueous Na ₂ CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-10% MeOH in DCM to give

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 37 (7 mg, 4%). LC-MS (Method B) 502.1 [M+H] ⁺ ; RT 4.67 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.25 (s, 1 H), 8.18 (s, 1 H), 8.01 (d, J = 9.5 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.0, 1.3 Hz, 1 H), 6.79 (d, J = 9.5 Hz, 1 H), 4.75 (m, 2H), 4.29 (t, J = 7.3 Hz, 2H), 4.10-4.00 (m, 1 H), 3.80 (td, J = 1 1.1 , 3.3 Hz, 1 H), 2.85-2.76 (m, 3H), 2.46-2.41 (m, 2H), 2.01-1.93 (m, 1 H), 1.47 (q, J = 1 1.2 Hz, 1 H), 1.37-1.27 (m, 1 H), 1.26-1.14 (m, 2H).

Example 38:-

1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin-2-ylVoctahvdr o-1 ,3-benzoxazol-6-vnamino)ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one

38

a)

1 -(2-{[(3aR,6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H ,8H-pyrimido[5,4-b ][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydro quinoxalin-2-one 38a

A solution of

(3aR,6R7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H7 H,8H-pyrimido[5,4-b][1 ,4 ]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b (76 mg, 0.18 mmol) and

2-(6,7-difluoro-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (prepared as described in WO2008009700 A1 20080124) (40 mg, 0.18 mmol) in DCM (10 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (189 mg, 0.89 mmol) was added and stirred for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 -(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7 H,8H-pyrimido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinox alin-2-one 38a (110 mg, 97%) which was used without further purification. LC-MS (Method A) 634.1 [M+H] ⁺ ; RT 2.38 min b)

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octah ydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 38

To a stirring solution of

1 -(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7 H,8H-pyrimido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinox alin-2-one 38a (1 10 mg, 0.17 mmol) in DCM (10 ml_) was added TFA (0.94 ml_) followed by CF3SO3H (0.22 mL). The reaction was stirred at room temperature for 72 h then diluted with MeOH (5 mL) and DCM (10 mL), basified to pH 8-9 with saturated aqueous Na ₂ CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-10% MeOH in DCM to give

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 38 (15 mg, 17%). LC-MS (Method B) 514.0 [M+H] ⁺ ; RT 4.75 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.26 (s, 1 H), 8.25 (s, 1 H), 7.98 (dd, J = 10.7, 8.5 Hz, 1 H), 7.92 (dd, J = 12.7, 7.4 Hz, 1 H), 4.75 (m, 2H), 4.22 (t, J = 6.9 Hz, 2H), 4.05 (td, J 1 1.8, 3.4 Hz, 1 H), 3.79 (td, J = 1 1.2, 3.4 Hz, 1 H), 2.88-2.76 (m, 3H), 2.44-2.34 (m, 2H), 2.01-1.8 (m, 1 H), 1.45 (q, J = 10.9 Hz, 2H), 1.33-1.17 (m, 2H).

Example 39:- (3aR,6R,7aR)-N-(2-{7-r2-(methylazaniumyl)ethoxy1-2-oxo-1 ,2- dihvdroquinolin-1 -yl)ethyl)-2-oxo-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin- 6-yl)- octahydro-1 ,3-benzoxazol-6-aminium dichloride

39

a) te/f-butyl N-(2-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)-N- methylcarbamate 39a

A solution of te/f-butyl N-(2-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)carbamate 9d (200 mg, 0.48 mmol) in THF (7 mL) was cooled in a NaCI ice bath. NaH (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added and the mixture stirred for 30 min. lodomethane (0.1 mL, 1.61 mmol) was added and the mixture stirred at ambient temperature for 17 h. The mixture was evaporated in vacuo and the residue dissolved in DCM (20 mL), MeOH (1 mL), Dl water (5 mL) and passed through an SPE phase separator. The organic fraction was evaporated to give te/f-butyl N-(2-{[1-(2,2- diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)-N-methylcarbamate 39a (210 mg, 102%) as a light brown oil. ¹ H NMR (Method C) (CDC ): δ ppm 7.47 (d, J = 9.4 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 1 H), 7.04 (s, 1 H), 6.64 (dd, J = 8.5, 2.1 Hz, 1 H), 6.38 (d, J = 9.2 Hz, 1 H), 4.65 (t, J = 5.2 Hz, 1 H), 4.21 (d, J = 5.3 Hz, 2H), 4.00 (d, J = 17.0 Hz, 2H), 3.67-3.58 (m, 2H), 3.49 (s, 2H), 3.42 - 3.33 (m, 2H), 2.85 (s, 3H), 1.31 (s, 9H), 0.98 (t, J = 6.9 Hz, 6H). b) terf-butyl N-methyl-N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinolin7yl]oxy}ethyl)carbamate 39b

To a stirred solution of te/f-butyl N-(2-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)-N-methylcarbamate 39a (100 mg, 0.23 mmol) in THF (5 mL) at room temperature was added aqueous HCI (1 M, 1 mL). After stirring for 120 h, saturated aqueous NaHCC was added and the mixture extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with saturated brine, dried (MgSCU), filtered and concentrated to give te/f-butyl N-methyl-N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinolin7yl]oxy}ethyl)carbamate 39b (67 mg, 80.8%). (Method A) 361 +H [M+H] ⁺ ; RT 2.46 min.

c) terf-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}ethyl)-N-methylcarbamate 39c

A solution of te/f-butyl N-methyl-N-(2-{[2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinolin7yl]oxy}ethyl)carbamate 39b (76.6 mg, 0.15 mmol) and (3aR,6R,7aR)-6- amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3 ,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-2-one 1 c (60 mg, 0.14 mmol) in DCM (6 mL) was stirred at room temperature over molecular sieves (4A) for 10 min. NaBH(OAc)3 (106.8 mg, 0.50 mmol) was added and stirring continued for 2 h. Saturated aqueous NaHCC (5 mL) was added and the resulting mixture passed through an SPE phase separator. The organic phase was concentrated under reduced pressure and the residue purified by chromatography eluting with 0-100% EtOAc in petroleum ether and 0-20% MeOH in DCM. The fractions were concentrated under reduced pressure to give te/f-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)-N-methylcarbamate 39c (43mg, 37.6%) as a white solid. (Method A) 769.3 [M+H] ⁺ ; RT 3.49 min. d) (3aR,6R,7aR)-N-(2-{7-[2-(methylazaniumyl)ethoxy]-2-oxo-1,2-d ihydroquinolin-1-yl}ethyl)-

2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-oc tahydro-1,3-benzoxazol-6- aminium dichloride 39

TFA (0.2 mL, 2.6 mmol) and CF3SO3H (0.05 mL, 0.56 mmol) were added to a stirred solution of te/f-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo- 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-2-oxo-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)- 2-OXO-1, 2-dihydroquinolin-7-yl]oxy}ethyl)-N-methylcarbamate 39c (43 mg, 0.06 mmol)) in DCM (6 mL) at room temperature. After 1 h the reaction was diluted with MeOH (5 mL) and DCM (5 mL). Saturated aqueous NaaCC was added, adjusting the pH to 9, and the mixture was passed through an SPE phase separator. The aqueous phase was further extracted with DCM/MeOH (2:1, 2 x 20 mL) and the combined organic fractions concentrated under reduced pressure and the residue purified by chromatography eluting with 0-20% 2M ΝΗβ/ΜβΟΗ in DCM. The relevant fractions were evaporated, re-dissolved in MeOH, treated with 1M HCI in ether and evaporated to afford (3aR,6R,7aR)-N-(2-{7-[2- (methylazaniumyl)ethoxy]-2-oxo-1,2-dihydroquinolin-1-yl}ethy l)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-6-am inium dichloride 39 (7 mg, 15.6%) as a white solid. MS (Method B) 549.2 [M+H] ⁺ ; RT 4.22 min. (Method C) (DMSO- d6): δ ppm 11.30 (s, 1 H), 9.92 (br s, 2H), 9.06 (br s, 2H), 7.92 (d, J = 9.5 Hz, 1 H), 7.73 (d, J = 8.7 Hz, 1H), 7.44 (d, J= 8.5 Hz, 1H), 7.40 (d, J= 2.2 Hz, 1H), 7.18 (d, J= 8.6 Hz, 1H), 6.98 (dd, J= 8.5, 2.1 Hz, 1H), 6.51 (d, J= 9.4 Hz, 1H), 4.71-4.62 (m 1H), 4.64 (s, 3H), 4.59 (d, J= 5.9 Hz, 2H), 4.11 (td, J= 11.6, 3.3 Hz, 1H), 3.82 (td, J= 11.3, 3.3 Hz, 1H), 3.52 (m, 1H), 3.26-3.11 (m, 2H), 2.88 (dq, J= 11.9, 3.7 Hz, 1H), 2.73 (dt, J= 9.6, 4.0 Hz, 1H), 2.66 (q, J= 7.0, 6.1 Hz, 3H),2.52 (m, 2H), 2.33-2.23 (m, 1H), 2.01 (q, J= 11.4 Hz, 1H), 1.79- 1.66 (m, 1H), 1.43 (qd, J= 12.2, 3.7 Hz, 1H).

Example 40:- 6-r3-(fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-

Pyridor3,2-biri,41oxazin-6-yl)-octahvdro-1,3-benzoxazol-6 -vnamino)methyl)-2- hvdroxyphenvnpyridine-2-carbonitrile

a) 6-[3-({[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-2- hydroxyphenyl]pyridine-2-carbonitrile 40a

To a solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (151 mg, 0.36 mmol) in DCM (10 mL) at room temperature was added 6-(3-formyl-2-hydroxyphenyl)pyridine-2- carbonitrile 18c (83 mg, 0.37 mmol) and molecular sieves (4A). The reaction was stirred at room temperature for 2 h. NaBH(OAc)3 (226 mg, 1.07 mmol) was added and the mixture stirred for a further 16 h. Saturated aqueous K2CO3 (10ml_) was added and the organic phase separated, dried over MgSCU, filtered and concentrated to give 6-[3-({[(3aR,6R,7aR)- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-2-oxo- octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-2-hydroxyphenyl]pyridine-2- carbonitrile 40a (170 mg, 75.5%), which was used without further purification. LC-MS (Method A) 633.2 [M+H] ⁺ , RT 2.81 min.

b) 6-[3-({[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}methyl)-2-hydroxyphenyl]pyridine-2- carbonitrile 40

To a solution of 6-[3-({[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)-2- hydroxyphenyl]pyridine-2-carbonitrile 40a (169 mg, 0.27 mmol) in DCM (10 mL), under nitrogen was added TFA (0.2 mL, 2.67 mmol) and CF3SO3H (0.12 mL, 1.34 mmol). The reaction mixture was allowed to stir at room temperature for 1 h then quenched with MeOH (1 mL). Saturated aqueous K2CO3 (10 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (10 mL). The combined organic extracts were dried over MgSCU, filtered and concentrated. The residue was purified by chromatography using

0- 40% MeOH in DCM to give 6-[3-({[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-6-yl]amino}meth yl)-2-hydroxyphenyl]pyridine- 2-carbonitrile 40 (25.3 mg, 18.5 %) TLC: R _f = 0.34 (silica gel, DCM/MeOH 19:1, v/v). LC-MS (Method B) 513.1 [M+H] ⁺ RT 6.13 min. ¹ H NMR (Method E) (CDC ): δ ppm 8.19 (d, J= 8.5 Hz, 1H), 7.97 (t, J= 8.5 Hz, 1H), 7.85-7.73 (br s, 1H), 7.77 (d, J= 8.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.34 (d, J= 8.5 Hz, 1H), 7.33 (d, J= 7.5 Hz, 1H), 7.32 (d, J= 8.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1 H), 4.64 (s, 2H), 4.05 - 3.93 (m, 3H), 3.83 ( td, J = 12.2 Hz, 2.6 Hz, 1 H), 2.97-2.81 (m, 1H), 2.79-2.64 (m, 2H), 2.21 (d, J= 10.2 Hz, 1H), 1.79- 1.60 (m, 1H), 1.54-1.36 (m, 1H), 1.35-1.21 (m, 1H).

Example 41 :-

1- (2-fr(3aR,6R,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri, 41oxazin-2-ylVoctahvdr o-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5 -naphthyridin-2-one

41 a)

1-(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4-b ][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro- 1,5-naphthyridin-2-one 41a

A solution of

(3aR,6R,7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H^yrimido[5,4-b][1,4 ]oxazin-2-yl}-octahydro-1,3-benzoxazol-2-one 33b (78 mg, 0.18 mmol) and

2-(7-methoxy-2-oxo-1,2-dihydro-1,5-naphthyridin-1-yl)acet aldehyde (prepared as described in WO 2011148962 A1 (40 mg, 0.18 mmol) in DCM (10 ml_)was stirred, at room

temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (155 mg, 0.73 mmol) was added and stirred for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give

1 -(2-{[(3aR _I 6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H _I 8H-pyrimido[5 _I 4-b][1 _I 4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-nap hthyridin-2-one 41 a (107 mg, 93%) which was used without further purification. LC-MS (Method A) 628.2 [M+H] ⁺ ; RT 2.10 min. b)

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 41

To a stirring solution of

1 -(2-{[(3aR,6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H ,8H-pyrirnido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-nap hthyridin-2-one 41 a (107 mg, 0.17 mmol) in TFA (4 ml_), cooled to 0°C, was added

CF3SO3H (0.22 ml_). The reaction was allowed to warm to room temperature and stirred for 17 h, then quenched with MeOH (5 ml_), diluted with DCM (40 ml_), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-10% MeOH in DCM to give

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 41 (13 mg, 15%). LC-MS (Method B) 508.1 [M+H] ⁺ ; RT 4.39 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.29 (d, J = 2.4 Hz, 1 H), 8.25 (s, 1 H), 7.88 (d, J = 9.7 Hz, 1 H), 7.50 (d, J 2.5 Hz, 1 H), 6.67 (d, J = 9.7 Hz, 1 H), 4.75 (m, 2H), 4.29 (t, J = 7.1 Hz, 2H), 4.05 (td, J = 1 1.7, 3.4 Hz, 1 H), 3.99 (s, 3H), 3.80 (td, J = 1 1.2, 3.3 Hz, 1 H), 2.88-2.74 (m, 3H), 2.44-2.39 (m, 2H), 2.02-1.91 (m, 1 H), 1.47 (q, J = 1 1.2 Hz, 1 H), 1.38-1.15 (m, 3H).

Example 42:-

7-methoxy-1 -{2-r(2-oxo-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6-yl) -octahydro-1 , 3-benzoxazol-6-yl)amino1ethyl)-1 ,2-dihydro-1 ,5 -naphthyridin-2-one.

a)

7-methoxy-1 -{2-[(3-{4-[(4-methoxyphe^^

6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl)amino]ethyl}-1 ,2-dihydro-1 ,5-naphthyridin-2-one 42a

6- [(3aS,6S,7aS)-6-amino-2-oxo-3a,4,5,6,7,7a-hexahydro-1 ,3-benzoxazol-3-yl]-4-[(4- methoxyphenyl)methyl]pyrido[3,2-b][1 ,4]oxazin-3-one 29c (150 mg, 0.35 mmol) and 2-(7- methoxy-2-oxo-1 ,5-naphthyridin-1-yl)acetaldehyde (77 mg, 0.35 mmol) (prepared as described in WO201 1 148962A1) were added to DCM (20 ml) over 3 angstrom molecular sieves and the mixture was stirred overnight. To this was added sodium

triacetoxyborohydride (224 mg, 1.06 mmol) and the reaction was again stirred overnight. The reaction quenched with saturated Na2CC>3 (50 ml) solution extracted with DCM (2 x 30 ml), dried MgSCU and concentrated in vacuo to give 6-[(3aS,6S,7aS)-6-[2-(7-methoxy-2- oxo-1 ,5-naphthyridin-1-yl)ethylamino]-2-oxo-3a,4,5,6,7,7a-hexahyd ro-1 ,3-benzoxazol-3-yl]- 4-[(4-methoxyphenyl)methyl]pyrido[3,2-b][1 ,4]oxazin-3-one 42a (221 mg, 100% yield) as a yellow solid. The product was used crude without further purification. LC-MS (Method A) 627.1 [M+H] ⁺ ; RT 2.66 min. b)

7- methoxy-1 -{2-[(2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-ben zoxazol-6-yl)amino]ethyl}-1 ,2-dihydro-1 ,5-naphthyridin-2-one. 42

To a room temperature solution

of 7-methoxy-1 -{2-[(3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido

[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl)amino]ethyl}-1 ,2-dihydro-1 ,5-n aphthyridin-2-one 42a (221 mg, 0.35 mmol) in DCM (15 ml_) under N2 was added CF3CO2H (2.7 ml_, 35.27 mmol) followed by CF3SO3H (156 uL, 1.76 mmol) . The orange/red coloured reaction mixture was allowed to stir for 1 hour, then diluted with MeOH (1 ml_) which decolourised the reaction. The mixture was carefully poured on to saturated aqueous potassium carbonate solution (100 ml) and extracted with DCM (2 X 75 ml_). The organic extracts were dried (MgS0 ₄ ), evaporated and the residue purified via column chromatography (5 to 20% MeOH in EtOAc) to afford a yellow foam. The foam was dissolved in DCM (5 ml), treated with diethyl ether (5 ml) and the precipitate filtered and dried to afford

7-methoxy-1 -{2-[(2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-ben zoxazol-6-yl)amino]ethyl}-1 ,2-dihydro-1 ,5-naphthyridin-2-one 42 (69 mg, 36% yield) as a white solid. LC-MS (Method A) 507.1 [M+H] ⁺ ; RT 2.05 min. ¹ H NMR (Method C) (CDC ): δ 8.39 (s, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.86 (d, J = 9.7 Hz, 1 H), 7.30 (s, 2H), 7.19 (d, J = 2.5 Hz, 1 H), 6.74 (d, J = 9.7 Hz, 1 H), 4.60 (s, 2H), 4.50 - 4.27 (m, 2H), 4.07 - 3.88 (m, 4H), 3.85 - 3.71 (m, 1 H), 3.08 (t, J = 6.9 Hz, 2H), 2.97 - 2.78 (m, 1 H), 2.71 - 2.48 (m, 2H), 2.14 (brs, 1 H), 1.55 (q, J = 6.9 Hz, 2H), 1.45 - 1.30 (m, 2H).

Example 43: (3aR,6R,7aR)-6-r(2-{6-methoxy-3-oxo-3H,4H-pyridor2,3-blpyraz in-4- yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri ,41oxazin-6-yl)-octahydro-1 ,3- benzoxazol-2-one

a) (3aR,6R,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-2-one, 43a

To a solution of 2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyrazin-4-yl}acetaldeh yde (90 mg, 0.41 mmol) (prepared as described in EP2022793A1) in DCM (5 ml_) over 4 A molecular sieves was added (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (174 mg, 0.41 mmol) and the reaction stirred at room temperature for 2h. Sodium triacetoxyborohydride (391 mg, 1.84 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was basified with saturated aqueous NaHC03 and extracted with DCM (20 ml_). The organic extracts were dried over MgS0 ₄ , filtered and concentrated under reduced pressure to give (3aR,6R7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyrazi n-4-yl}ethyl)amino]- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-2-one (200 mg, 99 %) as a brown solid. LC-MS (Method A) 628.1 [M+H] ⁺ ; RT 2.86 min b) (3aR,6R,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 43

To a solution of (3aR,6R,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one 43a (200 mg, 0.31 mmol) in DCM (5 ml_) was added TFA (2 ml_) and CF3SO3H (0.2 ml_) dropwise and the reaction mixture was left to stir at room temperature for 1 h. The reaction was quenched with MeOH (5 ml_) and the mixture evaporated. The residue was basified with saturated aqueous NaHCC (50 ml_) and extracted with DCM (25 ml_). The organic extracts were washed with H2O, brine, dried (Na2SC>4) , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in EtOAc) to give an orange solid. The solid was dissolved in DCM (2 ml_), triturated with diethyl ether (10 ml_) and the precipitate filtered, dried and evaporated to give (3aR,6R,7aR)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3- b]pyrazin-4-yl}ethyl)amino]-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 43 (40 mg, 21 %) as a white solid. LC-MS (Method A) 508.1 [M+H] ⁺ ; RT 2.22 min.

NMR (Method C) (CDC ) δ ppm: 8.16 (s, 1 H), 8.03 (d, J = 8.5, 1 H), 7.32 (d, J = 8.5, 1 H), 7.30 (d, J = 8.5, 1 H), 6.75 (d, J = 8.5, 1 H), 4.61 (s, 2H), 4.58 (t, J = 6.5, 2H), 4.04 (s, 3H), 3.95 (m, 1 H), 3.78 (m, 1 H), 3.18-3.10 (m, 2H), 2.89 (m, 1 H), 2.66 (m, 1 H), 2.60 (m, 1 H), 2.10 (m, 1 H), 1.55-1.65 (m, 1 H), 1.42-1.31 (m, 2H).

Example 44:-

1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin-2-ylVoctahvdr

0-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8 -naphthyridin-2-one

44

a)

1 -(2-{[(3aR _I 6R7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H _I 8H-pyrimido[5 _I 4-b][1 _I 4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-nap hthyridin-2-one 44a

A solution of

(3aR,6R7aR)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H7 H,8H-pyrimido[5,4-b][1 ,4 ]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 33b (78 mg, 0.18 mmol) and 2-(7-methoxy-2- oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)acetaldehyde (prepared as described in

WO2008009700) (40 mg, 0.18 mmol) in DCM (10 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (194 mg, 0.92 mmol) was added and stirred for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHCC and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and purified via silica gel chromatography using 0-10% MeOH in DCM to give 1-(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2- dihydro-1 ,8-naphthyridin-2-one 44a (40 mg, 35%). LC-MS (Method A) 628.2 [M+H] ⁺ ; RT 2.39 min. b)

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octah ydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 44

To a stirring solution of

1 -(2-{[(3aR,6R,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7 H,8H-pyrimido[5,4-b][1 ,4]ox azin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-nap hthyridin-2-one 44a (40 mg, 0.06 mmol) in DCM (5 ml_) was added TFA (0.17 ml_) followed by CF3SO3H (0.04 ml_). The reaction was stirred at room temperature for 17 h then diluted with MeOH (5 ml_) and DCM (15 ml_), basified to pH 8-9 with saturated aqueous Na ₂ CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-10% MeOH in DCM to give

1 -(2-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 44 (13 mg, 41 %). LC-MS (Method B) 508.1 [M+H] ⁺ ; RT 4.65 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.25 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 9.4 Hz, 1 H), 6.74 (d, J = 8.3 Hz, 1 H), 6.50 (d, J = 9.4 Hz, 1 H), 4.75 (m, 2H), 4.45-4.42 (m, 2H), 4.05 (td, J = 1 1.8, 3.5 Hz, 1 H), 4.00 (s, 3H), 3.79 (td, J = 1 1.1 , 3.3 Hz, 1 H), 2.91-2.77 (m, 3H), 2.47-2.37 (m, 2H), 2.01-1.98 (m, 1 H), 1.48 (q, J = 1 1.2 Hz, 1 H), 1.39-1.15 (m, 2H).

Example 45:- (3aS,6S,7aS)-6-r(2-{6-methoxy-3-oxo-3H,4H-pyridor2,3-blpyraz in-4- yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6 -yl)-octahydro-1 ,3- benzoxazol-2-one

a) (3aS,6S,7aS)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-2-one, 45a

To a solution of 2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyrazin-4-yl}acetaldeh yde (82 mg, 0.37 mmol) (prepared as described in EP2022793 A1) in DCM (5 ml_) over 4 A molecular sieves was added (3aS,6S,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (160 mg, 0.37 mmol) and the reaction stirred at room temperature for 2h. Sodium triacetoxyborohydride (393 mg, 1.69 mmol) was added and the mixture left to stir at room temperature for 0.5 h. The reaction was basified with saturated aqueous NaHC03 and extracted with DCM (20 ml_). The organic extracts were dried over MgSCU, filtered and concentrated under reduced pressure to give (3aS,6S,7aS)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one (250 mg, 99 %) as a brown solid. LC-MS (Method A) 628.1 [M+H] ⁺ ; RT 2.87 min b) (3aS,6S,7aS)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4-yl}ethyl)amino]- 3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 45

To a solution of (3aS,6S,7aS)-6-[(2-{6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyraz in-4- yl}ethyl)amino]-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-2-one (60 mg, 0.10 mmol) in DCM (5 mL) was added TFA (2 mL) and CF3SO3H (0.2 mL) dropwise and the mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH (5 mL) and evaporated. The residue was basified with saturated aqueous NaHCC>3 (50 mL) and extracted with DCM. The combined organic extracts were washed with H2O, brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in EtOAc) to give an orange solid. The solid was dissolved in DCM (2 mL), triturated with diethyl ether (10 mL) and the precipitate filtered and dried to give (3aS,6S,7aS)-6-[(2- {6-methoxy-3-oxo-3H,4H-pyrido[2,3-b]pyrazin-4-yl}ethyl)amino ]-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 45 (14 mg, 8 %) as a white solid. LC-MS (Method A) 508.1 [M+H] ⁺ ; RT 2.22 min. NMR (Method C) (CDCb) <5 ppm: 8.18 (s, 1 H), 8.03 (d, J = 8.5, 1 H), 7.32 (d, J = 8.5, 1 H), 7.29 (d, J = 8.5, 1 H), 6.75 (d, J = 8.5, 1 H), 4.61 (m, 4H), 4.04 (s, 3H), 3.93 (m, 1 H), 3.78 (m, 1 H), 3.25-3.13 (m, 2H), 2.94 (m, 1 H), 2.69 (m, 1 H), 2.60 (m, 1 H), 2.13 (m, 1 H), 1.55-1.65 (m, 1 H), 1.42-1.31 (m, 2H).

Example 46:-

5-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino)ethyl)-6-oxo-5,6-dihvdro-1 ,5-naphthyridine-3-carbonit

46

a) 5-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-nap hthyridine-3-carbonitrile 46a

A solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (100 mg, 0.23 mmol) and 6-oxo-5-(2-oxoethyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile (prepared as described in WO 2008009700 A1 20080124) (50 mg, 0.23 mmol) in DCM (15 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (199 mg, 0.94 mmol) was added and stirred for 90 min. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure to give

5-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridi ne-3-carbonitrile 46a (137 mg, 94%) which was used without further purification. LC-MS (Method A) 622.3 [M+H] ⁺ ; RT 1.28 min. b)

5-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 46

To a stirring solution of

5-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridi ne-3-carbonitrile 46a (137 mg, 0.22 mmol) in DCM (10 ml_) was added TFA (0.60 ml_) followed by CF3SO3H (0.14 ml_). The reaction was stirred at room temperature for 168 h then diluted with MeOH (5 ml_) and DCM (15 ml_), basified to pH 8-9 with saturated aqueous Na2C03 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

5-(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 46 (41.5 mg, 38%). LC-MS (Method B) 502.1 [M+H] ⁺ ; RT 4.97 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.18 (s, 1 H), 8.88 (d, J = 1.5 Hz, 1 H), 8.70 (s, 1 H), 8.01 (d, J = 9.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.40 (dd, J = 8.6, 1.4 Hz, 1 H), 7.05 (d, J = 9.8 Hz, 1 H), 4.76-4.73 (m, 1 H), 4.61 (s, 2H), 4.48-4.44 (m, 1 H), 4.30-4.26 (m, 2H), 2.85-2.78 (m, 2H), 2.73-2.63 (m, 1 H), 2.47-2.40 (m, 1 H), 2.27-2.20 (m, 1 H), 1.74 (m, 1 H), 1.53-1.47 (m, 2H), 1.01-0.90 (m, 1 H).

Example 47:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1(methyl)amino)ethyl)-2-oxo-1 ,2-dihvdroquinoline-7-carbonitrile

47

a) 1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-2-oxo-1 ,2-dihydro quinoline-7-carbonitrile 47a

A solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)rnethyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 59a (97 mg, 0.16 mmol) in DCM (4 ml_) and MeOH (10 ml_) and formaldehyde solution (36.5-38%)(0.06 ml_) were stirred at room temperature for 2 h. NaBH(OAc) ₃ (132 mg, 0.6 mmol) was added and stirred for 90 min. The reaction was basified to pH 8 with saturated aqueous NaHCC and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-10% MeOH in DCM to give a residue containing

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-2-oxo-1 ,2-dihydroqui e-7-carbonitrile 47a (110 mg, 1 10%) which was used without further purification. LC-MS (Method A) 635.3 [M+H] ⁺ ; RT 1.34 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 47

To a stirring solution of

1 -(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl](methyl)arnino}ethyl)-2-oxo-1 ,2-dihydroquinolin e-7-carbonitrile 47a (1 10 mg, 0.17 mmol) in DCM (10 ml_) was added TFA (0.47 ml_) followed by CF3SO3H (0.08 ml_). The reaction was stirred at room temperature for 1 hour then diluted with MeOH (5 ml_) and DCM (15 ml_), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl](methyl)amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 47 (14.7 mg, 16%). LC-MS (Method B) 515.1 [M+H] ⁺ ; RT 5.57 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.17 (s, 1 H), 8.09 (s, 1 H), 8.00 (d, J = 9.5 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 6.78 (d, J = 9.6 Hz, 1 H), 4.74 (br. s, 1 H), 4.60 (br. s, 2H), 4.42-4.31 (m, 3H), 2.66 (br. s, 3H), 2.43 (br. s, 1 H), 2.35 (br. s, 3H), 1.99 (m, 1 H), 1.69 (t, J = 13.4 Hz, 1 H), 1.48 (m, 1 H), 1.26-1.22 (m, 1 H), 1.15- 1.05 (m, 1 H).

Example 48:-1 -(2-fr(3aS,6S,7aS)-3-f2,2-dimethyl-3-oxo-2H,3H,4H-pyridor3,2 - blH ,41oxazin-6-yl)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2- dihydro-1 ,8-naphthyridin-2-one

48

a) tert- butyl

N-[(3aS,6S7aS)-3-{2,2-dimethyl-3-oxo-2H,3H,4H^yrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octah ydro-1 ,3-benzoxazol-6-yl]carbamate 48a

To a mixture of te/f-butyl N-[(3aS,6S,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate (800 mg, 3.12 mmol), 6-bromo-2,2-dimethyl-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-3-one (882 mg, 3.43mmol) (BMCL, 2015, vol. 25, p. 3636 - 3643) and K ₂ C0 ₃ (862 mg, 6.24 mmol) in 1 ,4-dioxane (anhydrous, 15 ml_) under IS^ was added Cul (148 mg, 0.78 mmol) and trans- 1 ,2-diaminocyclohexane (94 uL, 0.78 mmol). The reaction mixture was heated at 1 10°C for 2 h. Further Cul (148 mg, 0.78 mmol) and frans-1 ,2-diaminocyclohexane (94 uL, 0.78 mmol) were added and the mixture heated at reflux for 17 h. The reaction was allowed to cool and the mixture concentrated under reduced pressure. The isolated residue was mixed with H2O and extracted with EtOAc. The combined organic extracts were dried over MgSCU, filtered and concentrated to afford a black gum. The residue was purified by silica gel chromatography using 50% Et20 in heptane to give te/f-butyl

N-[(3aS,6S,7aS)-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3,2-b] [1 ,4]oxazin-6-yl}-2-oxo-octah ydro-1 , 3-benzoxazol-6-yl]carbamate 48a (550 mg, 41 % yield) as a yellow foam. LC-MS (Method A) 433.1 [M+H] ⁺ ; RT 2.87 min. b) (3aS,6S,7aS)-6-amino-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3 ,2-b][1 ,4]oxazin-6-yl} octa hydro-1 ,3-benzoxazol-2-one 48b tert- butyl

N-[(3aS,6S,7aS)-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3,2-b] [1 ,4]oxazin-6-yl}-2-oxo-octah ydro-1 , 3-benzoxazol-6-yl]carbamate 48a (0.5g, 1.16 mmol) was dissolved in HCI (5-6 N in IPA, 0.51 ml_) and the mixture stirred for 1 h. Et20 (175 ml) was added and the reaction quenched with saturated aqueous Na2CC>3 adjusting the pH to 8. The mixture was extracted with DCM (2 x 75 ml_) and the organic extracts were dried (MgSCU) and evaporated under reduced pressure to afford (3aS,6S7aS)-6-amino-3-{2,2-dimethyl-3-oxo-2H,3H,4H^yrido[3,2 -b][1 ,4]oxazin-6-y^ octa hydro-1 ,3-benzoxazol-2-one 48b (305 mg, 0.87 mmol, 75% yield) as a yellow foam. LC-MS (Method A) 333.1 [M+H] ⁺ ; RT 1.98 min. c) 1-(2-{[(3aS,6S,7aS)-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3, 2-b][1 ,4]oxazin-6-yl}-2- oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

(3aS,6S,7aS)-6-amino-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrid o[3,2-b][1 ,4]oxazin-6-yl}octa hydro-1 ,3-benzoxazol-2-one 48b (126 mg, 0.38 mmol), 2-(7-methoxy-2-oxo-1 ,2-dihydro- 1 ,8-naphthyridin-1-yl)acetaldehyde (prepared as described in WO2008009700) (83 mg, 0.38 mmol) and molecular sieves (3A) were added to DCM (10 ml_) and stirred for 1 h at room temperature. NaBH(OAc)3 (242 mg, 1.14 mmol) was added and the mixture stirred for 2 h. The reaction mixture was purified by silica gel chromatography using 10-20% MeOH in EtOAc to give a white foam. DCM (2 ml_) and Et20 (20 ml_) were added and the mixture sonicated. The precipitate was filtered, washed with Et20 and dried to afford 1-(2- {[(3aS,6S,7aS)-3-{2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-2-oxo- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 48 (45 mg, 0.08 mmol, 21 %) as a white solid. LC-MS (Method A) 535.2 [M+H] ⁺ ; RT 2.60 min. ¹ H NMR (Method C) (CDC ): δ ppm 7.97 (s, 1 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.58 (d, J = 9.3 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 6.59 (d, J = 9.3 Hz, 1 H), 4.65 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.95 (td, J = 11.8 Hz, J = 3.4 Hz 1 H), 3.79 (td, J = 11.8 Hz, J = 3.4 Hz, 1 H), 3.19-3.06 (m, 2H), 2.99-2.81 (m, 1 H), 2.75-2.64 (m, 1 H), 2.64-2.56 (m, 1 H), 2.20-1.87 (m, 1 H), 1.62-1.55 (m, 2H), 1.54 (s, 3H), 1.52 (s, 3H), 1.43-1.34 (m, 2H).

Example 49:-1 -(2-{r(3aR,6R,7aR)-3-{6H,7H-ri,41dioxinor2,3-clpyridazin-3-y l)-2-oxo- octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2- one

a) 2-[(3,6-dichloropyridazin-4-yl)oxy]ethan-1-ol 49a

To a solution of ethylene glycol (21.28 ml_, 381.6 mmol) in THF (90 ml_) at 0°C was added NaH (60%, 1.31 g, 54.52 mmol). Once the addition was complete 3,4,6-trichloropyridazine (10 g, 54.52 mmol) in THF (10 ml_) was added and the reaction stirred at 0°C for 1 h. The reaction was allowed to warm to room temperature and stirred for 17 h. The mixture was reduced in volume by evaporation, saturated aqueous NaHCC>3 (30 ml_) added and the mixture extracted with DCM (3 x 35 ml_) and EtOAc (35 ml_). The combined organic extracts were washed with water (40 ml_), dried over MgS0 ₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 3% MeOH in DCM to give 2-[(3,6-dichloropyridazin-4-yl)oxy]ethan-1-ol 49a (4.52 g, 39%). LC-MS (Method A) 210.9 [M+H] ⁺ 1.29 min. b) 3-chloro-6H, 7H-[1 , 4]dioxino[2,3-c]pyridazine 49b

To a solution of 2-[(3,6-dichloropyridazin-4-yl)oxy]ethan-1-ol 49a (4.52 g, 21.61 mmol) in 1 , 4-dioxane (250 ml_) was added NaH (60%, 2.07 g, 86.44 mmol) and the reaction heated to 1 10°C for 18 h. After cooling, the reaction was quenched with iced water, reduced in volume and extracted with DCM (3 x 75 ml_). The combined organic extracts were washed with H2O, dried over MgS0 ₄ and concentrated. The crude material was purified by silica gel chromatography eluting with 0-3% MeOH in EtOAc to give 3-chloro-6H,7H-[1 ,4]dioxino[2,3- c) pyridazine 49b (1.22 g, 33%). LC-MS (Method A) 173.0 [M+H] ⁺ 1.27 min. c) te/f-butyl N-[(3aR,6R,7aR)-3-{6H,7H-[1 ,4]dioxino[2,3-c]pyridazin-3-yl}-2-oxo-octahydro-1 , 3-benzoxoazol-6-yl]carbamate 49c te/f-butyl N-[(3aR,6R,7aR)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 1 a (1.01 g, 3.95 mmol), Pd(OAc) ₂ (35.5 mg, 0.16 mmol), (+/-)-BINAP (197 mg, 0.32 mmol) and K ₃ P0 ₄ (2.1 g, 9.87 mmol) were added to a flask under a N2 atmosphere. A solution of 3-chloro-6H, 7H-[1 , 4]dioxino[2, 3-c]pyridazine 49b (0.681 g, 3.95 mmol) in 1 , 4-dioxane (30 ml_) was added and the reaction heated to 1 10°C for 18 h. (+/-)-BINAP (197 mg, 0.32 mmol) and Pd(OAc)2 (35.45 mg, 0.16 mmol) were added and the reaction stirred at 1 10°C for a further 48 h. The reaction was allowed to cool, diluted with H2O and extracted with EtOAc (3 x 30 ml_). The combined organic extracts were washed with brine, dried over MgS0 ₄ and concentrated to give a residue containing te/f-butyl N-[(3aR,6R,7aR)-3-{6H,7H- [1 ,4]dioxino[2,3-c]pyridazin-3-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 49c (1.799 g, 1 16%) which was used without further purification. LC-MS (Method A) 393.1 [M+H] ⁺ 2.40 min. d) (3aR,6R,7aR)-6-amino-3-{6H,7H-[1 ,4]dioxino[2,3-c]pyridazin-3-yl}-octahydro-1 ,3- benzoxazonol-2-one 49d

HCI (5-6N in IPA, 20 mL) was added to a solution of terf-butyl N-[(3aR,6R,7aR)-3-{6H, 7H- [1 , 4]dioxino[2,3-c]pyridazin-3-yl}-2-oxo-octahydro-1 , 3-benzoxoazol-6-yl]carbamate 49c (1.8 g, 4.58 mmol) in DCM (15 mL) and the reaction stirred at room temperature for 2 h. H2O was added and the phases separated. The organic phase was further extracted with H2O and the aqueous extracts combined. KaCC was added adjusting the pH to 8 and the mixture extracted with DCM. The organic extracts were dried over MgS0 ₄ and concentrated under reduced pressure to give (3aR,6R,7aR)-6-amino-3-{6H,7H-[1 ,4]dioxino[2,3- c]pyridazin-3-yl}-octahydro-1 ,3-benzoxazol-2-one 49d (116.3 mg, 9%). LC-MS (Method A) 293.1 [M+H] ⁺ 1.13 min. e) 1-(2-{[3aR,6R,7aR)-3-{6H,7H-[1 ,4]dioxino[2,3-c]pyridazin-3-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-napthyridin-2-one 49

To a solution of (3aR,6R,7aR)-6-amino-3-{6H,7H-[1 ,4]dioxino[2,3-c]pyridazin-3-yl}- octahydro-1 ,3-benzoxazonol-2-one 49d (1 16 mg, 0.40 mmol) in DCM (10 mL) over molecular sieves (4A) was added 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)acetaldehyde (87 mg, 0.40 mmol) (prepared as described in WO2008009700) and acetic acid (0.1 mL). The reaction was heated to 40°C for 18 h. Sodium borohydride (45.16 mg, 1.19 mmol) was added and the reaction stirred at room temperature for 30 min. The mixture was decanted to remove the molecular sieves and saturated aqueous NaHC03 added, adjusting the pH to 8. The organic phase was washed with brine, dried over MgS0 ₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-20% MeOH in EtOAc) followed by prep. HPLC (Method B) to give 1-(2- {[3aR,6R,7aR)-3-{6H,7H-[1 ,4]dioxino[2,3-c]pyridazin-3-yl}-2-oxo-octahydro-1 ,3-benzoxazol- 6-yl]amino}ethyl)-7-methoxy-1 , 2-dihydro-1 ,8-napthyridin-2-one 49 (23 mg, 12%). LC-MS (Method A) 495.1 [M+H] ⁺ 1.96 min. ¹ H NMR (Method C) (CH ₃ OD): δ ppm 8.00 (d, J = 8.5 Hz, 1 H), 7.88 (d, J = 9.3 Hz, 1 H), 7.48 (s, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.60 (d, J = 9.4 Hz, 1 H), 4.69 (t, J = 7.2 Hz, 2H), 4.57 (dd, J = 5.8, 3.0 Hz, 2H), 4.52 - 4.36 (m, 2H), 4.15 (d, J = 3.2 Hz, 1 H), 4.10 (s, 3H), 3.99 (s, 1 H), 3.08 (td, J = 6.9, 2.8 Hz, 2H), 3.00 (td, J = 10.7, 5.2 Hz, 1 H), 2.84 - 2.71 (m, 1 H), 2.64 (s, 1 H), 2.17 (d, J = 12.6 Hz, 1 H), 1.68 - 1.57 (m, 1 H), 1.53 - 1.35 (m, 2H).

Example 50:-

5-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino)ethyl)-6-oxo-5,6-dihvdro-1 ,5-naphthyridine-3-carbonit

50

a)

5-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-nap hthyridine-3-carbonitrile 50a

A solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (100 mg, 0.23 mmol) and 6-oxo-5-(2-oxoethyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile (prepared as described in WO 2008009700 A1 20080124) (50 mg, 0.23 mmol) in DCM (15 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (199 mg, 0.94 mmol) was added and stirred for 2 h. The reaction was basified to pH 8-9 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure to give a residue containing

5-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridi ne-3-carbonitrile 50a (182 mg, 125%) which was used without further purification. LC-MS (Method A) 622.1 [M+H] ⁺ ; RT 2.50 min. b)

5-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 50 To a stirring solution of

5-(2-{[(3aR _I 6R7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H _I 4H-pyrido[3 _I 2-b][1 _I 4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-6- oxo-5,6-dihydro-1,5-naphthyridi ne-3-carbonitrile 50a (182 mg, 0.29 mmol) in DCM (15 ml_) was added TFA (0.80 ml_) followed by CF3SO3H (0.18 ml_). The reaction was stirred at room temperature for 30 min then diluted with MeOH (5 ml_) and DCM (15 ml_), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-10% MeOH in DCM to give

5-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 50 (60.5 mg, 41%). LC-MS (Method B) 502.0 [M+H] ⁺ ; RT 4.84 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.22 (s, 1H), 8.89 (d, J= 1.6 Hz, 1H), 8.72 (d, J= 1.6 Hz, 1H), 8.02 (d, J= 9.8 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 7.06 (d, J= 9.8 Hz, 1H), 4.62 (s, 2H), 4.30 (t, J= 7.0 Hz, 2H), 4.04 (td, J= 11.7, 3.3 Hz, 1H), 3.75 (td, J= 11.1, 3.2 Hz, 1H), 2.87 (br. s, 2H), 2.77 (m, 2H), 2.46-2.39 (m, 1H), 1.96 (m, 1H), 1.47 (br. s, 1H), 1.34-1.29 (m, 1H), 1.25 (m, 1H).

Example 51 :-

1-(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vn(methyl)amino)ethyl)-7-methoxy-1 ,2-dihydro-1 ,5 -naphthyridin-2-o ne

51

a)

1-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl](methyl) amino}ethyl)-7-methoxy-1,2-dih ydro-1,5-naphthyridin-2-one 51a A solution of

1 -(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H^yrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-napht hyridin-2-one 30a (1 10 mg, 0.18 mmol) in DCM (4 ml_), MeOH (10 mL) and formaldehyde solution (36.5-38%)(0.07 mL) was stirred at room temperature for 2 h. NaBH(OAc) ₃ (149 mg, 0.70 mmol) was added and the reaction stirred for 1 h. The reaction was basified to pH 8 with saturated aqueous NaHCC>3 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a crude residue containing

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 , 5-naphthyridin-2-one 51 a which was used without further purification. LC-MS (Method A) 641.2 [M+H] ⁺ ; RT 2.48 min. b)

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 51

To a stirring solution of

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl](methyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 , 5-naphthyridin-2-one 51 a (1 14 mg, 0.18 mmol) in DCM (10 mL) was added TFA (0.47 mL) followed by CF3SO3H (0.11 mL). The reaction was stirred at room temperature for 1 h then diluted with MeOH (5 mL) and DCM (15 ml), basified to pH 8-9 with saturated Na ₂ C0 ₃ and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl](methyl)amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 51 (29 mg, 31 %). LC-MS (Method B) 521.2 [M+H] ⁺ ; 4.98 min, ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.18 (s, 1 H), 8.27 (d, J = 2.3 Hz, 1 H), 7.87 (d, J = 9.6 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 1 H), 7.42 (d, J = 2.5 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 1 H), 6.66 (d, J = 9.6 Hz, 1 H), 4.77-4.72 (m, 1 H), 4.62 (m, 2H), 4.42-4.38 (m, 1 H), 4.35-4.30 (m, 2H), 3.99 (s, 3H), 2.68-2.64 (m, 3H), 2.45-2.42 (m, 1 H), 2.38 (s, 3H), 2.05-1.97 (m, 1 H), 1.73-1.66 (m, 1 H), 1.54-1.48 (m, 1 H), 1.28-1.20 (m, 1 H), 1.15-1.08 (m, 1 H).

Example 52:-

(3aS,6SJaS)-6-r(2-{2-methoxy-7-oxo-7H,8H-pyridor2,3-dlp

-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6-yl)-octahydro-1 ,3-benzoxazol-2-one

a) 1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 52a

To a solution of

(3aS,6S7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H^yrido[3,2-b][1 ,4]ox azin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (209 mg, 0.49 mmol) and

2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl}acet aldehyde 2b (108 mg, 0.49 mmol) in DCM (20 ml_) was added a few drops of AcOH and the mixture stirred at room temperature for 2 h. NaBH(OAc)3 (313 mg, 1.48 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The mixture was adjusted to pH 8-9 with saturated Na2CC>3 and extracted with DCM (100 ml_). The organic layer was washed with brine, dried over MgSCU, filtered and concentrated to give

1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 52a, (209 mg, 67 % ), which was used without further purification. LC-MS (Method A) 628.2 [M+H] ⁺ ; RT 2.61 min. b) (3aS,6S,7aS)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8-yl}ethyl)amino]

3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 52 To a solution of

1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydr oquinoxalin-2-one 52a (209 mg, 0.33 mmol) in DCM (20 mL) was added TFA (382 μΙ_, 5.00 mmol) followed by CF3SO3H (147 μΙ_, 1.67 mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with MeOH (1 mL), adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 mL). The organic extract was washed with brine, dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 10 g KP-Si cartridge) using 0-50 % MeOH in DCM to give

(3aS,6S,7aS)-6-[(2-{2-methoxy-7-oxo-7H,8H-pyrido[2,3-d]pyrim idin-8-yl}ethyl)amino]-3-{3-o xo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 52 (39 mg, 23 %) as a white solid. LC-MS (Method B) 508.1 [M+H] ⁺ ; RT 5.58 min. ¹ H NMR (Method C) (DMSO): δ ppm 1 1.24 (br s, 1 H), 8.92 (s, 1 H), 7.95 (d, J = 9.5 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 6.57 (d, J = 9.5 Hz, 1 H), 4.62 (s, 2H), 4.34 (m, 2H), 4.06 (td, J = 1 1.8, 3.3 Hz, 1 H), 4.02 (s, 3H), 3.74 (td, J = 1 1.2, 3.3 Hz, 1 H), 2.86 (m, 2H), 2.77 (m, 2H), 2.44 (m, 1 H), 1.98 (d, J = 12.9 Hz, 1 H), 1.46 (q, J = 1 1.2 Hz, 1 H), 1.32 (m, 1 H), 1.22 (m, 1 H).

Example 53:-

(3aS,6SJaR)-6-({2-r2-(methylsulfanyl)-7-oxo-7H,8H-pyridor 2,3-dlpyrimidin-8-yl1ethyl)a mino)-3-{3-oxo-2H,3H,4H-pyridor3,2-biri ,41oxazin-6-yl)-octahydro-1 ,3-benzoxazol-2-on

a) 5-bromo-N-(2,2-dimethoxyethyl)-2-(methylsulfanyl)pyrimidin-4 -amine 53a

5-bromo-4-chloro-2-(methylsulfanyl)pyrimidine (25 g, 104.40 mmol) , K2CO3 (19 g, 135.700 mmol) and 2,2-dimethoxyethan-1 -amine (23 mL, 208.80 mmol) were added to DMF (200 mL) and the mixture was heated at 50°C for 18 h. The reaction was evaporated to dryness and quenched with water (300 mL), extracted with diethyl ether (3 x 250 ml), washed with brine and dried over MgSCU and evaporated to

give 5-bromo-N-(2,2-dimethoxyethyl)-2-(methylsulfanyl)pyrimidin-4 -amine 53a (31 g, 96 %) as a clear gum. ¹ H NMR (Method C) (CDCb): δ ppm 8.02 (s, 1 H), 5.49 (s, 1 H), 4.44 (dd, J = 5.5 Hz, 1 H), 3.59 (dd, J = 5.5 Hz, J = 5.5 Hz, 2H), 3.37 (s, 6H), 2.43 (s, 3H). b) Butyl (2E)-3-{4-[(2,2-dimethoxyethyl)amino]-2-(methylsulfanyl)pyri midin-5-yl}prop-2- enoate 53b

5-bromo-N-(2,2-dimethoxyethyl)-2-(methylsulfanyl)pyrimidi n-4-amine 53a (18.2 g, 59.10 mmol), triethylamine (20 mL, 143.50 mmol), butyl prop-2-enoate (84.8 mL, 591.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.30 mmol) were combined and heated to 100 ^° C for 18 h. Further butyl prop-2-enoate (100 mL, 402.30 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (2.0 g, 2.48 mmol)). The reaction was heated at reflux for another 18 h. The reaction was evaporated to dryness and then quenched with water (150 mL), extracted with ether (3 x 500 mL) and dried over MgSCU. The solvent was evaporated to afford an orange gum. The mixture was purified by chromatography using 0- 50 % EtOAc in heptane to give butyl

(2E)-3-{4-[(2,2-dimethoxyethyl)amino]-2-(methylsulfanyl)pyri midin-5-yl}prop-2-enoate 53b (20.1 g, 96 %) as a very pale yellow oil. ¹ H NMR (Method C) (CDCb): δ ppm 8.10 (s, 1 H), 7.44 (d, J = 15.9 Hz, 1 H), 6.22 (d, J = 15.9 Hz, 1 H), 5.29 (t, J = 5.4 Hz, 1 H), 4.46 (t, J = 5.4 Hz, 1 H), 4.14 (t, J = 6.4 Hz, 2H), 3.64 (dd, J = 5.4 Hz, J = 5.4 Hz, 2H), 3.37 (s, 6H), 2.46 (s, 3H), 1.61 (m, 2H), 1.36 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). c) 8-(2,2-dimethoxyethyl)-2-(methylsulfanyl)-7H,8H-pyrido[2,3-d ]pyrimidin-7-one 53c

Butyl (2E)-3-{4-[(2,2-dimethoxyethyl)amino]-2-(methylsulfanyl)pyri midin-5-yl}prop-2-enoate 53b (4.04 g, 1 1.37 mmol) was taken up in methanol (40 mL) and to this was added catalytic sodium methoxide (31 mg, 0.57 mmol). The reaction was heated at 60 ^° C for 4 h. The reaction was complete after this time and then treated with saturated aqueous NH ₄ CI solution (0.5 mL) and evaporated to dryness. The residue was taken up in DCM (50 mL) and the white solid formed (NH4CI) was filtered off, washed with further DCM (30 mL) and the supernatant evaporated to dryness. The residue was purified by chromatography using 0-40 % EtOAc in DCM. Relevant fractions were combined and evaporated to dryness to afford a colourless oil which slowly solidified. Trituration with 10 % EtOAc/heptane afforded 8-(2,2-dimethoxyethyl)-2-(methylsulfanyl)-7H,8H^yrido[2,3-d] pyrimidin-7-one 53c as a fluffy white solid. ¹ H NMR (Method C) (CDC ): δ ppm 8.53 (s, 1 H), 7.53 (d, J = 9.5 Hz, 1 H), 6.57 (d, J = 9.5 Hz, 1 H), 4.89 (t, J = 5.6 Hz, 1 H), 4.53 (d, J = 5.6 Hz, 2H), 3.31 (s, 6H), 2.55 (s, 3H). d) 2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-y l]acetaldehyde 53d

8-(2,2-dimethoxyethyl)-2-(methylsulfanyl)-7H,8H-pyrido[2, 3-d]pyrimidin-7-one 53c (273 mg, 0.97 mmol) was added to 2M HCI (4.85 ml_, 9.70 mmol) and THF (10 ml_) and the reaction heated at 60°C for 18 h. The mixture was adjusted to pH 8-9 with saturated Na2CC>3 and extracted with EtOAc (2 x 50 ml_). The organic layer was washed with brine, dried over MgSCU, filtered and concentrated to give

2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-y l]acetaldehyde 53d (209 mg, 91 %) as a white solid, which was used without further purification. LC-MS (Method A) 236.1 [M+H] ⁺ ; RT 1.13 min. e) (3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-p yrido[3,2-b][1 ,4]oxa zin-6-yl}-6-({2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d ]pyrimidin-8-yl]ethyl}amin o)-octahydro-1 ,3-benzoxazol-2-one 53e

To a solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (370 mg, 0.87 mmol) and 2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-y l]acetaldehyde 53d (205 mg, 0.87 mmol) in DCM (40 ml_) was added a few drops of AcOH and the mixture stirred at room temperature for 2 h. NaBH(OAc)3 (554 mg, 2.62 mmol) was added and the reaction mixture stirred at room temperature for 1 h. The mixture was adjusted to pH 8-9 with saturated Na2CC>3 and extracted with DCM (150 ml_). The organic layer was washed with brine, dried over MgSCU, filtered and concentrated. The crude was purified by

chromatography (Biotage 25 g KP-Si cartridge) using 0-50 % MeOH in DCM to give

(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin-6-yl }-6-({2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimid in-8-yl]ethyl}amino)-octahydro-1 ,3-benzoxazol-2-one 53e (183 mg, 32 %). LC-MS (Method A) 644.2 [M+H] ⁺ ; RT 2.86 min. f) (3aS,6S,7aR)-6-({2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2, 3-d]pyrimidin-8- yl]ethyl}amino)-3-{3-oxo-2H,3H,4H^yrido[3 _^

2-one 53

To a solution of

(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H^yr ido[3,2-b][1 ,4]oxazin-6-yl }-6-({2-[2-(methylsulfanyl)-7-oxo-7H,8H^yrido[2,3-d]pyrimidi n-8-yl]ethyl}amino)-octahydro^ ,3-benzoxazol-2-one 53e (180 mg, 0.28 mmol) in DCM (20 mL) was added TFA (320 μΙ_, 4.19 mmol) followed by CF3SO3H (124 μΙ_, 1.40 mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with MeOH (1 mL), adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with DCM (100 mL). The organic extract was washed with brine, dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 10 g KP-Si cartridge) using 0-25 % MeOH in DCM to give

(3aS,6S,7aR)-6-({2-[2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2, 3-d]pyrimidin-8-yl]ethyl}amino) -3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 53 (24 mg, 16 %). LC-MS (Method B) 524.1 [M+H] ⁺ ; RT 6.05 min. ¹ H NMR (Method C) (CDCI3): δ ppm 8.62 (s, 1 H), 7.94 (br s, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 9.4 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 6.64 (d, J = 9.4 Hz, 1 H), 4.69 (m, 1 H), 4.63 (s, 2H), 4.54 (m, 3H), 3.05 (m, 2H), 2.89 (m, 1 H), 2.63 (s, 3H), 2.48 (m, 1 H), 2.44 (m, 1 H) 1.90 (m, 1 H), 1.54 (m, 1 H), 1.42 (m, 1 H), 1.1 1 (m, 1 H).

Example 54:- (3aR,6R,7aR)-N-{2-r7-(2-azaniumylethoxy)-2-oxo-1 ,2-dihydroquinolin-1 - yl1ethyl N-methyl-2-oxo-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6- yl)-octahvdro- 1 3-benzoxazol-5-aminium dichloride

54 a) terf-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-5-yl](methyl)amino}ethyl)-2- oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 54a

Formaldehyde solution (36.5-38% in H20, 0.05 mL) was added to a stirred solution of N-(2- {[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2 H,3H,4H-pyrido[3,2- b] [1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl]oxy}ethyl)carbamate 23a (99 mg, 0.13 mmol) in DCM (5 mL). The mixture was stirred for 10 min and NaBH(OAc)3 (83.4 mg, 0.39 mmol) added. After 1 h, volatiles were removed under reduced pressure and the residue dissolved in DCM (5 mL) and MeOH (0.5 mL). Saturated aqueous NaHCC>3 (5 mL) was added and the mixture passed through an SPE phase separator. The organic phase was evaporated under reduced pressure and purified by chromatography eluting with 0-6% MeOH/DCM to give terf-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-5-yl](methyl)amino}ethyl)-2- oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 54a (151 mg , 149.7%). LC-MS (Method A) 769.3 [M+H] ⁺ ; RT 3.93 min. b) (3aR,6R,7aR)-N-{2-[7-(2-azaniumylethoxy)-2-oxo-1 ,2-dihydroquinolin-1-yl]ethyl}-N- methyl-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-5- aminium dichloride 54

TFA (0.49 mL, 6.44 mmol) and CF3SO3H (0.12 mL, 1.39 mmol) were added to a solution of terf-butyl N-(2-{[1-(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3- oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-5-yl](methyl)amino}ethyl)-2- oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 54a (151 mg, 0.2 mmol)) in DCM (15 mL) at room temperature. After 1 h the reaction was diluted with MeOH (5 mL) and DCM (10 mL). Saturated aqueous Na2C03was added, adjusting the pH to 8, and the mixture was passed through an SPE phase separator. The aqueous phase was further extracted with DCM/MeOH (4: 1 , 2 x 30 mL) and the combined organics concentrated under reduced pressure. The residue was purified by preparative LCMS (Method B) to afford a white solid. This was dissolved in a minimum volume of MeOH, treated with 1 M HCI in ether and evaporated to afford (3aR,6R,7aR)-N-{2-[7-(2-azaniumylethoxy)-2-oxo-1 ,2-dihydroquinolin- 1-yl]ethyl}-N-methyl-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-5-aminium dichloride 54 (18 mg, 16.7%) as a white solid. LC-MS (Method B) 549.2 [M+H] ⁺ ; RT 4.51 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.59 (br s, 1H), 11.27 (d, J= 4.6 Hz, 1H), 8.19 (br s, 3H), 7.93 (dd, J= 9.5, 1.5 Hz, 1H), 7.74 (d, J= 8.7 Hz, 1H), 7.45 (d, J= 8.5 Hz, 1H), 7.33 (t, J =2.7 Hz, 1H), 7.21 (dd, J= 8.6, 6.8 Hz, 1H), 6.98 (dd, J = 8.7, 2.0 Hz, 1H), 6.52 (dd, J= 9.4, 3.7 Hz, 1H), 4.75 (m, 2H), 4.64 (d, J= 2.6 Hz, 2H), 4.51 (m, 2H), 4.16 (dtd, J= 14.8, 11.5, 3.3 Hz, 1H), 3.91 -3.75 (m, 2H), 3.50-3.38 (m, 1H), 3.31 -3.18 (m, 3H), 2.96 (m, 4H), 2.74 (dd, J= 24.4, 9.9 Hz, 1H), 2.32 (m, 1H), 2.17 (m, 1H), 1.86-1.67 (m, 1H), 1.53- 1.40 (m, 1H).

Example 55:-

5-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-yl1amino)ethyl)-6-oxo-5,6-dihydro-^

55

a)5-(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-ox o-2H,3H,4H-pyrido[3,2-b][1,4]ox azin-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)- 6-oxo-5,6-dihydro-1,5-naphthyr idine-3-carbonitrile 55a

A solution of

(3aS,6S,7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1,4]ox azin-6-yl}-octahydro-1,3-benzoxazol-2-one 29c (100 mg, 0.23 mmol) and

6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthyridine-3-carb onitrile (prepared as described in WO 2008009700 A1) (50 mg, 0.23 mmol) in DCM (15 mL) were stirred at room temperature for 2 h. NaBH(OAc)3 (249 mg, 1.17 mmol) was added and stirred for 17 h. The reaction was basified to pH 8 with saturated aqueous NaHC03, diluted with DCM (10 mL) and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure to give a crude residue containing

5-(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-6- oxo-5,6-dihydro-1,5-naphthyridi ne-3-carbonitrile 55a (198 mg, 136%) which was used without further purification. LC-MS (Method A) 622.2 [M+H] ⁺ ; RT 2.53 min. b)5-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][ 1,4]oxazin-6-yl}-octahydro-1, 3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1,5-naphthy ridine-3-carbonitrile 55

To a stirring solution of

5-(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)rnethyl]-3-oxo-2H ,3H,4H-pyrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-6- oxo-5,6-dihydro-1,5-naphthyridi ne-3-carbonitrile 55a (198 mg, 0.32 mmol) in DCM (15 mL) was added TFA (0.86 mL) followed by CF3SO3H (0.20 mL). The reaction was stirred at room temperature for 1 h then diluted with MeOH (5 mL) and DCM (15 mL), basified to pH 8-9 with saturated aqueous Na2CC>3 and passed through an SPE phase separator. The organic portion was

concentrated under reduced pressure and the residue purified via silica gel

chromatography using 0-20% MeOH in DCM to give

5-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1,5-naphthyri dine-3-carbonitrile 55 (39 mg, 25%). LC-MS (Method B) 502.2 [M+H] ⁺ ; RT 5.11 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.21 (br. s, 1H), 8.89 (d, J= 2.0 Hz, 1H), 8.71 (d, J= 1.7 Hz, 1H), 8.02 (d, J= 9.8 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.16 (d, J= 8.6 Hz, 1H), 7.05 (d, J= 9.7 Hz, 1H), 4.62 (s, 2H), 4.27 (t, J= 6.9 Hz, 2H), 4.03 (td, J= 11.6, 3.3 Hz, 1H), 3.74 (td, J= 11.1, 3.3 Hz, 1H), 2.86- 2.80 (m, 2H), 2.79-2.71 (m, 2H), 2.44-2.37 (m, 1H), 2.13 (br. s, 1H) 1.95-1.92 (m, 1H), 1.43 (q, J= 11.2 Hz, 1H), 1.36-1.26 (m, 1H), 1.24-1.13 (m, 1H).

Example 56:-

1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-yl1amino)ethyl)-2-oxo-1,2-dihvdroquinoline- 7-carbonitrile

56 a) 1 -(2-{[(3aS,6S7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H ,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-c arbonitrile 56a

A solution of

(3aS,6S7aS)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H^yrido[3,2-b][1 ,4]ox azin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 29c (120 mg, 0.28 mmol) and 2-oxo-1-(2- oxoethyl)quinolone-7-carbonitrile (J. Med. Chem (2014) 57 (1 1), 4889-4905) (60 mg, 0.28 mmol) in DCM (15 ml_) was stirred at room temperature for 2 h. NaBH(OAc)3 (300 mg, 1.41 mmol) was added and stirred for 5 h. The reaction was basified to pH 8 with saturated aqueous NaHCC>3 passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and purified via silica gel chromatography using 0- 20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 56a (79 mg, 45%). LC-MS (Method A) 621.2 [M+H] ⁺ ; RT 2.70 min. b) 1 -(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 , 3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 56

To a stirring solution of

1 -(2-{[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 56a (79 mg, 0.13 mmol) in DCM (15 ml_) was added TFA (0.34 ml_) followed by CF3SO3H (0.01 ml_). The reaction was stirred at room temperature for 1 h then diluted with MeOH (5 ml_) and DCM (15 ml_), basified to pH 8-9 with saturated aqueous Na ₂ C03 and passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 56 (17 mg, 28%). LC-MS (Method B) 501.2 [M+H] ⁺ ; RT 5.36 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.23 (s, 1 H), 8.19 (d, J = 1.3 Hz, 1 H), 8.01 (d, J = 9.5 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.1 , 1.3 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 9.5 Hz, 1 H), 4.62 (s, 2H), 4.29 (t, J = 7.2 Hz, 2H), 4.04 (td, J = 1 1.8, 3.3 Hz, 1 H), 3.75 (td, J = 1 1.2, 3.4 Hz, 1 H), 2.85-2.74 (m, 4H), 2.45-2.42 (m, 1 H), 2.19 (br. s, 1 H), 1.99-1.96 (m, 1 H), 1.46 (q, J = 1 1.2 Hz, 1 H), 1.33 (m, 1 H), 1.28-1.16 (m, 1 H).

Example 57:- 6-r3-(fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin, 41oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)methyl)phenyllpyridine-2-carbonitri le

a)

(3aS,6S,7aS)-6-amino-3-{3-oxo-2H,3H,4H^yrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-ben zoxazol-2-one 57a

To a solution of

tert-butylN-[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]- 3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4 ]oxazin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29b (615 mg, 1.17 mmol) in DCM (50 mL) was added TFA (1.35 mL, 17.59 mmol) followed by CF3SO3H (519 μί, 5.86 mmol) and the mixture was stirred at room temperature for 15 min. The reaction was quenched with MeOH (6 mL), adjusted to pH 8-9 with saturated aqueous Na2CC>3 and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine, dried (MgSCU), filtered and concentrated under reduced pressure to give

(3aS,6S,7aS)-6-amino-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-ben zoxazol-2-one 57a (273.3 mg, 76%) as a white solid. LC-MS (Method A) 305.1 [M+H] ⁺ ; RT 1.65 min. b) 6-[3-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}methyl)phenyl]pyridine-2-carbonitri le 57

(3aS,6S,7aS)-6-amino-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-ben zoxazol-2-one 57a (100 mg, 0.33 mmol) and 6-(3-formylphenyl)pyridine-2-carbonitrile (68 mg, 0.33 mmol) in DCM (15 mL) were stirred for 4 h over molecular sieves (4 A). NaBH(OAc)3 (208.9 mg, 0.99 mmol) was added and the mixture stirred at ambient temperature for 72 h. The mixture was filtered and the filtrate concentrated down under reduced pressure. The residue was purified by silica chromatography using 0-10% I PA in DCM to give 6-[3-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}methyl)phenyl]pyridine-2-carbonitri le 57 (49 mg, 28.5%). LC-MS (Method A) 497.1 [M+H] ⁺ ; RT 2.37 min. ¹ H NMR (Method C) (CDC ): δ ppm 8.05 (d, J = 1.7 Hz, 1 H), 7.97 (dd, J = 8.2, 1.0 Hz, 1 H), 7.93 - 7.87 (m, 2H), 7.64 (dd, J = 7.5, 1.0 Hz, 1 H), 7.51 - 7.44 (m, 2H), 7.35 - 7.28 (m, 2H), 4.63 (s, 2H), 4.02 - 3.92 (m, 3H), 3.83 (td, J = 1 1.1 , 3.3 Hz, 1 H), 2.91 (td, J = 10.8, 5.2 Hz, 1 H), 2.77 - 2.71 (m, 1 H), 2.71 - 2.64 (m, 1 H), 2.20 (dt, J = 14.7, 5.0 Hz, 1 H), 1.69 (q, J = 1 1.4 Hz, 1 H), 1.51 (qd, J = 12.6, 12.0, 3.9 Hz, 1 H), 1.40 (qd, J = 12.2, 3.4 Hz, 1 H).

Example 58:-

1 -(2-fr(3aS,6S,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1(2-aminoethyl)amino)ethyl)-2-oxo-1 ,2-dihvdroquinoline-7-carbonit rile

a)1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-c arbonitrile 58a

A solution of (3aS,6S,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 4c (200 mg, 0.47 mmol) and 2-OXO-1 -(2-oxoethyl)-1 ,2-dihydroquinoline-7-carbonitrile (100 mg, 0.47 mmol) (J . Med. Chem (2014) 57 (11), 4889-4905) in DCM (20 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (499 mg, 2.36 mmol) was added and stirred at room temperature for 90 min. The reaction was basified to pH 8 with saturated NaHCC and the resulting mixture was passed through an SPE phase separator. The organic portion was collected and concentrated under reduced pressure to give

1 -(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz j _n- 6-y|}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 58a (270 mg, 92%) which was used without further purification. LC-MS (Method A) 621.3 [M+H] ⁺ ; RT 2.30 min. b) tert-butyl

N-(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)eth yl]amino}ethyl)carbamate 58b

A solution of

1 -(2-{[(3aS,6S7aR)-3-{4-[(4-methoxyphenyl)rnethyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 58a (50 mg, 0.08 mmol) and tert-butyl N-(2-oxoethyl)carbamate (25.6 mg, 0.16 mmol) in DCM (5 mL) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (85.4 mg, 0.4 mmol) was added and stirred for 17 h. Another portion of tert-butyl N-(2-oxoethyl)carbamate (12.8 mg, 0.08 mmol) was added and stirred for 1 h. The reaction was quenched with MeOH (1 mL), basified to pH 8 with saturated NaHCC and the resulting mixture was passed through an SPE phase separator. The aqueous portion was extracted with DCM:IPA (4: 1 , 20 mL), the organics combined and concentrated under reduced pressure to give tert-butyl

N-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)eth yl]amino}ethyl)carbamate 58b (82 mg, 133%) which was used without further purification. LC-MS (Method A) 764.3 [M+H] ⁺ ; RT 3.39 min. c) 1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3 -benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 58

To a stirring solution of tert-butyl

N-(2-{[(3aS,6S,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H, 3H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl][2-(7-cyano-2-oxo-1 ,2-dihydroquinolin-1 -yl)eth yl]amino}ethyl)carbamate 58b (82 mg, 0.1 1 mmol) in DCM (5 mL) was added TFA (0.1 mL) followed by CF3SO3H (0.04 mL). The reaction was stirred for 1 h then quenched with MeOH (1 mL) and basified with saturated Na2C03 to pH 8-9. The mixture was diluted with

DCM:IPA (4: 1 , 10 mL), passed through an SPE phase separator and the organic portion concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aS,6S,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl](2-aminoethyl)amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 58 (5.6 mg, 10%). LC-MS (Method B) 544.1 [M+H] ⁺ ; RT 5.84 min. ¹ H NMR (Method C) (DMSO- d6): δ ppm 8.07 (s, 1 H), 8.05 (d, J = 9.6 Hz, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.70 (dd, J = 8.0, 1.2 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 6.83 (d, J = 9.5 Hz, 1 H), 4.74 (m, 1 H), 4.60 (s, 3H), 4.42-4.30 (m, 4H), 2.84-2.79 (m, 2H), 2.79-2.69 (m, 6H), 2.09-2.03 (m, 1 H), 1.65 (m, 1 H), 1.48 (d, J = 13.0 Hz, 1 H), 1.25-1.21 (m, 1 H), 1.09-1.06 (m, 1 H).

Example 59:-

1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vnamino)ethyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile

a)1 -(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]ox azin-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-c arbonitrile 59a

A solution of (3aR,6R,7aR)-6-amino-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H ,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 1 c (80 mg, 0.19 mmol) and 2-OXO-1 -(2-oxoethyl)-1 ,2-dihydroquinoline-7-carbonitrile (J . Med. Chem (2014) 57 (1 1), 4889-4905) (40 mg, 0.19 mmol) in DCM (5 ml_) was stirred, at room temperature, over molecular sieves (3A) for 2 h. NaBH(OAc)3 (200 mg, 0.94 mmol) was added and stirred at room temperature for 2 h. The reaction was basified to pH 8 with saturated aqueous NaHCC and the resulting mixture was passed through an SPE phase separator. The organic portion was concentrated under reduced pressure and the residue purified via silica gel chromatography using 0-20% MeOH in DCM to give

1 -(2-{[(3aR,6R,7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H-pyrido[3,2-b][1 ,4]oxaz in-6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-7-car bonitrile 59a (75 mg, 64%). LC-MS (Method A) 621.1 [M+H] ⁺ ; RT 2.49 min. b)1-(2-{[(3aR,6R7aR)-2-oxo-3-{3-oxo-2H,3H,4H^yrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1, 3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1,2-dihydroquinoline-7- carbonitrile 59

To a stirring solution of

1-(2-{[(3aR,6R7aR)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3 H,4H^yrido[3,2-b][1,4]oxaz in-6-yl}-2-oxo-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-2- oxo-1,2-dihydroquinoline-7-car bonitrile 59a (75 mg, 0.12 mmol) in DCM (15 ml_) was added TFA (0.2 ml_) followed by CF3SO3H (0.05 ml_). The reaction was stirred at room temperature for 30 min then quenched with MeOH (5 ml_) and basified with saturated aqueous Na2CC>3 to pH 8-9. The resulting mixture was diluted with DCM (15 ml_), passed through an SPE phase separator and the organic portion concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-20% MeOH in DCM to give

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-2-oxo-1,2-dihydroquinoline-7-ca rbonitrile 59 (20.6 mg, 32%). LC-MS (Method B) 501.1 [M+H] ⁺ ; RT 5.50 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.21 (s, 1H), 8.18 (s, 1H), 8.01 (d, J= 9.5 Hz, 1H), 7.92 (d, J= 8.1 Hz, 1H), 7.66 (dd, J = 7.9, 1.3 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 8.5 Hz, 1H), 6.79 (d, J= 9.5 Hz, 1H), 4.62 (s, 2H), 4.29 (t, J =7.2 Hz, 2H), 4.07-4.00 (m, 1H), 3.75 (td, J= 11.2, 3.4 Hz, 1H), 2.85-2.72 (m, 4H), 2.43 (m, 1H), 2.08 (m, 1H), 1.97 (m, 1H), 1.45 (q, J = 11.1 Hz, 1H), 1.37- 1.27 (m, 1H), 1.25-1.19 (m, 1H).

Example 60:- 1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-vnamino)propyl)-2-oxo-1,2-dih ydroquinoline-7- carbonitrile

a) 7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydroquinolin-2-one 60a A solution of 7-bromo-1 ,2-dihydroquinolin-2-one (1.5 g, 6.68 mmol), 3-bromo-1 , 1- dimethoxypropane (0.96 ml_, 7.03 mmol) and cesium carbonate (6.54 g, 20.03 mmol) in DMF (100 ml_) washeated overnight at 100 ^° C. H ₂ 0 (250 ml_) was added, extracted with EtOAc (3 x 100 ml_), dried with MgS0 ₄ and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with (0-100% EtOAc in petroleum ether) to give a colourless solid as 7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydroquinolin-2- one 60a (740 mg, 34%). LC-MS (Method A) 296.0 [M-OMe] ⁺ ; RT 2.78 min. b) 1-(3,3-dimethoxypropyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 60b

A solution of 7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydroquinolin-2-one 60a (740 mg, 2.27 mmol), Palladium tetrakis (131 mg, 0.1 1 mmol) and zinc cyanide (159 mg, 1.4 mmol) in DMF (3 ml_) was sealed in a microwave vial and irradiated at 150 ^° C for 90 min. H2O (50 ml_) was added, extracted with EtOAc (3 x 30 ml_), dried over MgS0 ₄ and concentrated under reduced pressure to give a yellow solid. Purification via silica gel chromatography eluting with(0-100% EtOAc in petroleum ether) gave 1-(3,3-dimethoxypropyl)-2-oxo-1 ,2- dihydroquinoline-7-carbonitrile 60b (340 mg, 51 %). LC-MS (Method A) 241.1 [M-OMe] ⁺ ; RT 2.32 min.

c) 2-oxo-1-(3-oxopropyl)-1 ,2-dihydroquinoline-7-carbonitrile 60c

A solution of 1-(3,3-dimethoxypropyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 60b in HCI (2M solution in THF, 5 mL) was stirred at room temperature for 2 h. H2O (20 mL) was added, extracted with EtOAc (3 x 30 mL), dried over MgS0 ₄ and concentrated under reduced pressure to give an off white solid 2-oxo-1-(3-oxopropyl)-1 ,2-dihydroquinoline-7- Carbonitrile 60c (210 mg, 82 %). LC-MS (Method A) 227.5 [M+H] ⁺ ; RT 1.47 min. d) (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d

To a solution of te/f-butyl

N-[(3aS,6S,7aS)-3-{4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4 H-pyrido[3,2-b][1 ,4]oxazin- 6-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29b (6.26g, 1 1.93 mmol) in DCM (60 mL) under nitrogen, was added TFA (9.14 mL, 1 19.34 mmol) followed by CF3SO3H (3.59 mL, 40.57 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was quenched with MeOH (5 mL) and solvent removed in vacuo to afford a brown/white solid. To this was added MeOH (40 mL) and DCM (10 mL) and the mixture was sonicated for 20 min and filtered. The solid was suspended in DCM (40 mL), stirred for 20 min and filtered to give (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (4.32 g, 10.33 mmol, 86%) as a white solid. LC-MS (Method A) 305.1 [M+H] ⁺ ; RT 1.68 min. e) 1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}propyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 60

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d (130 mg, 0.43 mmol) and 2-oxo-1-(3- oxopropyl)-1 ,2-dihydroquinoline-7-Carbonitrile 60c (97 mg, 0.42 mmol) in DCM (5 mL) and triethylamine (0.17 mL and 1.28 mmol) were stirred for 2 h over molecular sieves (4 A). NaBH(OAc)3 (271 mg, 1.28 mmol) was added and the mixture stirred at room temperature for 2 h. Sat. aqueous Na2C03 (20 mL) was added and the mixture extracted with DCM (3 x 20 mL), dried over MgS0 ₄ and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with 0-10% MeOH in DCM to give 1-(3- {[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}propyl)-2-oxo-1 ,2-dihydroquinoline-7-carbonitrile 60 (16 mg, 8%) as a white solid. LC-MS (Method A) 515.3 [M+H] ⁺ , RT 2.41 min. ¹ H NMR (Method C) (CDC ): δ ppm 8.00 (bs, 1 H) 7.91 (d, J = 1.5 Hz, 1 H), 7.71 (d, J = 9.5 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0, 1 H), 7.35 - 7.29 (m, 2H), 6.84 (d, J = 9.5 Hz, 1 H), 4.64 (s, 2H), 4.47- 4.38 (m, 2H), 3.98 (td, J = 1 1.8, 3.3 Hz, 1 H), 3.86 (td, J = 1 1.8, 3.3 Hz, 1 H), 2.88 - 2.61 (m, 5H), 2.22 (d, J = 12.7 Hz, 1 H), 2.01-1.93 (m, 2H), 1.70-1.43 (m, 4H).

Example 61 :-1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 thiazin-6- yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

61 a) tert-butyl N-[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]carbamate 61 a

A solution of te/f-butyl N-[(3aS,6S,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29a (1 g, 3.01 mmol), 6-chloro-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-3-one (WO201408832 A1), K3PO4 (1.66 g, 7.8 mmol) and XPhos Pd G2 (306 mg, 0.39 mmol) in DMA (5 ml_) was subjected to microwave irradiation at 150 ^° C for 90 min under nitrogen. On cooling H2O (20 ml_) was added and the mixture extracted with EtOAc (3 x 20 ml_), dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash column chromatographychromatography eluting with 0-100% EtOAc in petroleum ether to give tert- butyl N-[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]carbamate 61 a (800 mg, 48%) as a yellow oil. LC-MS (Method A) 421.4 [M+H] ⁺ , RT 2.84 min.

b) (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium chloride 61 b

A solution of tert-butyl N-[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin- 6-yl}-octahydro-1 ,3-benzoxazol-6-yl]carbamate 61 a (700 mg, 1.66 mmol) and HCI in MeOH (4M, 20 ml_) in DCM (100 ml_) was stirred at room temperature for 17 h. The reaction was concentrated in vacuo to give (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]thiazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium chloride 61 b (600 mg, 100%) as a brown solid. LC-MS (Method A) 321.1 [M+H] ⁺ , RT 2.05 min. c)1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]thiazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 61

Prepared as described in example 60e using 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8- naphthyridin-1-yl)acetaldehyde (prepared as described in WO2008009700)(36.0 mg, 0.17 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}- octahydro-1 ,3-benzoxazol-6-aminium chloride 61 b (73.5 mg, 0.21 mmol) to afford 1-(2- {[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 61 (56.4 mg, 52.4%) as a colourless solid. LC-MS (Method A) 523.3 [M+H] ⁺ , RT 2.60 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 10.97 (s, 1 H), 8.06 (d, J = 8.5, 1 H), 7.87 (d, J = 9.5, 1 H), 7.79 (d, J = 8.5, 1 H), 7.29 (d, J = 8.5, 1 H), 6.74 (d, J = 8.5, 1 H), 6.50 (d, J = 9.5, 1 H), 4.43 (m, 2H), 4.05 (m, 1 H), 4.00 (s, 3H), 3.74 (m, 1 H), 3.57 (d, J= 15, 1 H), 3.51 (d, J = 15, 1 H), 2.95 (m, 1 H), 2.88 (m, 2H), 2.80 (m, 1 H), 1.46 (m, 1 H), 1.30-1.21 (m, 4H)

Example 62:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,6- naphthyridin-2-one

62

a) butyl (2£)-3-(4-amino-6-methoxypyridin-3-yl)prop-2-enoate 62a

Butyl prop-2-enoate (3.6 mL, 24.6 mmol) and triethylamine (10.3 mL, 73.9 mmol) were added to a sealed microwave vial under nitrogen containing 5-bromo-2-methoxypyridin-4- amine (500 mg, 2.46 mmol) and tetrakis(triphenylphosphine)palladium(0)(142.3 mg, 0.12 mmol). The reaction mixture was irradiated at 150 °C in a Biotage Initiator for 1.3 h, allowed to cool to room temperature and then vented. The reaction mixture was filtered to remove solid side-product which was washed with DCM (3 x 20 mL). The filtrate was collected and concentrated under reduced pressure to afford a residue which was taken up in H20 (20 mL) and EtOAc (20 mL) and the resulting layers separated. The aqueous layer was further extracted with EtOAc (2 x 20 mL) and the extracts combined with the original organic layer, dried (MgSCU), filtered and concentrated under reduced pressure. The resulting crude product was purified via silica gel chromatography using a gradient of 0-50% EtOAc/DCM. Clean product fractions were collected and concentrated under reduced pressure to afford butyl (2£)-3-(4-amino-6-methoxypyridin-3-yl)prop-2-enoate 62a as a yellow solid (310 mg, 50%). LC-MS (Method A): 251.1 [M+H] ⁺ , RT: 2.84 min. b) 7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62b

A solution of butyl (2£)-3-(4-amino-6-methoxypyridin-3-yl)prop-2-enoate 62a (310 mg, 1.24 mmol) in EtOH (40 mL) with 3 A molecular sieves was stirred for 10 min under an atmosphere of nitrogen. Sodium hydride (60% dispersed in mineral oil, 49.5 mg, 1.24 mmol) was added to the reaction mixture and heated at 60 °C for 3 h under nitrogen. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate quenched with saturated aqueous NH4CI (10 mL). The resulting solid was filtered under vacuum to afford ethyl (2£)-3-(4-amino-6-methoxypyridin-3-yl)prop-2-enoate which was immediately taken up in EtOH (20 mL) and allowed to stand at room temperature in the presence of 3 A molecular sieves under a nitrogen atmosphere for 17 h. Sodium hydride (60% dispersed in mineral oil, 134.9 mg, 3.37 mmol) was added to the reaction mixture and heated at 80 °C for 1 h under nitrogen. The reaction mixture was allowed to cool to room temperature, filtered and washed with EtOH (20 mL). The collected filtrate was quenched with sat. NH4CI (20 mL) and H2O (20 mL) and then concentrated under reduced pressure until the precipitation of a white solid was observed. The solid was filtered, washed with Et20 (20 mL) and dried under vaccum to afford 7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62b as a white solid (153 mg, 70%). LC-MS (Method A): 177.0 [M+H] ⁺ , RT: 1.10 min. c) 1-(2,2-dimethoxyethyl)-7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62c

2-bromo-1 , 1-dimethoxyethane (0.15 mL, 1.25 mmol) was added to a saturated solution of 7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62b (170 mg, 0.97 mmol) and cesium carbonate (408 mg, 1.25 mmol) in DMF (5 mL) and heated at 80 °C under nitrogen for 17 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (20 ml_) and extracted with Et20 (4 x 40 ml_). The combined organic extracts were dried (MgS0 ₄ ), filtered and concentrated under reduced pressure. The resulting crude product was purified via silica gel chromatography using a gradient of 0-100% EtOAc/DCM. Clean product fractions were collected and concentrated under reduced pressure to afford 1-(2,2- dimethoxyethyl)-7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62c as a white solid (31 mg, 12%). LC-MS (Method A): 265.0 [M+H] ⁺ , RT: 1.76 min.

d) 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,6-naphthyridin-1-yl)acetaldehyde 62d

Aq. HCI (3M, 5 ml_, 15 mmol) was added to a solution of 1-(2,2-dimethoxyethyl)-7-methoxy- 1 ,2-dihydro-1 ,6-naphthyridin-2-one 62c (31 mg, 0.12 mmol) in THF (1 ml_) and stirred at room temperature for 17 h. The reaction mixture was quenched with solid NaHC03 to pH 8 and diluted with H2O (20 ml_). Volatile organic solvent was removed under reduced pressure and the resulting aqueous extracted with EtOAc (3 x 20 ml_). The organic extracts were combined, dried (MgS0 ₄ ), filtered and concentrated under reduced pressure to afford an impure sample of 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,6-naphthyridin-1-yl)acetaldehyde 62d as a white solid (30 mg, 1 17%). LC-MS (Method A): 219.0 [M+H] ⁺ , RT: 1.47 min.

e) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,6-naphthyridin- 2-one 62

Prepared as described in example 60e using 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,6- naphthyridin-1-yl)acetaldehyde 62d (30 mg, 0.38 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium

trifluoroacetate 60d (63 mg, 0.15 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7- methoxy-1 ,2-dihydro-1 ,6-naphthyridin-2-one 62 as a white solid (10.9 mg, 16%). LC-MS (Method A): 507.1 [M+H] ⁺ , RT: 2.18 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.2 (br. s, 1 H), 8.56 (s, 1 H), 7.92 (d, J = 9.5 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 6.90 (s, 1 H), 6.48 (d, J = 9.5 Hz, 1 H), 4.63 (s, 2H), 4.16 (t, J = 7.4 Hz, 2H), 4.05 (td, J = 1 1.7, 3.3 Hz, 1 H), 3.95 (s, 3H), 3.75 (td, J = 1 1.1 , 3.3 Hz, 1 H), 3.81-2.74 (m, 3H), 2.59- 2.53 (m, 1 H), 2.00-1.95 (m, 2H), 1.38-1.25 (m, 3H). Example 63:- (3aS,6S,7aS)-6-r(2-{3-methoxy-6-oxo-5H,6H-pyridor2,3-blpyraz in-5- yl)ethyl)amino1-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6 -yl)-octahvdro-1,3- benzoxazol-2-one

Prepared as described in Example 60e using 2-{3-methoxy-6-oxo-5H,6H-pyrido[2,3- b]pyrazin-5-yl}acetaldehyde (PCT Int. Appl., 2008009700)(48.2 mg, 0.22 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-6-aminium trifluoroacetate 60d (92 mg, 0.22 mmol) to afford (3aS,6S,7aS)-6- [(2-{3-methoxy-6-oxo-5H,6H-pyrido[2,3-b]pyrazin-5-yl}ethyl)a mino]-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-2-on e 63 (45 mg, 40.3%). LC-MS (Method A) 508.3 [M+H] ⁺ ; RT2.15 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.24 (s, 1H), 8.23 (s, 1H), 7.96 (d, J= 9.5 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.18 (d, J= 8.5 Hz, 1H), 6.74 (d, J= 9.5 Hz, 1H), 4.62 (s, 2H), 4.39 (t, J =7.2 Hz, 2H), 4.11-4.01 (m, 4H), 3.75 (td, J = 11.2, 3.4 Hz, 1H), 2.91-2.72 (m, 4H), 2.45-2.42 (m, 1H), 2.06 (br. s, 1H), 1.99-1.96 (m, 1H), 1.46 (q, J= 11.2 Hz, 1H), 1.33 (m, 1H), 1.28-1.16 (m, 1H).

Example 64:-

4-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)ethyl)-3-oxo-3,4-dihydroquinoxaline -6-carbonitrile

64

Prepared as described in example 60e using

(3aS,6S7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin -6-yl}-octahydro-1,3-benzox azol-6-aminium trifluoroacetate 60d (313 mg, 0.75 mmol) and

3- oxo-4-(2-oxoethyl)-3,4-dihydroquinoxaline-6-carbonitrile (prepared as described in WO2006137485) (143.6 mg, 0.67 mmol) to afford

4- (2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4] oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline-6- carbonitrile 64 (245 mg, 65%) as a pale orange solid. LC-MS (Method B) 502.1 [M+H] ⁺ ; RT 6.24 min. ¹ H NMR (Method C) (CDC ): δ ppm 8.40 (s, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.61 (dd, J = 8.2, 1.6 Hz, 1H), 7.34-7.30 (m, 2H), 4.63 (s, 2H), 4.35 (t, J= 6.8 Hz, 2H), 3.95 (td, J= 11.8, 3.4 Hz, 1H), 3.79 (td, J= 11.0, 3.4 Hz, 1H), 3.14-3.04 (m, 2H), 2.88-2.81 (m, 1H), 2.71-2.66 (m, 1H), 2.60-2.56 (m, 1H), 2.14-2.08 (m, 1H), 1.56-1.48 (m, 1H), 1.41-1.31 (m, 2H).

Example 65:- 1-(2-fr(3aS,6S,7aR)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-bir i,41oxazin-

2-yl)-octahvdro-1,3-benzoxazol-6-vnamino)ethyl)-6,7-diflu oro-1,2-dihydroquinoxalin-2- one

a) 1-(2-{[(3aS,6S,7aR)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2- dihydroquinoxalin-2-one 65a

Prepared as in the method described in example 16d using (3aS,6S,7aR)-6-amino-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3- benzoxazol-2-one 16c (113.9 mg, 0.27 mmol) and

2-(6,7-difluoro-2-oxo-1 ,2-dihydroquinoxalin-1 -yl)acetaldehyde (60.0 mg, 0.27 mmol) (prepared as described in WO2008009700) to afford 1-(2-{[(3aS,6S,7aR)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 65a (195 mg, 1 15%) - used without purification. LC-MS (Method A) 634.1 [M+H] ⁺ ; RT 2.53 min. b) 1-(2-{[(3aS,6S,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1 ,4]oxazin-2-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 65

Prepared as in the method described in Example 16e using 1-(2-{[(3aS,6S,7aR)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 65a (195.0 mg, 0.31 mmol). The crude material was purified via silica gel chromatography using 0-20% MeOH/DCM followed by prep. HPLC (Method B) 0.1 % NH ₃ in MeCN/H ₂ 0 to afford 1-(2- {[(3aS,6S,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 65 (4.8 mg, 3%). LC- MS (Method A) 514.2 [M+H] ⁺ ; RT 1.79 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.26 (s, 1 H), 8.19 (s, 1 H), 8.05-7.74 (m, 2H), 4.74-4.67 (m, 3H), 4.43-4.35 (m, 1 H), 4.28-4.17 (m, 2H), 2.87-2.78 (m, 2H), 2.73-2.61 (m, 1 H), 2.47-2.37 (m, 1 H), 2.20-2.13 (m, 1 H), 1.82-1.67 (m, 1 H), 1.54-1.45 (m, 1 H), 1.41-1.26 (m, 1 H), 1.08-0.92 (m, 1 H).

Example 66:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin-

2-yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2- one

a) tert-butyl N-[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H,7H,8 H- pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 66a

A solution of a 2: 1 mixture of 2-bromo-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4- b] [1 ,4]oxazin-7-one and 2-chloro-8-[(4-methoxyphenyl)methyl]-6H,7H,8H-pyrimido[5,4- b][1 ,4]oxazin-7-one 16a (1.37 g, 3.9 mmol), te/f-butyl

N-[(3aS,6S,7aS)-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]carbamate 29a (1.00 g, 3.9 mmol), trans-1 ,2-diaminocyclohexane (89.1 mg, 0.78 mmol), Cul (148.6 mg, 0.78 mmol) and K2CO3 (1.08 g, 7.8 mmol) in 1 ,4-Dioxane (35 mL) was stirred at 1 10 °C for 17 h. Cul (148.6 mg, 0.78 mmol) and trans-1 ,2-diaminocyclhexane (89.1 mg, 0.78 mmol) were added and the mixture stirred at 1 10 °C for a further 17 h . The reaction was allowed to cool to room temperature and the remaining solid was filtered, washed with EtOAc and the filtrate concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography using 0-100% EtOAc in DCM to afford tert-butyl N-[(3aS,6S,7aS)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]carbamate 66a (514.0 mg, 25%) as a white solid. LC-MS (Method A) 526.3 [M+H] ⁺ ; RT 2.94 min. b) (3aS,6S,7aS)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H- pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 66b

TFA (4.8 mL, 62.7 mmol) was added to a solution of tert-butyl N-[(3aS,6S,7aS)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]carbamate 66a (514 mg, 0.98 mmol) in DCM (15 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue dissolved in DCM (10 mL), washed with sat. aq. NaHC03, brine (1 mL) and passed through a SPE phase separator. The aqueous phase was further extracted with a mixture of DCM:MeOH (4: 1 , 25 mL) and passed through a SPE phase separator.The organic filtrates were combined and concentratedunder reduced pressure to afford . (3aS,6S,7aS)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H- pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 66b (214 mg, 51 %). ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.32 (s, 1 H), 7.48-7.26 (m, 2H), 6.97-6.74 (m, 2H), 5.14-5.04 (m, 2H), 4.97-4.88 (m, 2H), 4.13-4.00 (m, 1 H), 3.80-3.72 (m, 1 H), 3.72 (s, 3H), 2.87-2.79 (m, 1 H), 2.32-2.26 (m, 1 H), 2.14-2.06 (m, 1 H), 2.09-1.94 (m, 2H), 1.81-1.74 (m, 1 H), 1.56-1.46 (m, 1 H), 1.28-1.15 (m, 2H). c) 1-(2-{[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2- dihydroquinoxalin-2-one 66c

A solution of 2-(6,7-difluoro-2-oxo-1 ,2-dihydroquinoxalin-1-yl)acetaldehyde (50.0 mg, 0.22 mmol) and (3aS,6S,7aS)-6-amino-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H ,7H,8H- pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-2-one 66b (94.9 mg, 0.22 mmol) in DCM (15 mL) was stirred at room temperature over molecular sieves (3A) for 2 h.

NaBH(OAc)3 (189.1 mg, 0.89 mmol) was added and the reaction stirred at room temperture for a further 3 h. The reaction was adjusted to pH 8 with saturated aqueous NaHCC>3 and passed through a SPE phase separator. The organic filtrate was concentrated under reduced pressure to afford1-(2-{[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-o xo- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 66c which used without

purification, (assumed quantitative). LC-MS (Method A) 634.3 [M+H] ⁺ ; RT 2.65 min. d) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1 ,4]oxazin-2-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 66

TFA (1.01 mL, 13.2 mmol) and CF3SO3H (0.23 mL, 2.63 mmol) were added to a solution of 1-(2-{[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2- dihydroquinoxalin-2-one 66c (238. mg, 0.38 mmol) in DCM (15 mL) and the reaction stirred at room temperature for 140 h. The reaction was quenched with MeOH (5 mL), neutralised with saturated aqueous NaHCC>3, diluted with DCM (30 mL) and passed through an SPE phase separator. The organic filtrate was concentrated under reduced pressure andthe resulting residue purified via silica gel chromatography using 0-20% MeOH in DCM. Clean product fractions were collected and concentrated under reduced pressure to afford an off white residue. The residue was dissolved in a minimum volume of DCM and Et20 added until a precipitate crashed out. Solvent was removed under reduced pressure to afford 1-(2- {[(3aS,6S,7aS)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1 ,2-dihydroquinoxalin-2-one 66 (1 1.9 mg, 6%) as an off white solid. LC-MS (Method A) 514.2 [M+H] ⁺ ; RT 1.77 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.26 (s, 1 H), 8.25 (s, 1 H), 7.99-7.88 (m, 2H), 4.79-4.67 (m, 2H), 4.27- 4.17 (m, 2H), 4.10-3.99 (m, 1 H), 3.84-3.74 (m, 1 H), 2.90-2.74 (m, 3H), 2.44-2.36 (m, 2H), 1.99-1.90 (m, 1 H), 1.52-1.40 (m, 1 H), 1.38-1.03 (m, 2H).

Example 67:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f7-oxo-6H,7H,8H-pyrimidor5,4-biri ,41oxazin- 2-yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

a) 1-(2-{[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo-6H, 7H,8H-pyrimido[5,4- b] [1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2- dihydro-1 ,8-naphthyridin-2-one 67a

Prepared as described in example 66c using (3aS,6S,7aS)-6-amino-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-octahydro-1 ,3- benzoxazol-2-one 66b (97.5 mg, 0.23 mmol) and 2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8- naphthyridin-1-yl)acetaldehyde (50 mg, 0.23 mmol) (prepared as described in WO2008009700). The crude material was purified via silica gel chromatography using 0- 20% MeOH in DCM to afford 1-(2-{[(3aS,6S,7aS)-3-{8-[(4-methoxyphenyl)methyl]-7-oxo- 6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 67a (130 mg, 90%). LC-MS (Method A) 628.3 [M+H] ⁺ ; RT 2.31 min b) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1 ,4]oxazin-2-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 67

Prepared as described in example 66d using 1-(2-{[(3aS,6S,7aS)-3-{8-[(4- methoxyphenyl)methyl]-7-oxo-6H,7H,8H-pyrimido[5,4-b][1 ,4]oxazin-2-yl}-2-oxo-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 67a (130.2 mg, 0.21 mmol). The crude material was purified via silica gel chromatography using 0-20% MeOH/DCM to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4- b][1 ,4]oxazin-2-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one 67 (33.8 mg, 32%) as an off white solid. LC-MS (Method B) 508.2 [M+H] ⁺ ; RT 4.54 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.25 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.87 (d, J = 9.4 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 6.51 (d, J = 9.4 Hz, 1 H), 4.79- 4.67 (m, 2H), 4.48-4.38 (m, 2H), 4.09-4.02 (m, 1 H), 4.00 (s, 3H), 3.83-3.76 (m, 1 H), 2.95- 2.85 (m, 2H), 2.85-2.76 (m, 1 H), 2.47-2.39 (m, 2H), 2.03-1.94 (m, 1 H), 1.52-1.43 (m, 1 H), 1.40-1.16 (m, 2H).

Example 68:-

4-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro-

1 ,3-benzoxazol-6-vnamino)ethyl)-3-oxo-3,4-dihydroquinoxaline- 6-carbonitrile

68

Prepared as described in the method in Example 60e using 3-oxo-4-(2-oxoethyl)-3,4- dihydroquinoxaline-6-carbonitrile (WO 2006137485 A 1 (95 mg, 0.45 mmol) and (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 74a (205 mg, 0.49 mmol) to afford 4-(2-{[(3aR,6R7aR)-2-oxo-3-{3-oxo-2H,3H,4H^yrido[3,2-b][1,4] oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-3-oxo-3,4-dihydroquinoxaline-6- carbonitrile 68 (91 mg, 39%). LC-MS (Method A) 502.2 [M+H] ⁺ ; RT 2.31 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.25 (s, 1 H), 8.39 (s, 1 H), 8.29 (s, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.41 (d, J= 8.3 Hz, 1H), 7.18 (d, J= 8.3 Hz, 1H), 4.62 (s, 2H), 4.27 (t, J= 6.8 Hz, 2H), 4.05 (td, J = 11.2, 3.4 Hz, 1 H), 3.76 (td, J = 11.2, 3.4 Hz, 1 H), 2.92-2.85 (m, 2H), 2.81-2.74 (m, 2H), 2.44-2.39 (m, 1H), 2.14-2.07 (m, 1H), 1.97-1.91 (m, 1H), 1.45 (q, J= 11.1 Hz, 1H), 1.33 (q, J = 11.1 Hz, 1H), 1.20 (q, J = 11.1 Hz, 1H).

Example 69:-1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-b in,41oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5- naphthyridin-2-one

69

Prepared as described in Example 60e using 2-(7-methoxy-2-oxo-1,5-naphthyridin-1- yl)acetaldehyde (77 mg, 0.35 mmol) (prepared as described in WO2011148962A1) and (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-6-aminium trifluoroacetate 74a (53.2 mg, 0.24 mmol) and (102 mg, 0.24 mmol) to afford 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 69 (20 mg, 16%) as a colourless solid. LC-MS (Method D) 507.2 [M+H] ⁺ , RT 1.81 min. ¹ H NMR (Method E) (DMSO-d6): δ ppm 11.21 (s, 1H), 8.29 (d, J= 2.5, 1H), 7.87 (d, J= 9.5, 1H), 7.50 (d, J= 8.5, 1H), 7.41 (d, J= 8.5, 1H), 7.16 (d, J= 8.5, 1H), 6.67 (d, J= 9.5, 1H), 4.61 (s, 2H), 4.28 (t, J= 7.0, 2H), 4.03 (m, 1H), 3.99 (s, 3H), 3.74 (m, 1H), 3.17 (d, J= 5.0, 1H), 2.85-2.74 (m, 4H), 2.12 (m, 1H), 1.97 (m, 1H), 1.45 (q, J= 11.0, 1H), 1.31 (m, 1H), 1.22 (m, 1H) Example 70:-

1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)ethyl)-6,7-difluoro-1,2-dihydroquin oxalin-2-one

Prepared as described in example 60e using

(3aR,6R7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin -6-yl}-octahydro-1,3-benzo xazol-6-aminium trifluoroacetate 74a (200.0 mg, 0.48 mmol) and

2-(6,7-difluoro-2-oxo-1,2-dihydroquinoxalin-1-yl)acetalde hyde (prepared as described in WO2008009700) (96.5 mg, 0.43 mmol) to afford

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-6,7-difluoro-1,2-dihydroquinoxa lin-2-one 70 (132.5 mg, 54%) as an orange solid. LC-MS (Method B) 513.2 [M+H] ⁺ ; RT 6.52 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.20 (br s, 1 H), 8.27 (s, 1 H), 8.00-7.89 (m, 2H), 7.42 (d, J = 8.6 Hz, 1H), 7.17 (d, J= 8.6, 1H), 4.62 (s, 2H), 4.22 (t, J= 6.9 Hz, 2H), 4.04 (td, J= 11.8, 3.3 Hz, 1H), 3.74 (td, J= 11.1, 3.3 Hz, 1H), 2.88-2.82 (m, 2H), 2.81-2.71 (m, 2H), 2.43-2.38 (m, 1H), 2.09 (brs, 1H), 1.99-1.91 (m, 1H), 1.44 (q, J= 11.1 Hz, 1H), 1.37-1.27 (m, 1H), 1.24- 1.14 (m, 1H).

Example 71 :-

6-r3-(fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-b iri,41oxazin-6-ylVoctahvdro-

1,3-benzoxazol-6-vnamino)methyl)phenvnpyridine-3-carbonit rile

71

Prepared as in the method described in example 60e using 6-(3-formylphenyl)pyridine-3-carbonitrile (WO2014170821) (140.0 mg, 0.67mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-6-aminium trifluoroacetate 60d (305.5 mg, 0.67 mmol) to afford 6-[3-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}methyl)phenyl]pyridine-3-carbonitrile 71 (31.4mg, 9%) LC-MS (Method A) 497.8 [M+H] ⁺ ; RT 2.07min. ¹ H NMR (Method C) (CDC ): δ ppm 8.96 (dd, J = 2.2, 0.9 Hz, 1H), 8.06 (s, 1H), 8.03 (dd, J= 8.3, 2.2 Hz, 1H), 7.95-7.90 (m, 1H), 7.88 (dd, J = 8.4, 0.9 Hz, 1H), 7.81 (s, 1H), 7.52 - 7.46 (m, 2H), 7.36 - 7.29 (m, 2H), 4.64 (s, 2H), 4.01 - 3.91 (m, 3H), 3.82 (td, J= 11.0, 3.2 Hz, 1H), 2.88 (td, J= 10.9, 5.3 Hz, 1H), 2.75 - 2.64 (m, 2H), 2.19 (d, J= 12.2 Hz, 1H), 1.69-1.18 (m, 3H).

Example 72:- (3aR,6R,7aR)-6-({r2-hydroxy-3-(5-methoxypyridazin-3- yl)phenyl1methyl)amino)-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41 oxazin-6-yl)-octahvdro-

1 ,3-benzoxazol-2-one

72

a) 2-(benzyloxy)-3-(5-methoxypyridazin-3-yl)benzaldehyde 72a

A mixture of 2-(benzyloxy)-3-(4,4,5,5-tetramethyl-1 ,3-dioxolan-2-yl)benzaldehyde (250 mg, 0.74 mmol)(prepared as in the method described for the intermediate in example 18b starting from 18a), 3-chloro-5-methoxypyridazine (0.09 mL, 0.74 mmol), (XPhos)(35.24 mg, 0.07 mmol), XPhos Pd G2 (58.3 mg, 0.07 mmol) and CsCOs (722 mg, 2.22 mmol) in a mixture of monoglyme (2.4 mL) and H2O (0.4 mL)(deoxygenated by bubbling N2 through) was stirred at 60 °C for 24 h. The mixture was allowed to cool, diluted with EtOAc (10 mL) and washed with H2O (4 mL). The organic phase was dried (MgSCU) and the resultant material purified by silica gel chromatography using 40 -100% EtOAc in petroleum ether to afford 2-benzyloxy-3-(5-methoxypyridazin-3-yl)benzaldehyde (134 mg, 56.6 % ). LC-MS (Method A) 321.0 [M+H] ⁺ ; RT 2.51 min. ¹ H NMR (Method C) (CDC ): δ ppm 10.37 (d, J = 0.8 Hz, 1 H), 8.90 (d, J = 3.0 Hz, 1 H), 8.21 (dd, J = 7.6, 1.9 Hz, 1 H), 7.98 (dd, J = 7.7, 1.9 Hz, 1 H), 7.50 - 7.39 (m, 2H), 7.34 - 7.27 (m, 3H), 7.16 - 7.10 (m, 2H), 4.75 (s, 2H), 3.73 (s, 3H). b) (3aR,6R,7aR)-6-({[2-(benzyloxy)-3-(5-methoxypyridazin-3-yl)p henyl]methyl}amino)-3-{4- [(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 72b

Prepared as in the method described in example 1 d using (3aR,6R,7aR)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-2-one 1 c (160. mg, 0.3800mmol) and 2-(benzyloxy)-3-(5-methoxypyridazin-3- yl)benzaldehyde 72a (126.19mg, 0.3900mmol) to afford (3aR,6R,7aR)-6-({[2-(benzyloxy)-3- (5-methoxypyridazin-3-yl)phenyl]methyl}amino)-3-{4-[(4-metho xyphenyl)methyl]-3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 72b (59 mg, 22 % ). ¹ H NMR (Method C) (CDCb): δ ppm 8.87 (d, J= 3.0, 1.5 Hz, 1H), 7.84 (dd, J= 7.7, 1.7 Hz, 1H), 7.47 (dd, J= 7.6, 1.8 Hz, 1H), 7.44 (d, J= 2.9, 1.9 Hz, 1H), 7.34- 7.26 (m, 6H), 7.21 - 7.13 (m, 4H), 6.85 - 6.77 (m, 2H), 5.19 (s, 2H), 4.71 (s, 2H), 4.66 - 4.59 (m, 2H), 3.95-3.82 (m, 3H), 3.79-3.69 (m, 7H), 2.76 (dq, J= 10.4, 5.1, 4.3 Hz, 1H), 2.64 - 2.55 (m, 1 H), 2.33 - 2.25 (m, 1 H), 1.98 (d, J = 11.7 Hz, 1 H), 1.56 (q, J = 11.3 Hz, 1H), 1.36-1.19 (m, 2H). c) (3aR,6R,7aR)-6-({[2-hydroxy-3-(5-methoxypyridazin^

2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 72

Prepared as in the method described in Example 1d using (3aR,6R,7aR)-6-({[2- (benzyloxy)-3-(5-methoxypyridazin-3-yl)phenyl]methyl}amino)- 3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-2-one 72b (50.1 mg, 0.07 mmol) to afford (3aR,6R,7aR)-6-({[2-hydroxy-3-(5- methoxypyridazin-3-yl)phenyl]methyl}amino)-3-{3-oxo-2H,3H,4H -pyrido[3,2-b][1,4]oxazin-6- yl}-octahydro-1,3-benzoxazol-2-one 72 (10 mg, 28 % yield). LC-MS (Method A) 519.2

[M+H] ⁺ ; RT2.51min. ¹ H NMR (Method C) (CDCb): δ ppm 8.77 (d, J= 2.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.44-7.38 (m, 2H), 7.33-7.26 (m, 2H), 6.95 (t, J =7.7 Hz, 1H), 4.62 (d, J = 1.2 Hz, 2H), 4.27 - 3.70 (m, 7H), 3.09 - 2.98 (m, 1 H), 2.80 - 2.66 (m, 2H), 2.30 - 2.20 (m, 1H), 1.85- 1.75 (m, 1H), 1.69-1.56 (m, 1H), 1.46-1.34 (m, 1H).

Example 73:-

(3aS,6SJaS)-6-({r3-(6-methoxypyridin-2-yl)phenyl1methyl)a mino)-3-{3-oxo-2H,3H,4H- pyridor3,2-biri ,41oxazin-6-yl)-octahydro-1 ,3-benzoxazol-2-one

73 a) (SaS.eSJaSJ-S^-Ii^methoxypheny methyll-S-oxo^H.SH^H-pyridop^-blll.^oxazin- 6-yl}-6-({[3-(6-methoxypyridin-2-yl)phenyl]methyl}amino)-oct ahydro-1,3-benzoxazo

73a

Prepared as in the method described in example 29d using (3aS,6S,7aS)-6-amino-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-2-one (188.0 mg, 0.44 mmol) 29c and 3-(6-methoxypyridin-2-yl)benzaldehyde (103.9 mg, 0.49 mmol) (prepared according to WO 2014170821) to afford (3aS,6S,7aS)-3- {4-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-6-({[3-(6- methoxypyridin-2-yl)phenyl]methyl}amino)-octahydro-1,3-benzo xazol-2-one 73a (137.0 mg, 50% yield). LC-MS (Method A) 622.3 [M+H] ⁺ ; RT 3.33 min. ¹ H NMR (Method C) (CDCb): δ ppm 7.99 (d, J= 1.8 Hz, 1H), 7.95 (dt, J= 7.8, 1.5 Hz, 1H), 7.64 (dd, J= 8.2, 7.4 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 7.39-7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.16 (m, 2H), 6.85-6.79 (m, 2H), 6.71 (dd, J= 8.2, 0.7 Hz, 1H), 5.19 (s, 2H), 4.71 (s, 2H), 4.05 (s, 3H), 3.98-3.88 (m, 3H), 3.76 (s, 4H), 2.84 (td, J= 10.7, 5.2 Hz, 1H), 2.67 (d, J= 11.2 Hz, 1H), 2.28 (dd, J = 11.9, 3.3 Hz, 1H), 2.01 (s, 1H), 1.63 (q, J= 11.3 Hz, 1H), 1.38-1.26 (m, 2H). b) (3aS,6S,7aS)-6-({[3-(6-methoxypyridin-2-yl)phenyl]methyl}ami no)-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-2-one 73

Prepared as in the method described in example 1e using (3aS,6S,7aS)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-6-({[3-(6- methoxypyridin-2-yl)phenyl]methyl}amino)-octahydro-1,3-benzo xazol-2-one 73a (165.0 mg, 0.27 mmol) to afford

(3aS,6S,7aS)-6-({[3-(6-methoxypyridin-2-yl)phenyl]methyl}ami no)-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-2-on e 73 (21.8 mg, 15%). LC-MS (Method B) 502.2 [M+H] ⁺ ; RT6.54 min. ¹ H NMR (Method C) (CDCb): δ ppm 8.01 (s, 1H), 7.96 (d, J= 7.6 Hz, 1H), 7.64 (dd, J= 8.2, 7.4 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 7.40-7.28 (m, 4H), 6.70 (dd, J= 8.2, 0.7 Hz, 1H), 4.63 (d, J= 0.8 Hz, 2H), 4.04 (s, 3H), 4.03-3.91 (m, 3H), 3.86-3.72 (m, 1H), 2.91 (d, J= 11.1 Hz, 1H), 2.77-2.66 (m, 2H), 2.19 (d, J= 13.5 Hz, 1H), 1.74-1.46 (m, 2H), 1.44-1.34 (m, 1H).

Example 74:- 1-(3-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-vnamino)propyl)-2-oxo-1,2-dih vdroquinoline-7- carbonitrile

(3aR,6R7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 74a (175 mg, 0.42 mmol)(prepared using the method described in example 60d starting with te/f-butyl N-[(3aR,6R,7aR)-3-{4-[(4- methoxyphenyl)methyl]-3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-2-oxo-octahydro-1 ,3- benzoxazol-6-yl]carbamate 1b) and 2-oxo-1-(3-oxopropyl)-1 ,2-dihydroquinoline-7- carbonitrile 60c (95 mg, 0.419 mmol) in DCM (5 ml_) and triethylamine (0.17 ml_, 1.26 mmol) were stirred for 2 h over molecular sieves (4 A). NaBH(OAc)3 (271 mg, 1.25 mmol) was added and the mixture stirred at room temperature for 2 h. Sat. aqueous Na2CC>3 (20 ml_) was added and the mixture extracted with DCM (50 ml_), dried over MgSCU and concentrated under reduced pressure. The residue was purified by silica chromatography using 0-10% MeOH in EtOAc to give 1-(3-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}propyl)-2-oxo-1 ,2- dihydroquinoline-7-carbonitrile 74 (20 mg, 10 %) as a white solid. LC-MS (Method A) 515.3 [M+H] ⁺ , RT 2.43 min. ¹ H NMR (Method C) (CDC ): δ ppm 7.99 (br s, 1 H), 7.90 (s, 1 H), 7.71 (d, J = 9.5 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8,0, 1.3 Hz, 1 H), 7.38 - 7.28 (m, 2H), 6.84 (d, J = 9.5 Hz, 1 H), 4.64 (s, 2H), 4.47-4.38 (m, 2H), 3.98 (td, J = 10.9, 3.3 Hz, 1 H), 3.86 (td, J = 10.9, 3.3 Hz, 1 H), 2.87 - 2.61 (m, 5H), 2.21 (d, J = 12.4 Hz, 1 H), 2.01- 1.92 (m, 2H), 1.70 - 1.43 (m, 4H).

Example 75:- (3aS,6S,7aS)-N-{2-r7-(2-azaniumylethoxy)-2-oxo-1 ,2-dihydroquinolin-1 - vnethyl)-2-oxo-3-{3-oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6- yl)-octahvdro-1,3- benzoxazol-6-aminium dichloride

a) tert-butyl N-(2-{[1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3, 2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7- yl]oxy}ethyl)carbamate 75a

Prepared using the method described in example 60e using te/f-butyl N-(2-{[2-oxo-1-(2- oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 9f (166.7 mg, 0.43 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d (418.3 mg, 0.43 mmol) to afford tert-butyl N-(2- {[1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][ 1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 75a (215 mg, 78%) - isolated without purification. LC-MS (Method A) 635.3 [M+H] ⁺ , RT 2.87 min.

b) (3aS,6S,7aS)-N-{2-[7-(2-azaniumylethoxy)-2-oxo-1 ,2-dihydroquinolin-1-yl]ethyl}-2-oxo-3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium dichloride 75

TFA (0.3 mL, 3.92 mmol) was added to a solution of tert-butyl N-(2-{[1-(2-{[(3aS,6S,7aS)-2- oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}ethyl)carbamate 75a (100 mg, 0.16 mmol) in DCM (3 mL) and stirred for 90 min. NH ₃ in MeOH (7N) was added to adjust the pH of the reaction mixture to 8. The crude product was pre absorbed onto silica using MeOH then purified using silica gel chromatography with 0-20% MeOH/DCM followed by 0-20% NH3 in MeOH/DCM. Clean product fractions were collected and concentrated (with Et20 azetroping) under reduced pressure. The resulting white solid was dissolved in a minimum volume of MeOH/DCM and HCI (1 M in Et20, 2 mL). The solution was concentrated under reduced pressure and the resulting brown solid was dried under house vacuum to afford (3aS,6S7aS)-N-{2-[7-(2-azaniumylethoxy)-2-oxo-1,2-dihydroqui nolin-1-yl]ethyl}-2-oxo-3-{3- oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-be nzoxazol-6-aminium dichloride 75 (7.7 mg, 8.2%). LC-MS (Method B) 535.4 [M+H] ⁺ , RT 4.84 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.29 (s, 1H), 9.92 (br. s, 2H), 8.24-8.19 (m, 3H), 7.92 (d, J = 9.5 Hz, 1H), 7.72 (d, J= 8.8 Hz, 1H), 7.44 (d, J= 8.5 Hz, 1H), 7.40-7.33 (m, 1H), 7.18 (d, J= 8.5 Hz, 1H), 7.00-6.97 (m, 1H), 6.51 (d, J= 9.5 Hz, 1H), 4.73-4.59 (m, 1H), 4.64 (s, 3H), 4.57-4.48 (m, 2H), 4.19-4.04 (m, 1H), 3.88-3.77 (m, 1H), 3.57-3.47 (m, 1H), 3.31-3.23 (m, 2H), 3.23-3.12 (m, 2H), 2.93-2.83 (m, 1H), 2.77-2.69 (m, 1H), 2.32-2.24 (m, 1H), 2.07-1.96 (m, 1H), 1.81-1.66 (m, 1H), 1.50-1.38 (m, 1H).

Example 76:- 1-(3-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

Prepared as in the method described in example 60e using (3aR,6R,7aR)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzox azol-6-aminium

trifluoroacetate 74a (205 mg, 0.49 mmol) and 3-(7-methoxy-2-oxo-1,2-dihydro-1,8- naphthyridin-1-yl)propanal 85b (104 mg, 0.45 mmol) to afford 1-(3-{[(3aR,6R,7aR)-2-oxo-3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3 -benzoxazol-6- yl]amino}propyl)-7-methoxy-1,2-dihydro-1,8-naphthyridin-2-on e 76 (106 mg, 43%). LC-MS (Method A) 521.3 [M+H] ⁺ ; RT 2.52 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (br. s, 1H), 8.07 (d, J= 8.4 Hz, 1H), 7.88 (d, J= 9.4 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.52 (d, J = 9.4 Hz, 1 H), 4.64 (s, 2H), 4.44 (dd, J = 8.1, 6.3 Hz, 2H), 4.09-3.97 (m, 4H), 3.75 (td, J= 11.1, 3.3 Hz, 1H), 2.82-2.71 (m, 2H), 2.71- 2.59 (m, 2H), 2.43 (dd, J= 8.4, 4.3 Hz, 1H), 2.06-1.93 (m, 1H), 1.93-1.78 (m, 2H), 1.48 (q, J = 11.2 Hz, 1H), 1.40-1.16 (m, 2H). Example 77:-5-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-b in,41thiazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)ethyl)-6-oxo-5,6-dihvdro-1 ,5-naphthyridine-3- carbonitrile

Prepared as in the method described in example 60e using

6-oxo-5-(2-oxoethyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile (prepared as described in WO2008009700A1) (15.7 mg, 0.074 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium chloride 61b (32.8 mg, 0.092 mmol) to afford 5-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]thiazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-6-oxo-5,6-dihydro-1 ,5- naphthyridine-3-carbonitrile 77 (20.1 mg, 42%) as a colourless solid. LC-MS (Method A) 518.2 [M+H] ⁺ , RT 2.22 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 10.95 (s, 1 H), 8.89 (s, 1 H), 8.71 (s, 1 H), 8.02 (d, J = 9.5, 1 H), 7.78 (d, J = 8.5, 1 H), 7.29 (d, J= 9.67, 1 Hj, 7.05 (d, J = 9.5, 1 H), 4.34-4.22 (m, 2H), 4.04 (m, 1 H), 3.74 (td, J = 1 1.0, 3.5, 1 H), 3.60-3.49 (m, 2H), 2.95 (m, 1 H), 2.89-2.83 (m, 2H), 2.79 (m, 1 H), 2.44-2.40 (m, 2H), 1.93 (m, 1 H), 1.44 (m, 1 H), 1.15-1.10 (m, 1 H), 0.91-0.82 (m, 1 H).

Example 78:- fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,41oxa zin-6-ylV octahydro-1 ,3-benzoxazol-6-vnr2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1 - vDethyllcarbamovDmethanaminium chloride

78 a) tert-butyl N-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]carbamoyl}methyl)carbamate 78a

N-Boc-glycine (0.03 mL, 0.17 mmol), 1-Hydroxybenzotriazole hydrate (29.5 mg, 0.22 mmol), EDCI (48.3 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added to a solution

of1 -(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3 -benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 29 (85 mg, 0.17 mmol) in THF (3 mL) and DMF (0.3 mL) and the reaction mixture stirred at room temperature for 17 h under nitrogen. Further DMF (0.70 mL), EDCI (48.3 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added and the reaction mixture stirred for a further 17 h at room temperature under nitrogen. DCM (40 mL) and H2O (5 mL) were added and the resulting organic layer separated through a SPE phase separator. The organic filtrate was collected and concentrated under reduced pressurewith toluene and Et20 azeotroping to afford a white solid/gum. Crude product was purified via silica gel chromatography using a gradient of 0-100% petroleum ether/EtOAc followed by 0-20% MeOH/EtOAc. Product fractions were collected and concentrated under reduced pressure to afford tert-butyl N-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]carbamoyl}methyl)carbamate 78a (19 mg, 17.1 %). LC-MS (Method A) 664.4 [M+H] ⁺ , RT 2.88 min.

b) {[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]carbamoyl}methanaminium chloride 78 HCI (4M in Dioxane, 2 mL, 2.69 mmol) was added to a solution of tert-butyl N- ({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1- yl)ethyl]carbamoyl}methyl)carbamate 78a (20.0 mg, 0.03 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature for 6 h then concentrated under reduced pressure with Et20 azeotroping to afford a yellow solid. The crude product was purified via prep. HPLC (Method B) using 0.1 % NH ₃ in MeCN/H ₂ 0. Clean fractions were collected and concentrated under reduced pressure with Et20 azeotroping to afford a white solidwhich was dissolved in MeOH and HCI (1 M in Et20, 0.1 mL). The mixture was concentrated under reduced pressure with Et20 azeotroping to afford {[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl][2-(7-methoxy-2-oxo-1 ,2- dihydro-1 ,8-naphthyridin-1-yl)ethyl]carbamoyl}methanaminium chloride 78 (7.8 mg, 43%) as a white solid. LC-MS (Method B) 564.3 [M+H] ⁺ , RT 6.20 min. ¹ H NMR (rotamers)(Method C) (DMSO-d6): δ ppm 1 1.31-1 1.21 (m, 1 H), 8.19-8.04 (m, 4H), 8.00-7.88 (m, 1 H), 7.48-7.42 (m, 1 H), 7.24-7.20 (m, 1 H), 6.83-6.75 (m, 1 H), 6.61-6.50 (m, 1 H), 4.66-4.62 (m, 2H), 4.61- 4.54 (m, 1 H), 4.55-4.40 (m, 1 H), 4.28-4.13 (m, 2H), 4.13-4.06 (m, 3H), 4.02-3.75 (m, 2H), 3.72 - 3.45 (m, 2H), 2.95-2.82 (m, 1 H), 2.38-2.24 (m, 2H), 2.03-1.78 (m, 3H), 1.55-1.44 (m, 1 H).

Example 79:-

1 -(3-{r(3aR,6RJaR)-2-oxo-3-{7-oxo-6H JH,8H-pyrimidor5,4-biri,41oxazin-2-yl)-octahydr -1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8 -naphthyridin-2-one

79 Prepared as in the method described in example 60e using

(3aR,6R,7aR)-6-amino-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][1,4]o xazin-2-yl}-octahydro-1,3- benzoxazol-6-aminium trifluoroacetate (prepared from example 33a using the method described in example 60d) (246 mg, 0.49 mmol) and

3-(7-methoxy-2-oxo-1,2-dihydro-1,8-naphthyridin-1-yl)propana l 85b (104 mg, 0.45 mmol) to afford

1-(3-{[(3aR,6R,7aR)-2-oxo-3-{7-oxo-6H,7H,8H-pyrimido[5,4-b][ 1,4]oxazin-2-yl}-octahydro-1, 3-benzoxazol-6-yl]amino}propyl)-7-methoxy-1,2-dihydro-1,8-na phthyridin-2-one 79 (50 mg, 19%). LC-MS (Method A) 522.3 [M+H] ⁺ ; RT 1.74 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 8.25 (s, 1H), 8.07 (d, J= 9.2 Hz, 1H), 7.87 (d, J= 8.3 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.50 (d, J= 9.2 Hz, 1H), 4.72 (s, 2H), 4.75-4.38 (m, 3H), 4.06 (td, J= 11.2, 3.4 Hz, 1H), (4.00 s, 3H), 3.79 (td, J= 11.2, 3.4 Hz, 1H), 2.76-2.58 (m, 3H), 2.46-2.37 (m, 2H), 2.03-1.94 (m, 1H), 1.89-1.79 (m, 2H), 1.47 (q, J = 11.1 Hz, 1H), 1.38-1.17 (m, 2H).

Example 80:- (3aR,6R,7aR)-6-({r3-(6-methoxypyridin-2-yl)phenvnmethyl)amin o)-3-{3- oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6-yl)-octahydro-1,3-be nzoxazol-2-one

80

Prepared as in the method described in example 74 using

3-(6-methoxypyridin-2-yl)benzaldehyde (104 mg, 0.49 mmol) (WO 2014170821A1)

(128. mg, 0.60 mmol) and (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n- 6-yl}-octahydro-1,3-benzoxazol-6-aminium trifluoroacetate 74a (233.1 mg, 0.56 mmol) to afford (3aR,6R,7aR)-6-({[3-(6-methoxypyridin-2-yl)phenyl]methyl}ami no)-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzox azol-2-one 80 (34 mg, 11.%). LC-MS (Method B) 502.3 [M+H] ⁺ ; RT 6.24 min. ¹ H NMR (Method C) (CDC ): δ ppm 8.01 - 7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.64 (dd, J= 8.2, 7.4 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 7.39 - 7.28 (m, 4H), 6.70 (dd, J = 8.2, 0.7 Hz, 1 H), 4.63 (s, 2H), 4.05 (s, 3H), 4.03 - 3.90 (m, 3H), 3.82 (td, J= 11.1, 3.3 Hz, 1H), 2.94-2.84 (m, 1H), 2.73 -2.65 (m, 2H), 2.17 (dd, J = 12.2, 4.3 Hz, 1H), 1.64 (q, J= 11.4 Hz, 1H), 1.51 - 1.34 (m, 2H).

Example 81 :- 1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1thiazin-6- yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5- naphthyridin-2-one

Prepared as described in example 60e using

2-(7-methoxy-2-oxo-1,2-dihydro-1,5-naphthyridin-1-yl)acetald ehyde (prepared as described in WO2011148962A1) (17.0 mg, 0.08 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]thiazin-6-yl}-octahydro-1,3-benzoxazol-6-a minium chloride 61b (34.7 mg, 0.10 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]thiazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2-dihydro-1 ,5- naphthyridin-2-one 81 (18.5 mg, 36 %) as a colourless solid. LC-MS (Method A) 523.2

[M+H] ⁺ , RT2.27 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 10.96 (s, 1H), 8.29 (d, J = 2.5, 1H), 7.87 (d, J= 8.5, 1H), 7.79 (d, J= 8.5, 1H), 7.51 (d, J= 2.5, 1H), 7.28 (d, J= 8.5, 1H), 6.67 (d, J= 9.5, 1H), 4.32-4.29 (m, 2H), 4.06 (m, 1H), 3.99 (s, 3H), 3.74 (td, J= 11.0, 3.5, 1H), 3.57 (d, J= 15.0, 1H), 3.51 (d, J= 15.0), 2.97 (m, 1H), 2.89-2.80 (m, 3H), 2.45 (m, 1H), 1.98 (m, 1H), 1.48 (m, 1H), 1.31-1.21 (m, 4H).

Example 82:-

5-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahydro- 1,3-benzoxazol-6-yl1amino)propyl)-6-oxo-5,6-dihvdro-1,5-naph thyridine-3-carbonitrile

a) 7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 82a

7-bromo-1 ,2-dihydro-1 ,5-naphthyridin-2-one (3.77 g, 16.70 mmol) (prepared according to WO2013078441), Cs ₂ C0 ₃ (1.60 g, 4.91 mmol) and 3-bromo-1 , 1-dimethoxypropane (2.97 mL, 21.78 mmol) were added to DMF (50 mL) and heated at 60 °C for 17 h. The reaction was quenched with H2O (100 mL) and extracted with Et20 (2 x 100 mL). The combined organic extracts were dried (MgSCU), filtered and concentrated under reduced pressure to afford an orange gum. Purification via column chromatography using a gradient of 50-100% EtOAc in heptane afforded 7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin- 2-one 82a (1.72 g, 31 %) as a yellow solid. LC-MS (Method A) 328.9 [M+H] ⁺ ; RT 0.53 min. b) 5-(3,3-dimethoxypropyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82b

7-bromo-1-(3,3-dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 82a (1.7 g, 5.20 mmol), XPhos Pd G2 (204 mg, 0.26 mmol) and zinc cyanide (0.92 g, 7.79 mmol) were heated in DMF (50 mL) at 100 °C for 1 h. The reaction was diluted with Et ₂ 0 (100 mL), filtered, and the filtrate concentrated under reduced pressure to afford a viscous yellow gum. The crude product was purified via column chromatography using a gradient of 50- 100% EtOAc in petroleum ether to afford 5-(3,3-dimethoxypropyl)-6-oxo-5,6-dihydro-1 ,5- naphthyridine-3-carbonitrile 82b (1.42 g, 99%) as a yellow gum which solidified on standing. LC-MS (Method A) 274.0 [M+H] ⁺ ; RT 1.40 min. ¹ H NMR (Method C): (CDC ) δ ppm 8.73 (d, J = 1.6 Hz, 1 H), 8.1 1 (d, J = 1.6 Hz, 1 H), 7.94 (d, J = 9.8 Hz, 1 H), 7.05 (d, J = 9.8 Hz, 1 H), 4.49 (t, J = 5.0 Hz, 1 H), 4.38-4.27 (m, 2H), 3.40 (s, 6H), 2.04 (td, J = 7.7, 5.0 Hz, 2H). c) 6-oxo-5-(3-oxopropyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82c 5- (3,3-dimethoxypropyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82b (1.42 g, 5.2 mmol) was added to aq. HCI (3 M, 10 ml_, 51.9 mmol) and THF (10 ml_) and the mixture stirred at room temperature for 2 h The reaction mixture was quenched with H2O (30 ml_), basified with solid K2CO3 and extracted with Et20 /EtOAc (1 : 1) (2 x 75 ml). The extracts were combined, dried (MgSCU), filtered and concentrated under reduced pressure to afford an off white solid. Crude product was triturated with Et20 and the resulting solid was filtered and dried under vacuum to afford

6- oxo-5-(3-oxopropyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82c (450 mg, 38%) as a white solid. ¹ H NMR (Method C) (CDCI3) δ ppm 9.86 (s, 1 H), 8.75 (d, J = 1.9 Hz, 1 H), 8.09 (d, J = 1.9 Hz, 1 H), 7.96 (dd, J = 9.8, 0.9 Hz, 1 H), 7.04 (d, J = 9.8 Hz, 1 H), 4.53 (t, J = 6.9 Hz, 2H), 3.01 (td, J = 6.9, 0.9 Hz, 2H). d) 5-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahyd ro-1 ,3-benzoxazol-6-yl]amino}propyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82

Prepared as described in example 60e using (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (150 mg, 0.36 mmol) and 6-oxo-5-(3-oxopropyl)-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82c (81 mg, 0.36 mmol) to afford

5-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}propyl)-6-oxo-5,6-dihydro-1 ,5-naphthyridine-3-carbonitrile 82 (63 mg, 34%). LC-MS (Method A) 516.1 [M+H] ⁺ ; RT 1.75 min. ¹ H NMR (Method C) (DMSO- d6):5 ppm 1 1.24 (s, 1 H), 8.92 (d, J = 1.6 Hz, 1 H), 8.76 (d, J = 1.6 Hz, 1 H), 8.04 (d, J = 9.8 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 1 H), 7.06 (d, J = 9.8 Hz, 1 H), 4.63 (s, 2H), 4.30 (t, J = 7.3 Hz, 2H), 4.07 (td, J = 11.7, 3.4 Hz, 1 H), 3.77 (td, J = 1 1.0, 3.4 Hz, 1 H), 3.40-3.30 (m, 1 H), 2.89-2.60 (m, 4H), 2.06 (d, J = 1 1.4 Hz, 1 H), 1.90-1.73 (m, 2H), 1.56 (m, 1 H), 1.36 (dd, J = 16.1 , 7.2 Hz, 2H).

Example 83:-

1 -(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8 -naphthyridin-2-one

83

Prepared following the method described in example 60e using

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3-benzox azol-6-aminium trifluoroacetate 60d (550.0 mg, 1.32 mmol) and 3-(7-methoxy-2-oxo-1,2- dihydro-1,8-naphthyridin-1-yl)propanal 85b (290.1 mg, 1.25 mmol) to afford

1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b] [1,4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}propyl)-7-methoxy-1,2-dihydro-1,8-naph thyridin-2-one 83 (296.3 mg, 43%) as a white solid. LC-MS (Method B) 521.2 [M+H] ⁺ ; RT 6.87 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (br s, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 7.88 (d, J = 9.4 Hz, 1 H), 7.42 (d, J= 8.5 Hz, 1H), 7.18 (d, J= 8.5 Hz, 1H), 6.75 (d, J= 8.5 Hz, 1H), 6.52 (d, J= 9.4 Hz, 1H), 4.63 (s, 2H), 4.43 (t, J= 7.3, 2H), 4.05 (td, J= 11.8, 3.3 Hz, 1H), 4.01 (s, 3H), 3.74 (td, J= 11.2, 3.3 Hz, 1H), 2.79-2.68 (m, 2H), 2.67-6.59 (m, 2H), 2.45-2.40 (m, 1H), 2.01-1.95 (m, 1H), 1.88-1.80 (m, 2H), 1.46 (q, J= 11.2 Hz, 1H), 1.37-1.28 (m, 1H), 1.28-1.18 (m, 1H).

Example 84:-

1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)ethyl)-7-fluoro-1,2-dihydroquinoxal in-2-one

84

Prepared as in the method described in example 60e using

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3-benzox azol-6-aminium trifluoroacetate 60d (225 mg, 0.54 mmol) and

2-(7-fluoro-2-oxo-1,2-dihydroquinoxalin-1-yl)acetaldehyde (prepared as described in WO 2008009700) (105.4 mg, 0.51 mmol) to afford

1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-7-fluoro-1,2-dihydroquinoxalin- 2-one 84 (116.3 mg, 44%) as a pale yellow solid. LC-MS (Method B) 495.3 [M+H] ⁺ ; RT 6.48 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.21 (br s, 1H), 8.21 (s, 1H), 7.89 (dd, J= 8.6, 6.1 Hz, 1H), 7.63 (dd, J = 11.1, 2.6 Hz, 1H), 7.42 (d, J= 8.6 Hz, 1H), 7.26 (td, J= 8.6, 2.6 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 4.62 (s, 2H), 4.23 (t, J= 7.0 Hz, 2H), 4.04 (td, J= 11.8, 3.3 Hz, 1H), 3.74 (td, J = 11.1, 3.3 Hz, 1H), 2.89-2.82 (m, 2H), 2.79-2.73 (m, 2H), 2.44-2.38 (m, 1H), 2.11 (br s, 1H), 1.99-1.92 (m, 1H), 1.44 (q, J = 11.1 Hz, 1H), 1.37-1.28 (m, 1H), 1.25-1.24 (m, 1H).

Example 85:- 1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1thiazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8- naphthyridin-2-one

85

a) 1-(3,3-dimethoxypropyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 85a

7-methoxy-1,2-dihydro-1,8-naphthyridin-2-one (0.9 g, 5.11 mmol), CsCOs (1.6 g, 4.91 mmol) and 3-bromo-1,1-dimethoxypropane (0.91 mL, 6.64 mmol) were suspended in DMF (50mL) and heated to 90°C for 1 h. H2O (100 mL) was added and the mixture extracted with Et20 (2 x 100 mL). Organics were combined, dried (MgS0 ₄ ) and solvent evaporated to afford an orange gum. Purification via column chromatography eluting with 50-100% Et20 in heptane yielded 1-(3,3-dimethoxypropyl)-7-methoxy-1,2-dihydro-1,8-naphthyrid in-2-one 85a (0.87 g, 2.97 mmol, 58 %) as a yellow solid. LC-MS (Method A) 301.2 [M+Na] ⁺ ;RT 2.45 min. b) 3-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)propanal 85b

1-(3,3-dimethoxypropyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 85a (0.64 g, 2.3 mmol) was added to THF (15ml_) and HCI (3M, 10 mL, 2.3 mmol) and the mixture was stirred at 60°C for 27 h. The mixture was allowed to cool and sat. aqueous Na2CC>3 (100 mL) was added then extracted with DCM (2 x 100 mL), dried (MgS0 ₄ ) and solvent evaporated under reduced pressure to afford 3-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,8- naphthyridin-1-yl)propanal 85b (320 mg, 1.24 mmol, 53.9% yield) as a yellow gum which solidified. ¹ H NMR (Method C) ¹ H-NMR (CDCb) δ: 9.78 (s 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 9.5 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 6.50 (d, J = 9.5 Hz, 1 H), 4.65 (t, J = 7.3 Hz, 2H), 3.95 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H). c) 1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 85

A solution of (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}- octahydro-1 ,3-benzoxazol-6-aminium chloride 61b (200 mg, 0.56 mmol) in DCM (10 mL) and triethylamine (0.23 mL, 1.68 mmol) was stirred over molecular sieves (4 A) for 2 h. 3- (7-methoxy-2-oxo-1 ,2-dihydro-1 ,8-naphthyridin-1-yl)propanal 85b (1 17 mg, 0.56 mmol) was added and stirred for 17 h then NaBH(OAc)3 (356 mg, 1.17 mmol) added and stirring continued for a further 17 h. Sat. aqueous NaHCC (20 mL) was added and the mixture extracted with DCM (3 x 20 mL), dried over MgS0 ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% MeOH in EtOAc to give 1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,8-naphthyridin-2-one 85 (3 mg, 4%) - as a white solid. LC-MS (Method A) 537.3 [M+H] ⁺ , RT 2.76 min. ¹ H NMR (Method C) (CDCb): δ ppm 8.40 (s, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.68 - 7.58 (m, 2H), 7.43 (d, J = 8.4 Hz, 1 H), 6.67-6.60 (m, 2H), 4.67-4.57 (m, 2H), 4.03 (s, 3H), 3.99 - 3.79 (m, 2H), 3.48 (s, 2H), 3.00-2.95 (m, 1 H), 2.89-2.82 (m, 1 H), 2.79-2.77 (m, 2H), 2.67-2.65 (m, 1 H), 2.25-2.22 (m, 3H), 1.85 - 1.72 (m, 1 H), 1.63 (d, J = 12.8 Hz, 1 H), 1.49 - 1.34 (m, 1 H).

Example 86:-

1 -(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1 ,3-benzoxazol-6-vnamino)ethyl)-7-fluoro-1 ,2-dihydroquinoxalin-2-one

Prepared as in the method described in example 60e using

(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3-benzo xazol-6-aminium trifluoroacetate 74a (200.0 mg, 0.48 mmol) and

2- (7-fluoro-2-oxo-1,2-dihydroquinoxalin-1-yl)acetaldehyde (prepared as described in WO 2008009700) (93.6 mg, 0.45 mmol) to afford

1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-7-fluoro-1,2-dihydroquinoxalin- 2-one 86 (93.9 mg, 40%) as a pale yellow solid. LC-MS (Method B) 495.3 [M+H] ⁺ ; RT 6.46 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (br s, 1H), 8.21 (s, 1H), 7.89 (dd, J= 8.6, 6.1 Hz, 1H), 7.64 (dd, J = 11.1, 2.6 Hz, 1H), 7.42 (d, J= 8.6 Hz, 1H), 7.26 (td, J= 8.6, 2.6 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 4.62 (s, 2H), 4.23 (t, J= 7.0 Hz, 2H), 4.04 (td, J= 11.8, 3.3 Hz, 1H), 3.74 (td, J = 11.1, 3.3 Hz, 1H), 3.14-2.92 (m, 1H) 2.88-2.83 (m, 2H), 2.79-2.72 (m, 2H), 2.44-2.38 (m, 1H), 1.98-1.92 (m, 1H), 1.45 (q, J = 11.1 Hz, 1H), 1.37-1.27 (m, 1H), 1.26-1.14 (m, 1H).

Example 87:-

(3aR,6RJaR)-6-r(2-{3-methoxy-6-oxo-5H,6H-pyridor2,3-blpyr azin-5-yl)ethyl)amino1-3-{

3- oxo-2H,3H,4H-pyridor3,2-biri,41oxazin-6-yl)-octahydro-1,3-be nzoxazol-2-one

Prepared as in the method described in Example 60e using

2-{3-methoxy-6-oxo-5H,6H-pyrido[2,3-b]pyrazin-5-yl}acetal dehyde (55 mg, 0.25

mmol)(WO2008009700) and (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-6-aminium trifluoroacetate 74a (105 mg, 0.25 mmol) to afford

(3aR,6R,7aR)-6-[(2-{3-methoxy-6-oxo-5H,6H-pyrido[2,3-b]pyraz in-5-yl}ethyl)amino]-3-{3-ox o-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benz oxazol-2-one 87 (19 mg, 15%). LC-MS (Method A) 508.3 [M+H] ⁺ ; RT 2.31 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.24 (s, 1H), 8.23 (s, 1H), 7.96 (d, J= 9.5 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.74 (d, J= 9.5 Hz, 1H), 4.62 (s, 2H), 4.39 (t, J= 7.2 Hz, 2H), 4.11-4.01 (m, 4H), 3.75 (td, J= 11.2, 3.4 Hz, 1H), 2.91-2.72 (m, 4H), 2.45-2.42 (m, 1H), 2.06 (br. s, 1H), 1.99-1.96 (m, 1H), 1.46 (q, J= 11.2 Hz, 1H), 1.37-1.29 (m, 1H), 1.28-1.16 (m, 1H).

Example 88:-

1-(3-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro-

1,3-benzoxazol-6-vnamino)propyl)-6,7-difluoro-1,2-dihydro quinoxalin-2-one

Prepared as in the method described in Example 60e using

3-(6,7-difluoro-2-oxo-1,2-dihydroquinoxalin-1-yl)propanal (114 mg, 0.48 mmol) (WO 2012108376) and (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}- octahydro-1,3-benzoxazol-6-aminium trifluoroacetate 74a (200 mg, 0.48 mmol) to afford 1-(3-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}propyl)-6,7-difluoro-1,2-dihydroquinox alin-2-one 88 (111 mg, 44%). LC-MS (Method A) 527.3 [M+H] ⁺ ; RT 2.61 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.25 (br. s, 1H), 8.27 (s, 1H), 8.10-7.94 (m, 2H), 7.42 (d, J= 8.3 Hz, 1H), 7.18 (d, J= 8.3 Hz, 1H), 4.62 (s, 2H), 4.22 (t, J= 7.4 Hz, 1H), 4.06 (td, J= 11.2, 3.4 Hz, 1H), 3.75 (td, J = 11.2, 3.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.71-2.54 (m, 4H), 2.53-2.42 (m, 2H), 2.06-1.94 (m, 1H), 1.80-1.70 (m, 2H), 1.52-1.20 (m, 3H).

Example 89:-1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-b in,41oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(prop-2-en-1 -yloxy)-1 ,2- dihydroquinolin-2-one

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3- benzoxazol-6-aminium trifluoroacetate 60d (250 mg, 0.60 mmol) was added to DCM (30 ml_) to afford a pink insoluble mixture. Trimethylamine (0.41 ml_, 2.96 mmol) (reaction decolourised) was added and all the solid dissolved after 5 min. To this was added

2-[2-oxo-7-(prop-2-en-1-yloxy)-1,2-dihydroquinolin-1-yl]a cetaldehyde 9b (145 mg, 0.60 mmol) and 3A molecular sieves and the mixture stirred for 17h. NaBH(OAc)3 (380 mg, 1.79) was added and the mixture stirred for a further 72 h. The reaction was quenched with sat. aq. K ₂ CO ₃ (50 ml_), extracted with DCM (1 X 50 ml_), dried over MgS0 ₄ and solvent evaporated to afford an orange foam. Purification via column chromatography eluting with DCM and then 5% MeOH/DCM gave a white solid. This was triturated with Et20 (50 ml_) and the solid was filtered and air dried to give

1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-7-(prop-2-en-1-yloxy)-1,2-dihyd roquinolin-2-one 89 (268 mg, 83% yield) as a white solid. LC-MS (Method A) 532.3 [M+H] ⁺ ; RT 2.58 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (s, 1H), 7.82 (d, J= 9.4 Hz, 1H), 7.65 (d, J= 8.7 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.18 (d, J= 8.5 Hz, 1H), 7.06 (d, J= 2.3 Hz, 1H), 6.93 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 6.43 (d, J= 9.4 Hz, 1H), 6.14-6.04 (m, 1H), 5.47 (d, J= 17.3 Hz, 1H), 5.31 (d, J= 10.5 Hz, 1H), 4.77-4.73 (m, 2H), 4.63 (s, 2H), 4.26 (t, J= 7.4 Hz, 2H), 4.08 (t, J = 11.7 Hz, 1H), 3.76 (td, J= 11.2, 3.4 Hz, 1H), 2.96-2.67 (m, 4H), 2.45-2.42 (m, 2H), 2.06- 1.94 (m, 1H), 1.49 (q, J= 11.2 Hz, 1H), 1.35-1.21 (m, 2H).

Example 90:-

1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)propyl)-6,7-difluoro-1,2-dihydroqui noxalin-2-one

Prepared as described in example 60e using

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}-octahydro-1,3-benzox azol-6-aminium trifluoroacetate 60d (108.0 mg, 0.26 mmol) and

3-oxo-4-(2-oxoethyl)-3,4-dihydroquinoxaline-6-carbonitrile (prepared as described in WO 2012108376) (58.6 mg, 0.25 mmol) to afford 1-(3-{[(3aS,6S7aS)-2-oxo-3-{3-oxo-2H,3H,4H^yrido[3,2-b][1,4] oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}propyl)-6,7-difluoro-1,2-dihydroquinox alin-2-one 90 (21.0 mg, 15%) as a yellow solid. LC-MS (Method B) 527.3 [M+H] ⁺ ; RT 6.53 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (br s, 1 H), 8.26 (s, 1 H), 8.01-7.93 (m, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.18 (d, J= 8.5 Hz, 1H), 4.63 (s, 2H), 4.23 (t, J =7.2 Hz, 2H), 4.06 (td, J= 11.8, 3.3 Hz, 1H), 3.75 (td, J= 11.1, 3.3 Hz, 1H), 2.81-2.74 (m, 1H), 2.72-2.57 (m, 3H), 2.48-2.42 (m, 1H), 2.05-1.97 (m, 1H), 1.82-1.73 (m, 2H), 1.48 (q, J = 11.1 Hz, 1H), 1.38-1.21 (m, 2H).

Example 91 :-1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin ,41oxazin-6- -octahvdro-1,3-benzoxazol-6-yl1amino)ethyl)-7-propoxy-1,2-di hvdroquinolin-2-one

1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b] [1,4]oxazin-6-yl}-octahydro-1,3b enzoxazol -6-yl]amino}ethyl)-7-(prop-2-en-1-yloxy)-1,2-dihydroquinolin -2-one 89 (168 mg, 0.32 mmol) was dissolved in THF (10 ml_)/EtOH (30 ml_) and to this was added Palladium, 10 wt. % on carbon powder (dry) (16.8 mg, 0.16 mmol). The mixture was stirred under an atmosphere of H2 for 48 h. The reaction was filtered, evaporated and the concentrated residue purified via column chromatography eluting with 0 to 5 % MeOH in DCM to afford 1- (2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4] oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}ethyl)-7-propoxy-1,2-dihydroquinolin-2 -one 91 (6 mg, 3.38%) as a white solid. LC-MS (Method A) 534.3 [M+H] ⁺ ; RT 2.68 min. ¹ H NMR (Method C) (DMSO- d6): δ ppm 11.23 (s, 1H), 7.82 (d, J= 9.4 Hz, 1H), 7.65 (d, J= 8.7 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.18 (d, J= 8.5 Hz, 1H), 7.06 (d, J= 2.3 Hz, 1H), 6.93 (dd, J= 8.7 Hz, 2.3 Hz, 1H), 6.43 (d, J= 9.4 Hz, 1H), 4.63 (s, 2H), 4.27 (t, J= 7.4 Hz, 2H), 4.11 -4.02 (m, 3H), 3.76 (td, J= 11.2, 3.4 Hz, 1H), 2.96-2.67 (m, 4H), 2.45-2.42 (m, 2H), 2.06-1.94 (m, 1H), 1.80 (sextet, J= 7.3 Hz, 2H), 1.49 (q, J= 11.2 Hz, 1H), 1.35-1.21 (m, 2H), 1.04 (t, J= 7.3 Hz, 3H). Example 92:-

1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bi ri,41oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)propyl)-7-fluoro-1,2-dihydroquinoxa lin-2-one

Prepared as described in example 60e using

(3aS,6S7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin -6-yl}-octahydro-1,3-benzox azol-6-aminium trifluoroacetate 60d (100.0 mg, 0.24 mmol) and

3-(6-fluoro-2-oxo-1,2-dihydroquinoxalin-1-yl)propanal (prepared as described in WO 2012108376) (50.0 mg, 0.23 mmol) to afford

1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}propyl)-7-fluoro-1,2-dihydroquinoxalin -2-one 92 (66.4 mg, 55%) as a yellow solid. LC-MS (Method B) 509.2 [M+H] ⁺ ; RT 6.28 min. ¹ H NMR (Method C) (DMSO- d6): δ ppm 11.24 (br s, 1H), 8.20 (s, 1H), 7.90 (dd, J= 8.5, 6.2 Hz, 1H), 7.68 (dd, J= 11.1, 2.6 Hz, 1H), 7.42 (d, J= 8.5 Hz, 1H), 7.26 (td, J= 8.5, 2.6 Hz, 1H), 7.17 (d, J= 8.5 Hz, 1H), 4.62 (s, 2H), 4.23 (dd, J= 8.5, 6.2 Hz, 2H), 4.05 (td, J= 11.8, 3.3 Hz, 1H), 3.75 (td, J = 11.1, 3.3 Hz, 1H), 2.80-2.74 (m, 1H), 2.71-2.57 (m, 3H), 2.49-2.40 (m, 1H), 2.05-1.98 (m, 1H), 1.81-1.73 (m, 2H), 1.48 (q, J= 11.1 Hz, 1H), 1.39-1.26 (m, 1H), 1.28-1.20 (m, 1H).

Example 93:- 1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahydro-1 ,3-benzoxazol-6-yl1amino}propyl)-7-(difluoromethoxy)-1 ,2-dihydro-1 ,5- naphthyridin-2-one

a) 7-(difluoromethoxy)-2-methoxy-1 ,5-naphthyridine 93a

Sodium chlorodifluoroacetate (1.3 g, 8.5 mmol) was added to a stirred solution of 6- methoxy-1 ,5-naphthyridin-3-ol (prepared as described in WO2010084152) (500 mg, 2.8 mmol) and Cs ₂ C0 ₃ (2.78 g, 8.5 mmol) in DMF (5.7 mL) and heated to 100 °C for 17 h under nitrogen. The reaction mixture was allowed to cool to room temperature and diluted with a 10% MeOH/DCM solution (20 mL). The reaction mixture was filtered through a pad of celite and washed with 10% MeOH/DCM (40 mL). The filtrate was collected and concentrated under reduced pressure and the resulting crude product purified by chromatography using a gradient of 0-5% MeOH/DCM. Clean product fractions were collected and concentrated under reduced pressure to afford 7-(difluoromethoxy)-2-methoxy-1 ,5-naphthyridine 93a (196 mg, 31 %) as a white solid. LC-MS (Method A): 227.1 [M+H] ⁺ , RT: 2.80 min.

b) 7-(difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93b

HCI (6M in isopropanol) (2.0 mL, 12 mmol) was added to a stirred solution of 7- (difluoromethoxy)-2-methoxy-1 ,5-naphthyridine 93a (196 mg, 0.87 mmol) in I PA (10 mL) and heated to 100 °C for 2 h. The reaction mixture was allowed to cool to room temperature and quenched with 2M NaOH solution to pH 8-9. Volatile organic solvent was removed under reduced pressure and the resulting saturated aqueous solution filtered under reduced pressure to afford 7-(difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93b (139 mg, 76%) as a white solid. LC-MS (Method A): 213.0 [M+H] ⁺ , RT: 1.38 min. c) 7-(difluoromethoxy)-1-(3,3-dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93c

3-Bromo-1 , 1-dimethoxypropane (0.15 mL, 1.1 mmol) was added to a stirred solution of 7- (difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93b (140 mg, 0.66 mmol) and CS2CO3 (280 mg, 0.86 mmol) in DMF (2.5 mL) and heated to 60 °C for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (20 mL) and extracted with Et20 (3 x 40 mL). Organic extracts were combined, dried (MgS04) and concentrated under reduced pressure to afford crude product. The crude product was purified by chromatography using a gradient of 0-100% EtOAc/DCM. Clean product fractions were collected and concentrated under reduced pressure to afford 7-(difluoromethoxy)-1-(3,3- dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93c (61.9 mg, 30%) as a white solid. LCMS (Method A): 315.1 [M+H] ⁺ , RT: 2.28 min.

d) 3-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydro-1 ,5-naphthyridin-1-yl]propanal 93d

HCI (3M, 0.33 mL, 0.98 mmol) was added to a solution of 7-(difluoromethoxy)-1-(3,3- dimethoxypropyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93c (61.9 mg, 0.2 mmol) in THF (2 mL) and heated to 60 °C for 2 h. The reaction mixture was allowed to cool to room temperature and quenched with solid NaHC03 to pH 8 and diluted with H2O (20 mL). Volatile organic solvent was removed under reduced pressure and the resulting aqueous extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried (MgS04) and concentrated under reduced pressure to afford 3-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydro- 1 ,5-naphthyridin-1-yl]propanal 93d (47.8 mg, 91 %) as a white solid. LC-MS (Method A): 269.0 [M+H] ⁺ , RT: 1.37 min. e) 1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

I , 3-benzoxazol-6-yl]amino}propyl)-7-(difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93

Prepared as described in example 60e using 3-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydro-1 ,5- naphthyridin-1-yl]propanal 93d (41 mg, 0.15 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium

trifluoroacetate 60d (70.3 mg, 0.17 mmol) to afford 1-(3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}propyl)-7- (difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93 (40.1 mg, 47%) as a white solid. LC-MS (Method A): 557.2 [M+H] ⁺ , RT: 2.38 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm

I I .26 (s, 1 H), 8.48 (d, 1.9 Hz, 1 H), 7.97 (d, 1.9 Hz, 1 H), 7.96 (d, 9.9 Hz, 1 H), 7.53 (t, 73.2 Hz, 1 H), 7.43 (d, 8.6 Hz, 1 H), 7.17 (d, 8.6 Hz, 1 H), 6.86 (d, 9.9 Hz, 1 H), 4.63 (s, 2H), 4.27 (t, 7.2 Hz, 2H), 4.05 (td, 11.9, 3.2 Hz, 1 H), 3.75 (td, 1 1.2, 3.2 Hz, 1 H), 2.78-2.75 (m, 1 H), 2.68-2.58 (m, 3H), 2.02 (d, 1.3 Hz, 1 H), 1.74 (t, 7.2 Hz, 2H), 1.51-1.44 (m, 1 H), 1.37-1.23 (m, 3H). Example 94:- 1-r(2S)-3-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2- biri,41oxazin-6-yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)-2-hvdroxypropyn-7-fluoro- 1 ,2-dihydroquinoxalin-2-one & 1-r(2R)-3-{r(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H- Pyridor3,2-biri,41oxazin-6-yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)-2-hvdroxypropyn- 7-fluoro-1 2-dihydroquinoxalin-2-one

94

a) rac-7-fluoro-1 -(oxiran-2-ylmethyl)-1 ,2-dihydroquinoxalin-2-one 94a

7-fluoro-1 ,2-dihydroquinoxalin-2-one (1.0 g, 6.09 mmol), CsCOs (1.6 g, 4.91 mmol) and 2- (bromomethyl)oxirane (0.68 mL, 7.92 mmol) were mixed with DMF (50 mL) and stirred for 17 h. The mixture was quenched with sat. N H4CI (50 mL), extracted with Et20 (2 x 75 ml), dried (MgSCU), and evaporated to afford a yellow liquid. The crude was purified via silica gel chromatography eluting with Et20 to afford rac-

7-fluoro-1 -(oxiran-2-ylmethyl)-1 ,2-dihydroquinoxalin-2-one 94a (420 mg, 31 % yield) as a white solid. b) 1-[(2S)-3-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}-2-hydroxypropyl]-7-fluoro-1 ,2-dihydroquinoxalin-2- one & 1-[(2R)-3-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}-2-hydroxypropyl]-7-fluoro-1 ,2-dihydroquinoxalin-2- one 94

(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 74a (247 mg, 0.59 mmol),

7-fluoro-1 -(oxiran-2-ylmethyl)-1 ,2-dihydroquinoxalin-2-one 94a (130 mg, 0.59 mmol) and triethylamine (0.33 mL, 2.36 mmol) were added to EtOH (30 mL) and heated at 69°C for 10 h. The reaction was evaporated and purified via silica gel chromatography, eluting with 0- 10% MeOH in EtOAc to afford a solid. This solid was dissolved in DCM and Et ₂ 0 added to afford a precipitate which was filtered and air dried to give 1-[(2S)-3-{[(3aR,6R,7aR)-2-oxo- 3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}-2- hydroxypropyl]-7-fluoro-1 ,2-dihydroquinoxalin-2-one & 1-[(2R)-3-{[(3aR,6R,7aR)-2-oxo-3-{3- oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}-2- hydroxypropyl]-7-fluoro-1 ,2-dihydroquinoxalin-2-one 94 (53.6 mg, 17%) as a white solid. LC-MS (Method A) 525.2 [M+H] ⁺ ; RT 2.22 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.28 (s, 1 H), 8.22 (s, 1 H), 7.89 (dd, J = 7.4 Hz, J = 5.2 Hz 1 H), 7.68 (d, J = 7.4 Hz, 1 H), 7.43 (t, J = 8.3 Hz, 1 H), 7.24 (dd J = 7.4 Hz, J = 7.4 Hz, 1 H), 7.17 (d, J = 8.3 Hz, 1 H), 5.06 (brs, 1 H), 4.63 (s, 2H), 4.28-4.17 (m, 2H), 4.06 (td, J = 1 1.2, 3.4 Hz, 1 H), 3.97 - 3.81 (m, 1 H), 3.76 (td, J = 1 1.2, 3.4 Hz, 1 H), 2.82-2.62 (m, 4H), 2.08-1.81 (m, 3H), 1.59-1.46 (m, 1 H), 1.40-1.21 (m, 2H).

Example 95:- 1 -r(2S)-3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2- biri ,41oxazin-6-yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)-2-hvdroxypropyn-7-fluoro- 1 ,2-dihydroquinoxalin-2-one & 1 -r(2R)-3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H- Pyridor3,2-biri ,41oxazin-6-yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)-2-hvdroxypropyn- 7-fluoro-1 ,2-dihydroquinoxalin-2-one

(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d (247 mg, 0.59 mmol), rac-7-fluoro-1-(oxiran-2- ylmethyl)quinoxalin-2-one 94a (130 mg, 0.59 mmol) and triethylamine (0.33 mL, 2.36 mmol) were added to EtOH (30 mL) and heated at 69°C for 10 h. The reaction was evaporated and purified via silica gel column chromatography eluting with 0-10% MeOH in EtOAc to afford a solid which was dissolved in DCM. Et20 was added to afford a precipitate which was filtered and air dried to give 1-[(2S)-3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}-2-hydroxypropyl]-7- fluoro-1 ,2-dihydroquinoxalin-2-one & 1-[(2R)-3-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzoxazol-6-yl ]amino}-2-hydroxypropyl]-7- fluoro-1, 2-dihydroquinoxalin-2-one 95 (45 mg, 14% yield) as a white solid. LC-MS (Method A) 525.2 [M+H] ⁺ ; RT 2.20 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.28 (s, 1H), 8.22 (s, 1H), 7.89 (dd, J= 7.4 Hz, J = 5.2 Hz 1H), 7.68 (d, J= 7.4 Hz, 1H), 7.43 (t, J= 8.3 Hz, 1H), 7.24 (dd J= 7.4 Hz, J= 7.4 Hz, 1H), 7.17 (d, J= 8.3 Hz, 1H), 5.06 (brs, 1H), 4.63 (s, 2H), 4.28-4.17 (m, 2H), 4.06 (td, J= 11.2, 3.4 Hz, 1H), 3.97-3.81 (m, 1H), 3.76 (td, J = 11.2, 3.4 Hz, 1H), 2.82-2.62 (m, 4H), 2.08-1.81 (m, 3H), 1.59-1.46 (m, 1H), 1.40-1.21 (m, 2H).

Example 96: 1-(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1thiazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,5- naphthyridin-2-one

96

Prepared as described in example 60e using 3-(7-methoxy-2-oxo-1,2-dihydro-1,5- naphthyridin-1-yl)propanal (prepared according to WO2011148962) (63.2 mg, 0.15 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]thiazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium chloride 61b (144.6 mg, 0.35 mmol) to afford 1-(3-{[(3aS,6S,7aS)-2- oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]thiazin-6-yl}-octahy dro-1,3-benzoxazol-6- yl]amino}propyl)-7-methoxy-1,2-dihydro-1,5-naphthyridin-2-on e 96 as a white solid (10 mg, 10%). LC-MS (Method A): 537.2 [M+H] ⁺ , RT: 2.44 min. ¹ H NMR (Method C) (CDC ): δ ppm 10.98 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 9.7 Hz, 1H), 7.79, d, J = 8.3 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.29, d, J = 8.3 Hz, 1H), 6.68 (d, J = 9.7 Hz, 1H), 4.31 (t, J = 7.2 Hz, 2H), 4.08 (td, J = 11.8, 3.3 Hz, 1H), 4.00 (s, 3H), 3.79-3.73 (m, 1H), 3.57 (d, J = 14.9 Hz, 1H), 3.53 (d, J = 14.9 Hz, 1H), 3.00-2.94 (m, 1H), 2.59-2.53 (m, 1H), 2.04-1.99 (m, 2H), 1.82-1.71 (m, 2H), 1.54-1.42 (m, 2H), 1.33-1.24 (m, 3H). Example 97:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-yl1amino)ethyl)-7-r2-(morpholin-4-yl)ethoxy1 -1 ,2- dih droquinolin-2-one

a)1-(2,2-diethoxyethyl)-7-[2-(morpholin-4-yl)ethoxy]-1 ,2-dihydroquinolin-2-one 97a

K2CO3 (450 mg, 3.25 mmol) was added to a solution of 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2- dihydroquinolin-2-one 9d (300 mg, 1.08 mmol) and 4-(2-bromoethyl)morpholine (800 mg, 4.12 mmol) in NMP (3 mL) and heated at 90 °C under nitrogen for 17 h. Water and EtOAc were added and the resulting layers separated. The aqueous phase was further extracted with EtOAc and 20% MeOH/DCM. Organic extracts were combined with the original organic layer and concentrated under reduced pressure to afford a brown residue. The crude product was purified via silica gel chromatography using a gradient of 0-100% EtOAc/petroleum ether followed by 0-15% MeOH/EtOAc. Clean product fractions were collected and concentrated under reduced pressure to afford 1-(2,2-diethoxyethyl)-7-[2- (morpholin-4-yl)ethoxy]-1 ,2-dihydroquinolin-2-one 97a (269 mg, 63%) as a clear oil. LC-MS (Method A) 391.2 [M+H] ⁺ ; RT 1.71 min.

b) 2-{7-[2-(morpholin-4-yl)ethoxy]-2-oxo-1 ,2-dihydroquinolin-1-yl}acetaldehyde 97b

Aqueous HCI (1 M, 10 mL, 10 mmol) was added to a solution of 1-(2,2-diethoxyethyl)-7-[2- (morpholin-4-yl)ethoxy]-1 ,2-dihydroquinolin-2-one 97a (260 mg, 0.67 mmol) in THF (10 mL) and stirred at room temperature for 7 h. The reaction mixture was adjusted to pH 7-8 using saturated aqueous Na2C03 and concentrated under reduced pressure to afford a yellow residue. This residue was diluted with EtOAc (100 mL), stirred for 1 h at room temperature and the resulting solid filtered. The filtrate was collected and concentrated under reduced pressure to afford 2-{7-[2-(morpholin-4-yl)ethoxy]-2-oxo-1 ,2-dihydroquinolin-1- yl}acetaldehyde 97b (109 mg, 41 %, 80% purity) as a light brown gum and used without further purification. LC-MS (Method A) 317.2 [M+H] ⁺ ; RT 1.36 min. c) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-[2-(morpholin-4-yl)ethoxy] -1 ,2-dihydroquinolin-2-one 97 Prepared as described in example 60e using 2-{7-[2-(morpholin-4-yl)ethoxy]-2-oxo-1 ,2- dihydroquinolin-1-yl}acetaldehyde 97b (105.0 mg, 0.27 mmol) and (3aS,6S,7aS)-2-oxo-3- {3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (11 1.1 mg, 0.27 mmol). The reaction mixture was quenched with sat. aq. Na ₂ CC>3 (5 mL) and mixed with 20% MeOH in DCM (100 mL) before passing through a SPE phase separator. The organic filtrate was concentrated under reduced pressure and the resulting residue purified via silica gel chromatography using 0-100% EtOAC/DCM, 0- 20% MeOH/EtOAc and then 0-20% NH ₃ in MeOH/EtOAc. Clean product fractions were concentrated under reduced pressure with ether azeotroping to afford 1-(2-{[(3aS,6S,7aS)- 2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-7-[2-(morpholin-4-yl)ethoxy]-1 ,2-dihydroquinolin-2-one 97 (9.4 mg, 5%) as an off white solid. LC-MS (Method A) 605.3 [M+H] ⁺ , RT 1.66 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 7.82 (d, J = 9.3 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.42 (d, J = 8.4, 1 H), 7.16 (d, J = 8.6, 1 H), 7.06-7.02 (m, 1 H), 6.91 (dd, J = 8.7, 2.2 Hz, 1 H), 6.42 (d, J = 9.3 Hz, 1 H), 4.62 (s, 2H), 4.20-4.31 (m, 3H), 4.09-3.98 (m, 2H), 3.80-3.70 (m, 1 H), 3.65-3.52 (m, 3H), 3.43-3.24 (m, 4H), 2.85-2.76 (m, 3H), 2.76-2.72 (m, 2H), 2.46-2.36 (m, 2H), 2.04-1.96 (m, 1 H), 1.56-1.40 (m, 1 H), 1.39-1.28 (m, 1 H), 1.24-1.20 (m, 2H).

Example 98: 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(difluoromethoxy)-1 ,2-dihydro-1 ,5- na hthyridin-2-one

a) 7-(difluoromethoxy)-1-(2,2-dimethoxyethyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 98a

2-Bromo-1 , 1-dimethoxypropane (0.08 mL, 0.7 mmol) was added to a stirred solution of 7- (difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 93b (1 15 mg, 0.54 mmol) and CS2CO3 (230 mg, 0.70 mmol) in DMF (3 mL) and heated to 80 ^° C for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (20 mL) and extracted with Et20 (3 x 40 mL). Organic extracts were combined, dried (MgSCU) and concentrated under reduced pressure to afford crude product. Crude product was purified by chromatography using a gradient of 0-60% EtOAc/DCM. Clean product fractions were collected and concentrated under reduced pressure to afford 7-(difluoromethoxy)-1-(2,2-dimethoxyethyl)- 1 ,2-dihydro-1 ,5-naphthyridin-2-one 98a as a white solid (74.2 mg, 46%). LCMS (Method A): 301.1 [M+H] ⁺ , RT: 2.26 min. b) 2-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydro-1 ,5-naphthyridin-1-yl]acetaldehyde 98b

3M HCI (0.57 mL, 1.71 mmol) was added to a solution of 7-(difluoromethoxy)-1-(2,2- dimethoxyethyl)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 98a (74.2 mg, 0.25 mmol) in THF (5 mL) and heated to 60 °C for 2 h under nitrogen. The reaction mixture was allowed to cool to room temperature and quenched with solid NaHC03 to pH 8 and diluted with H2O (20 mL). Volatile organic solvent was removed under reduced pressure and the resulting aqueous extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried (MgS04) and concentrated under reduced pressure to afford 2-[7-(difluoromethoxy)-2-oxo-

1.2- dihydro-1 ,5-naphthyridin-1-yl]acetaldehyde 98b as a white solid (53.9 mg, 86%). LC-MS (Method A): 255.0 [M+H] ⁺ , RT: 1.60 min. c) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

1.3- benzoxazol-6-yl]amino}ethyl)-7-(difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 98 Prepared as described in Example 60e using 2-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydro-1 ,5- naphthyridin-1-yl]acetaldehyde 98b (53.9 mg, 0.21 mmol) and (3aS,6S,7aS)-2-oxo-3-{3- oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (97.6 mg, 0.23 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7- (difluoromethoxy)-1 ,2-dihydro-1 ,5-naphthyridin-2-one 98 as a white solid (84.3 mg, 73%). LC-MS (Method A): 543.2 [M+H] ⁺ , RT: 2.23 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.23 (s, 1 H), 8.46 (d, 2.2 Hz, 1 H), 7.96 (d, 9.7 Hz, 1 H), 7.94 (d, 2.3 Hz, 1 H), 7.52 (t, 73.2 Hz, 1 H), 7.41 (d, 8.3 Hz, 1 H), 7.16 (d, 8.7 Hz, 1 H), 6.85 (9.83 Hz, d, 1 H), 4.62 (s, 2H), 4.25 (t, 6.9 Hz, 2H), 4.02 (td, 11.9, 3.3 Hz, 1 H), 3.73 (d, 1 1.5, 3.3 Hz, 1 H), 2.85-2.78 (m, 2H), 2.77-2.71 (m, 2H), 2.42-2.38 (m, 1 H), 2.13 (br. S, 1 H), 1.96-1.92 (m, 1 H), 1.42 (q, 1 1.3 Hz, 1 H), 1.35-1.26 (m, 1 H), 1.23-1.13 (m, 1 H). Example 99: 1 -(3-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl}-octahydro-1 ,3-benzoxazol-6-yl1amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,5- naphthyridin-2-one

Prepared as described in example 60e using 3-(7-methoxy-2-oxo-1 ,2-dihydro-1 ,5- naphthyridin-1-yl)propanal (prepared according to WO201 1 148962) (73 mg, 0.31 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d (144.6 mg, 0.35 mmol) to afford 1-(3- {[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-yl]amino}propyl)-7-methoxy-1 ,2-dihydro-1 ,5-naphthyridin-2-one 99 as a white solid (10.6 mg, 6%). LC-MS (Method A): 521.2 [M+H] ⁺ , RT: 2.10 min. ¹ H NMR (Method C) (CDC ): δ ppm 8.31 (d, 2.31 Hz, 1 H), 7.88 (d, 9.8 Hz, 1 H), 7.34-7.30 (m, 2H), 7.20 (d, 2.3 Hz, 1 H), 6.77 (d, 9.8 Hz, 1 H), 4.64 (s, 2H), 4.41-4.31 (m, 2H), 3.99 (s, 3H), 3.96 (td, 1 1.2, 3.2 Hz, 1 H), 3.82 (td, 1 1.2, 3.3 Hz, 1 H), 2.82-2.77 (m, 1 H), 2.73-2.66 (m, 3H), 2.64-2.60 (m, 1 H), 2.18-2.14 (m, 1 H), 1.99-1.94 (m, 2H), 1.58 (q, 1 1.2 Hz, 2H), 1.41-1.37 (m, 1 H).

Example 100:- (3aS,6S,7aS)-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41oxazin-6-ylV 6-r(2-f6- oxo-5H,6H-pyridor2,3-blpyrazin-5-yl)ethyl)amino1-octahydro-1 ,3-benzoxazol-2-one

a) 3-chloro-N-(2,2-dimethoxyethyl)pyrazin-2-amine 110a

A solution of 2,3-dichloropyrazine (2.5 g, 16.78 mmol), 2,2-dimethoxyethan-1-amine (2.34 ml_, 17.78 mmol) and K ₂ C0 ₃ (4.64 g, 33.56 mmol) in DMF (50 ml_) was heated to 60 ^° C for 24 h. 2,2-dimethoxyethan-1-amine (2.34 ml_, 17.78 mmol) was added and heating continued for a further 24 h. After cooling, H2O (50 ml_) was added and the mixture extracted with diethyl ether (3 x 20 ml_), dried over MgSCU and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-20% EtOAc in pet ether to give 3-chloro-N-(2,2-dimethoxyethyl)pyrazin-2-amine 100a (1.46 g, 40%) as a colourless oil. LC-MS (Method A) 186.0 [M-OMe] ⁺ ; RT 2.13 min. b) Butyl (2E)-3-{3-[(2,2-dimethoxyethyl)amino]pyrazin-2-yl}prop-2-eno ate 100b

A solution of 3-chloro-N-(2,2-dimethoxyethyl)pyrazin-2-amine 100a (1.3 g, 5.97 mmol), Pd(OAc) ₂ (134 mg, 0.60 mmol), di-tert-butyl(3-phenylphenyl)phosphane (267 mg, 0.90 mmol), butyl prop-2-enoate (4.7 ml_, 33.10 mmol) in triethylamine (18 ml_) in a microwave vial was irradiated in the microwave at 150 ^° C for 90 m. After cooling the reaction was concentrated under reduced pressure and purified by silica gel chromatography using 0- 20% EtOAc in pet ether to give butyl (2E)-3-{3-[(2,2-dimethoxyethyl)amino]pyrazin-2- yl}prop-2-enoate 100b (910 mg, 49%) as a yellow solid. LC-MS (Method A) 310.0 [M+H] ⁺ , RT 3.15 min.

c) 5-(2,2-dimethoxyethyl)-5H,6H-pyrido[2,3-b]pyrazin-6-one 100c

A solution of butyl (2E)-3-{3-[(2,2-dimethoxyethyl)amino] pyrazin-2-yl}prop-2-enoate 100b (910 mg, 2.94 mmol) followed by sodium hydride (60% in mineral oil) (71 mg, 1.47 mmol) in dry ethanol (50 ml_) and heated to 80 ^° C for 1 h. After this time the reaction was complete, quenched with ammonium chloride and extracted with EtOAc to give a yellow solid as 5- (2,2-dimethoxyethyl)-5H,6H-pyrido[2,3-b]pyrazin-6-one 100c (691 mg, 100%). LC-MS (Method C) 204.0 [M+H] ⁺ , RT 1.70 min. d) 2-{6-oxo-5H,6H-pyrido[2,3-b]pyrazin-5-yl}acetaldehyde 100d

A solution of 5-(2,2-dimethoxyethyl)-5H,6H-pyrido[2,3-b]pyrazin-6-one 100c (240 mg, 1.02 mmol) and HCI in MeOH (4M, 5 mL) in THF (5mL) was stirred at room temperature for 2 h. H2O (20 mL) was added and the mixture extracted with EtOAc (3 x 20 mL), dried over MgSCU and concentrated under reduced pressure to give 2-{6-oxo-5H,6H-pyrido[2,3- b]pyrazin-5-yl}acetaldehyde 100d (110 mg, 57%) as a white solid. ¹ H NMR (Method C) (CDC ): δ ppm 9.75 (s, 1 H), 8.53 (d, J = 2.4 Hz, 1 H), 8.45 (d, J = 2.4 Hz, 1 H), 7.98 (d, J = 9.8 Hz, 1 H), 7.04 (d, J = 9.8 Hz, 1 H), 5.35 (s, 2H). e) (3aS,6S,7aS)-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-6-[(2-{6-oxo-5H,6H- pyrido[2,3-b]pyrazin-5-yl}ethyl)amino]-octahydro-1 ,3-benzoxazol-2-one 100

Prepared as described in Example 60e from 2-{6-oxo-5H,6H-pyrido[2,3-b]pyrazin-5- yl}acetaldehyde 100d (50 mg, 0.26 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (121 mg, 0.26 mmol). Purified by silica gel chromatography using 0-20% MeOH in EtOAc. The isolated residue was then dissolved in DCM (1 mL) and triturated with diethyl ether (3 mL) to give (3aS,6S,7aS)-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-6-[(2-{6-oxo- 5H,6H-pyrido[2,3-b]pyrazin-5-yl}ethyl)amino]-octahydro-1 ,3-benzoxazol-2-one 100 (12 mg, 10%) as a white solid. LC-MS (Method A) 478.2 [M+H] ⁺ , RT 1.94 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.24 (s, 1 H), 8.71 (s, 1 H), 8.63 - 8.58 (m, 1 H), 8.03 (d, J = 9.7 Hz, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 9.7 Hz, 1 H), 4.62 (s, 2H), 4.43 (s, 2H), 4.06 (t, J = 1 1.3 Hz, 1 H), 3.74 (m, 1 H), 2.90-2.60 (m, 4H), 2.59 - 2.45 (m, 1 H), 1.99 (m, 1 H), 1.46 (m, 1 H), 1.33 (m, 1 H), 1.24 (m, 1 H).

Example 101 :- 1 -(2-fr(3aS,6S ,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41oxazin-6 yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)ethyl)-7-(difluoromethoxy)-1 ,2-dihydro quinolin-2-one

a) 1 -(2,2-diethoxyethyl)-7-(difluoromethoxy)-1 ,2-dihydroquinolin-2-one 101 a

1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d (1.1 g, 3.97mmol), sodium chlorodifluoroacetate (1.21 g, 7.93 mmol) and K2CO3 (0.66 g, 4.76 mmol) were added to DMF (25 mL)/ H ₂ 0 (2.5 mL) and the mixture heated at 100 °C for 7 h. A further sodium chlorodifluoroacetate (1.2 1 g, 7.93 mmol) and potassium carbonate (0.66 g, 4.76 mmol) were added and the mixture further heated at 100 °C for 17 h. The mixture was quenched with H2O (100 mL), extracted with Et20 (2 x 100 mL), dried over MgSCU and evaporated to afford a yellow liquid. Purification via silica gel chromatography using 60% Et20 in petroleum ether gave

1 -(2,2-diethoxyethyl)-7-(difluoromethoxy)-1 ,2-dihydroquinolin-2-one 101 a (618 mg, 48% yield) as a clear liquid. ¹ H NMR (Method C) (CDC ): δ ppm 7.67 (d, J = 9.3 Hz, 1 H), 7.54 - 7.48 (m, 2H), 6.99 (dd, J = 8.5, 2.2 Hz, 1 H), 6.66 (d, J = 9.3 Hz, 1 H), 6.59 (t, J = 73.2 Hz, 1 H), 4.80 (t, J = 5.3 Hz, 1 H), 4.36 (d, J = 5.3 Hz, 2H), 3.81 - 3.74 (m, 2H), 3.57 - 3.48 (m, 2H), 1.12 (t, J = 7.0 Hz, 6H). b) 2-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydroquinolin-1 -yl]acetaldehyde 101 b

1 -(2,2-diethoxyethyl)-7-(difluoromethoxy)-1 ,2-dihydroquinolin-2-one 101 a (0.6 g, 1.83 mmol) was added to THF (5 mL) and HCI (3.0 N, 5 mL, 1.83 mmol) and the mixture was stirred at 60 °C for 1 h. The mixture was quenched with H2O (50 mL), extracted with Et20 (2 x 50 mL), dried (MgS04) and solvent evaporated to afford a white solid. DCM and petroleum ether were added and the DCM evaporated to afford a white precipitate which was filtered and dried to

give 2-[7-(difluoromethoxy)-2-oxo-1 ,2-dihydroquinolin-1 -yl]acetaldehyde 101 b (370 mg, 80% yield) as a white solid. LC-MS (Method A) 254.0 [M+H] ⁺ ; RT 2.04 min. ¹ H NMR (Method C) (CDCb): δ ppm 9.74 (s, 1 H), 7.74 (d, J = 9.3 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.04 (dd, J = 8.5, 2.1 Hz, 1 H), 6.74 - 6.66 (m, 2H), 6.57 (t, J = 73.0 Hz, 1 H), 5.14 (s, 2H). c) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6

yl}-octahydro-1,3-benzoxazol-6-yl]amino}ethyl)-7-(difluor omethoxy)-1,2-dihydro

quinolin-2-one 101

Prepared as described in example 60e using

2-[7-(difluoromethoxy)-2-oxo-1,2-dihydroquinolin-1-yl]acetal dehyde 101b (91 mg, 0.36 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}- octahydro-1,3-benzoxazol-6-aminiumtrifluoroacetate 60d (150 mg, 0.36 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6yl}-octahydro-1,3-b enzoxazol-6-yl]amino}ethyl)-7-(difluoromethoxy)-1,2-dihydro quinolin-2-one 101 (95 mg, 49%). LC-MS (Method A) 542.2 [M+H] ⁺ ; RT 2.52 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.26 (s, 1H), 7.92 (d, J= 9.2 Hz, 1H), 7.80 (d, J= 8.7 Hz, 1H), 7.45 (t, J= 62 Hz, 1H), 7.45-7.39 (m, 2H), 7.17 (d, J= 8.5 Hz, 1H), 7.10 (d, J= 2.3 Hz, 1H), 6.59 (d, J= 9.4 Hz, 1H), 4.62 (s, 2H), 4.32-4.24 (m, 2H), 4.06 (td, J= 11.2, 3.4 Hz, 1H), 3.76 (td, J= 11.2, 3.4 Hz, 1H), , 2.91-2.75 (m, 4H), 2.45-2.42 (m, 2H), 2.06-1.94 (m, 1H), 1.40-1.21 (m, 3H).

Example 102:- 1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl -octahvdro-1,3-benzoxazol-6-vnamino)ethyl)-7-methoxy-1,2-dih ydroquinolin-2-one

Prepared as described in example 60e using 2-(7-methoxy-2-oxo-1,2-dihydroquinolin-1- yl)acetaldehyde (WO2008009700)(78 mg, 0.36 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-octahydro-1,3-benzox azol-6-aminiumtrifluoro acetate 60d (150 mg, 0.36 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-methoxy-1 ,2- dihydroquinolin-2-one 102 (97 mg, 51%). LC-MS (Method A) 506.1 [M+H] ⁺ ; RT2.21 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.23 (s, 1H), 7.82 (d, J= 9.4 Hz, 1H), 7.66 (d, J= 8.7 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.18 (d, J = 8.5 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 6.92 (dd, J = 8.7 Hz, 2.3 Hz, 1 H), 6.43 (d, J = 9.4 Hz, 1 H), 4.62 (s, 2H), 4.32-4.24 (m, 2H), 4.06 (td, J = 1 1.2, 3.4 Hz, 1 H), 3.91 (s, 3H), 3.76 (td, J = 1 1.2, 3.4 Hz, 1 H), 2.91-2.76 (m, 4H), 2.45-2.42 (m, 2H), 2.06-1.94 (m, 1 H), 1.40-1.21 (m, 3H).

Example 103:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdro-1 ,3-benzoxazol-6-vnamino)ethyl)-7-(azetidin-3-yloxy)-1 ,2- dih droquinolin-2-one

tert-butyl 3-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1- carboxylate 103a a) 1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d (0.20 g, 0.72 mmol) , tert- butyl 3-bromoazetidine-1-carboxylate (0.34 g, 1.44 mmol) and K2CO3 (0.30 g, 2.16 mmol) were mixed with NMP (3 mL) and heated to 90 °C for 17 h under nitrogen. The reaction mixture was allowed to cool to room temperature, partitioned between EtOAc (50 mL) and H2O (50 mL) and the organic phase separated. The aqueous phase was further extracted with EtOAc (2 x 50 mL) and the extracts combined with the original organic layer and concentrated under reduced pressure to give a residue. The residue was partitioned between Et20 (30 mL) and H2O (30 mL) and the layers separated. The organic layer was further washed with H2O (2 x 30 mL), brine (30 mL) and concentrated under reduced pressure. The residue was dissolved in DCM and H2O and passed through a SPE phase separator. The DCM filtrate was collected and concentrated under reduced pressure to give a clear oil. Purification via silica gel chromatography using 0-100% EtOAc /pet ether gave tert-butyl 3-{[1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1- carboxylate 103a (210.0 mg, 67%) as a white gum. LC-MS (Method A) 387.2 [M-OEt] ⁺ , RT 3.32 min b) tert-butyl 3-{[2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103b

HCI (1 M in H ₂ 0, 1.5 ml_, 0.49 mmol) was added to a solution of tert-butyl 3-{[1-(2,2- diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103a (210 mg, 0.49 mmol) in THF (4.5 ml_) and. and stirred at room temperature for 2 h then left standing with no stirring for 90 h. The pH of the reaction mixture was adjusted to 8 using sat. aqueous NaHCC>3 and then the reaction mixture was extracted with EtOAc (2 x 50 ml_). Organic extracts were combined, washed with brine and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography using 0-100% EtOAc/petroleum ether. Clean fractions were combined and concentrated under reduced pressure with ether azeotroping to afford tert-butyl 3-{[2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103b (86 mg, 49%) as a white solid. LC- MS (Method A) 359.2 [M+H] ⁺ , RT 2.63 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 9.69 (s, 1 H), 7.92 (d, J = 9.4 Hz, 1 H), 7.70 (d, J = 8.6 Hz, 1 H), 6.81 (dd, J = 8.6, 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 6.49 (d, J = 9.4 Hz, 1 H), 5.26 (s, 2H), 5.16-5.1 1 (m, 1 H), 4.40-4.27 (m, 2H), 3.85-3.72 (m, 2H), 1.39 (s, 9H). c) tert-butyl 3-{[1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b ][1 ,4]oxazin-6-yl}- octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1- carboxylate 103c

Triethylamine (0.19 ml_, 1.35 mmol) was added to a solution of tert-butyl 3-{[2-oxo-1-(2- oxoethyl)-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103b (80 mg, 0.20 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3- benzoxazol-6-aminium trifluoroacetate 60d (132.1 mg, 0.22 mmol) in DCM (10ml_) in the presence of . 3A molecular sieves and stirred at room temperature for 10 min under nitrogen. NaBH(OAc)3 (280. mg, 1.32 mmol) was added to the reaction mixture and stirred for a further 17 h. The reaction mixture was diluted with DCM (20 ml_) and MeOH (1 ml_). Sat. aq. NaHCOs was added adjusting the pH to 8, then the mixture passed through a SPE phase separator. The aqueous phase was further extracted with DCM (20 ml_) and the extracts passed through a SPE phase separator. The combined organic filtrates were concentrated under reduced pressure to give a crude residue (175 mg). The residue was purified via silica gel chromatography using 0-100% EtOAc/pet ether and 0-20% MeOH/EtOAc. The clean fractions were collected and concentrated under reduced pressure with Et ₂ 0 azeotroping to afford tert-butyl 3-{[1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo

1.2- dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103c (105.0 mg, 80%) as a white solid. LC-MS (Method A) 647.4 [M+H] ⁺ , RT 2.95 min. d) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

1.3- benzoxazol-6-yl]amino}ethyl)-7-(azetidin-3-yloxy)-1 ,2-dihydroquinolin-2-one 103

TFA (0.33 mL, 4.25 mmol) was added to a solution of tert-butyl 3-{[1-(2-{[(3aS,6S,7aS)-2- oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6- yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl]oxy}azetidine-1-carboxylate 103c (58.9 mg, 0.09 mmol) in DCM (5 mL) and the reaction mixture stirred at room temperature for 3.5 h and allowed to stand for 17 h. The reaction mixture was concentrated under reduced pressure and the resulting residue dissolved in DCM (75 mL) and MeOH (1 mL). The pH was adjusted to 8 using sat. aq. NaHCC>3 and the organic layer passed through a SPE phase separator. The aqueous phase was further extracted with DCM (75 mL) and MeOH (1 mL) and the separated organic filtrates were combined and concentrated under reduced pressure to afford a white solid. Product remained in the aqueous phase so product was further extracted with 20% MeOH/DCM (3 x 50 mL) and passed through a SPE phase separator. All organic filtrates were combined with the isolated white solid and concentrated under reduced pressure. The crude material was purified via silica gel chromatography using 0-20% MeOH/DCM, NH ₃ in 0-20% MeOH/DCM and then via prep. HPLC (Method B) 0.1 % NH ₃ in MeCN/H ₂ 0 to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo- 2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7- (azetidin-3-yloxy)-1 ,2-dihydroquinolin-2-one 103 (5.0 mg, 10%). LC-MS (Method B) 547.2 [M+H] ⁺ , RT 6.33 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 7.82 (d, J = 9.5 Hz, 1 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 8.6 Hz, 1 H), 6.90-6.83 (m, 1 H), 6.80-6.74 (d, J = 8.5 Hz, 1 H), 6.43 (d, J = 9.5 Hz, 1 H), 5.21-5.12 (m, 1 H), 4.62 (s, 2H), 4.24 (t, J = 7.5 Hz, 2H), 4.09-4.01 (m, 1 H), 3.88-3.79 (m, 2H), 3.79-3.70 (m, 1 H), 3.59-3.52 (m, 2H), 2.86-2.68 (m, 5H), 2.05-1.94 (m, 1 H), 1.48 (d, J = 1 1.3 Hz, 1 H), 1.38-1.17 (m, 3H).

Example 104:- 1 -(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,41 oxazin-6- yl)-octahvdrc-1 ,3-benzoxazol-6-yl1amino}ethyl)-7-(1 -methyl-1 H-pyrazol-3-yl)-1 ,2- dihydroquinolin-2-one

a) 1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl trifluoromethanesulfonate 104a

1-(2,2-diethoxyethyl)-7-hydroxy-1 ,2-dihydroquinolin-2-one 9d (1.5 g, 5.41 mmol) was dissolved in DCM (80 ml_) and N-phenyl bis-trifluoromethane sulfonimide (1.9 g, 5.41 mmol) and triethylamine (0.98 ml_, 7.03 mmol) added. The mixture was stirred for 17 h and then evaporated to 80% of the initial volume. This was quenched with H2O (100 ml_), extracted with petroleum ether (2 x 50 ml_), dried (MgSCU) and the solvent evaporated to afford a clear gum. This was purified by silica gel chromatography, eluting with Et20 and then 50% Et20 :50 % EtOAc to afford a yellow gum. To this was added Et20 and the mixture rapidly stirred, filtered and dried to give 1-(2,2-diethoxyethyl)-2-oxo-1 ,2- dihydroquinolin-7-yl trifluoromethanesulfonate 104a (1.5 g, 68%) as a white solid. ¹ H NMR (Method C) (CDCI3): δ ppm 7.71 (d, J = 9.3 Hz, 1 H), 7.68 (d, J = 2.2 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.13 (dd, J = 8.5, 2.2 Hz, 1 H), 6.74 (d, J = 9.3 Hz, 1 H), 4.80 (t, J = 5.3 Hz, 1 H), 4.35 (d, J = 5.3 Hz, 2H), 3.81 - 3.75 (m, 2H), 3.56 - 3.49 (m, 2H), 1.12 (t, J = 7.0 Hz, 6H). b) 1 -(2,2-diethoxyethyl)-7-(1 -methyl-1 H-pyrazol-3-yl)-1 ,2-dihydroquinolin-2-one 104b

1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinolin-7-yl trifluoromethanesulfonate 104a (500 mg, 1.22 mmol) was dissolved in THF (30 ml_)/water (7 ml_) and to this was added 1 -methyl-3-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (305 mg, 1.47 mmol), XPhos Pd G2 (48 mg, 0.06 mmol) and K3PO4 (518 mg, 2.44 mmol) The mixture was stirred at 40 °C for 1 h then at room temperature over 72 h. The reaction was quenched with H2O (50 ml_), extracted with Et20 (2 x 50 ml_), dried (MgSCU) and the solvent evaporated to afford a yellow gum. This was purified via column chromatography, eluting with Et20 and then EtOAc to afford 1 -(2,2-diethoxyethyl)-7-(1 -methyl-1 H-pyrazol-3-yl)-1 ,2-dihydroquinolin-2-one 104b (280 mg, 64%) as a yellow gum which solidified on standing. LC-MS (Method A) 342.2 [M+H] ⁺ ; RT 2.44 min; ¹ H NMR (Method C) (CDC ): δ ppm 7.86 (s, 2H), 7.76 (s, 1H), 7.68 (d, J= 9.2 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 9.2 Hz, 1 H), 4.82 (t, J = 5.3 Hz, 1 H), 4.45 (d, J = 5.3 Hz, 2H), 3.98 (s, 3H), 3.83 - 3.76 (m, 2H), 3.58 - 3.50 (m, 2H), 1.12 (t, J= 7.0 Hz, 6H). c) 2-[7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydroquinolin-1- yl]acetaldehyde 104c

1- (2,2-diethoxyethyl)-7-(1-methyl-1H-pyrazol-3-yl)-1,2-dihydro quinolin-2-one 104b (280 mg, 0.82 mmol) was stirred with aq.HCI (3N, 5.0 mL) in THF (5 mL) at room temperature for 2 h. The reaction was quenched with H2O (50 mL), extracted with EtOAc (2 x 50 mL), dried (MgSC) and concentrated to give

2- [7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydroquinolin-1-yl ]acetaldehyde 104c (100 mg, 45%) as a white solid which was used with no further purification. LC-MS (Method A) 268.0 [M+H] ⁺ ; RT 1.77 min; ¹ H NMR (Method C) (CDCb): δ ppm 9.71 (s, 1H), 7.79 (s, 1H), 7.74 (d, J= 9.2 Hz, 1H), 7.68 (s, 1H), 7.59 (d, J= 8.5 Hz, 1H), 7.36 (d, J= 8.5, 1H), 7.06 (s, 1H), 6.71 (d, J= 9.2 Hz, 1H), 5.18 (s, 2H), 3.97 (s, 3H). d) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin-6-yl}-octahydro- 1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(1-methyl-1 H-pyrazol-3-yl)-1 ,2-dihydroquinolin-2-one 104

Prepared as described in example 60e using (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (150 mg, 0.36 mmol) and

2- [7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydroquinolin-1-yl ]acetaldehyde 104c (96 mg, 0.36 mmol) to give 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1, 4]oxazin- 6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-7-(1-methyl-1 H-pyrazol-3-yl)-1 ,2- dihydroquinolin-2-one 104 (10 mg, 5%). LC-MS (Method A) 556.2 [M+H] ⁺ ; RT 2.16 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.24 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.72-7.67 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 9.3 Hz, 1H), 4.62 (s, 2H), 4.35 (s, 2H), 4.07 (d, J = 12.4 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 1H), 3.40 (m, 1H), 2.80 (d, J = 43.8 Hz, 4H), 1.99 (s, 1H), 1.47 (s, 1H), 1.28 (d, J = 43.4 Hz, 2H), 1.04 (d, J = 6.0 Hz, 1H).

Example 105:-

3- r6-(fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-biri,4 1oxazin-6-ylVoctahvdro- 1,3-benzoxazol-6-vnamino)methyl)pyridin-2-vnbenzonitrile

105

Prepared as described in example 60e using 3-(6-formylpyridin-2-yl)benzonitrile (121.63mg, 0.58 mmol) and (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazi n-6-yl}- octahydro-1,3-benzoxazol-6-aminium trifluoroacetate 60d (244.4 mg, 0.58 mmol) to afford 3-[6-({[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1,3- benzoxazol-6-yl]amino}methyl)pyridin-2-yl]benzonitrile 105 (28 mg, , 10% yield) . LC-MS (Method A) 497.1 [M+H] ⁺ ; RT 2.59 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm δ 11.26 (s, 1H), 8.79-8.71 (m, 1H), 8.57 (dt, J= 8.0, 1.5 Hz, 1H), 8.17 (d, J= 7.9 Hz, 1H), 8.07 (t, J = 7.8 Hz, 1H), 7.98 (dt, J= 7.7, 1.4 Hz, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.45 (d, J= 8.6 Hz, 1H), 7.22 (d, J= 8.6 Hz, 1H), 4.65 (s, 2H), 4.63-4.49 (m, 2H), 4.17 (td, J = 11.8, 3.4 Hz, 1 H), 3.86 (td, J = 11.3, 3.3 Hz, 1 H), 3.61 - 3.48 (m, 1 H), 3.00 - 2.90 (m, 1H), 2.84 - 2.73 (m, 1H), 2.38-2.27 (m, 1H), 2.12 - 1.88 (m, 1H), 1.69 (q, J= 12.9, 12.3 Hz, 1H), 1.54- 1.39 (m, 1H).

Example 106:-. 1-(2-fr(3aR,6R,7aR)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-

6-yl)-octahvdro-1,3-benzoxazol-6-vnamino)ethyl)-2-oxo-1,2 -dihydroquinoline-6- carbonitrile

106

Prepared as described in example 60e using (3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 74a (121 mg, 0.39 mmol) and 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-6-carbonitrile 107c (80 mg, 0.38 mmol) to give 1-(2-{[(3aR,6R,7aR)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline- 6-carbonitrile 106 (40 mg, 21%). LC-MS (Method A) 501.1 [M+H] ⁺ ; RT 2.30 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 11.22 (s, 1H), 8.31 (d, J= 2.2 Hz, 1H), 8.02 (dd, J= 8.9, 2.2 Hz, 1H), 7.97 (d, J= 9.5 Hz, 1H), 7.80 (d, J= 8.9 Hz, 1H), 7.42 (d, J= 8.7 Hz, 1H), 7.17 (d, J= 8.7 Hz, 1H), 6.76 (d, J= 9.5 Hz, 1H), 4.63 (s, 2H), 4.30 (t, J= 7.3 Hz, 2H), 4.04 (td, J = 11.8, 3.3 Hz, 1H), 3.83-3.66 (m, 1H), 2.88-2.69 (m, 4H), 2.45-2.31 (m, 1H), 2.03-1.85 (m, 1H), 1.46 (q, J = 11.1 Hz, 1H), 1.39-1.12 (m, 3H).

Example 107: 1-(2-fr(3aS,6S,7aS)-2-oxo-3-f3-oxo-2H,3H,4H-pyridor3,2-bin,4 1oxazin-6- yl)-octahvdro-1,3-benzoxazol-6-vnamino)ethyl)-2-oxo-1,2-dihy droquinoline-6- carbonitrile

107 a) 6-bromo-1 -(2,2-diethoxyethyl)-1 ,2-dihydroquinolin-2-one 107a

6-Bromo-1 ,2-dihydroquinolin-2-one (1.0 g, 4.46 mmol), Cs ₂ C0 ₃ (1.8, 5.89 mmol) and bromoacetaldehyde diethyl acetal (0.74 ml_, 4.79 mmol) were dissolved in DMF (10 ml_) and heated in the microwave at 100 °C for 3 h. The reaction was quenched with H2O (50 ml_) and extracted with Et20 (2 x 50 ml_). The organic extracts were combined, dried (MgS0 ₄ ), filtered and concentrated under reduced pressure to afford a yellow gum. This was purified via column chromatography eluting with 40-100% EtOAc in petroleum ether to afford 6-bromo-1 -(2,2-diethoxyethyl)-1 ,2-dihydroquinolin-2-one as yellow oil (850 mg, 56%). LC-MS (Method A) 295.9 [M-OEt] ⁺ ; RT 2.78 min. b) 1-(2,2-diethoxyethyl)-2-oxo-1 ,2-dihydroquinoline-6-carbonitrile 107b

A solution of 6-bromo-1 -(2,2-diethoxyethyl)-1 ,2-dihydroquinolin-2-one 107a (886 mg, 2.61 mmol), zinc cyanide (183 mg, 1.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) in DMF (4 ml_) was heated in a microwave reactor at 100 °C for 90 min. The reaction was diluted with H2O (30 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic extracts were dried (MgS0 ₄ ), filtered and concentrated under reduced pressure to afford crude product as an oil which solidified on standing. Crude product was purified via column chromatography using 60% petroleum ether in EtOAc to afford 1-(2,2- diethoxyethyl)-2-oxo-1 ,2-dihydroquinoline-6-carbonitrile 107b (210mg, 28%) as a white solid. Product was used directly without further purification. c)2-oxo-1-(2-oxoethyl)-1 ,2-dihydroquinoline-6-carbonitrile 107c Aqueous HCI (3N, 7.7 ml_, 30.7 mmol) was added to a solution of 1-(2,2-diethoxyethyl)-2- oxo-1 ,2-dihydroquinoline-6-carbonitrile 107c (500 mg, 1.75 mmol) in THF (5 ml_) and stirred at room temperature for 2 h. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml). The organic extracts were combined, dried (MgS04), filtered and concentrated under reduced pressure to afford 2-oxo-1-(2-oxoethyl)-1 ,2- dihydroquinoline-6-carbonitrile 107c (290 mg, 78%) as a white solid. LC-MS (Method A) 213.2 [M+H] ⁺ ; RT 0.75 min. ¹ H NMR (Method C) (CDC ): δ 9.76 (s, 1 H), 7.93 (s, 1 H), 7.78- 7.72 (m, 2H), 7.09 (d, J = 8.5 Hz, 1 H), 6.86 (d, J = 9.3 Hz, 1 H), 5.22 (s, 2H). d) 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-

I , 3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline-6-carbonitrile 107

Prepared as described in example 60e using (3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H- pyrido[3,2-b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-aminium trifluoroacetate 60d (228 mg, 0.54 mmol) and 2-oxo-1 -(2-oxoethyl)-1 ,2-dihydroquinoline-6-carbonitrile 107c (110 mg, 0.52 mmol) to afford 1-(2-{[(3aS,6S,7aS)-2-oxo-3-{3-oxo-2H,3H,4H-pyrido[3,2- b][1 ,4]oxazin-6-yl}-octahydro-1 ,3-benzoxazol-6-yl]amino}ethyl)-2-oxo-1 ,2-dihydroquinoline- 6-carbonitrile 107 (100 mg, 38%). LC-MS (Method A) 501.1 [M+H] ⁺ ; RT 2.29 min. ¹ H NMR (Method C) (DMSO-d6): δ ppm 1 1.22 (s, 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 8.02 (dd, J = 8.9, 2.2 Hz, 1 H), 7.97 (d, J = 9.5 Hz, 1 H), 7.80 (d, J = 8.9 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.17 (d, J = 8.7 Hz, 1 H), 6.76 (d, J = 9.5 Hz, 1 H), 4.63 (s, 2H), 4.30 (t, J = 7.3 Hz, 2H), 4.04 (td, J =

I I .8, 3.3 Hz, 1 H), 3.83-3.66 (m, 1 H), 2.88-2.69 (m, 4H), 2.45-2.31 (m, 1 H), 2.03-1.85 (m, 1 H), 1.46 (q, J = 1 1.1 Hz, 1 H), 1.39-1.12 (m, 3H).

Example 108 - Antibacterial susceptibility testing

Minimum Inhibitory Concentrations (MICs) versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition. CLSI document M07-A10, 2015). The broth dilution method involves a twofold serial dilution of compounds in 96-well microtitre plates, giving a typical final concentration range of 0.25-128 μg/mL and a maximum final concentration of 1 % DMSO. The bacterial strains tested include the Gram-positive strains Staphylococcus aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619, Enterococcus faecalis ATCC 29212, Enterococcus faecium ATCC 19434, the fluoroquinolone-resistant Enterococcus faecium ATCC 700221 and the Gram negative strains Acinetobacter baumannii NCTC 13420, Acinetobacter baumannii ATCC 19606, Enterobacter cloacae NCTC 13406, Escherichia coli ATCC 25922, E. coli ATCC BAA-2452, E. coli NCTC 13476, E. coli MG1655 and the gyrase A mutants E. coli MG1655 S83L and E. coli MG1655 D87G derived from the isogenic parent strain E. coli MG1655, Haemophilus influenzae ATCC 49247, Klebsiella pneumoniae ATCC 700603, Klebsiella pneumoniae NCTC 13443, Mycobacterium smegmatis ATCC 19420 (a recognised fast-growing and non-pathogenic surrogate for M. tuberculosis {Tuberculosis, 2010, 90:333), Neisseria meningitidis ATCC 13090, Pseudomonas aeruginosa ATCC 27853.

Strains are grown in cation-adjusted Muller-Hinton broth at 37°C in an ambient atmosphere. The MIC is determined as the lowest concentration of compound that inhibits growth following a 16-20 h incubation period. The data reported correspond to the modes of three independent experiments and is reported in Table 1.

All compounds tested show activity against both Gram-negative and Gram-positive bacteria. Compounds 1 and 76 in particular, exhibited excellent activity against both Gram- negative and Gram-positive bacteria. Compounds 1 -4, 7, 12, 14-16, 18, 22, 24-31 , 33-38, 41 -52, 53-57, 59-70, 74, 76-79, 81 -95, 99-102, 104 and 106 showed excellent activity against the Gram-positive strains S. aureus and S. pneumoniae. Compounds 4, 21 , 22, 34, 45, 55, 56, 68, 69, 77, 80, 81 , 85, 88, 90, 101 , 102 and 105 exhibited excellent activity against all strains of A. baumannii and E. coli tested, including those which are resistant to fluoroquinolone antibiotics and other antibiotics. Compounds 14, 21 , 24, 35, 40, 43, 59-61 , 63, 74, 76, 87, 92 and 93 exhibited excellent activity against all strains of A. baumannii, E. coli, E. cloacae, P. aeruginosa and H. influenzae strains tested.

Table 1 - MIC values of reference compound and test compounds 1 -107 against Gram-negative and Gram-positive bacterial strains

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CIP = ciprofloxacin; Ab = Acinetobacter baumannii; Eel = Enterobacter cloacae; Ec = Escherichia coli; Hi = Haemophilus influenzae; Kp = Klebsiella pneumoniae; Ms = Mycobacterium smegmatis; Nm = Neisseria meningitidis; Pa = Pseudomonas aeruginosa; Sa = Staphylococcus aureus; Ef = Enterococcus faecalis; Efm = Enterococcus faecium; Sp = Streptococcus pneumoniae

In Table 1 , an MIC (in μςΛη..) of less or equal to 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 100 is assigned the letter C; and a MIC of over 100 is assigned the letter D.

Table 2 - Fold increase in MIC against fluoroquinolone-resistant single point mutant Escherichia coli strains (MG1655 S83L and MG1655 D87G) compared to the isogenic parent strain E. coli MG1655.

CIP = ciprofloxacin; LEV ^: = levofloxacin

1 : S83L mutation on DNA gyrase subunit GyrA

2: D87G mutation on DNA gyrase subunit GyrA Compounds 1 -59, 61 -69, 72-88, and 91 -105 showed no significant (lower than or equal to 2-fold change) loss of activity against the E. coli MG1655 fluoroquinolone-mutant strains. Thus all compounds tested were less susceptible to the gyrase S83L and D87G mutations than the fluoroquinolone antibiotics ciprofloxacin and levofloxacin.

Example 109 Antibacterial susceptibility testing of biodefence microorganisms

MICs against strains of Bacillus anthracis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis and Yersinia pestis were measured using the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10, 2015). Two-fold serial dilutions of compounds were tested in triplicate over the concentration range 0.03 to 64 μg/mL. Doxycycline was included as a control antibiotic. Assay medium was CA-MHB (supplemented with 2% IsoVitalex in the case of F. tularensis). Cultures were incubated in the presence of compound for up to 24 hours, up to 38 hours (F. tularensis) or 24-48 hours (Y. pestis). The MIC is reported as the lowest concentration of compound that visually inhibited growth of the test organism.

In Table 3 a MIC (in μg/mL) of less than 1 is assigned the letter A; a MIC equal to or greater than 1 but less than or equal to 4 is assigned the letter B; a MIC greater than 4 but less than or equal to 16 is assigned the letter C; a MIC greater than 16 but less than or equal to 64 is assigned the letter D; and a MIC greater than 64 is assigned the letter E.

Table 3: MICs against biodefence microorganisms

DOX - doxycycline The compound of the invention tested proved to be active against all of the Gram-negative and Gram-positive biodefence pathogens evaluated.

Example 110- Antibacterial susceptibility testing of anaerobes

Antibacterial susceptibility of anaerobes to compounds of the invention was determined by measuring the minimum inhibitory concentration (MIC) using the agar dilution method according to the guidelines of the CLSI (Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard- Eighth Edition. CLSI document M11-A8, 2012). Reference organisms were Clostridium difficile ATCC 700057, Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741. Strains of anaerobic bacteria were contemporary clinical isolates from diverse infection types and geographic locations. Stock solutions of vancomycin and ciprofloxacin were made in water at 5, 120 μg/mL. Stock solution of metronidazole was made in DMSO at 5, 120 μg/mL. Stock solutions of compounds were made in DMSO at 12,800 μg/mL. Compounds were diluted to 100-fold the test range concentrations in DMSO and 400 of the 100 ^χ solutions were added to 39.6 mL of Brucella blood agar supplemented with haemin and vitamin K1. Isolates were sub-cultured twice on Brucella blood agar plates at 35°C for 48 h in an anaerobic cabinet. Colonies were re-suspended in Brucella broth to a turbidity of 0.5 McFarland and 100 μί of the suspension was transferred to a 96-well plate. The antibacterial agent containing plates were inoculated with 1 μΙ_ of bacterial suspension using a Masturi ^® Dot inoculator. Plates were incubated at 35°C for 48 h in anaerobic conditions and MICs were read visually following CLSI guidelines. The MIC was defined as the lowest concentration of compound that inhibited visible growth.

In Tables 4 to 14 a MIC (in μg/mL) of less than 1 is assigned the letter A; a MIC equal to or greater than 1 but less than or equal to 4 is assigned the letter B; a MIC greater than 4 but less than or equal to 16 is assigned the letter C; a MIC greater than 16 but less than or equal to 64 is assigned the letter D; and a MIC greater than 64 is assigned the letter E. Table 4: MICs against reference strains of anaerobic bacteria

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

Compounds tested proved to be active against the exemplary obligate anaerobic reference bacterial strains of C. difficile, B. fragilis and B. thetaiotaomicron.

Table 5: MICs against strains of Clostridium perfringens

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of C. perfringens, exemplary obligate anaerobic bacterium.

Table 6: MICs against strains of Finegoldia magna

Strain MTZ VAN CIP 21 27

1 A A D A B

2 A A A A D

3 B A D A B

4 A A A A D

5 B A A A D

6 B A A A D 7 B A C A E

8 B A D A B

9 B A A A E

10 B A D A C

1 1 B A A A D

12 A A A A D

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of F. magna, exemplary obligate anaerobic bacterium.

Table 7: MICs against strains of Parvimonas micra

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. micra, exemplary obligate anaerobic bacterium.

Table 8: MICs against strains of Peptoniphilus harei

Strain MTZ VAN CIP 21 27

1 B A B A A

2 A A B A A

3 A A C A A

4 B A B A A 5 A A B A A

6 A A B A A

7 A A B A A

8 A A B A A

9 B A B A A

10 A A B A A

1 1 A A B A A

12 B A B A A

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. harei, exemplary obligate anaerobic bacterium.

Table 9: MICs against strains of Peptostreptococcus anaerobius

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. anaerobius, exemplary obligate anaerobic bacterium.

Table 10: MICs against strains of Propionibacterium acnes

Strain MTZ VAN CIP 21 27

1 D A B A B

2 D A B A A

3 D A B A A

4 D A A A A 5 D A B A B

6 D A B A B

7 D A B A B

8 D A B A B

9 D A B A B

10 D A B A B

1 1 D A B A A

12 D C B A B

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. acnes, exemplary obligate anaerobic bacterium.

Table 11 : MICs against strains of Bacteroides fragilis

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of B. fragilis, an exemplary obligate anaerobic bacterium.

Table 12: MICs against strains of Bacteroides thetaiotaomicron

Strain MTZ VAN CIP 21 27

1 A D D A C

2 A D D A B 3 B D C A C

4 B D C A C

5 B D C A B

6 B D D A C

7 A D D A C

8 B D C A B

9 A A A A A

10 B D C A B

1 1 B D D B C

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of B. thetaiotaomicron, an exemplary obligate anaerobic bacterium.

Table 13: MICs against strains of Prevotella bivia

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. bivia, an exemplary obligate anaerobic bacterium.

Table 14: MICs against strains of Prevotella melaninogenica

Strain MTZ VAN CIP 21 27

1 A E B A B

2 A C B A A

3 A E B A A 4 A E B A A

5 A D B A A

6 A E B A A

7 A D B A A

8 A C C A A

9 A C A A A

10 A E B A B

1 1 A E B A A

MTZ, metronidazole; VAN, vancomycin; CIP, ciprofloxacin

The compounds tested showed activity against the clinical isolates of P. melaninogenica, an exemplary obligate anaerobic bacterium.

Example 111 - Human cell viability assay

Compounds are assessed for potential non-specific cytotoxic effects against a human hepatic cell line (HepG2 ATCC HB-8065). HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10% FBS and 1 mM sodium pyruvate. After 24 h compound dilutions are prepared in Dulbecco's minimum essential media (DMEM) supplemented with final concentrations of 0.001 % FBS, 0.3% bovine albumin and 0.02% HEPES and added to cells. Compounds are tested in two-fold serial dilutions over a final concentration range of 1-128 μg/mL in a final DMSO concentration of 1 % vol/vol. Chlorpromazine is used as a positive control. Cells are incubated with compound at 37°C and 5% CO2 for a further 24 h, after which time the CellTiter-Glo reagent (Promega) is added. Luminescence is measured on a BMG Omega plate reader. Data are analysed using GraphPad Prism software to determine the concentration of compound that inhibits cell viability by fifty percent (IC50). The results are provided in Table 14.

In Table 14, an IC50 (in μg/mL) of less than 1 is assigned the letter D; an IC50 of from 1 to 10 is assigned the letter C; an IC50 of from 10 to 100 is assigned the letter B; and an IC50 of over 100 is assigned the letter A. Table 14 - IC ₅ o values against HepG2 cell line

Compounds 1 -17, 19-103 show low toxicities against HepG2 human hepatic cell line. In particular, compounds 1 -3, 5-7, 9-10, 12-14, 16, 19-24, 37, 39, 42-44, 46, 48-53, 54-55, 58, 63, 65-67, 69, 75, 77, 78, 92-98 and 100 showed no detectable toxicity against the tested human hepatic cell line. These compounds therefore show an excellent therapeutic benefit relative to their hepatic toxicities. Compounds 4, 8, 11 , 15, 17, 25, 29, 36, 38, 40, 45, 47, 56, 59-61 , 64, 68, 70-74, 76, 79-91 , 99, and 101 -105 also demonstrate an acceptable level of hepatic toxicity relative to therapeutic activity. This indicates that these compounds have the potential to have an excellent therapeutic benefit relative to their hepatic toxicity.