BR112016021187B1 - CHEMICAL COMPOUNDS AND COMBINATION INCLUDING THEM - Google Patents

Abstract

CHEMICAL COMPOUNDS AND COMBINATION INCLUDING THEM. The present invention relates to a compound of formula (I); or a pharmaceutically acceptable salt thereof; a process for preparing such a compound; and for the use of such a compound in the treatment of an ENaC-mediated disease state (such as asthma, CF or COPD).

Description

[001] The present invention relates to pyrazine derivatives having pharmaceutical activity, processes for preparing such derivatives, pharmaceutical compositions comprising such derivatives and the use of such derivatives as active therapeutic agents.

[002] Hydration of the lung airway epithelium ensures efficient ciliary function, and mucociliary clearance (MCC) is a critical first-line innate airway defense mechanism. Failure of adequate mucus clearance produces mucus stasis and risk of airway obstruction and predisposes to chronic bacterial infection. Mucus hypersecretion, mucus thickening, and reduced rates of mucociliary clearance are well-established features of the pathophysiology of Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD), and contribute significantly to the morbidity and mortality of the diseases. Poor MCC leads to airway obstruction by static mucus, which impairs lung function and serves as a niche for infection by facilitating bacterial colonization and leading to increased rates and severity of disease exacerbations.

[003] The pathophysiology of CF is well characterized and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leading to airway dehydration, and remains one of the most common fatal inherited disorders worldwide. Although CF is a complex multiorgan disease, morbidity and mortality are primarily determined by chronic obstructive pulmonary disease that evolves from early-onset mucus clogging in the small airways, chronic neutrophilic airway inflammation, and bacterial infection.

[004] The pathophysiology of COPD is complex and poorly understood. Current clinical guidelines describe COPD as a disease state characterized by airflow limitation that is not fully reversible. Airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases. The most important contributing source of such particles and gases is tobacco smoke. COPD patients have a variety of symptoms, including coughing, shortness of breath, and excessive sputum production; Such symptoms arise from dysfunction of several cellular compartments, including neutrophils, macrophages, and epithelial cells.

[005] Adequate airway hydration is of essential importance for the maintenance of MCC and proper mucus water content. The regulation of airway hydration is strongly linked to the movement of water and electrolytes over the epithelial cell layer. The periciliary fluid (PCL) on the epithelial surface of the airways around the cilia separates the viscous mucus layer from the epithelial surface and facilitates ciliary beating. PCL volume/depth has been shown to be a strong determinant of MCC rate.

[006] ENaC (the Epithelial Sodium Channel) is a voltage-gated, amiloride-sensitive ion channel widely expressed in epithelia of the respiratory, urinary, digestive, genital, and skin systems. Systemically, ENaC plays a key role in electrolyte homeostasis and fluid volume balance by regulating Na+ transport along the renal epithelia. Through the control of sodium transport, ENaC controls the osmotic gradient in the airway epithelium and thereby regulates PCL volume. ENaC-mediated sodium transport blockade reduces the osmotic gradient in the epithelium, leads to water retention on the surface of the airways (increased PCL volume), and enhancement of mucus hydration and MCC rate.

[007] A role for ENaC as a key regulator of airway surface fluid volume and mycociliary clearance (MCC) in vivo is established in the literature. Studies on α-β- and y-ENaC (-/-) mice, respectively, show a critical role of ENaC function in perinatal lung fluid clearance (Barker et al., J. Clin. Invest., 1998. 102( 8):1634;Bonny and Hummler, Kidney Int., 2000. 57(4):1313;Pradervand et al., Proc.Natl.Acad.Sci.USA.,1999.96(4):1732. Transgenic mice overexpressing ENaC β-subunit show increased airway Na+ absorption, ASL volume depletion, mucus dehydration, and decreased MCC. Mice develop severe lung disease with clinical features similar to CF and COPD, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation, defective bacterial clearance, and emphysema (Mall et al., Nature Med., 2004. 10:487; Mall et al., Am. J. Respir. Crit. Care Med., 2007. 177:730). The mortality rate among transgenics during the first 20 days of life is around 50% due to extensive mute clogging of the airways resulting in asphyxia, however mortality is significantly reduced by administration of amiloride to the lungs of mice for 14 days after birth (Mall et al., ATS Poster abstract #G55, 2008).

[008] Furthermore, humans with Pseudohypoaldosteronism 1 (PHA1), a disease caused by loss-of-function mutations in genes encoding α-β- and y-ENaC, show increased ASL volume and an upregulation of MCC (Kerem et al ., N. Engl. Med., 1999. 341:156). Treatment of normal subjects with an ENaC channel blocking compound amiloride increases ASL volume and MCC rates ( Sood et al., Am. J. Crit. Care Med., 2003. 167:158 ).

[009] Amiloride and benzamil are pharmaceutically active pyrazine derivatives known to block the epithelial sodium channel.

[0010] In summary, this report describes, in part, a compound of formula (I):

[0011] where:

[0012] R1 is selected from hydrogen or C1-4 alkyl;

[0013] m is 1 or 2;

[0014] A is selected from phenyl or heterocyclyl;

[0015] X is selected from -C(=O)-, -C(=O)-NR4- or -O-C(=O)-NR5-;

[0016] n is 2 or 3;

[0017] R2

[0018] is selected from hydrogen or C1-8 alkyl;

[0019] R3 is C5-6 alkyl-OH, wherein said C5-6 alkyl group is also substituted by an additional 3- or 4-OH group; It is

[0020] R4 and R5 are selected from hydrogen or C1-4 alkyl;

[0021] or a pharmaceutically acceptable salt thereof.

[0022] This report also describes, in part, pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0023] This report also describes, in part, a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0024] This report also describes, in part, a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an ENaC-mediated disease state.

[0025] This report also describes, in part, a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of an ENaC-mediated disease state.

[0026] This report also describes, in part, a method of treating or preventing an ENaC-mediated disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0027] Other aspects of the invention will become apparent to one skilled in the art from reading this report.

[0028] The compounds of the invention can exist in salt form or non-salt form (i.e., as a free base), and the present invention encompasses both salt and non-salt forms.

[0029] Compounds described in this report may form acid addition salts. In general, an acid addition salt can be prepared using various inorganic or organic acids. Such salts can typically be formed, for example, by mixing the compound with an acid (eg, a stoichiometric amount of an acid) using various methods known in the art. This mixing can occur in water, an organic solvent (eg, ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous/organic mixture.

[0030] In another aspect of the invention acid addition salts are, for example, trifluoroacetate, formate, acetate or hydrochloric acid.

[0031] The skilled person will be aware of the general principles and techniques of preparation of pharmaceutical salts such as those described, for example, in Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

[0032] Compounds and salts described in this report may include one or more chiral (ie, asymmetric) centers. To the extent that a structure or chemical name in this report does not indicate chirality, the structure or name is intended to encompass any single stereoisomer (that is, any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers ( for example a racemate). In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (eg, a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis, for example, from a chiral starting material.

[0033] When in solid crystalline form, a compound of formula (I) may be in the form of a cocrystal with another chemical entity and the invention encompasses all such cocrystals.

[0034] The compounds of the invention can exist as a solvate (such as a hydrate) as well as unsolvated forms, and the present invention encompasses all such solvates.

[0035] Compounds and salts described in this report can exist in various tautomeric forms and the invention encompasses all such tautomeric forms. "Tautomers" are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.

[0036] Compounds and salts described in this report may be isotopically labeled (or "radiolabeled"). In that case, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include 2H (also written as "D" for deuterium), 3H (also written as "T" for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O and 36Cl. The radionuclide that is used will depend on the specific application of that radiolabeled derivative. for example, for in vitro receptor labeling and competition assays, 3H or 14C are often useful. For radioimaging applications, 11C is often useful. In some embodiments, the radionuclide is 3H. In some embodiments, the radionuclide is 14C. In some embodiments, the radionuclide is 11C.

[0037] Straight or branched chain alkyl moieties and groups, for example, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl or C5-6 alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, such as methyl or n-hexyl.

[0038] Heterocyclyl is a non-aromatic 5- or 6-membered ring, comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. An example of a heterocyclyl is a non-aromatic 5- or 6-membered ring comprising one or two nitrogen atoms; or an N-oxide thereof, or an S-oxide or S-dioxide thereof, for example pyrrolidinyl or piperidinyl, such as piperidin-4-yl. For the avoidance of doubt, substituents on the heterocyclyl ring may be attached via a carbon atom or a heteroatom.

[0039] The term "pharmaceutically acceptable" is used to characterize a portion (e.g., a salt, dosage form, or excipient) as being suitable for use in the intended patient.

[0040] In a particular aspect R1 is replaced by the phenyl group in position 2 relative to the point of attachment to the remainder of formula (I).

[0041] In a further aspect R1 is C1-4 alkyl.

[0042] In a further aspect R1 is methyl.

[0043] In an additional aspect m is 1.

[0044] In yet another aspect A is selected from phenyl or piperidinyl.

[0045] In a further aspect A is phenyl.

[0046] In a further aspect A is piperidinyl.

[0047] In another aspect X is -C(=O)-NR4-.

[0048] In a further aspect X is -C(=O)-NH-.

[0049] In one aspect, where the group X is -C(=O)-NR4-, then the carbonyl of X is bonded to A and the amino group of X to (CH2)n. In another aspect, where the group X is -C(=O)-NR4-, then the amino group of X is bonded to A and the carbonyl group of X to (CH2)n.

[0050] In one aspect, where the group X is -O-C(=O)-NR5-, then the ether oxygen of X is bonded to A and the amino group of X to (CH2)n. In another aspect, where the group X is -O-C(=O)-NR5-, then the amino group of X is bonded to A and the ether oxygen of X to (CH2)n.

[0051] In another aspect the group X is replaced by the group A at position 4 relative to the point of attachment to the remainder of the compound of formula (I).

[0052] In another aspect n is 2.

[0053] In a further aspect R2 is C1-8 alkyl.

[0054] In yet another aspect R2 is n-hexyl.

[0055] In another aspect, R3 is C5 alkyl-OH, wherein said C5 alkyl group is also substituted by an additional 3 -OH groups.

[0056] In another aspect, R3 is C6 alkyl-OH, wherein said C6 alkyl group is also substituted by an additional 4 -OH groups.

[0057] In an additional aspect R3 is selected from the following:

[0058] In another aspect, R3 is selected from the following:

[0059] In an additional aspect R3 is selected from the following:

[0060] In another aspect, R3 is selected from (2S,3R,4R)-2,3,4,5-tetrahydroxypentyl, (2S,3R,4R,5R)-2,3,4,5,6 -pentahydroxyhexyl, (2R,3R,4R, 5R)-2,3,4,5,6-pentahydroxyhexyl or (2R,3S,4S)-2,3,4,5-tetrahydroxypentyl.

[0061] In a further aspect, R3 is selected from (2S,3R,4R)-2,3,4,5-tetrahydroxypentyl, (2S,3R,4R 5R)-2,3,4,5,6 -pentahydroxyhexyl or (2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl.

[0062] In another aspect R5 is hydrogen.

[0063] In a further aspect, R1 is C1-4 alkyl; m is 1 or 2; A is phenyl or piperidinyl; X is selected from –C(=O)–, –C(=O)–NR4– or –O–C(=O)–NR5–; n is 2 or 3; R2 is hydrogen or C1-8 alkyl; R3 is C5-6 alkyl–OH, wherein said C5-6 alkyl group is also substituted by an additional 3 or 4 –OH groups; and R4 and R5 are both hydrogen.

[0064] In a further aspect, R1 is C1-4 alkyl; m is 1; A is phenyl or piperidinyl; X is –C(=O)–NH–; n is 2; R2 is C1-8 alkyl; R3 is selected from the following:

[0065] In a further aspect, R1 is C1-4 alkyl; m is 1; A is phenyl; X is -C(=O)-NH-; n is 2; R2 is C1-8 alkyl; and R3 is selected from the following:

[0066] In a further aspect of the invention the compounds of the invention exhibit R stereochemistry at the carbon center marked with an asterisk (*) in formula (Ia) below:

[0067] An example of a compound of the invention is: 3,5-diamino-6-chloro-N-(2-(2-methylbenzyl)-3-(((1-(3-((2,3,4 ,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2 -(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methylamino )-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino )-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl(2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methylamino)- 2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(4-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)butanoyl)piperidin-4-yl)methylamino )-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(2-(2-methylbenzyl)-3-((1-(3-(2,3,4,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4 -yl)methylamino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino )-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino) -2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino) -2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 4-((3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl 2-(hexyl(2,3,4,5,6-penta -hydroxyhexyl)amino)ethylcarbamate; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino) -2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)amino)-2 -(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl(2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2 -(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-(3-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)phenethylamino)-2-(2- methylbenzyl)propyl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.

[0068] Another example of a compound of the invention is: 3,5-diamino-6-chloro-N-(2-(2-methylbenzyl)-3-(((1-(3-(((2S,3R, 4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl) carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5, 6-pentahydroxyhexyl)amino )ethylcarbamoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl((2S,3R,4R,5R)-2,3,4,5, 6-pentahydroxyhexyl)amino )propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin -4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(4-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino )butanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(2-(2-methylbenzyl)-3-((1-(3-((2S,3R,4R,5R)-2,3,4,5,6 -pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methylamino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((1-(3-(hexyl((2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino )propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2R,3R,4R,5R)-2,3,4,5, 6-pentahydroxyhexyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4, 5,6-pentahydroxyhexyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 4-((3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl-2-(hexyl((2S,3R,4R,5R)- 2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamate; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4,5, 6-pentahydroxyhexyl) amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl) carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-((4-((2-(hexyl((2R,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)ethyl) carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-(3-(3-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino) ethylcarbamoyl)phenethylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.

[0069] Another example of a compound of the invention is: 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-(((1-(3-((( 2S, 3R, 4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4, 5-tetrahydroxypentyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(2-(hexyl((2S,3R,4R,5R)-2, 3,4,5,6-penta -hydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R,5R)-2, 3, 4, 5,6-penta -hydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R)-2,3, 4,5-tetrahydroxypentyl)amino )propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(4-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-penta -hydroxyhexyl)amino)butanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-((1-(3-((2S, 3R, 4R,5R)-2,3,4 ,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methylamino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2R,3R,4R,5R)-2, 3,4,5,6-penta -hydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2R,3R,4R,5R)-2, 3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 4-(((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl 2-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamate; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((S)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((S)-3-((4-((2-(hexyl((2R,3S,4S)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-(3-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-penta- hydroxyhexyl)amino)ethylcarbamoyl)phenethylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.

[0070] Another aspect of the invention is any of the embodiments described above with the proviso that any of the specific examples are individually rejected. For example, another aspect is any of the embodiments described above with the proviso that any of the compounds selected from the above list of examples of compounds of the invention is individually rejected.

[0071] In some embodiments, the compound is a compound of formula (I) excluding at least one compound cited in the examples below. To illustrate, in some such embodiments, the compound is a compound of formula (I) excluding the compound described in example X, where X can be 1, 2, 3, and the like. In other embodiments, the compound is a compound of formula (I) excluding the compounds described in the Y examples, where Y can be any combination of 1, 2, 3, etc.

[0072] Compounds of formula (I) can be prepared from compounds of formula (II) according to scheme 1, wherein R1, R2, R3, A, X, m and m are as defined in formula (I), and in that p = m-1. Scheme 1: a) NaH(OAc)3, AcOH, THF or NaBH4, MeOH

[0073] Alternatively, compounds of formula (I) may be prepared in a manner described in scheme 2, wherein R1, R2, R3, A, X, m and m are as defined in formula (I), and wherein Y is halogen , for example chlorine, bromine or iodine ep = m-1. Scheme 2: a) NaH or K2CO3 or Cs2CO3 or DIEA, DMF.

[0074] Alternatively, compounds of formula (I) can be prepared by introducing R3 into a final step by reductive alkylation of suitable polyhydroxylated alkylaldehydes, such as hexoses or pentoses (the R3-aldehyde), as described in Scheme 3, and in that R1, R2, R3, A, X, m and m are as defined in formula (I). The polyhydroxyalkyl chains present in R3 may be protected by any suitable alcohol protecting groups, for example as described by PGM Wuts, Th. W. Greene, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 2006. Furthermore, as the skilled person will be aware, and as described in the examples herein, additional amino groups present in the compounds of formula (II) may be protected by suitable amino protecting groups, for example as described in Wuts and Greene (above), such as by di-tert-butyl dicarbonate (Boc) or fluorenylmethyloxycarbonyl (FMoc) protecting groups. Scheme 3: a) NaBH(OAc)3 or NaBH3CN, AcOH, THF or NaBH4, MeOH

[0064] Compounds of formula (II) can be prepared enantioselectively by methods as described in Scheme 5(JCD Müller-Hartwieg, L. La Vecchia, H. Meyer, AK Beck, D. Seebach, Org. Synth. 85 (2008) , 295.) or by the method shown in Schemes 4, and 6, wherein R1 is as defined in formula (I). Scheme 4: a) i) L-proline, DMF, ii) NaBH4, MeOH; b) Phthalimide, PPh3, DEAD, THF; c) CH3NH2, EtOH, d) Boc2O, DCM, TEA; e) Pd(OH)2, H2, MeOH, 4.92 kg/cm2 (70 psi); f) (3-chloro-5-(1H-imidazol-1-ylcarbonyl)pyrazine-2,6-diamine, DIPEA, NMP; g) TFA, DCM; h) NaOH, THF. Scheme 5: a) BuLi, THF; b) TiCl4, TEA, DCM; c) LiOH, H2O2, THF, H2O; d) (COCl)2, NH4OH, DCM; e) BH3*THF; f) MPN; g) TFA, DCM; h) NaOH, THF. Scheme 6: a) Diallylcarbonate, Lipase PS-C Amano II, MTBE; b) Acid (eg D-tartrate), recrystallization; c) 10M NaOH, MTBE; d) (BOC) 2 O, MTBE; e) LiBH4, Pd(PPh3)4, THF; f) CDl; iPrOAc; g) TFA, DCM; h) NaOH, THF.

[0065] Schemes 4, 5 and 6 describe access to the (R)-enantiomer of compounds of formula (II). The reactions described in these schemes can equally be applied to access the related (S)-enantiomer, using starting materials of reversed absolute configuration or enzymes of different stereospecificity.

[0066] Alternatively, compounds of formula (II) with (S)-configuration can be prepared as shown in Scheme 7. Scheme 7: a) CDI; iPrOAc; b) LiBH4, Pd(PPh3)4, THF.

[0067] The method described in step (a) of Scheme 6 comprises enzyme-mediated desimetrization of diamine(III) using diallylcarbonate.

[0068] Suitable enzymes for this reaction include lipases, in particular lipases that originate from Candida Antarctica or Pseudomonas Cepacia. Suitable enzymes include IMM CALB (Candida Antartica Lipase B), IMM CALBY (Candida Antartica Lipase B), Novozym 435 (Candida Antarctica Lipase B), Amano Lipase PS-C1 (Pseudomonas Cepacia Lipase), Amano Lipase PS-IM (Pseudomonas Cepacia Lipase ) and Amano Lipase PS-D (Pseudomonas Cepacia Lipase), such as Amano Lipase PS-C1, Amano Lipase PS-D and Amano Lipase PS-IM. The reaction can be carried out in a range of polar and non-polar solvents, and mixtures thereof, including tert-butyl dimethyl ether (TBME), tetrahydrofuran (THF), methyl-THF (MeTHF, e.g., 2-methyl- THF), heptanes, cyclohexane and toluene, such as MeTHF. The reaction can be carried out over a range of temperatures, for example 0 °C to 50 °C, for example 15 °C to 35 °C, for example about 30 °C. The enantiomeric excess of the resulting crude product can optionally be increased by resolution procedures known to those skilled in the art, for example by crystallization of a tartrate salt.

[0069] In a further aspect of the invention there is provided a process for preparing a compound of formula (IV) wherein R1 is as defined above (such as the compound (R)-allyl-(3-amino-2-(2 - methylbenzyl)propyl)carbamate):

[0070] comprising desimetrization of diamine (III) mediated by the enzyme diamine (III) in the presence of diallylcarbonate, and optionally further performing an enantiomeric resolution. In a further aspect, the enzyme is selected from one that originates from either Candida Antarctica or Pseudomonas Cepacia, such as IMM CALB (Candida Antartica Lipase B), IMM CALBY (Candida Antartica Lipase B), Novozym 435 (Candida Antarctica Lipase B) , Amano Lipase PS-C1 (Pseudomonas Cepacia Lipase), Amano Lipase PS-IM (Pseudomonas Cepacia Lipase) and Amano Lipase PS-D (Pseudomonas Cepacia Lipase). In another aspect, the enzyme is selected from Amano Lipase PS-C1, Amano Lipase PS-D and Amano Lipase PS-IM, such as Amino Lipase PS-IM.

[0071] In another aspect of the invention there is provided the compound (R)-allyl-(3-amino-2-(2-methylbenzyl)propyl)carbamate.

[0072] In a further aspect there is provided the use of the compound (R)-allyl-(3-amino-2-(2-methylbenzyl)propyl)carbamate as a pharmaceutical intermediate. In a further aspect, there is provided the use of the compound (R)-allyl-(3-amino-2-(2-methylbenzyl)propyl)carbamate as an intermediate in the manufacture of a compound of formula (I).

[0073] Detailed processes for the compounds of the invention are also described in the examples below.

[0074] Compounds and salts described in this report can generally be used in methods to treat various disorders in animals, particularly mammals. Mammals include, for example, humans.

[0075] The compounds of the invention, and pharmaceutically acceptable salts thereof, have activity as pharmaceuticals, in particular as ENaC modulators, and can be used in the treatment of respiratory tract disease, bone and joint diseases, and other disorders autoimmune and allergic.

[0076] Disease states that can be treated with a compound of the invention, or a pharmaceutically acceptable salt thereof, include, but are not limited to, diseases of the respiratory tract, such as: obstructive airways diseases including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hypersensitivity; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis, antineoplastic therapy complicating with fibrosis and chronic infection, including tuberculosis and aspergillosis and other fungal infections; lung transplant complications; vasculitic and thrombotic disorders of the pulmonary vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medication, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection, including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS), and adenovirus; acute lung damage; or adult respiratory distress syndrome (ARDS).

[0077] In a further aspect of the invention, diseases of the respiratory tract that can be treated with a compound of the invention, or a pharmaceutically acceptable salt thereof, include: chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; bronchiectasis; cystic fibrosis; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of hypersensitivity of airways.

[0078] In yet another aspect of the invention, disease states that can be treated with a compound of the invention, or a pharmaceutically acceptable salt thereof, include chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma, chronic bronchitis and bronchiectasis .

[0079] Yet in another aspect of the invention, the disease state that can be treated with a compound of the invention, or a pharmaceutically acceptable salt thereof, is chronic obstructive pulmonary disease (COPD).

[0080] In one aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of COPD.

[0081] In a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.

[0082] In a further aspect of the invention there is provided a method of treating or preventing COPD in a mammal suffering from, or at risk of, said disease, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0083] Yet in another aspect of the invention, the disease state that can be treated with a compound of the invention, or a pharmaceutically acceptable salt thereof, is cystic fibrosis (CF).

[0084] In one aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of CF.

[0085] In a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of CF.

[0086] In a further aspect of the invention there is provided a method of treating or preventing CF in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0087] When a compound or salt described in this report is administered to treat a disorder, a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate symptoms or other deleterious effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder becoming worse.

[0088] In some embodiments where a combination therapy is used, the amount of the compound or salt described in this report and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient. In this context, the combined amounts are "therapeutically effective amounts" if they are, when combined, sufficient to reduce or completely alleviate symptoms or other deleterious effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder becoming worse. Typically, such amounts can be determined by one skilled in the art, for example, starting with the dosage range described in this report for the compound or salt and an approved or otherwise published dosage range of the other compound(s). (s) pharmaceutically active(s).

[0089] In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a mammal, such as a human, said ingredient is usually formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore, in another aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0090] In a further aspect, the present invention provides a process for preparing said composition which comprises mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition, for example, will comprise from 0.05 to 99% by weight (percent by weight), such as from 0.05 to 80% by weight, for example from 0.10 to 70 % by weight, such as from 0.10 to 50% by weight, active ingredient, all percentages by weight being based on the total composition.

[0091] The pharmaceutical compositions of this invention can be administered in a standard manner for the disease or condition for which it is desired to treat, for example, by topical administration (such as to the lung and/or airways or to the skin), inhalation , oral, rectal or parenteral. For these purposes the compounds of this invention can be formulated by methods known in the art. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule containing between 0.1 mg and 1 g of active ingredient.

[0092] Each patient may receive, for example, a dose of 0.0001 mgkg-1 to 10 mgkg-1, for example, in the range of 0.005 mgkg-1 to 5 mgkg-1, of the active ingredient administered, for example, 1 to 4 times a day.

[0093] In one embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated by inhaled administration (including oral and nasal inhalation).

[0094] The compound of formula (I) may be administered using a suitable delivery device, for example from a dry powder inhaler, a metered dose inhaler, a nebuliser or a nasal delivery device. Such devices are well known.

[0095] Dry powder inhalers can be used to administer the compound of formula (I), alone or in combination with a pharmaceutically acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture. The dry powder inhaler can be single dose or multi dose and can use a dry powder or a capsule containing powder.

[0096] Accordingly in one embodiment, the compound of formula (I), or a pharmaceutical composition containing a compound of formula (I), is administered via a dry powder inhaler (DPI).

[0097] The DPI can be "passive" or triggered by inspiration, or "active" where the powder is dispersed by some mechanism other than the patient's inhalation, for example, an internal supply of compressed air. Currently, three types of passive dry powder inhalers are available: single-dose, multi-unit-dose or multi-dose (reservoir) inhalers. In single-dose devices, individual doses are provided, usually in gelatin capsules, and must be loaded into the inhaler before use, examples of which include the Spinhaler® (Aventis), Rotahaler® (GlaxoSmithKline), AeroliserTM (Novartis) devices , Inhalator® (Boehringer) and Eclipse (Aventis). Multi-unit dose inhalers contain multiple doses individually packaged, either as multiple gelatin capsules or in blister packs, examples of which include the Diskhaler® (GlaxoSmithKline), Diskus® (GlaxoSmithKline), Nexthaler® (Chiesi) and Aerohaler® (Boehringer) devices . In multi-dose devices, the drug is stored in a bulk powder reservoir from which individual doses are measured, examples of which include Genuair® (AstraZeneca), Turbuhaler® (AstraZeneca), Easyhaler® (Orion), Novolizer ® (ASTA Medica), Clickhaler® (Innovata Biomed), Spiromax® (Teva) and Pulvinal® (Chiesi).

[0098] An inhalable pharmaceutical composition for use in an DPI can be prepared by mixing finely divided active ingredient (having an aerodynamic diameter generally equal to or less than 10 μm, such as equal to or less than 5 μm, for example, from 1 to 5 μm) with a carrier substance, for example a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Suitably the active ingredient particles adhere to the carrier particles to form an ordered (interactive) powder mixture. The powder particles may have a mass median diameter of 20 to 1000 µm, more usually 50 to 500 µm.

[0099] Alternatively, an inhalable pharmaceutical composition can be prepared by processing a finely divided powder (for example, consisting of finely divided active ingredient and finely divided carrier particles) into spheres which break up during the inhalation procedure.

[00100] The powder blend can then, as required, be dispersed into hard gelatine capsules, each containing the desired dose of the active ingredient. Alternatively the powder mixture can be loaded into the reservoir of a multi-dose inhaler, for example the Genuair®, or the Turbuhaler®.

[00101] In another embodiment, the compound of formula (I) is administered via a metered dose inhaler, particularly a pressurized metered dose inhaler (pMDI). The pMDI contains the active as a suitable solution or suspension in a pressurized container. The asset is released by actuating a valve on the pMDI device. Trigger can be manual or inspiration triggered. In manually actuated pMDIs, the device is actuated by the user when he inhales, for example by pressing a suitable release mechanism on the pMDI device. Inspiration-triggered pMDIs are triggered when the patient inhales through the pMDI mouthpiece. This can be advantageous when activating the device is timed with the patient's inhalation and can result in a more consistent dosage of the active. Examples of pMDI devices include, for example, Rapihaler® (AstraZeneca).

[00102] An inhalable pharmaceutical composition for use in a pMDI can be prepared by dissolving or dispersing the compound of formula (I) in a suitable propellant and with or without additional excipients such as solvent agents (e.g. ethanol), surfactants, lubricants or stabilizers. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P134a and P227, each of which can be used alone or in combination with other propellants and/or surfactant and/or other excipients.

[00103] In another embodiment, the compound of formula (I) is administered via a metered dose inhaler in combination with a spacer. Suitable spacers are well known and include Nebuchamber® (AstraZeneca) or Volumatic® (GlaxoSmithKline).

[00104] In another embodiment, the compound of formula (I) is administered by means of a nebulizer. Suitable nebulizers are well known and include eFlow® (PARI GmbH).

[00105] An inhalable pharmaceutical composition for use in a nebulizer can be prepared by dispersing or preferably dissolving the compound of formula (I) in a suitable aqueous medium. The composition may also include, for example, pH adjustment and/or tonicity adjustment, surfactants and preservatives. For example, a composition suitable for inhalation from a nebuliser comprises a compound of formula (I) dispersed in an aqueous medium (mg/g in Mill-Q water) comprising sodium chloride (9 mg/g); dried over citric acid (0.0735 mg/g); sodium citrate (0.19 mg/g); benzalkonium chloride (0.1 mg/g), EDTA (ethylenediamine tetraacetic acid, 0.1 mg/g) and Polysorbate 80 (0.3 mg/g).

[00106] In another embodiment, the compound of formula (I) is administered nasally as a spray from a suitable nasal delivery device, for example a spray pump or an MDI. Alternatively, the compound can be administered nasally as a powder using a suitable DPI device, e.g. Rhinocort®, Turbuhaler® (AstraZeneca).

[00107] An inhalable pharmaceutical composition for use in a spray pump or MDI nasal delivery device can be prepared by dispersing or preferably dissolving the compound of formula (I) in a suitable aqueous medium. The composition may also include, for example, suitable pH and/or tonicity adjustment, surfactants, preservatives, lubricants, flavors or viscosity modifiers. If required, additives to enhance absorption from the nasal cavity can be included, such as a suitable bioadhesive polymer. Dry powder compositions suitable for nasal delivery are as hereinbefore described with respect to delivery of DPI. However, where it is desirable to limit penetration of the compound into the lungs and keep the compound in the nasal cavity, it may be necessary to use the compound as well as larger particle sizes, for example such as an average particle diameter greater than about 10 µm. , for example, from 10 μm to 50 μm.

[00108] Accordingly, the present invention also provides an inhaler device (e.g. a dry powder inhaler, in particular a multi unit dose dry powder inhaler, or a pMDI inhaler) containing an inhalable pharmaceutical composition.

[00109] The invention also relates to a combination therapy, in which a compound of the invention, or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concomitantly, sequentially or in admixture, for the treatment of one or more of the conditions listed above. Such a combination can be used in combination with one or more other active ingredients.

[00110] In a further aspect of the present invention there is provided a pharmaceutical composition (e.g. for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as CF or COPD) comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from: a) a beta-adrenoceptor agonist; b) a muscarinic receptor antagonist c) a joint muscarinic receptor antagonist and beta-adrenoceptor agonist; d) a Toll-like receptor agonist (such as a TLR7 or TLR9 agonist) e) an adenosine antagonist; f) a glucocorticoid receptor agonist (steroidal or non-steroidal); g) a p38 antagonist; h) an IKK2 antagonist; i) a PDE4 antagonist; j) a modulator of chemokine receptor function (such as a CCR1, CCR2B, CCR5, CXCR2 or CXCR3 receptor antagonist); k) a CRTh2 antagonist; or l) an osmolyte, for example an ionic osmolyte, such as hypertonic saline as defined below.

[00110] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as terbutaline (for example, as the sulfate salt), salmeterol (eg, as the xinafoate salt), salbutamol (albuterol) (eg, as the sulfate salt), procaterol (eg, as the hydrochloride salt), pirbuterol (eg, as the acetate salt), orciprenaline (metaproterenol) (eg, as the sulfate salt), milveterol (eg, as the hydrochloride salt), levosalbutamol (levalbuterol) (eg, as the hydrochloride salt), abediterol , isoprenaline (isoproterenol) (for example, as the hydrochloride salt), indacaterol (for example, with the maleate salt), vilanterol (for example, as the trifenatate (triphenylacetic acid) salt), formoterol (for example, as the fumarate salt, e.g., the dihydrate salt of the fumarate), carmoterol, bitolterol (for example, as the mesylate salt), olodaterol, bedoradrine (for example, as the sulfate salt), bambuterol (for example, as the the hydrochloride salt), arformoterol (for example, as the tartrate salt), PF-610355 (2-[3-[2-[[(2R)-2-hydroxy-2-[4-hydroxy-3-( methanesulfonamido)phenyl]ethyl]amino]-2-methyl-propyl]phenyl]-N-[[3-(4-hydroxyphenyl)phenyl]methyl]acetamide), N-(2-diethylaminoethyl)-N-[2-[ 2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]ethyl]-3-[2-(1-naphthyl)ethoxy]propanamide, N-cyclohexyl-3- [2-(3-fluorophenyl)ethylamino]-N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]ethyl]propanamide, or N-cyclo -hexyl-N-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]ethyl]-3-[2-[3-(1-methylpyrazole- 4-yl)phenyl]ethoxy]propanamide.

[00111] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a muscarinic receptor antagonist (for example, an M1, M2 or M3 antagonist, such as a muscarinic receptor antagonist selective M3) such as tiotropium (for example, as the bromide salt), oxotropium (for example, as the bromide salt), ipratropium (for example, as the bromide salt), glycopyrronium bromide (for example, as a racemic mixture of stereoisomers, either as the stereoisomer R,R,R,S,S,R, or S,S, or as a mixture comprising two or more of the stereoisomers R,R,R,S, S,R, or S,S), aclidinium (for example, as the bromide salt), GSK573719 (3-[2-[3-(5-cyclohexyloxycarbonyl-thiophen-2-yl)-ureido]-3-(4-hydroxy -phenyl)-propionylamino]-1-(3-hydroxy-benzyl)-1-methyl-piperidinium), BEA2180BR 8-methyl-8-aza-bicyclo[3,2,1]oct-6-en-3-yl [(3R)-1-[2-oxo-2-(2-hydroxy-di-thiophen-2-yl-acetic acid)(hydroxy-di-thiophen-2-yl-acetic) salt, ester (e.g., as the hydrobromide salt), 1-phenylcycloheptanecarboxylate pyridylamino)ethyl] quinuclidin-1-io-3-yl] (for example, as the bromide salt), or 2-[(4-chlorophenyl)methoxy]ethyl-[[2-[(R)-cyclohexyl -hydroxy-phenyl-methyl]oxazol-5-yl]methyl]-dimethyl-ammonium (for example, as the napadisylate salt).

[00112] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an agent that is a muscarinic joint receptor antagonist (for example, an M1, M2 or M3, such as a selective M3 antagonist) and a beta-adrenoceptor agonist such as PF4348235 ([1-[9-[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl] ethyl]amino]nonyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate), 3-[2-[2-chloro-3-[[8-(2 -ethylthiazole-4-carbonyl)-11-oxa-3,8-diazaspiro[5,5]undecan-3-yl]methyl]phenyl]ethoxy]-N-cyclopentyl-N-[2-[2-(5- hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]ethyl]propanamide, N-butyl-N-[2-[2-(5-hydroxy-3-oxo-4H-1,4 -benzoxazin-8-yl)ethylamino]ethyl]-3-[2-[3-[2-[8-(2-isopropylthiazole-4-carbonyl)-11-oxa-3,8-diazaspiro[5,5] undecan-3-yl]ethyl]phenyl]ethoxy]propanamide, or 7-[(1R)-2-[2-[2-fluoro-5-[[8-(2-isopropylthiazole-4-carbonyl)-11- oxa-3,8-diazaspiro[5,5]undecan-3-yl]methyl]phenyl]ethylamino]-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one.

[00113] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a Toll-like receptor agonist (including a TLR7 or TLR9 agonist) such as loxoribine (7-allyl -2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-purine-6,8-dione), 2 Methyl-[3-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(3-morpholinopropyl)amino]methyl]phenyl]acetate (for example, as the hydrobromide, hydrochloride or dimaleate salt), 4-(dimethylamino)butyl 2-[4-[[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl]phenyl]acetate (for example, such as disaccharin, difumaric acid, di-1-hydroxy-2-naphthoic acid or monobenzoic acid salt), or 5'-TCG AAC GTT CGA AGA TGA TGA T (described as SEQ ID 171 in WO 2004/0158179) .

[00114] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an adenosine antagonist such as regadenoson, ATL-313 (4-[3-[6-amino- 9-[(2R,3R,4S,5S)-5-(cyclopropylcarbamoyl)-3,4-dihydroxy-tetrahydrofuran-2-yl]purin-2-yl]prop-2-ynyl]piperidine-1-carboxylate of methyl), or apadenoson (4-[3-[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-tetrahydrofuran-2-yl] methyl purin-2-yl]prop-2-ynyl]cyclohexanecarboxylate).

[00115] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a glucocorticoid receptor agonist (steroidal or non-steroidal) such as triamcinolone, triamcinolone acetonide, prednisone, furoate of momethasone, latreednol ethabonate, fluticasone propionate, fluticasone van, acetonid fluosolone, dexamethasone cypcylatis, clerk, clobetasol propionate, clergy, budesonide propionate, bechlomethasone dippopionate, alclometasona diplomatona , 2-Furoato de (1r ,3aS,3bS,10aR,10bS,11S,12aS)-1-{[(cyanomethyl)thio]carbonyl}-7-(4-fluorophenyl)-11-hydroxy-10a,12a-dimethyl-1,2,3, 3a,3b,4,5,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl, (1R,2R,3aS) methoxyacetate ,3bS,10aS,10bR,11S,12aS)-10b-fluoro-1-{[(fluoromethyl)sulfanyl]carbonyl}-7-(6-fluoropyridin-3-yl)-11-hydroxy-2,10a,12a- trimethyl-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl, 2,2,2-Trifluoro-N-[(1S,2R)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-(3-methoxyphenyl)-1-methylethyl]acetamide , 3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]-N-( 3-pyridylmethyl)benzamide,3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy ]indazol-1-yl]-N-[(3R)-1,1-dioxothiolan-3-yl]benzamide, or 3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)- 1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide.

[00116] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a p38 antagonist such as PH797804 (3-[3-bromo-4-(2,4- difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4,N-dimethyl-benzamide), losmapimod, PF03715455 (1-[5-tert-butyl-2-(3-chloro -4-hydroxy-phenyl)pyrazol-3-yl]-3-[[2-[[3-[2-(2-hydroxyethylsulfanyl)phenyl]-[1,2,4]triazolo[4,3-a] pyridin-6-yl]sulfanyl]phenyl]methyl]urea), N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxo-quinazolin-3-yl]benzamide, or N-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-pyrazin-1-yl] benzamide.

[00117] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a phosphodiesterase (PDE) inhibitor such as methylxanthanine including theophylline and aminophylline or a selective PDE isoenzyme inhibitor (including a PDE4 inhibitor or a PDE4D isoform inhibitor) such as tectomilast, roflumilast, oglemilast, ibudilast, GPD-1116 (3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8] naphthyridin-4-one), ronomilast, NVP ABE 171 (4-[8-(2,1,3-benzoxadiazol-5-yl)-1,7-naphthyridin-6-yl]benzoic acid), RPL554 (2- [(2E)-9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea) , CHF5480 ([(Z)-2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)vinyl](2S)-2-(4-isobutylphenyl)propanoate), or GSK256066 ( 6[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methyl-quinoline-3-carboxamide).

[00118] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an IKK2 antagonist, such as 5-(2-isopropylisoindolin-5-yl)-3- [1-(2-methoxyethylsulfonyl)-4-piperidyl]-1H-indole-7-carboxylic acid.

[00119] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a chemokine receptor function modulator such as a CCR1, CCR2, CCR2A, CCR2B, CCR3 antagonist , CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 or CCR11 (for the C-C family), for example a CCR1, CCR2B or CCR5 receptor antagonist; CXCR1, CXCR2, CXCR3, CXCR4 or CXCR5 (for the C-X-C family), for example, a CXCR2 or CXCR3 receptor antagonist; or CX3CR1 for the C-X3-C family. For example, the present invention relates to the combination of a compound of the invention with PS-031291 (2-[(4-chloro-benzyl)-methyl-amide] 1-[(4-trifluoromethyl-phenyl)-amide] of pyrrolidine-1,2-dicarboxylic acid), CCX-354 (1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2- yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone), vicriviroc, maraviroc, cenicriviroc, navarixin (2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1 -(5-methyl-2-furyl)propyl]amino]-3,4-dioxo-cyclobuten-1-yl]amino]benzamide), SB656933 (1-(2-chloro-3-fluoro-phenyl)-3- (4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)urea), N-[1-[(3R)-3-(3,5-difluorophenyl)-3-(1-methylsulfonyl-4 -piperidyl)propyl]-4-piperidyl]-N-ethyl-2-(4-methylsulfonylphenyl)acetamide, N-[2-[(2S)-3-[[1-[(4-chlorophenyl)methyl]-4 - piperidyl]amino]-2-hydroxy-2-methyl-propoxy]-4-hydroxy-phenyl]acetamide, 2-[2-chloro-5-[(2S)-3-(5-chlorospiro[3H-benzofuran] acid -2,4'-piperidin]-1'-yl)-2-hydroxy-propoxy]-4-(methylcarbamoyl)phenoxy]-2-methyl-propanoic, N-[2-[(2,3-difluorophenyl)methylsulfanyl ]-6-[(1R,2S)-2,3-dihydroxy-1-methylpropoxy]pyrimidin-4-yl]azetidine-1-sulfonamide, or N-[2-[(2,3-difluorophenyl)methylsulfanyl ]-6-[[(1R,2R)-2,3-dihydroxy-1-methylpropyl]amino]pyrimidin-4-yl]azetidine-1-sulfonamide.

[00120] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or activator protein antagonist of 5-lipoxygenase (FLAP), such as TA270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), PF-4191834 (2H-pyran-4-carboxamide, tetra- hydro-4-[3-[[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl]-), setileuton, CMI977 (1-[4-[(2S,5S)-5 -[(4-fluorophenoxy)methyl]tetrahydrofuran-2-yl]but-3-ynyl]-1-hydroxy-urea), fiboflapon (3-[3-tert-butylsulfanyl-1-[[4-( 6-ethoxy-3-pyridyl)phenyl]methyl]-5-[(5-methyl-2-pyridyl)methoxy]indol-2-yl]-2,2-dimethyl-propanoic acid), GSK2190915 (1H-indol- 2-propanoic, 3-[(1,1-dimethylethyl)thio]-1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]-α,α-dimethyl-5-[(2-pyridinyl) )methoxy]-), lycofelone, quiflapon (3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(2-quinolylmethoxy)indol-2-yl]-2,2-dimethyl acid -propanoic), veliflapon ((2R)-2-cyclopentyl-2-[4-(2-quinolylmethoxy)phenyl]acetic acid), ABT080 (4,4-bis[4-(2-quinolylmethoxy)phenyl]pentanoic acid) , zileuton, zafirlucast, or montelucast.

[00121] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a CRTh2 antagonist or a DP2 antagonist, such as ACT129968 (2-[2-[( 5-acetyl-2-methoxy-phenyl)methylsulfanyl]-5-fluoro-benzimidazol-1-yl]acetic acid), AMG853 (2-[4-[4-(tert-butylcarbamoyl)-2-[(2-chloro -4-cyclopropyl-phenyl)sulfonylamino]phenoxy]-5-chloro-2-fluoro-phenyl]acetic), AM211 (2-[3-[2-[[benzylcarbamoyl(ethyl)amino]methyl]-4-( trifluoromethyl)phenyl]-4-methoxyphenyl]acetic acid), 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methyl-indol-1-yl]acetic acid, (2S)-2- [4-chloro-2-(2-chloro-4-ethylsulfonyl-phenoxy)phenoxy]propanoic acid, 2-[4-chloro-2-[2-fluoro-4-(4-fluorophenyl)sulfonyl-phenyl]phenoxy] acetic acid, or (2S)-2-[2-[3-chloro-4-(2,2-dimethylpyrrolidine-1-carbonyl)phenyl]-4-fluoro-phenoxy]propanoic acid.

[00122] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an MK2 (MAPKAP kinase 2) antagonist, such as varesplabid, PF-3644022 ((10R)- 10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3 ,2-f]quinolin-8-one), or 4-benzoyl-D-phenylalanyl-D-seryl-D-tryptophyl-D-seryl-2,3,4,5,6-pentafluoro-D-phenylalanyl-3 -cyclohexyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D-arginine.

[00123] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a myeloperoxidase antagonist, such as resveratrol, piceatannol, 3-[[(2R)-tetrahydrofuran -2-yl]methyl]-2-thioxo-7H-purin-6-one, or 1-(2-isopropoxyethyl)-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one.

[00124] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an osmolyte. As used herein, an "osmolyte" is an osmotically active small molecule and is intended to encompass both ionic and non-ionic osmolytes. In a further aspect of the invention there is provided a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an ionic osmolyte, such as hypertonic saline.

[00125] In yet another aspect of the present invention there is provided a pharmaceutical composition (e.g., for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as CF or COPD) comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from: a) a beta-adrenoceptor agonist; b) a muscarinic receptor antagonist c) a joint muscarinic receptor antagonist and beta-adrenoceptor agonist; or d) a glucocorticoid receptor agonist (steroidal or non-steroidal); or e) an osmolyte, for example an ionic osmolyte, such as hypertonic saline as defined above.

[00126] In yet another aspect of the invention, the at least one additional active ingredient is a beta-adrenoceptor agonist. In another aspect, the at least one additional active ingredient is a muscarinic receptor antagonist. In a further aspect, the at least one further active ingredient is a glucocorticoid receptor agonist (steroidal or non-steroidal). In yet another aspect, the at least one additional active ingredient is a joint muscarinic receptor antagonist and beta-adrenoceptor agonist. In yet another aspect, the at least one additional active ingredient is an osmolyte.

[00127] The compounds described in this report are also illustrated in the examples below. These examples are provided for illustrative purposes only and are not limiting.ABREVIATIONS:

GENERAL METHODS

[00128] NMR spectra were recorded on a Bruker Avance, Avance II or Avance III spectrometer at a proton frequency of 400, 500 or 600 MHz. A JEOL EX-270 spectrometer is used if a proton frequency of 270 MHz is reported. The central peaks of δ-chloroform (H 7.26 ppm), acetone (H 2.04 ppm), dichloromethane-d2 (H 5.32 ppm), CH3OD (H 3.30 ppm) or DMSO-d6 (H 2 .49 ppm) were used as internal references. Slight variations in chemical shifts can occur, as is well known in the art, as a result of variations in sample preparation, such as variations in analyte concentration and including or omitting additives (e.g., NMR assay standards or trifluoroacetic acid). .

[00129] LC/MS experiments were performed using a Waters Acquity UPLC system combined with a Waters Xevo Q-ToF Mass Spectrometer in ESI mode. LC was conducted in two sets: 1) BEH C18 column (1.7 µm 2.1x50 mm) in combination with a gradient (2 to 95% B in 5 min) of 46 mM ammonium carbonate/ammonium buffer in pH 10 (A) and MeCN (B) at a flow rate of 1.0 mL/min 2) HSS C18 column (1.8 μm 2.1 x 50 mm) with a gradient (2 to 95% B in 5 min) of 10 mM aqueous Fa/1 mM ammonium formate buffer in pH 3 (A) and MeCN (B) at a flow rate of 1.0 ml/min.

[00130] Optical purity, indicated as enantiomeric excess (% ee), was determined by chiral HPLC using an Agilent 1100 series chromatograph. Method A: System equipped with Chiralpak IC 250 x 4.6 mm; 5 µm. As mobile phase heptane/iPrOH/ethanolamine (60:40:0.1) with a flow rate of 1 mL/min was used. The injection volume was 10 μL and the compound detection was performed by UV at 268 nm. Method B: System equipped with Chiralpak IC 150x4.6 mm, 3 µm. As mobile phase CO2, 120 bar (A) and MeOH (0.5% DEA) (B) was used in an A/B ratio of 80/20 with a flow rate of 4 mL/min. The injection volume was 5 μL.

[00131] Preparative HPLC was performed with a Waters FractionLynx system with integrated MS detection and equipped with Prep C18 OBD 5 µm 19 x 150 mm X-Bridge or Sunfire columns. Alternatively Gilson GX-281 with built-in UV detection was used, equipped with either Kromasil C8 10 µm, 20x250 ID or 50x250 ID mm. As eluent gradients of water/MeCN/AcOH (95/5/0.1) or water/0.05% TFA or water/0.1% NH4HCO3 (A) and MeCN (B) were applied.

[00132] Preparative SCF was performed with a Waters Prep100 SCF system with integrated MS detection, equipped with Waters Viridis 2-EP or Phenomenex Luna Hilic, 30 x 250 mm, 5 µm. As eluent gradients of CO2 (100g/min, 120 bar, 40 oC) (A) and MeOH/NH3 (20 mM) or MeOH (5% FA) or MeOH (B) were applied.

[00133] Unless otherwise stated, starting materials were commercially available or previously described in the literature. All commercial solvents and reagents were laboratory grade and were used as received unless otherwise noted.

[00134] Chemical names, as described in the examples below, were generated using the ChemDraw naming package (Ultra 11). The skilled person will be aware that different naming packages can produce different chemical names for the same compound. For illustration purposes only, the chemical names generated for examples 1 through 16 below using the ACD/Name 2012 naming package are respectively: 3,5-diamino-6-chloro-N-[(2R)-2-(2 -methylbenzyl)-3-({[1-(3-{[(2S, 3R,4R)-2,3,4,5-tetrahydroxypentyl]amino}propanoyl)piperidin-4-yl]methyl}amino) propyl]pyrazine-2-carboxamide; 1-deoxy-1-[(2-{[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2- methylbenzyl)propyl]amino}methyl)benzoyl]amino}ethyl)(hexyl)amino]-D-xylitol; 1-deoxy-1-{[2-({[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2) -methylbenzyl)propyl]amino}methyl)piperidin-1-yl]carbonyl}amino)ethyl](hexyl)amino}-D-glucitol; 3,5-diamino-6-chloro-N-[(2R)-3-({[1-(3-{hexyl[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]amino}propanoyl)piperidin-4-yl]methyl}amino)-2-(2-methylbenzyl)propyl]pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-[(2R)-3-({[1-(3-{hexyl[(2S,3R,4R)-2,3,4,5-tetrahydroxypentyl] amino}propanoyl)piperidin-4-yl]methyl}amino)-2-(2-methylbenzyl)propyl]pyrazine-2-carboxamide; 1-deoxy-1-[{4-[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2-methylbenzyl) )propyl]amino}methyl)piperidin-1-yl]-4-oxobutyl}(hexyl)amino]-D-glucitol; 3,5-diamino-6-chloro-N-[(2R)-2-(2-methylbenzyl)-3-({[1-(3-{[(2S,3R,4R,5R)-2,3 ,4,5,6-pentahydroxyhexyl]amino}propanoyl)piperidin-4-yl]methyl}amino)propyl]pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-[(2R)-3-({[1-(3-{hexyl[(2R,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]amino}propanoyl)piperidin-4-yl]methyl}amino)-2-(2-methylbenzyl)propyl]pyrazine-2-carboxamide; 1-deoxy-1-[(2-{[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2- methylbenzyl)propyl]amino}methyl)benzoyl]amino}ethyl)(hexyl)amino]-D-mannitol; 1-deoxy-1-[(2-{[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2- methylbenzyl)propyl]amino}methyl)benzoyl]amino}ethyl)(hexyl)amino]-D-glucitol; 1-deoxy-1-{[2-({[4-({[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2) -methylbenzyl)propyl]amino}methyl)phenoxy]carbonyl}amino)ethyl](hexyl)amino}-D-glucitol; 1-deoxy-1-[(2-{[4-(2-{[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-( 2-methylbenzyl)propyl]amino}ethyl)benzoyl]amino}ethyl)(hexyl)amino]-D-glucitol; 1-deoxy-1-[(2-{[4-(2-{[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-( 2-methylbenzyl)propyl]amino}ethyl)benzoyl]amino}ethyl)(hexyl)amino]-D-xylitol; 1-deoxy-1-[(2-{[4-({[(2S)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2- methylbenzyl)propyl]amino}methyl)benzoyl]amino}ethyl)(hexyl)amino]-D-xylitol; 5-deoxy-5-[(2-{[4-({[(2S)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-(2- methylbenzyl)propyl]amino}methyl)benzoyl]amino}ethyl)(hexyl)amino]-D-xylitol; 1-deoxy-1-[(2-{[3-(2-{[(2R)-3-{[(3,5-diamino-6-chloropyrazin-2-yl)carbonyl]amino}-2-( 2-methylbenzyl)propyl]amino}ethyl)benzoyl]amino}ethyl)(hexyl)amino]-D-glucitol. EXAMPLE 1 3,5-Diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-(((1-(3-(((2S,3R,4R)-2,3 ,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide Step 1 (3-(4-(((3-(3,5-Diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)piperidin-1-yl)-3 (R)-(9H-fluoren-9-yl)methyl-oxopropyl)carbamate

[00135] A mixture of (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (318 mg, 0.91 mmol) ( Intermediate A), (9H-fluoren-9-yl)methyl 3-(4-formylpiperidin-1-yl)-3-oxopropylcarbamate (440 mg, 1.08 mmol) (Intermediate F) and acetic acid (80 µL, 1.40 mmol) in dry THF (6 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (340 mg, 1.60 mmol) was added and the reaction mixture was stirred at 40 °C for a further 1.5 h. Water was added and the mixture stirred for 5 min and the solvents were evaporated. The residual material was partitioned between EtOAc and water. To the aqueous phase was added 10% NaHCO 3 (aq.) until pH 8-9 was reached. The phases were separated and the aqueous phase was extracted again with EtOAc. The combined yellow organic phases were dried over MgSO4, filtered and the solvents were evaporated. The crude product was purified by preparative HPLC (Kromasil C8; H2O/MeCN/AcOH 95/5/0.2). Relevant fractions were combined and concentrated in vacuo. 10% NaHCO 3 (aq.) was added and the water phase was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and evaporated. The residual viscous oil was dissolved in DCM/Heptane to give after evaporation the title compound as a solid, 196mg (29%, purity 87%).

[00136] LC/MS: m/z 739 [M+H]+ Step 2 (R)-3,5-diamino-N-(3-(((1-(3-aminopropanoyl)piperidin-4-yl) methyl)amino)-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide

[00137] 3-(4-((3-(3,5-Diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)piperidin-1-yl)-3-oxopropylcarbamate (R)-(9H-fluoren-9-yl)methyl (196 mg, 0.27 mmol) (from step 1) was dissolved in DCM (5 mL) and treated with piperidine (0.5 mL). The solution was stirred at room temperature for 3 h, then evaporated to leave a yellow solid.

[00138] The crude material was dissolved in THF (5 mL) and DIPEA (280 µL, 1.60 mmol) and treated with (BOQ2O (0.141 mL, 0.61 mmol) in THF (1 mL). The mixture was stirred at room temperature. After 3 h, LC/MS showed only minor conversion to mono-Boc protected product, most was still unreacted amine. A large excess of DIPEA and BOC2(O) was added and the mixture was stirred for 1 h at room temperature MeCN (2-3 ml) was added to increase solubility and the mixture was heated at 50 °C for 2 h, then at room temperature over the weekend.

[00139] The volatiles were evaporated in vacuo and the residue partitioned between EtOAc and water. The water phase was made acidic by addition of 0.5M citric acid. Brine was added to aid phase separation. The organic phase was washed with water and brine.

[00140] Solvent was evaporated and the residue was dissolved in DCM and purified by flash chromatography (EtOAc/Heptane, gradient 30 - 100% EtOAc). The solvents were evaporated to give the di-BOC protected title compound (96 mg).

[00141] The obtained di-BOC-protected material (96 mg) was dissolved in DCM (2 mL) and treated with TFA (0.5 mL), the solution was stirred at room temperature for 2.5 hours. The mixture was evaporated, the residue dissolved in water and purified by preparative HPLC (Kromasil C8; H2O/MeCN/HCO2H 95/5/0.2 to 60/40/0.2 for 16 min). Freeze drying provided the title compound as a solid (64mg, 45%).

[00142] LC/MS: m/z 517 [M+H]+

[00143] 1H NMR (500 MHz, MeOD) δ 1.13 - 1.34 (m, 2H), 1.83 - 2.06 (m, 3H), 2.29 - 2.39 (m, 1H) , 2.35 (s, 3H), 2.59 - 2.93 (m, 9H), 3.08 - 3.23 (m, 3H), 3.32 - 3.37 (m, 1H), 3 .67 - 3.74 (m, 1H), 3.87 - 3.96 (m, 1H), 4.52 - 4.6 (m, 1H), 7.11 - 7.22 (m, 4H) , 8.51 (s, 0.4H, formic acid residue). Step 3 3,5-Diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-(((1 -(3-(((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide

[00144] (R)-3,5-Diamino-N-(3-(((1-(3-aminopropanoyl)piperidin-4-yl)methyl)amino)-2-(2-methylbenzyl)propyl)-6 -chloropyrazine-2-carboxamide (900 mg, 1.74 mmol) was dissolved in methanol (10 mL). (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal (261 mg, 1.74 mmol) was added, followed by five drops of water. Sodium cyanoborohydride (328 mg, 5.22 mmol) was then added and pH adjusted to ~7.0 by addition of acetic acid. The resulting solution was stirred at room temperature for 18 h. Volatiles were removed and the resulting crude product was purified by preparative HPLC (H2O/MeCN/AcOH 95/5/0.2 to 60/40/0.2 for 20 min). The relevant fractions were collected and freeze-dried. The title compound was dissolved in 2M HCl (4 ml) and freeze dried, a procedure repeated three times, yielding the HCl salt of the title compound (144 mg, 11%).1H NMR (500 MHz, MeOD ) δ 1.30 (ddd, 2H), 1.84 - 2.13 (m, 3H), 2.32 - 2.45 (m, 4H), 2.62 - 2.77 (m, 2H), 2.81 - 2.98 (m, 7H), 3.15 (dd, 1H), 3.26 (d, 2H), 3.32 - 3.42 (m, 2H), 3.58 - 3, 83 (m, 6H), 3.95 (t, 1H), 4.06 (dd, 1H), 4.55 (s, 1H), 7.05 - 7.33 (m, 4H). ,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino )ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide METHOD A Step 1 ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S,3R tert-butyl ,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate

[00145] (3-(3,5-Diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate ( S)-tert-butyl (Intermediate E, 1.23 g, 1.73 mmol), (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal (0.521 g, 3.47 mmol) and DIPEA (0.303 mL, 1.73 mmol) was dissolved in MeOH (10 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (0.327 g, 5.20 mmol) and acetic acid (0.099 mL, 1.73 mmol) were added and stirring continued at 50 °C for 3 days. The reaction was cooled to room temperature, quenched by addition of 8% NaHCO 3 (aq), stirred for 15 min and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and 8% NaHCO 3 (aq) (50 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250x50 ID mm) using a gradient of 20 - 60% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 ml/min. Compounds were detected by UV at 268 nm. The compound was collected and freeze-dried to yield ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2- ( tert-butyl hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (1.21 g, 83%) as a white solid.

[00146] LC/MS: m/z 843.5 [M+H]+

[00147] 1H NMR (500 MHz, DMSO-d6) δ 0.74 - 0.85 (m, 3H), 1.12 - 1.27 (m, 6H), 1.27 - 1.45 (m, 11H), 2.20 (s, 3H), 2.25 - 2.35 (m, 1H), 2.39 - 2.66 (m, 6H), 2.9 - 3.06 (m, 1H) , 3.06 - 3.51 (m, 12H), 3.53 - 3.6 (m, 1H), 3.6 - 3.72 (m, 1H), 4.2 - 4.68 (m, 5H), 6.97 (bs, 2H), 7.03 - 7.19 (m, 6H), 7.72 (d, 2H), 7.78 - 7.99 (m, 1H), 8.21 - 8.36 (m, 1H). Step 2 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R) )-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00148] Acetyl chloride (5.69 mL, 80.0 mmol) was added dropwise to a chilled vial of ice bath MeOH (20 mL). The mixture was stirred for 5 min and ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl( tert-Butyl (2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (1.21 g, 1.43 mmol) was added. The reaction was stirred at room temperature for 1.5 h and was then evaporated in vacuo. The residue was dissolved in water and freeze-dried to yield 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R )-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.17 g, 100%) as a pale solid.

[00149] LC/MS: m/z 743.4 [M+H]+

[00150] 1H NMR (500 MHz, DMSO-d6) δ 0.8 - 0.9 (m, 3H), 1.2 - 1.33 (m, 6H), 1.62 - 1.74 (m, 2H), 2.26 (s, 3H), 2.3 - 2.41 (m, 1H), 2.59 - 2.74 (m, 2H), 2.74 - 2.85 (m, 1H) , 2.86 - 2.98 (m, 1H), 3.09 - 3.51 (m, 11H), 3.56 - 3.62 (m, 1H), 3.62 - 3.75 (m, 2H), 3.99 - 4.09 (m, 1H), 4.14 - 4.29 (m, 2H), 4.58 (s, 4H), 7 - 7.21 (m, 6H), 7 .62 (d, 2H), 7.92 (d, 2H), 8.27 (t, 1H), 8.91 - 9 (m, 1H), 9.16 (d, 2H), 9.52 ( d, 1H). Step 3 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetra- hydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00151] 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl ((2S,3R,4R)-2,3,4,5) dihydrochloride -tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.17 g, 1.43 mmol) was dissolved in water (15 mL) and basified by addition of 10% Na2CO3 (aq) to pH ~11. The product was extracted with EtOAc (5 x 70 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo to yield an oil/semi-solid. The residue was dissolved in acetonitrile/water and freeze-dried to yield 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R )-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.02 g, 96%) as a pale solid.

[00152] LC/MS: m/z 743.5 [M+H]+

[00153] 1H NMR (500 MHz, DMSO-d6) δ 0.75 - 0.85 (m, 3H), 1.12 - 1.26 (m, 6H), 1.31 - 1.43 (m, 2H), 1.94 - 2.05 (m, 1H), 2.24 (s, 3H), 2.35 - 2.49 (m, 5H), 2.54 - 2.65 (m, 4H) , 3.14 - 3.23 (m, 1H), 3.25 - 3.4 (m, 5H), 3.4 - 3.49 (m, 2H), 3.53 - 3.59 (m, 1H), 3.62 - 3.78 (m, 3H), 4.26 (d, 1H), 4.38 (d, 1H), 4.45 (t, 1H), 4.51 (d, 1H ), 6.96 (bs, 2H), 7.03 - 7.14 (m, 4H), 7.40 (d, 2H), 7.74 (d, 2H), 8.24 - 8.37 ( m, 2H). METHOD B 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4 ,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00154] A 5 L flange flask was charged with a solution of 4-formyl-N-(2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino) ethyl)benzamide (Intermediate I, 133 g, 108.5 g active, 0.26 mol) in EtOH (1500 mL), (R)-3,5-diamino-N-(3-amino-2-(2- methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (Intermediate A, 108.8 g, 0.31 mol), EtOH (230 mL) and DIPEA (64.4 mL, 0.37 mol). The mixture was heated to 40 °C for 1 h. To the clear solution was charged AcOH (45.4 ml, 0.79 mol). The solution was stirred at 40°C for 20 min. To this was charged NaCNBH3 (23.2 g, 0.37 mol) portionwise over 10 min, noting gas evolution. The mixture was stirred at 40°C overnight. The reaction was cooled to room temperature, carefully quenched with saturated aqueous NaHCO 3 (3100 mL) and stirred at room temperature for 1 h. The mixture was extracted with 10% MeOH/EtOAc (2 x 5000 mL) and 10% MeOH/DCM (5000 mL). The organic phases were combined and concentrated in vacuo to provide 271 g of crude material. NMR analysis indicated approximately 80% purity, with signs of NaCNBH3 present. The residue was dissolved in DCM (12 L) and IPA (770 ml). The mixture was washed with a mixture of saturated aqueous NaHCO 3 (2700 ml) and water (770 ml). The aqueous phase was extracted with DCM (1200 ml). The organics were combined and concentrated in vacuo to give 298 g (191 g active, 97%) as a yellow solid. HPLC-MS indicated 88.0% purity. 1H NMR indicated approximately 60% purity, with approximately 27 wt% IPA and approximately 8 wt% Intermediate A.

[00155] The crude thus obtained (290 g, 235 mmol) was diluted in hot MeOH (750 mL) and acetonitrile (15 L) was added continuously while evaporating an azeotrope from the mixture. After approx. 10 L of solvent was evaporated, the remaining mixture containing a gum like precipitate was stirred for another 4 d at room temperature.

[00156] The liquid phase was decanted from the residue type gum. To the residue, 2.5 L of acetonitrile was added and after stirring for 1 h the acetonitrile was decanted. The crude thus obtained (approx. 175 g) was subjected to a final purification by HPLC chromatography [CelluCoat 250 x 100 mm, 10 μm; mobile phase: MeOH / MeCN / TEA = 95:5:0.1; injected quantity: 1.0 g/cycle; cycle time: 3.5 min]. Yield of title compound: 148g (77%).

[00157] LC/MS: m/z 743.5 [M+H]+

[00158] 1H NMR (600 MHz, DMSO; in case of atropisomeric peaks, only the change in the main atropisomer is reported) δ 0.80 (t, 3H), 1.34 - 1.4 (m, 2H), 1 .09 - 1.24 (m, 6H), 1.34 - 1.4 (m, 2H), 2.00 (s, 1H), 2.00 (s, 1H), 2.24 (s, 3H ), 2.36 - 2.42 (m, 1H), 2.43 - 2.49 (m, 4H), 2.51 - 2.54 (m, 1H), 2.56 - 2.64 (m , 4H), 3.15 - 3.22 (m, 1H), 3.23 - 3.3 (m, 3H), 3.35 - 3.4 (m, 1H), 3.42 (s, 1H ), 3.43 - 3.49 (m, 1H), 3.54 - 3.59 (m, 1H), 3.62 - 3.7 (m, 2H), 3.74 (d, 1H), 4.27 (s, 1H), 4.39 (s, 1H), 4.46 (t, 1H), 4.52 (s, 1H), 6.96 (s, 1H), 7.03 - 7 .08 (m, 2H), 7.40 (d, 2H), 7.74 (d, 2H), 8.26 - 8.31 (m, 1H), 8.31 - 8.35 (m, 1H) ).

[00159] 13C NMR (151 MHz, DMSO) δ 13.91, 19.04, 22.08, 26.48, 26.61, 31.27, 34.23, 37.42, 38.60, 41, 55, 50.84, 53.06, 53.44, 54.55, 57.43, 62.65, 69.23, 71.12, 72.61, 112.95, 117.12, 125.54, 125.83, 126.89, 127.72, 129.63, 130.03, 132.85, 135.82, 138.74, 144.02, 152.69, 154.14, 165.55, 166.01.

[00160] Chiral HPLC (method A; Heptane/IPA/TEA 75:25:0.1): 98.9% ee, Rt = 14.75 min (R), 18.63 min (S).EXAMPLE 3 3 ,5-Diamino-6-chloro-N-((R)-3-((1-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-penta- hydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1: 2-(((2S,3R)-2,3-dihydroxy-3-((4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl) (9H-fluoren-9-yl)methyl (hexyl)amino)ethylcarbamate

[00161] In a 100 mL round bottom flask, 9H-fluoren-9-ylmethyl N-(2-aminoethyl)carbamate hydrochloride (1.50 g, 4.71 mmol, 1.0 equiv) was placed, (2R,4aR,7R,8R,8aS)-2-phenyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6,7,8-triol (1.51 g, 5, 63 mmol, 1.20 equiv), methanol (30 mL). After stirring the above mixture for 30 min, NaBH3CN (590 mg, 9.39 mmol, 2.00 equiv), AcOH (570 mg, 9.49 mmol, 2.0 equiv) were added. The resulting solution was stirred overnight at room temperature. Then hexanal (530 mg, 5.29 mmol, 1.50 equiv) was added, followed by more NaBH3CN (450 mg, 7.16 mmol, 2.00 equiv). The resulting solution was stirred for 5 hours at room temperature. Then it was concentrated under vacuum. The resulting mixture was washed with water, extracted with ethyl acetate and the organic layers combined and dried over Na2SO4. The solids were filtered. This resulted in 1.6 g (73%) of the title compound as a pale yellow oil.

[00162] LC/MS: m/z 619 [M+H]+

[00163] 1H NMR (300 MHz, CD3OD): 1.80 - 1.92 (m, 3H), 1.15 - 1.40 (m, 6H), 1.41 - 1.72 (m, 2H) , 2.88 - 3.15 (m, 5H), 3.33 - 3.43 (m, 2H), 3.55 - 3.61 (m, 1H), 3.67 - 3.83 (m, 1H), 3.85 - 4.12 (m, 3H), 4.22 - 4.40 (m, 4H), 5.57 (s, 1H), 7.33 - 7.65 (9H, m) , 7.67 (d, 2H), 7.83 (d, 2H). Step 2: (1R,2S)-3-((2-aminoethyl)(hexyl)amino)-1-[(2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4- yl]propane-1,2-diol

[00164] In a 50 mL round bottom flask, N-(2-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy 9H-fluoren-9-ylmethyl-2-phenyl-1,3-dioxan-4-yl]propyl](hexyl)amino]ethyl)carbamate (1.6 g, 2.59 mmol, 1.0 equiv), methanol (10 mL), diethylamine (5 mL). The resulting solution was stirred overnight at room temperature. The residue was applied to a silica gel column and eluted with ammonia/MeOH (1:100). This resulted in 600 mg (59%) of the title compound as a yellow solid.

[00165] LC/MS: m/z 397 [M+H]+Step 3: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl ((1-(2-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4- (9H-fluoren-9-yl)methyl yl)propyl)(hexyl)amino)ethylcarbamoyl)piperidin-4-yl)methyl)carbamate

[00166] In a 50 mL round bottom flask, were placed - 3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl (piperidin-4-ylmethyl)carbamate of (S)-(9H-fluoren-9-yl)methyl (Intermediate B, 400 mg, 0.60 mmol, 1.0 equiv), triethylamine (177 mg, 1.75 mmol, 3.0 equiv), triphosgene (173 mg, 0.58 mmol, 1.0 equiv) in DCM (5 mL). The resulting solution was stirred for 0.5 h at room temperature. The resulting mixture was washed with 3 x 10 mL of water. The resulting mixture was concentrated under vacuum to provide the intermediate chloroformamide which was added dropwise (dissolved in DCM) to a solution of triethylamine (177 mg, 1.75 mmol, 3.0 equiv) and (1R,2S)-3 -[(2-aminoethyl)(hexyl)amino]-1-[(2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl]propane-1,2-diol ( 347 mg, 0.88 mmol, 1.50 equiv) in DCM (5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC with DCM/MeOH (10:1). This resulted in 145 mg (22%) of the title compound as a yellow solid.

[00167] LC/MS: m/z 1090 [M+H]+ Step 4: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl (9H ((1-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methyl)carbamate -fluoren-9-yl)methyl

[00168] In an 8 mL flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(2- ( ((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl)amino (9H-fluoren-9-yl)methyl)ethylcarbamoyl)piperidin-4-yl)methyl)carbamate (144 mg, 0.13 mmol, 1.0 equiv), ethanol (0.5 mL), 4M HCl (3 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 120 mg (crude) of the title compound as a yellow oil.

[00169] LC/MS: m/z 1002 [M+H]+Step 5: 3,5-Diamino-6-chloro-N-((R)-3-((1-(2-(hexyl(( 2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00170] In a 50 mL round bottom flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( 9H-Fluoren-9-yl 2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methyl)carbamate )methyl (120 mg, 0.12 mmol, 1.0 equiv), diethylamine (2 mL) in N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC with the following conditions (2#-AnalyzeHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase, Waters with 0.05% TFA and ACN (23.0% ACN to 33.0% in 15 min); Detector, MS, UV 254 nm. This resulted in 8 mg (7%) of the title compound as a yellow solid.

[00171] LC/MS: m/z 780 [M+H]+

[00172] 1H NMR (300 MHz, CD3OD): 0.91 - 0.95 (m, 3H), 1.27 - 1.38 (m, 8H), 1.81 - 1.97 (m, 5H) , 2.36 (s, 4H), 2.62-2.69 (m, 1H), 2.86-2.96 (m, 7H), 3.31-3.55 (m, 3H), 3 .63-3.68 (m, 6H), 3.70-3.83 (m, 6H), 4.054.17 (m, 3H), 7.13-7.20 (m, 4H) EXAMPLE 4 3, 5-Diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl) )amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1: 3-((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propylamino ) benzyl propanoate

[00173] In a 100 mL round bottom flask, 4-methylbenzene-1-sulfonic acid benzyl 3-aminopropanoate (2.00 g, 5.69 mmol, 1.0 equiv), (2R,4aR ,7R,8R,8aS)-2-phenyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6,7,8-triol (2.29 g, 8.54 mmol, 1 .5 equiv), methanol (30 mL). After 30 min, NaBH3CN (720 mg, 11.46 mmol, 2.00 equiv), AcOH (680 mg, 11.32 mmol, 2.0 equiv) were added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layers were dried over anhydrous sodium sulfate. The solids were filtered. Removal of the solvents in vacuo left 1.9g (77%) of the title compound as a colorless oil which was used directly in the next step.

[00174] LC/MS: m/z 967 [M+H]+ Step 2: 3-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5 Benzyl -hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl)amino)propanoate

[00175] In a 100 mL round bottom flask, 3-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy-2- benzyl phenyl-1,3-dioxan-4-yl]propyl]amino]propanoate (1.90 g, crude), hexanal (660 mg, 6.59 mmol, 1.5 equiv), methanol (30 mL). After 30 min, NaBH3CN (550 mg, 8.75 mmol, 2.0 equiv) and AcOH (530 mg, 8.83 mmol, 2.0 equiv) were added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated, diluted with ethyl acetate and washed with water, the organic layers were dried over anhydrous sodium sulfate. The solids were filtered. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 1.3 g (57%) of 3-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy-2-phenyl-1 Benzyl ,3-dioxan-4-yl]propyl](hexyl)amino]propanoate as pale yellow oil.

[00176] LC/MS: m/z 516 [M+H]+ Step 3: Acid 3-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)- 5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl)amino)propanoic

[00177] In a 100 mL round bottom flask, 3-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy-2- Benzyl phenyl-1,3-dioxan-4-yl]propyl](hexyl)amino]propanoate (1.3 g, 2.52 mmol, 1.0 equiv), Pd/C (5 wt%, 700 mg) , ethanol (20 mL). To the above mixture was added H2 (g). The resulting solution was stirred under an H2 atmosphere overnight at room temperature. The solids were filtered. The filtrate was concentrated under vacuum. This resulted in 0.5 g (47%) of 3-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy-2-phenyl- 1,3-dioxan-4-yl]propyl](hexyl)amino]propanoic acid as a colorless oil. LC/MS: m/z 426 [M+H]+ Step 4: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1 -(3-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl (9H-fluoren-9-yl)methyl)(hexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate

[00178] In a 50 mL round bottom flask, 3-[[(2S,3R)-2,3-dihydroxy-3-[(2R,4R,5R)-5-hydroxy-2 -phenyl-1,3-dioxan-4-yl]propyl](hexyl)amino]propanoic (381.49 mg, 0.90 mmol, 3.00 equiv), 3-(3,5-diamino-6-chloropyrazine (S)-(9H-fluoren-9-yl)methyl-2-(2-methylbenzyl)propyl(piperidin-4-ylmethyl)carbamate (Intermediate B, 200.0 mg, 0.30 mmol , 1.0 equiv), HATU (170.5 mg, 0.45 mmol, 1.5 equiv), DIEA (57.9 mg, 0.45 mmol, 1.5 equiv), N,N-dimethylformamide (5 mL). The resulting solution was stirred for 2 h at room temperature. Water was added to the above mixture and the suspension was extracted with ethyl acetate. The organic layers combined and washed with brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=10:1). Relevant fractions were collected and after removal of volatiles resulted in 200 mg (62%) of the title compound as a yellow solid.

[00179] LC/MS: m/z 1076 [M+H]+ Step5:(S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl( (9H-(9H-)(9H-(9H- fluoren-9-yl)methyl

[00180] In a 50 mL round bottom flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( 3-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)( (9H-fluoren-9-yl)methyl hexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate (step 4, 200 mg, 0.19 mmol, 1.0 equiv) and HCl solution (4M in ethanol, 2 mL). The resulting solution was stirred overnight at room temperature. Evaporation of volatiles resulted in 200 mg of crude title compound as a yellow solid.

[00181] LC/MS: m/z 987 [M+H]+ Step 6: 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexH(( 2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00182] In a 25 mL round bottom flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( (9H-fluoren-9- 3-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate yl)methyl (step 5200 mg, 0.20 mmol, 1.00 equiv), methanol (6 mL), diethylamine (3 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC with the following conditions (Prep-HPLC-019): Column, XSelect CSH Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase, WATERS with 0.05% TFA and MeCN (22.0% MeCN to 30.0% in 8 min, to 100% in 1 min, held 100% in 1 min, to 22% in 2 min) ; Detector, UV 254/220 nm. This resulted in 38 mg (21%) of 3,5-diamino-6-chloro-N-[(2R)-3-([[1-(3-[hexyl[(2S,3R,4R,5R)- 2,3,4,5,6-pentahydroxyhexyl]amino]propanoyl)piperidin-4-yl]methyl]amino)-2-[(2-methylphenyl)methyl]propyl]pyrazine-2-carboxamide; trifluoroacetic acid as a yellow solid.

[00183] 1H NMR (300 MHz, CD3OD): δ 0.95 - 0.97 (m, 3H), 1.22 -1.50 (m, 8H), 1.70 - 2.10 (m, 5H ), 2.30 - 2.51 (m, 4H), 2.63 - 2.81 (m, 2H), 2.88 - 3.16 (m, 7H), 3.16 - 3.20 (m , 2H), 3.34 - 3.78 (m, 5H), 3.51 - 3.87 (m, 7H), 3.95 - 4.10 (m, 1H), 4.10 - 4.25 (m, 1H), 4.54 (d, 1H), 7.14 - 7.22 (m, 4H).

[00184] LC/MS: m/z 765 [M+H]+ EXAMPLE 5 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexH((2S ,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1: (1-(3-tert-butoxycarbonylaminopropanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (S)-(9H-fluoren-9-yl)methyl

[00185] One vial (25 mL) (S)-(9H-fluoren-9-yl)methyl chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl(piperidin-4-ylmethyl)carbamate (Intermediate B , 300 mg, 0.45 mmol), 3-(tert-butoxycarbonylamino)propanoic acid (100 mg, 0.53 mmol), DIPEA (145 mg, 1.13 mmol), HATU (342 mg, 0.9 mmol) and DMF (10 mL) were added. The reaction was stirred for 6 h at room temperature. The mixture was diluted with 25 mL of ethyl acetate and washed with water (3 x 25 mL). The organic layer was dried over anhydrous Na2SO4. The precipitation was filtered and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column with dichloromethane / methanol (20:1, v/v) to give the title compound (280 mg, 67%) as pale yellow solid.

[00186] LC/MS: m/z 839 [M+H]+ Step2: (1-(3-aminopropanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2- (S)-(9H-fluoren-9-yl)methyl carboxamido)-2-(2-methylbenzyl)propyl)carbamate

[00187] In a 50 mL round bottom flask were placed (1-(3-tert-butoxycarbonylaminopropanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)- (S)-(9H-fluoren-9-yl)methyl 2-(2-methylbenzyl)propyl)carbamate (step 1, 216 mg, 0.26 mmol, 1.0 equiv) and hydrogen chloride (4M in methanol , 5 mL). The resulting solution was stirred for 1 h at room temperature. Evaporation of volatiles resulted in 190 mg of crude title compound as a yellow solid.

[00188] LC/MS: m/z 739 [M+H]+ Step 3: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl( (9H-fluoren-9-(1-(3-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate yl)methyl

[00189] In a 50 mL round bottom flask, were placed (1-(3-aminopropanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2 (S)-(9H-fluoren-9-yl)methyl-(2-methylbenzyl)propyl)carbamate (step 2, 190 mg, 0.26 mmol, 1.0 equiv), (3R,4S,5R)- oxane-2,3,4,5-tetrol (39 mg, 0.26 mmol, 1.0 equiv), methanol (6 mL). After 30 min, NaBH3CN (66 mg, 1.05 mmol, 4.0 equiv) was added slowly at 0 °C. The resulting solution was stirred overnight at room temperature. Then hexanal (39 mg, 0.39 mmol, 1.0 equiv) was added, followed by more NaBH 3CN (66 mg, 1.05 mmol, 4.0 equiv). The resulting solution was stirred for 5 h at room temperature. The solvent was removed to give the crude product, which was used in the next step directly without further purification.

[00190] LC/MS: m/z 957 [M+H]+ Step 4: 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl(( 2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00191] In a 50 mL round bottom flask were placed (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(3 (9H-fluoren-9-yl)methyl-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate (step 3, 230 mg, 0.24 mmol, 1.00 equiv), methanol (5 mL), diethylamine (0.5 mL). The resulting solution was stirred for 3 h at room temperature. The crude product was purified by preparative HPLC with the following conditions (Prep-HPLC-019): Column, XSelect CSH Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase, WATERS with 0.05% TFA and MeCN (18.0% MeCN to 35.0% in 8 min, to 100.0% in 1 min, held 100.0% in 1 min, to 18, 0% in 2 min); Detector, UV 254/220 nm. This resulted in 36.9 mg (16%) of the title compound as a yellow solid.

[00192] LC/MS: m/z 735 [M+H]+

[00193] 1H NMR (300 MHz, CD3OD): δ 0.96 (d, 3H), 1.26-1.40 (m, 8H), 1.81-2.01(m, 5H), 2, 37 (s, 4H), 2.62-2.94 (m, 9H), 3.17-3.47 (m, 7H), 3.55-3.78 (m, 6H), 3.98 ( d, 1H), 4.15 (s, 1H), 4.56 (d, 1H), 7.14-7.21 (m, 4H). EXAMPLE 6 3,5-diamino-6-chloro-N- ((R)-3-((1-(4-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)butanoyl)piperidin-4-yl )methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1: ((1-(4-((tert-butoxycarbonyl)amino)butanoyl)piperidin-4-yl)methyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-( (S)-(9H-fluoren-9-yl)methyl 2-methylbenzyl)propyl)carbamate

[00194] In a 50 mL round bottom flask were placed (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl) (piperidin-4-ylmethyl)carbamate (S)-(9H-fluoren-9-yl)methyl (Intermediate B, 900 mg, 1.35 mmol), 4-((tert-butoxycarbonyl)amino)butanoic acid (821 mg, 4.04 mmol), HATU (2305 mg, 6.06 mmol), and DIEA (1.06 mL, 6.06 mmol) in DMF (10 mL) to give a yellow solution. The resulting solution was stirred at 25 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give crude product. The crude product was purified by flash chromatography on silica gel, eluted by a gradient of 20 to 70% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give the title compound (834 mg, 73%) as a yellow solid.

[00195] LC/MS: m/z 853 [M+H]+ Step 2:(1-(4-aminobutanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2) (S)-(9H-fluoren-9-yl)methyl-carboxamido)-2-(2-methylbenzyl)propyl)carbamate

[00196] ((1-(4-((tert-butoxycarbonyl)amino)butanoyl)piperidin-4-yl)methyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-( (S)-(9H-fluoren-9-yl)methyl 2-methylbenzyl)propyl)carbamate (step 1, 834 mg, 0.98 mmol) was dissolved in a methanolic solution of HCl (4M) and stirred at room temperature for 1 h. The solvent was evaporated in vacuo to give the title compound as a yellow solid.

[00197] LC/MS: m/z 753 [M+H]+ Step 3: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl( (1-(4-((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl) (9H-fluoren-9-yl)methyl propylamino)butanoyl)piperidin-4-yl)methyl)carbamate

[00198] In a 25 mL round bottom flask were placed (1-(4-aminobutanoyl)piperidin-4-yl)methyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2- (S)-(9H-fluoren-9-yl)methyl (2-methylbenzyl)propyl)carbamate (step 2, 250 mg, 0.33 mmol, 1.0 equiv), (2R,4aR,7R,8R, D-glucose acetal-protected 8aS)-2-phenyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6,7,8-triol (133 mg, 0.50 mmol, 1 .5 equiv) and methanol (5 mL). The mixture was stirred for 30 min, then NaBH 3 CN (41 mg, 0.65 mmol, 2.0 equiv) and AcOH (40 mg, 0.67 mmol, 2.00 equiv) were added. The resulting solution was stirred overnight at room temperature. The solvent was removed under reduced pressure to give 210 mg (crude) of (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( 4-((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propylamino)butanoyl) (9H-fluoren-9-yl)methyl piperidin-4-yl)methyl)carbamate as a yellow solid.

[00199] LC/MS: m/z 1005[M+H]+ Step 4: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl ((1-(4-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4- (9H-fluoren-9-yl)methyl yl)propyl)(hexyl)amino)butanoyl)piperidin-4-yl)methyl)carbamate

[00200] (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(4-((2S,3R)-2,3 (9H) -dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propylamino)butanoyl)piperidin-4-yl)methyl)carbamate -fluoren-9-yl)methyl (210 mg, crude) was dissolved in MeOH (5 mL), hexanal (42 mg, 0.42 mmol, 2.00 equiv) was added, followed by NaBH3CN (26 mg, 0. 41 mmol, 2.00 equiv) and AcOH (25 mg, 0.42 mmol, 2.00 equiv). The resulting mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The residue was taken up with water and extracted with 3 x 20 mL of ethyl acetate. The organic layers combined and concentrated in vacuo and yielded 152 mg (67%) of the title compound as a crude yellow oil.

[00201] LC/MS: m/z 1089 [M+H]+ Step 5: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl (9H(1-(4-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)butanoyl)piperidin-4-yl)methyl)carbamate - fluoren-9-yl)methyl

[00202] In a 25 mL round bottom flask were placed (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(4 -(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl (9H-fluoren-9-yl)methyl)amino)butanoyl)piperidin-4-yl)methyl)carbamate (step 4, 152 mg, 0.14 mmol, 1.00 equiv), HCl (4M in ethanol, 5 mL) and ethanol (1 mL). The resulting solution was stirred overnight at room temperature. Evaporation of volatiles resulted in 138 mg of crude title compound as a yellow oil.

[00203] LC/MS: m/z 1002 [M+H]+ Step 6: 3,5-diamino-6-chloro-N-((R)-3-((1-(4-(hexyl(( 2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)butanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00204] In a 25 mL round bottom flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( (9H-fluoren-9- 4-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)butanoyl)piperidin-4-yl)methyl)carbamate yl)methyl (step 4, 138 mg, 0.14 mmol, 1.0 equiv), diethylamine (2 mL), N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (110 mg) was purified by preparative HPLC with the following conditions: Column, XSelect CSH Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase, WATERS with 0.05% TFA and MeCN (23% MeCN to 30% in 8 min, to 100% in 1 min, held 100% in 1 min, to 23.0% in 2 min); Detector, uv 254/220 nm. 15.7 mg (13%) of the title compound as trifluoroacetate was obtained as a yellow solid.

[00205] LC/MS: m/z 779.5 [M+H]+

[00206] 1H NMR (300 MHz, CD3OD): 0.92 - 0.96 (m, 3H), 1.21 - 1.39 (m, 8H), 1.78 - 2.03 (m, 7H) , 2.36 (s, 4H), 2.61-2.69 (m, 4H), 2.87-2.93 (m, 5H), 3.13-3.31 (m, 5H), 3 .32-3.36 (m, 1H), 3.63-3.77 (s, 6H), 3.783.96 (m, 1H), 4.15-4.18 (m, 1H), 4.84 -4.86 (m, 1H), 7.13-7.20 (m, 4H). EXAMPLE 7 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-((1-(3-((2S,3R,4R,5R)-2,3 ,4,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methylamino)propyl)pyrazine-2-carboxamide Step 1: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(3-((2S,3R)-2,3 (9H) -dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propylamino)propanoyl)piperidin-4-yl)methyl)carbamate -fluoren-9-yl)methyl

[00207] In a 25 mL round bottom flask were placed 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R) -2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (Example 5 / step 2, 20 mg, 0.27 mmol, 1.0 equiv,) and (2R,4aR,7R,8R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6,7,8-triol of Acetal-protected D-glucose (218 mg, 0.81 mmol, 3.0 equiv) in methanol (5 mL). The resulting solution was stirred for 0.5 h at room temperature. NaBH3CN (34 mg, 0.54 mmol, 2.0 equiv), AcOH (30 mg, 0.50 mmol, 2.0 equiv) were added. The resulting mixture was stirred overnight at room temperature. Quenching with water and extractive preparation resulted after removal of solvents in 220 mg of the crude title compound as a yellow solid.

[00208] LC/MS: m/z 992 [M+H]+ Step 2: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl (9H-fluoren-9 ((1-(3-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methyl)carbamate -yl)methyl

[00209] In a 25 mL round bottom flask, (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-( 3-((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propylamino)propanoyl) (9H-fluoren-9-yl)methyl piperidin-4-yl)methyl)carbamate (step 1, 200 mg, 0.20 mmol, 1.0 equiv), ethanol (1.5 mL) and HCl (4M in ethanol, 5 mL). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. 180 mg of the crude title compound was obtained as a yellow solid.

[00210] LC/MS: m/z 904 [M+H]+ Step3: 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-((1- (3-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methylamino)propyl)pyrazine-2-carboxamide

[00211] In a 25 mL round bottom flask were placed N-[(2S)-3-[(3,5-diamino-6-chloro-3,4-dihydropyrazin-2-yl)formamido]- 2-[(2-methylphenyl)methyl]propyl]-N-[[1-(3-[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino] 9H-fluoren-9-ylmethyl propanoyl)piperidin-4-yl]methyl]carbamate (step 2, 180 mg, 0.20 mmol, 1.0 equiv), diethylamine (2 mL), and N,N-dimethylformamide (4 mL). The resulting solution was stirred for 4 h at room temperature and then concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC using the following conditions: Column, XBridge Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase, WATERS with 0.05% TFA and ACN (16.0% ACN to 26.0% in 15 min); Detector, MS, UV 254/220 nm. This resulted in 15.5 mg (10%) of the trifluoroacetate of the title compound as a yellow solid.

[00212] LC/MS: m/z 681.4 [M+H]+

[00213] 1H NMR (300 MHz, CD3OD): 1.12-1.43 (m, 2H), 1.87-2.12(m, 3H), 2.14(s, 4H), 2.62 -2.75(m, 2H), 2.87-2.93(m, 7H), 3.01-3.19(m, 3H), 3.31-3.37(m, 1H), 3 .77-3.80 (m, 5H), 3.87-3.95(m, 2H), 4.07-4.58(s, 1H), 4.80-4.96(d, 1H) , 7.13-7.20 (m, 4H). EXAMPLE 8 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexH((2R,3R, 4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step1: (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(3-(((2R,3R)-2,3 -dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl)amino)propanoyl)piperidin-4-yl)methyl )(9H-fluoren-9-yl)methyl carbamate

[00214] Sodium cyanoborohydride (57.0 mg, 0.91 mmol) was added portionwise to a mixture of hexanal (45.5 mg, 0.45 mmol) and ((S)-3-(3.5 -diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)((1-(3-(((2R,3R)-2,3-dihydroxy-3-((2R, (9H-fluoren-9-yl)methyl 4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate [ prepared by an analogous procedure as described for Example 7 / step 1; starting instead of the acetal-protected D-mannitol (2R,4aR,7S,8R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6,7,8-triol] (300 mg, 0.30 mmol) in MeOH (20 mL). The resulting solution was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM: MeOH = 25:1) to give ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl) ((1-(3-(((2R,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4- (9H-fluoren-9-yl)methyl)(9H-fluoren-9-yl)methyl(yl)propyl)(hexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate (270 mg, 83%) as a yellow gum.

[00215] LC/MS: m/z 1076 [M+H]+ 1H NMR (300 MHz, CD3OD): δ 0.89 - 1.19 (m, 8H), 1.23 - 1.37 (m, 11H), 1.59 - 1.65 (m, 4H), 2.16 - 2.21 (m, 6H), 2.62 - 3.04 (m, 14H), 3.34 - 3.68 ( m, 2H), 3.87 - 3.96 (m, 4H), 4.11 - 4.27 (m, 4H), 4.70 - 4.80 (m, 2H), 5.57 (s, 1H), 7.07 - 7.29 (m, 4H), 7.31 - 7.50 (m, 7H), 7.50 - 7.53 (m, 4H), 7.78 (d, 2H) .Step 2:(S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl((1-(3-(hexyl((2R,3R,4R (9H-fluoren-9-yl)methyl ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate

[00216] ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)((1-(3-(((2R,3R)- 2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl)(hexyl)amino)propanoyl)piperidin-4- (9H-fluoren-9-yl)methyl yl)methyl)carbamate (270 mg, 0.25 mmol) was added to HCl (4M, aq., 15 mL) in ethanol (5 mL). After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure and provided the title compound (200 mg, 81%) as a yellow oil.

[00217] LC/MS: m/z 987 [M+H]+Step 3: 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl(( 2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00218] Diethylamine (3 ml) was added to ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)((1-(3- (9H-fluoren-9-yl) (hexyl((2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methyl)carbamate methyl (step 2, 200 mg, 0.20 mmol) in DMF (6 mL). The resulting mixture was stirred at 25°C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC. Column: X Bridge C18, 19*150mm, 5um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm, as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3,5-diamino-6-chloro-N-((R)-3-(((1-(3-(hexyl((2R,3R,4R,5R )-2,3,4,5,6-pentahydroxyhexyl)amino)propanoyl)piperidin-4-yl)methyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (23.5 mg ) as a yellow gum.

[00219] LC/MS: m/z 765.4 [M+H]+

[00220] 1H NMR (300 MHz, CD3OD): δ 0.94 (t, 3H), 1.29 - 1.40 (m, 8H), 1.80 - 2.04 (m, 5H), 2, 35 (s, 3H), 2.35 (m, 1H), 2.62 - 2.71 (m, 2H), 2.85 - 2.97 (m, 7H), 3.15 - 3.30 ( m, 4H), 3.31 - 3.69 (m, 4H), 3.71 - 3.83 (m, 6H), 4.03 - 4.06 (m, 2H), 4.86 - 4, 87(m, 1H),7.13 - 7.20 (m, 1H).EXAMPLE 9 3,5-Diamino-6-chloro-N-((R)-3-((4-((2 - (hexyl((2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine- 2-carboxamide Step 1 ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2R,3R,4R tert-butyl ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)carbamate

[00221] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate ( S)-tert-butyl (Intermediate E, 500 mg, 0.70 mmol), (3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5- tetraol (254 mg, 1.41 mmol) and DIPEA (0.123 mL, 0.70 mmol) were dissolved in MeOH (10 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (133 mg, 2.11 mmol) and acetic acid (0.040 mL, 0.70 mmol) were added and stirring continued for 18 h and then at 50 °C for 30 h. The reaction was cooled to room temperature, quenched by addition of 3M HCl (aq), stirred for 15 min and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and 8% NaHCO 3 (aq) (50 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 50 ID mm) using a gradient of 20 - 60% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Compounds were detected by UV at 268 nm. The compound was collected and freeze-dried to give the title compound (195 mg, 32%) as a colorless solid.

[00222] LC/MS: m/z 873.6 [M+H]+

[00223] 1H NMR (500 MHz, DMSO-d6) δ 0.76 - 0.85 (m, 3H), 1.13 - 1.27 (m, 6H), 1.3 - 1.44 (m, 11H), 2.21 (s, 3H), 2.24 - 2.38 (m, 1H), 2.39 - 2.53 (m, 4H), 2.57 - 2.66 (m, 2H) , 2.77 (d, 1H), 2.91 - 3.06 (m, 1H), 3.06 - 3.41 (m, 8H), 3.43 - 3.49 (m, 1H), 3 .51 (d, 1H), 3.55 - 3.65 (m, 3H), 4.23 - 4.55 (m, 5H), 6.97 (bs, 2H), 7.04 - 7.18 (m, 6H), 7.72 (d, 2H), 7.78 - 7.99 (m, 1H), 8.27 - 8.37 (m, 1H). Step 2 3,5-Diamine Dihydrochloride -6-chloro-N-((R)-3-((4-((2-(hexyl((2R,3R, 4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino )ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00224] To an ice-cooled flask of MeOH (5 mL, 124 mmol) was added acetyl chloride (1.42 mL, 20 mmol) dropwise. The mixture was stirred for 5 min and ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl ( tert-Butyl (2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)carbamate (190 mg, 0.22 mmol) was then added . The reaction was stirred at room temperature for 1.5 h and was then evaporated in vacuo. The residue was dissolved in water and freeze-dried to give the title compound (184 mg, 100%) as a pale solid.

[00225] LC/MS: m/z 773.4 [M+H]+

[00226] 1H NMR (500 MHz, DMSO-d6) δ 0.81 - 0.89 (m, 3H), 1.2 - 1.33 (m, 6H), 1.62 - 1.77 (m, 2H), 2.26 (s, 3H), 2.3 - 2.41 (m, 1H), 2.6 - 2.73 (m, 2H), 2.75 - 2.84 (m, 1H) , 2.86 - 2.97 (m, 1H), 3.11 - 3.27 (m, 3H), 3.27 - 3.45 (m, 5H), 3.45 - 3.52 (m, 2H), 3.52 - 3.76 (m, 5H), 3.89 - 3.99 (m, 1H), 4.03 - 4.48 (m, 7H), 6.88 - 7.23 ( m, 6H), 7.63 (d, 2H), 7.93 (d, 2H), 8.26 (t, 1H), 8.93 - 9.02 (m, 1H), 9.13 - 9 .34 (m, 2H), 9.55 (bs, 1H). EXAMPLE 10 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexH(( 2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1 ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S,3R,4R tert-butyl ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)carbamate

[00227] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate ( S)-tert-butyl (Intermediate E, 1.25 g, 1.76 mmol), (3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4, 5-tetraol (0.635 g, 3.52 mmol) and DIPEA (0.308 mL, 1.76 mmol) were dissolved in MeOH (10 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (0.332 g, 5.29 mmol) and acetic acid (0.101 mL, 1.76 mmol) were added and stirring continued for 40 h at 50 °C. The reaction was cooled to room temperature, quenched by addition of 8% NaHCO 3 (aq), stirred for 30 min and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and 8% NaHCO 3 (aq) (100 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 50 ID mm) using a gradient of 20 - 60% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Compounds were detected by UV at 268 nm. The compound was collected and freeze dried to yield ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-( tert-butyl hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)carbamate (1.26 g, 82%) as a white solid.

[00228] LC/MS: m/z 873.6 [M+H]+

[00229] 1H NMR (500 MHz, DMSO-d6) δ 0.73 - 0.86 (m, 3H), 1.1 - 1.27 (m, 6H), 1.27 - 1.46 (m, 11H), 2.20 (s, 3H), 2.24 - 2.38 (m, 1H), 2.38 - 2.49 (m, 3H), 2.53 - 2.69 (m, 3H) , 2.9 - 3.06 (m, 1H), 3.06 - 3.47 (m, 10H), 3.47 - 3.54 (m, 1H), 3.54 - 3.76 (m, 3H), 4.18 - 4.65 (m, 6H), 6.97 (bs, 2H), 7.03 - 7.19 (m, 6H), 7.72 (d, 2H), 7.78 - 8 (m, 1H), 8.24 - 8.37 (m, 1H).Step 2 3,5-Diamino-6-chloro-N-((R)-3-((4-(( 2-(hexyl ((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine -2-carboxamide

[00230] Acetyl chloride (5.69 mL, 80.0 mmol) was added dropwise to a chilled vial of ice bath MeOH (20 mL). The mixture was stirred for 5 min and ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl( tert-Butyl (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)carbamate (1.26 g, 1.44 mmol) was added to then added. The reaction was stirred at room temperature for 1.5 h and was then evaporated in vacuo. The residue was dissolved in water and freeze-dried to yield 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.29 g, 106 %) as a pale solid.

[00231] LC/MS: m/z 773.4 [M+H]+

[00232] 1H NMR (500 MHz, DMSO-d6) δ 0.78 - 0.89 (m, 3H), 1.18 - 1.32 (m, 6H), 1.62 - 1.76 (m, 2H), 2.26 (s, 3H), 2.33 - 2.44 (m, 1H), 2.67 (d, 2H), 2.73 - 2.84 (m, 1H), 2.84 - 2.96 (m, 1H), 3.1 - 3.44 (m, 9H), 3.44 - 3.54 (m, 2H), 3.55 - 3.62 (m, 1H), 3 .62 - 3.75 (m, 3H), 4.02 - 4.12 (m, 1H), 4.12 - 4.3 (m, 2H), 5.58 (bs, 5H), 6.91 - 7.21 (m, 6H), 7.64 (d, 2H), 7.94 (d, 2H), 8.25 (t, 1H), 8.97 - 9.06 (m, 1H), 9.28 (bs, 1H), 9.41 (bs, 1H), 9.70 (d, 1H). Step 3 3,5-diamino-6-chloro-N-((R)-3-(( 4-((2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl )propyl)pyrazine-2-carboxamide

[00233] 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4) dihydrochloride ,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.23 g, 1.45 mmol) was dissolved in water ( 15 ml) and basified by adding 10% Na2CO3 (aq) to pH ~11. The product was extracted with EtOAc (6 x 70 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo to give an oil/semi-solid. The residue was dissolved in acetonitrile/water and freeze-dried to yield 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (1.08 g, 96 %) as a pale solid.

[00234] LC/MS: m/z 773.4 [M+H]+

[00235] 1H NMR (500 MHz, DMSO-d6) δ 0.75 - 0.84 (m, 3H), 1.13 - 1.26 (m, 6H), 1.32 - 1.42 (m, 2H), 1.94 - 2.05 (m, 1H), 2.24 (s, 3H), 2.34 - 2.49 (m, 6H), 2.54 - 2.66 (m, 4H) , 3.14 - 3.23 (m, 1H), 3.25 - 3.35 (m, 4H), 3.35 - 3.42 (m, 1H), 3.42 - 3.47 (m, 1H), 3.47 - 3.54 (m, 1H), 3.55 - 3.61 (m, 1H), 3.61 - 3.77 (m, 4H), 4.26 - 4.33 ( m, 2H), 4.47 (d, 1H), 4.51 (d, 2H), 6.96 (bs, 2H), 7.04 - 7.14 (m, 4H), 7.40 (d , 2H), 7.74 (d, 2H), 8.26 - 8.37 (m, 2H). EXAMPLE 11 2-(hexyl((2S,3R,4R,5R)-2,3,4,5 4-(((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl ,6-pentahydroxyhexyl)amino)ethylcarbamate Step1: (R)-4-((3-(3,5-Diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl acetate

[00236] In a 50 mL pear-shaped flask was added (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (Intermediate A, 1.6 g, 4.59 mmol) and 4-formylphenyl acetate (0.753 g, 4.59 mmol) added to DCM (30 mL) to give a yellow solution. After stirring for 1 h, sodium triacetoxyborohydride (3.89 g, 18.4 mmol) was added and stirring was continued overnight. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo to afford (R)-4-(((3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl) acetate crude)propyl)amino)methyl)phenyl (1.70 g, 75%) as a yellow solid. The product was used in the next step directly without further purification.

[00237] LC/MS: m/z 467 [M+H]+ Step2: (S)-4-((tert-butoxycarbonyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)) acetate -2-(2-methylbenzyl)propyl)amino)methyl)phenyl

[00238] (BOC)2O (1.07 mL, 4.59 mmol) was added to a mixture of (R)-4-(((3-(3,5-diamino-6-chloropyrazine-2- carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)phenyl (1.9 g, 3.82 mmol) and Na2CO3 (0.81 g, 7.65 mmol) in a mixture of solvents dioxane (25 mL) /water (8 mL) at 0 °C. The mixture was allowed to come to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc, and washed with saturated brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of 10 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give the title compound (1.30g, 57%) as a yellow solid.

[00239] LC/MS: m/z 597 [M+H]+

[00240] 1H NMR (300 MHz, CD3OD): δ 1.47 (s, 9H), 2.25 - 2.2.51 (m, 7H), 2.54 - 2.65 (m, 2H), 3.05 - 3.22 (m, 2H), 3.31 - 3.39 (m, 2H), 4.13 - 4.45 (m, 2H), 6.93 - 7.00 (m, 2H) ), 7.06 - 7.10 (m, 6H). Step 3: (S)-tert-butyl 3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl(4-hydroxybenzyl)carbamate

[00241] NaOH (0.174 g, 4.35 mmol) in water (8 mL) was added dropwise to a cooled solution of (S)-4-(((tert-butoxycarbonyl)(3-(3, 5-Diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)phenyl (1.3 g, 2.18 mmol) in MeOH (20 mL). The reaction solution was stirred for 3 hours at room temperature. The reaction mixture was acidified with 2M aqueous HCl. The reaction mixture was extracted with EtOAc and the organic phase was washed with water and brine, dried over Na 2 SO 4 , filtered and evaporated to give the crude title compound (1.20 g, 99%) as a yellow solid.

[00242] LC/MS: m/z 555 [M+H]+Step 4: (S)-4-((tert-butoxycarbonyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)carbonochloridate) )-2-(2-methylbenzyl)propyl)amino)methyl)phenyl

[00243] In a 50 mL round bottom flask were added (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-hydroxybenzyl)carbamate S)-tert-butyl (250 mg, 0.45 mmol), DIEA (0.354 mL, 2.03 mmol) to THF (10 mL) to give a yellow solution. The mixture was cooled with an ice bath and triphosgene (200 mg, 0.68 mmol) was added. After stirring for 1 h, the reaction mixture was poured into water and extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the title compound (250mg, 90%) as a yellow oil.

[00244] LC/MS: m/z 617 [M+H]+ Step 5: ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl) propyl)(4-(((2-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan -4-yl)propyl)(hexyl)amino)ethyl)carbamoyl)oxy)benzyl)carbamate tert-butyl

[00245] In a 50 mL round bottom flask was added (1R,2S)-3-((2-aminoethyl)(hexyl)amino)-1-((2R,4R,5R)-5-hydroxy-2 -phenyl-1,3-dioxan-4-yl)propane-1,2-diol (Example 3 / step 2.96 mg, 0.24 mmol) and DIEA (0.064 mL, 0.36 mmol) dissolved in THF ( 10 mL) resulting in a colorless solution. (S)-4-(((tert-Butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)phenyl carbonochloridate (step 4, 150 mg, 0.24 mmol) was added at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic phases were dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative TLC (DCM: MeOH = 10: 1) to give the title compound (200 mg, 84%) as a yellow solid.

[00246] LC/MS: m/z 977 [M+H]+ Step 6: 2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino ) 4-(((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl ethylcarbamate

[00247] In a 25 mL round bottom flask was added ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-( ((2-(((2S,3R)-2,3-dihydroxy-3-((2R,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)propyl tert-butyl)(hexyl)amino)ethyl)carbamoyl)oxy)benzyl)carbamate (step 5, 200 mg, 0.20 mmol) to EtOH (1 mL) to give a yellow solution. Aqueous HCl (4M, 3 mL) was added and the resulting solution was stirred at room temperature for 12 h. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 µm silica, 50 mm diameter, 150 mm length) using a decreasing polarity gradient of water (0.05% TFA) and MeCN as eluent. Fractions containing the desired compound were evaporated to dryness to give the title compound (28.0mg, 13%) as a yellow solid.

[00248] LC/MS: m/z 789.4 [M+H]+

[00249] 1H NMR (300 MHz, CD3OD): δ 0.79 - 0.99 (m, 3H), 1.25 -1.55 (m, 6H), 1.69 - 1.91 (m, 2H ), 2.25 - 2.45 (m, 4H), 2.51 - 2.84 (m, 1H), 2.81 - 3.01 (m, 3H,), 3.28 - 3.31 ( m, 4H), 3.34 - 3.82 (m, 12H), 3.86 - 3.92 (m, 1H), 4.09 - 4.37 (m, 3H), 7.03 - 7, 35 (m, 6H), 7.453 (d, 2H). EXAMPLE 12 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S, 3R,4R,5R)-2,3,4, 5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1 EN06927-61 ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S, tert-butyl 3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)carbamate

[00250] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)phenethyl)carbamate ( S)-tert-butyl (Intermediate D, 500 mg, 0.69 mmol), (3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5- tetraol (249 mg, 1.38 mmol) and DIPEA (0.121 mL, 0.69 mmol) were dissolved in MeOH (5 mL) and stirred at 50 °C for 40 min before addition of sodium cyanoborohydride (130 mg, 2 .07 mmol) and acetic acid (0.044 mL, 0.76 mmol). Stirring was continued at 50 °C for 21 h and the reaction mixture was then allowed to cool to room temperature. The reaction was quenched by addition of 8% NaHCO3 (aq). The mixture was diluted with EtOAc (50 mL) and 8% NaHCO 3 (aq) (50 mL), stirred and the layers separated. The aqueous phase was extracted with EtOAc (4 x 50 mL). The combined organic phases were dried with Na2SO4(s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 50 ID mm) using a gradient of 20 - 60% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 ml/min. Compounds were detected by UV at 265 nm. The compound was collected and freeze-dried to give the title compound (385 mg, 63%) as a pale solid.

[00251] LC/MS: m/z 887.6 [M+H]+

[00252] 1H NMR (500 MHz, DMSO-d6) δ 0.80 (t, 3H), 1.12 - 1.26 (m, 6H), 1.29 - 1.43 (m, 11H), 2 .16 - 2.29 (m, 4H), 2.41 - 2.48 (m, 2H), 2.56 - 2.67 (m, 2H), 2.71 (t, 2H), 2.96 (dd, 1H), 3.02 - 3.42 (m, 12H), 3.44 (dd, 1H), 3.47 - 3.54 (m, 1H), 3.55 - 3.74 (m , 3H), 4.18 - 4.79 (m, 4H), 6.96 (bs, 2H), 7.06 - 7.19 (m, 6H), 7.72 (d, 2H), 7, 8 - 7.97 (m, 1H), 8.24 - 8.34 (m, 1H). Step 2 3,5-Diamino-6-chloro-N-((R)-3-((4 -((2-(hexyl ((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl) propyl)pyrazine-2-carboxamide

[00253] Acetyl chloride (1.42 mL, 20 mmol) was added dropwise to an ice-bath cooled solution of MeOH (5 mL, 124 mmol). The solution was stirred for 5 min and then added to ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-(( tert-Butyl 2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)carbamate (step 1, 385 mg, 0 .43 mmol). The reaction was stirred at room temperature for 2.5 h and was then concentrated in vacuo. The residue was dissolved in water and freeze-dried to give the title compound (369 mg, 99%) as a yellow solid.

[00254] LC/MS: m/z 787.4 [M+H]+

[00255] 1H NMR (500 MHz, DMSO-d6) δ 0.78 - 0.88 (m, 3H), 1.17 - 1.31 (m, 6H), 1.6 - 1.74 (m, 2H), 2.23 - 2.39 (m, 4H), 2.64 - 2.75 (m, 2H), 2.75 - 2.87 (m, 1H), 2.87 - 2.99 ( m, 1H), 3.05 (t, 2H), 3.09 - 3.44 (m, 11H), 3.44 - 3.54 (m, 2H), 3.55 - 3.75 (m, 1H). 4H), 4 - 4.1 (m, 1H), 4.69 (bs, 7H), 6.88 - 7.2 (m, 5H), 7.23 - 7.3 (m, 1H), 7 .36 (d, 2H), 7.88 (d, 2H), 8.24 (t, 1H), 8.85 - 9.16 (m, 3H), 9.63 (d, 1H). EXAMPLE 13 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl ((2S,3R,4R))-2,3,4,5- tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1: ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S,3R, tert-butyl 4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)carbamate

[00256] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)phenethyl)carbamate ( S)-tert-butyl (Intermediate D, 500 mg, 0.69 mmol), (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal (208 mg, 1.38 mmol) and DIPEA ( 0.121 mL, 0.69 mmol) was dissolved in MeOH (5 mL) and stirred at 50 °C for 40 min before adding sodium cyanoborohydride (130 mg, 2.07 mmol) and acetic acid (0.044 mL, 0. 76mmol). Stirring was continued at 50 °C for 21 h and was then allowed to cool to room temperature. The reaction was quenched by addition of 8% NaHCO3 (aq). The mixture was diluted with EtOAc (50 mL) and 8% NaHCO 3 (aq) (50 mL), stirred and the layers separated. The aqueous phase was extracted with EtOAc (4 x 50 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 50 ID mm) using a gradient of 20 - 60% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 ml/min. Compounds were detected by UV at 265 nm. The compound was collected and freeze-dried to yield ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4- ((2-( tert-butyl hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)carbamate (374 mg, 63%) as a pale solid.

[00257] LC/MS: m/z 857.6 [M+H]+

[00258] 1H NMR (500 MHz, DMSO-d6) δ 0.74 - 0.85 (m, 3H), 1.11 -1.28 (m, 6H), 1.28 - 1.44 (m, 11H), 2.14 - 2.29 (m, 4H), 2.46 (dd, 2H), 2.55 - 2.65 (m, 2H), 2.71 (t, 2H), 2.96 (dd, 1H), 3.02 - 3.51 (m, 14H), 3.52 - 3.6 (m, 1H), 3.6 - 3.71 (m, 1H), 4.17 - 4 .77 (m, 3H), 6.96 (bs, 2H), 7.05 - 7.2 (m, 6H), 7.72 (d, 2H), 7.8 - 7.97 (m, 1H ), 8.23 - 8.34 (m, 1H). Step 2: 3,5-Diamino-6-chloro-N-((R)-3-((4-((2-(hexyl ( (2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00259] Acetyl chloride (1.42 mL, 20.0 mmol) was added dropwise to an ice-bath cooled solution of MeOH (5 mL, 123.59 mmol). The solution was stirred for 5 min and then added to ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-(( tert-Butyl 2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)carbamate (374 mg, 0.44 mmol). The reaction was stirred at room temperature for 2.5 h and was then concentrated in vacuo. The residue was dissolved in water and freeze-dried to yield 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R )-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (361 mg, 100%) as a yellow solid .

[00260] LC/MS: m/z 757.4 [M+H]+

[00261] 1H NMR (500 MHz, DMSO-d6) δ 1 - 1.09 (m, 3H), 1.39 - 1.53 (m, 6H), 1.84 - 1.95 (m, 2H) , 2.50 (s, 3H), 2.53 - 2.62 (m, 1H), 2.86 - 2.97 (m, 2H), 2.97 - 3.07 (m, 1H), 3 .09 - 3.2 (m, 1H), 3.22 - 3.73 (m, 15H), 3.77 - 3.96 (m, 3H), 4.23 - 4.32 (m, 1H) , 4.84 (bs, 6H), 7.15 - 7.42 (m, 5H), 7.45 - 7.52 (m, 1H), 7.58 (d, 2H), 8.11 (d , 2H), 8.46 (t, 1H), 9.13 - 9.2 (m, 1H), 9.30 (d, 2H), 9.92 (d, 1H). EXAMPLE 14 3,5-Diamino-6-chloro-N-((S)-3-((4-((2-(hexyl((2S,3R, 4R)-2,3,4,5) acetic acid -tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1 ((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S,3R,4R tert-butyl)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate

[00262] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate ( R)-tert-butyl, (Intermediate H) (163 mg, 0.23 mmol), (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal (69.0 mg, 0.46 mmol ) and DIPEA (0.040 mL, 0.23 mmol) were dissolved in MeOH (4 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (14.44 mg, 0.23 mmol) and acetic acid (0.039 mL, 0.69 mmol) were added and the reaction heated to 50 °C for 20 h and then allowed to cool to room temperature. The reaction was quenched by addition of 8% NaHCO 3 (aq) and stirred for 30 min. The solvent was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and 8% NaHCO 3 (aq) (25 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (2 x 25 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 20 ID mm) using a gradient of 30 - 70% acetonitrile in H2O/ACN/AcOH 95/5/0.2 buffer over 20 minutes with a flow rate of 19 mL/min. Compounds were detected by UV at 265 nm. Product fractions were collected and freeze-dried to yield ((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2 - tert-butyl (hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (127 mg, 65.5%) as a solid.

[00263] 1H NMR (500 MHz, DMSO-d6) δ 0.75 - 0.84 (m, 3H), 1.13 -1.26 (m, 6H), 1.29 - 1.42 (m, 11H), 2.20 (s, 3H), 2.25 - 2.35 (m, 1H), 2.41 - 2.47 (m, 2H), 2.56 - 2.62 (m, 2H) , 2.89 - 3.05 (m, 1H), 3.07 - 3.15 (m, 1H), 3.2 - 3.49 (m, 13H), 3.52 - 3.59 (m, 1H), 3.61 - 3.69 (m, 1H), 4.21 - 4.35 (m, 2H), 4.35 - 4.55 (m, 3H), 6.96 (bs, 1H) , 7.04 - 7.19 (m, 6H), 7.71 (d, 2H), 7.77 - 7.98 (m, 1H), 8.24 - 8.32 (m, 1H).

[00264] MS ES+: m/z 843.4 [M+H]+ Step 2 3,5-Diamino-6-chloro-N-((S)-3-((4-((2- (hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00265] Acetyl chloride (0.711 mL, 10 mmol) was added dropwise to an ice-bath cooled vial of MeOH (2.5 mL, 61.79 mmol) and stirred for 5 min before addition of (( R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2S,3R,4R)-2, tert-Butyl 3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (127 mg, 0.15 mmol). The reaction was stirred at room temperature for 1 h and was then concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and 5% Na 2 CO 3 (aq) (25 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (5 x 25 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 20 ID mm) using a gradient of 5 - 45% acetonitrile in H2O/ACN/ACOH 95/5/0.2 buffer over 20 minutes with a flow rate of 19 mL/min. Compounds were detected by UV at 268 nm. The product was freeze dried to yield 3,5-diamino-6-chloro-N-((S)-3-((4-((2-(hexyl((2S,3R,4R)-2,3, 4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (100 mg, 82%) as a pale solid.

[00266] 1H NMR (500 MHz, DMSO-d6) δ 0.77 - 0.83 (m, 3H), 1.13 -1.25 (m, 6H), 1.32 - 1.41 (m, 2H), 1.90 (s, 4H), 1.96 - 2.05 (m, 1H), 2.24 (s, 3H), 2.35 - 2.55 (m, 6H), 2.55 - 2.63 (m, 4H), 3.14 - 3.23 (m, 2H), 3.24 - 3.4 (m, 9H), 3.4 - 3.49 (m, 4H), 3 .56 (q, 1H), 3.62 - 3.71 (m, 2H), 3.74 (d, 1H), 6.96 (bs, 2H), 7.04 - 7.14 (m, 4H ), 7.40 (d, 2H), 7.74 (d, 2H), 8.28 (t, 1H), 8.33 (t, 1H).

[00267] MS ES+: m/z 743.5 [M+H]+ EXAMPLE 15 3,5-Diamino-6-chloro-N-((S)-3-((4-((2- (hexyl((2R,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1 ((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2R,3S,4S tert-butyl)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate

[00268] (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate ( R)-tert-butyl, (Intermediate G) (163 mg, 0.23 mmol), (2S,3R,4S)-2,3,4,5-tetrahydroxypentanal (69.0 mg, 0.46 mmol ) and DIPEA (40.1 µl, 0.23 mmol) were dissolved in MeOH and stirred at room temperature for 1 h. Sodium cyanoborohydride (14.44 mg, 0.23 mmol) and acetic acid (39.5 µL, 0.69 mmol) were added and the reaction heated to 50 °C for 20 h and then allowed to cool to room temperature. The reaction was quenched by addition of 8% NaHCO 3 (aq) and stirred for 30 min. The solvent was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and 8% NaHCO 3 (aq) (25 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (5 x 25 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 20 ID mm) using a gradient of 30 - 70% acetonitrile in H2O/ACN/AcOH 95/5/0.2 buffer over 20 minutes with a flow rate of 19 ml/min. Compounds were detected by UV at 265 nm. Product fractions were collected and freeze-dried to yield ((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2 tert-butyl -(hexyl((2R,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (135 mg, 69.7%) as a solid.

[00269] 1H NMR (500 MHz, DMSO-d6) δ 0.79 (d, 3H), 1.16 (d, 6H), 1.36 (s, 11H), 2.20 (s, 3H), 2.31 (s, 1H), 2.50 (dt, 5H), 2.58 (s, 3H), 2.92 - 3.05 (m, 1H), 3.06 - 3.15 (m, 1H), 3.31 (s, 6H), 3.39 - 3.5 (m, 2H), 3.53 - 3.59 (m, 1H), 3.61 - 3.69 (m, 1H) , 4.22 - 4.34 (m, 2H), 4.34 - 4.55 (m, 3H), 6.97 (bs, 2H), 7.04 - 7.18 (m, 6H), 7 .71 (d, 2H), 7.78 - 7.97 (m, 1H), 8.25 - 8.32 (m, 1H).

[00270] MS ES+: m/z 843.5 [M+H]+ Step 2 3,5-Diamino-6-chloro-N-((S)-3-((4-((2- (hexyl((2R,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00271] Acetyl chloride (0.711 mL, 10 mmol) was added dropwise to an ice-bath cooled vial of MeOH (2.5 mL, 61.79 mmol) and stirred for 5 min before addition of (( R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexyl((2R,3S,4S)-2, tert-Butyl 3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)carbamate (135 mg, 0.16 mmol). The reaction was stirred at room temperature for 1 h and was then evaporated in vacuo. The residue was dissolved in EtOAc (25 mL) and 5% Na 2 CO 3 (aq) (25 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (5 x 25 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 20 ID mm) using a gradient of 5 - 45% acetonitrile in H2O/ACN/AcOH 95/5/0.2 buffer over 20 minutes with a flow rate of 19 ml/min. Compounds were detected by UV at 268 nm. The product was freeze dried to yield 3,5-diamino-6-chloro-N-((S)-3-((4-((2-(hexyl((2R,3S,4S)-2,3, 4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (93 mg, 70.2%) as a pale solid.

[00272] 1H NMR (500 MHz, DMSO-d6) δ 0.76 - 0.83 (m, 3H), 1.14 -1.25 (m, 6H), 1.31 - 1.42 (m, 2H), 1.91 (s, 3H), 1.95 - 2.06 (m, 1H), 2.24 (s, 3H), 2.35 - 2.54 (m, 6H), 2.60 (dd, 4H), 3.14 - 3.5 (m, 11H), 3.56 (q, 1H), 3.66 (dd, 2H), 3.74 (d, 1H), 6.96 ( s, 2H), 7.04 - 7.14 (m, 4H), 7.40 (d, 2H), 7.74 (d, 2H), 8.28 (t, 1H), 8.33 (t , 1H).

[00273] MS ES+: m/z 743.4 [M+H]+ EXAMPLE 16 3,5-diamino-6-chloro-N-((R)-3-(3-(2-(hexH((2S) ,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)phenethylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide Step 1 (S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl(3-(2-(hexyl((2S,3R,4R,5R) tert-butyl-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)phenethyl)carbamate

[00274] In a 50 mL round bottom flask were added (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(3-((2-( (S)-tert-butyl hexylamino)ethyl)carbamoyl)phenethyl)carbamate (intermediate D, 370 mg, 0.51 mmol) and (3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H -pyran-2,3,4,5-tetraol (138 mg, 0.77 mmol) in MeOH (15 mL) to give a yellow solution. After stirring the above mixture for 30 min, NaCNBH3 (32.1 mg, 0.51 mmol) was added. The resulting solution was stirred at 50°C for 16 hours. The solvent was removed under reduced pressure to give crude product ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(3-((2- tert-butyl (hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)carbamate (500 mg, 110%) as yellow solid . The product was used in the next step directly without further purification.

[00275] LC/MS: m/z 887 [M+H]+ Step 2 3,5-diamino-6-chloro-N-((R)-3-(3-(2-(hexyl((2S, 3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamoyl)phenethylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide

[00276] In a 50 mL round bottom flask was added ((S)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(3-( tert-Butyl (2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)carbamate (500 mg, 0.56 mmol) in HCl/MeOH (20 mL, 0.56 mmol) to give a yellow solution. The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 µm silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% NH4HCO3) and MeCN as eluents . Fractions containing the desired compound were evaporated to dryness to give 3,5-diamino-6-chloro-N-((R)-3-((3-((2-(hexyl((2S,3R,4R,5R )-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide (87 mg, 20%) as a yellow solid.

[00277] LC/MS: m/z 788 [M+H]+

[00278] 1H NMR (300 MHz, CD3OD, 25oC): δ0.85 - 0.91 (m,3H), 1.15 - 1.35 (m,6H), 1.39 - 1.59 (m, 2H), 2.12 - 2.25 (m, 1H), 2.31 (s, 3H), 2.57 - 2.89 (m, 13H, 3.29 - 3.33 (m, 2H), 3.38 - 3.64 (m, 3H), 3.66 - 3.84 (m, 6H), 7.09 - 7.16 (m, 4H), 7.38 (d, 2H), 7. 70 - 7.73 (m,2H) SYNTHESIS OF INTERMEDIATES Intermediate A (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide Step 1: Dimethyl 2-(2-methylbenzyl)malonate

[00279] A reactor was charged with dimethyl malonate (6.00 kg, 45.4 mol) and methanol (21.3 L). 25% NaOMe/MeOH (10.37 L, 45.2 mol) was added over 10 minutes and then 2-methyl benzylchloride (4.26 kg, 30.3 mol) was added over 1.5 h, keeping a reaction temperature below 30 °C. Saturated NH4Cl (53.1 L) was added to the reaction, resulting in pH 8.5. The product was extracted with isopropyl acetate (3 x 25 L) and the combined organic layers were washed with 10% brine (10 L) and concentrated under reduced pressure to afford the title compound as an oil (8.63 kg, 68 kg). weight%, 83%). The title compound so obtained contained dialkylated malonate. Purity by HPLC: 86%.

[00280] LC/MS: m/z 237 [M+H]+

[00281] 1H-NMR (DMSO-d6, 270 MHz) δ 7.17-7.05 (4H, m), 3.60 (6h, s), 3.82 (1H, t), 3.12 ( 2H, s), 2.21 (3H, s); 13C-NMR (DMSO-d6, 270 MHz) δ 169.5, 136.6, 136.3, 130.8, 129.5, 127.3, 126.4, 52.8, 52.0, 31, 8, 19,4.Step 2 2-(2-Methylbenzyl)malonamide

[00282] A reactor was charged with dimethyl-2-(2-methylbenzyl)malonate (step 1, 5.9 kg, 68 wt%, 17.0 mol) and methanol (14.8 L). 34% ammonium hydroxide (24 L, 36 equiv.) was added and the reaction was stirred at 25°C until judged complete by HPLC analysis. The solids were filtered and then MTBE (15.3 L) was added. After 30 min, the solids were filtered, washed with MTBE (2 x 15.3 L) and dried under reduced pressure at 60 °C to give the title compound as a white solid (3.2 kg, 91%).

[00283] LC/MS: m/z 206.9 [M+H]+

[00284] 1H-NMR (DMSO-d6, 270 MHz) δ 7.32-7.21 (2H, br s), 7.15 7.00 (6H, m), 3.33 (1H, t), 2.96 (2H, d), 2.28 (3H, s); 13C-NMR (DMSO-d6, 270 MHz) δ 171.0, 137.5, 136.0, 129.9, 128.9, 126.1, 125.6, 53.2, 32.5, 19, 1. Step 3 2-(2-Methylbenzyl)propane-1,3-diamine

[00285] A reactor was charged with 2-(2-methylbenzyl)malonamide (1.32 kg, 6.40 mol) and THF (5.4 L). The viscous mixture was cooled to 0 °C and 1 M THF-borane (25.6 L, 25.6 mol) was added over 2 h, maintaining a reaction temperature below 2 °C. The reaction was warmed to 15 °C and then stirred at 50 °C overnight. When HPLC analysis indicated less than 8% starting material remaining, the reaction mixture was quenched in 4M KOH (8 L), maintaining a temperature below 30 °C. The organic layer was concentrated under reduced pressure and the aqueous layer was extracted twice with MTBE (2 x 10 L). The combined MTBE extracts were added to the concentrated organic layer and the combined organic layers were then charged into a 6M HCl solution (10 L), maintaining a temperature below 30°C. The aqueous phase was washed with MTBE (10 L) and then basified with 6M KOH (12 L). The aqueous phase was extracted twice with THF (10 L then 5 L) and the combined organic phase was concentrated under reduced pressure. Toluene (5 L) was added and then azeotroped distilled to remove any residual water. The mixture was triturated with toluene (5 L) and the solids were filtered and washed with toluene (3 L). The filtrate was concentrated under reduced pressure providing the title compound as the free amine (1.13 kg, 70% yield). Purity by HPLC: 91%.

[00286] LC/MS: m/z 179.0 [M+H]+

[00287] 1H-NMR (CDCl3, 270 MHz) δ 7.12-7.00 (4H, m), 2.72-2.59 (4H, m), 2.52 (2H, d), 2, 27 (3H, s), 1.64 (1H, m), 1.48-1.25 (4H, br s); 13 C-NMR (CDCl3, 270 MHz) δ 139.0, 136.3, 130.5, 129.9, 126.2, 125.9, 44.7, 43.8, 34.3, 19.6. Step 4 2-(2-Methylbenzyl)propane-1,3-diamine L-Tartrate

[00288] To crude diamine (from step 3) (1.62 kg, 9.1 mol) was added ethanol (4 L). A solution of L-tartaric acid (1.62 kg, 10.8 mol) dissolved in ethanol (11 L) was added, maintaining the temperature below 40 °C. The mixture was stirred at 25 °C for 3 d and then the solids were filtered, washed with ethanol (2 x 2 L) and dried under reduced pressure at 50 °C to afford the title compound as its mono-L- tartrate (3.21 kg, quantitative production). Purity by HPLC: 92.2%.

[00289] LC/MS: m/z 179.0 [M+H]+

[00290] 1H-NMR (D2O, 270 MHz) δ 7.30-7.15 (4H, m), 4.27 (2H, s), 3.20-3.07 (2H, dd), 3, 04-2.94 (2H, dd), 2.79 (2H, d), 2.41 (1H, m), 2.27 (3H, s); 13C-NMR (D2O, 270 MHz) δ 178.4, 137.2, 135.7, 131.0, 130.0, 127.6, 126.7, 73.9, 40.5, 35.9, 32.8, 18.7. Step 5 (R)-Allyl (3-amino-2-(2-methylbenzyl)propyl)carbamate (1-(R))

[00291] A reactor was charged with 2-(2-methylbenzyl)propane-1,3-diamine L-tartrate salt (3.57 kg, 10.9 mol) and water (17 L). 10 M NaOH (17 L, 170 mol) was added, maintaining a reaction temperature below 25 °C. The mixture was stirred for 30 min at 25 °C for 3 d and then 2-MeTHF (14 L) was added. The layers were separated and the aqueous phase was extracted with 2-MeTHF (14 L). The combined organic phase was dried (sodium sulfate), filtered and concentrated under reduced pressure yielding the free diamine. A reactor was charged with the free diamine, 2-MeTHF (37.4 L) and diallyl carbonate (1.80 kg, 12.6 mol). Immobilized lipase Amano PS IM (5.61 kg, 3 equivalent weights) was added in portions over 30 min and the temperature was set at 30 °C. After 4 days, 1H NMR indicated less than 5% starting material left and the reaction mixture became clear, filtered through celite and concentrated under reduced pressure to provide the title compound (2.68 kg, 82% ee , 100% production). Purity by HPLC: 84.7%.

[00292] LC/MS: m/z 263.1 [M+H]+

[00293] 1H-NMR (CDCl3, 270 MHz) δ 7.15-7.05 (4H, m), 5.99-5.81 (1H, m), 5.80-5.60 (1H, br s), 5.35-5.15 (2H, m), 4.54 (2H, d), 3.40-3.14 (2H, m), 2.85-2.52 (4H, m) , 2.29 (3H, s), 1.90-1.77 (1H, m), 1.50-1.10 (2H, br s); 13C-NMR (CDCl3, 270MHz) δ 156.6, 138.1, 136.1, 133.0, 130.5, 129.7, 126.3, 125.9, 117.5, 65.4, 44 ,0, 43.4, 41.6, 34.2, 19.5. Step 6 (3-Amino-2-(2-methylbenzyl)propyl)carbamate (1-(R))-D-tartrate salt (R)-allyl.

Crude (R)-allyl (3-amino-2-(2-methylbenzyl)propyl)carbamate (2.68 kg, 10.2 mol) was added to EtOH (7.1 L). A solution of D-tartaric acid (1.53 kg, 10.2 mol) in EtOH (8 L) was added keeping the temperature below 25 °C. After approximately 1 h, a precipitate began to form and the mixture was allowed to stir overnight. MeCN (5 L) was added at 25 °C and the solids were filtered, washed with MeCN (2 x 5 L) and dried under reduced pressure at 40 °C to provide 2.94 kg of the title compound ((R) D-tartrate, 100% production) at a stoichiometric base/di-acid ratio = 2:1. Purity by HPLC: 91.6%.

[00295] LC/MS: m/z 263.1 [M+H]+

[00296] 1H-NMR (DMSO-d6, 270 MHz) δ 7.50 (1H, t), 7.22-7.05 (4H, m), 5.98-5.85 (1H, m), 5.35-5.12 (2H, m), 4.48 (2H, d), 3.95 (2H, s), 3.13-2.99 (2H, m), 2.90-2, 79 (1H, m), 2.75-2.58 (2H, m), 2.26 (3H, s), 2.08 (1H, m); 13C-NMR (DMSO-d6, 270 MHz) δ 174.6, 156.6, 137.4, 136.1, 133.7, 130.3, 129.7, 126.3, 125.8, 117, 0, 71.8, 64.4, 65.5, 37.6, 32.7, 19.1, 18.9.

[00297] Chiral HPLC (method A): 88.3% ee; rt = 11.14 min (S), 14.57 min (R). Step 7 (R)-allyl (3-Amino-2-(2-methylbenzyl)propyl)carbamate

[00298] To a 50 L vessel under nitrogen were added water (14.7 L) and MTBE (14.7 L), this was followed by the addition of (1-(R)) D-tartrate salt (3 (R)-allyl-amino-2-(2-methylbenzyl)propyl)carbamate (step 6, 2940 g). 10M NaOH (14.7 L) was added to the mixture and the temperature was maintained below 30 °C. The mixture was stirred for 30 min, the organics were separated and the aqueous re-extracted with MTBE (14.7 L). A portion of the organics was concentrated in vacuo (1 L) to give an extrapolated yield of 1779 g, 95%.

[00299] LC/MS: m/z 263.1 [M+H]+

[00300] 1H NMR (CDCl3, 270 MHz) δ 7.05-7.15 (4H, m), 5.80-5.99 (1H, m), 5.32-5.14 (m, 2H) , 4.52 (d, 2H), 3.15-3.38 (m, 2H), 2.55-2.81 (m, 2H), 2.54 (d, 2H), 2.29 (s , 3H), 1.76-1.87 (m, 1H). Step 8 (S)-allyl tert-butyl (2-(2-methylbenzyl)propane-1,3-diyl)dicarbamate

[00301] To a 50 L vessel under nitrogen was added (R)-allyl (3-amino-2-(2-methylbenzyl)propyl)carbamate (1740 g) dissolved in MTBE (29.4 L). This was followed by the addition of triethylamine (922ml). The mixture was cooled to 0 °C and treated with BOC-anhydride (1600 mL, 1518 g) dissolved in MTBE (3.48 L). The reaction was warmed to 20 °C and stirred for 2 h. The reaction was judged complete by 1H NMR. The reaction was charged with water (8.7 L) and stirred for 15 min. The organics were separated and washed with 5% citric acid (8.7 L) and brine (8.7 L) before drying over magnesium sulfate, filtering and concentrating in vacuo providing the title compound (2320 g, 94% ). 1H NMR indicated > 90% purity.

[00302] 1H NMR (CDCl3, 270 MHz) δ 7.02-7.10 (m, 4H), 5.82-5.99 (m, 1H), 5.55 (t, 1H), 5.32 -5.15 (m, 2H), 5.02 (t, 1H), 4.52 (d, 2H), 3.17-3.30 (m, 2H), 2.95-3.15 (m , 2H), 2.51 (d, 2H), 2.28 (s, 3H0, 1.87-1.95 (m, 1H), 1.43 (s, 9H). Step 9 (3-amino- (S)-tert-butyl 2-(2-methylbenzyl)propyl)carbamate

[00303] To a 50 L vessel under nitrogen was added (S)-allyl tert-butyl (2-(2-methylbenzyl)propane-1,3-diyl)dicarbamate (2330 g) dissolved in DCM (12, 9 L) and MeOH (10.3 L), this was followed by the addition of Pd(PPh3)4 (148.4 g). The reaction mixture was cooled to 5 °C and charged with NaBH4 (729 g) in portions over a period of 2 h. The reaction was warmed to 20 °C and stirred for 2 h. The reaction mixture was carefully quenched with water (46.6 L) and then stirred for 20 min. The organics were separated and the aqueous re-extracted with DCM (23.6L). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1679g, 100% yield (~80% pure by 1H NMR).

[00304] 1H NMR (CDCl3, 270 MHz) δ 7.02-7.15 (m, 4H), 5.22 (br s, 1H), 3.10-3.28 (m, 2H), 2, 62-2.80 (m, 2H), 2.52 (d, 2H), 2.29 (s, 3H), 1.75-1.82 (m, 1H), 1.92 (s, 9H) , 1.30 (br s, 2H). Step 10 (S)-tert-Butyl (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate

[00305] To a 5 L vessel under nitrogen were added 3,5-diamino-6-chloropyrazine-2-carboxylic acid (100 g), HBTU (202.8 g), THF (1200 mL) and DIPEA (111 mL ). The reaction was allowed to stir for 24 h at room temperature. To the reaction was added (S)-tert-butyl (3-amino-2-(2-methylbenzyl)propyl)carbamate (step 9, 148.6 g) dissolved in THF (1.49 L). It should be noted that the reaction exothermed to 10 °C during the addition. The reaction was allowed to stir for 24 h at room temperature, LCMS indicated 5% adduct remaining. The mixture was heated to 35 °C for 4 h. LC/MS indicated 2% adduct remaining. The reaction was stirred for an additional 1 h before being cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (1.5 L) and MTBE (1.5 L) and washed with saturated NaHCO 3 (1 L), 5% citric acid (700 mL) and brine (700 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in MTBE (1L) and concentrated again before being taken up in MTBE (500ml) and diethyl ether (500ml) and filtered to remove DIPEA salts. The filtrate was concentrated and analysis indicated some remaining DIPEA salts. The residue was triturated again with MTBE (750ml) and diethyl ether (750ml) and filtered again. The filtrate was concentrated to give the title compound (225 g, 94% (accounting for solvent and TMU).

[00306] LC/MS: m/z 349.2 [M+H]+

[00307] 1H NMR (CDCl3, 270 MHz) δ 7.46 (t, 1H), 7.13 (m, 4H), 5.52 (t, 1H), 5.22 (br s, 2H), 3 .62-3.75 (m, 1H), 3.00-3.40 (m, 5H), 2.80 (s, 3H), 2.49-2.75 (m, 2H), 1.95 -2.02 (m, 1H), 1.42 (s, 9H). Step 11 3,5-Diamino-N-[(2R)-3-amino-2-(2-methylbenzyl)propyl]-6-chloropyrazine-2-carboxamide

[00308] To a 20 L flange flask under nitrogen was added (S)-tert (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl) carbamate -butyl (step 10, 2215 g) in dioxane (6 L). The mixture was stirred for 20 min until complete dissolution. To the reaction was then added 4M HCl in dioxane (10 L). The reaction involved a considerable amount of gas and the temperature rose to 35 °C before cooling was applied. A viscous oily precipitate was observed in the reaction. LC/MS of the reaction mixture after 1 h indicated complete reaction. The supernatant liquid was decanted and concentrated in vacuo. The oily viscous solid was dissolved in water (6 L) and combined with the concentrated supernatant dissolved in water (2 L). The aqueous was washed with MTBE (5 L). The aqueous was then basified with 10M NaOH (2 L) and extracted with 2-Me-THF (4 x 10 L). The organics were dried, filtered and concentrated in vacuo. The residue was then concentrated from MTBE (2 x 4 L) to remove residual 2-MeTHF. The solid was triturated with MTBE:Heptane (9L:1.8L) and allowed to stir over the weekend. The solid was filtered and dried in an oven at 40 °C giving the title compound (1657 g, 96%).

[00309] 1H NMR (CDCl3, 270 MHz) δ 7.60 (t, 1H), 7.08-7.15 (m, 4H), 5.75 (br s, 2H), 5.12 (bs, 2H), 3.38-3.45 (m, 2H), 2.52-2.82 (m, 4H), 2.30 (s, 3H), 1.80-1.98 (m, 2H) , 1.20-1.28 (m, 2H). Step 12 (R)-3,5-Diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-(2R,3S)-2-benzoyl-3-(benzoyloxy)succinate 2-carboxamide

[00310] To a 5 L vessel under nitrogen were added 3,5-diamino-N-[(2R)-3-amino-2-(2-methylbenzyl)propyl]-6-chloropyrazine-2-carboxamide (127, 4g) and methanol (892ml). The mixture was warmed slightly to 30°C until all the solid dissolved. The reaction was cooled to room temperature and (+)-dibenzoyl-D-tartaric acid (65.5g) in methanol (458ml) was added. The reaction was allowed to stir, after ~2h the solid started to precipitate. The reaction was allowed to stir over the weekend. Isopropyl acetate (1.5 L) was added to the mixture and stirring was continued for 4 h. The precipitate was then filtered and washed with isopropyl acetate (2 x 1 L). The solid was then dried in an oven for 3 d at 40 °C. A total of 147.5 g (74%) was obtained at the stoichiometric ratio base / diacid = 2:1.

[00311] 1H NMR (CDCl3, 270 MHz): δ 7.60 (t, 1H), 7.08-7.15 (m, 4H), 5.75 (br s, 2H), 5.12 (b s , 2H), 3.38-3.45 (m, 2H), 2.52-2.82 (m, 4H), 2.30 (s, 3H), 1.80-1.98 (m, 2H ), 1.20-1.28 (m, 2H).

[00312] Chiral HPLC (method A): 98.7% ee, Rt = 11.93 min (R), 14.24 min (S). Step 13 (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide

[00313] (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine (2R,3S)-2-benzoyl-3-(benzoyloxy)succinate -2-carboxamide (20 g, 38.46 mmol) was suspended in 2-methyl-THF (200 mL) and water (200 mL) and cooled with an ice bath. Sodium hydroxide, 1M (42.3ml, 42.31mmol) was added slowly and the mixture was then stirred at 40°C until all material dissolved. The mixture was cooled to room temperature and the phases were separated. The aqueous phase was extracted with 2-methyl-THF (2 x 200 mL). The combined organic phases were washed with brine (200ml), dried with a phase separator and evaporated in vacuo to yield (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl )-6-chloropyrazine-2-carboxamide (13.3 g, 99%) as a pale solid.

[00314] LC/MS: m/z: 349.3 [M+H]+.

[00315] 1H NMR (500 MHz, DMSO-d6) δ 1.50 (bs, 2H), 1.76 - 1.87 (m, 1H), 2.26 (s, 3H), 2.4 - 2 .49 (m, 2H), 2.52 - 2.62 (m, 2H), 3.18 - 3.28 (m, 2H), 6.95 (bs, 2H), 7.04 - 7.17 (m, 4H), 8.14 (t, 1H).

[00316] Chiral HPLC (method B): 99.3% ee, Rt = 11.55 min (S), 13.28 min (R). [αβ0: +11.8 (c 1.0, MeCN). Intermediate B (S)-(9H-fluoren-9-yl) 3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl(piperidin-4-ylmethyl)carbamate methyl Step 1: (R)-tert-Butyl 4-((3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)piperidine-1-carboxylate

[00317] A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (122 mg, 0.57 mmol, 1.00 equiv) and 3,5-diamino- N-[(2R)-3-amino-2-[(2-methylphenyl)methyl]propyl]-6-chloropyrazine-2-carboxamide (Intermediate A, 200 mg, 0.57 mmol, 1.0 equiv) in dichloromethane (5 mL). The mixture was stirred for 1 h. Then sodium triacetoxyborohydride (486 mg, 2.29 mmol, 4.00 equiv) was added. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 3 x 10 mL of water, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 250 mg (80%) of the title compound as a yellow solid.

[00318] LC/MS: m/z: 546 [M+H]+. Step 2: 4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl) (S)-tert-butyl amino)methyl)piperidine-1-carboxylate

[00319] FMOC-chloride (19 mg, 0.07 mmol, 1.00 equiv) in dioxane (2.0 mL) was added dropwise to a mixture of 4-((3-(3,5-diamino- (R)-tert-Butyl 6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)piperidine-1-carboxylate (Step 1, 40 mg, 0.07 mmol, 1.0 equiv) and Na2CO3 (12 mg, 0.11 mmol, 1.5 equiv) in water/dioxane (1:2, 3 mL). The resulting solution was stirred for 2 h at room temperature, extracted with 3 x 5 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate. After removing the solvents in vacuo, 42 mg (75%) of the title compound was obtained as a yellow solid.

[00320] LC/MS: m/z: 768 [M+H]+ Step 3: 3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl(piperidin- (S)-(9H-fluoren-9-yl)methyl 4-ylmethyl)carbamate

[00321] A solution of 4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(3-(3,5-diamino-6-chloropyrazine- (S)-tert-Butyl 2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)piperidine-1-carboxylate (step 2, 20 mg, 0.03 mmol, 1.0 equiv) in HCl /MeOH (4M, 3 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 15 mg (86%) of N-[(2S)-3-[(3,5-diamino-6-chloropyrazin-2-yl)formamido]-2-[(2-methylphenyl)methyl]propyl] - 9H-Fluoren-9-ylmethyl N-(piperidin-4-ylmethyl)carbamate as a yellow solid.

[00322] LC/MS: m/z: 668 [M+H]+ Intermediate C (9H-fluoren-9-yl)methyl (2-aminoethyl)(hexyl)carbamate hydrochloride Step 1 tert-butyl (2-(benzyl(hexyl)amino)ethyl)carbamate

[00323] N-Benzylhexan-1-amine (2.69 g, 14.1 mmol), tert-butyl (2-oxoethyl)carbamate (4.48 g, 28.1 mmol) and DIPEA (2.46 mL , 14.1 mmol) were dissolved in MeOH (20 mL) and stirred at room temperature for 45 min. Sodium cyanoborohydride (1.77 g, 28.1 mmol) and acetic acid (0.806 mL, 14.1 mmol) were added and stirring continued for 18 h. The reaction was quenched by addition of 8% NaHCO 3 (aq) and stirred at room temperature for 1 h. The solvent was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on two 100 g Biotage® KP-SIL columns. A gradient of 5 - 50% EtOAc in heptane over 12 CV was used as the mobile phase. The product was collected and evaporated in vacuo to give tert-butyl (2-(benzyl(hexyl)amino)ethyl)carbamate (3.19 g, 68%) as a colorless oil.

[00324] LC/MS: m/z: 335.6 [M+H]+

[00325] 1H NMR (500 MHz, CDCl3) δ 0.84 - 0.92 (m, 3H), 1.19 - 1.35 (m, 6H), 1.38 - 1.66 (m, 11H) , 2.43 (t, 2H), 2.52 (t, 2H), 3.09 - 3.21 (m, 2H), 3.56 (s, 2H), 4.83 - 4.93 (m , 1H), 7.22 - 7.37 (m, 5H). Step 2 tert-butyl (2-(hexylamino)ethyl)carbamate

[00326] tert-Butyl (2-(benzyl(hexyl)amino)ethyl)carbamate (3.19 g, 9.54 mmol) was dissolved in MeOH (25 mL) and 20% Pd(OH)2/C (0.201 g, 0.29 mmol) added. The reaction was hydrogenated in a Buchi hydrogenator at (4 bar) and room temperature for 18 h. The reaction stalled. An additional 20% Pd(OH)2/C (200 mg, 0.28 mmol) was added and hydrogenation continued for 6 h, hydrogenation stalled. The catalyst was filtered, washed with MeOH and the filtrate concentrated in vacuo. The residue was dissolved in MeOH (15 mL), 20% Pd(OH) 2 /C (250 mg, 0.36 mmol) was added and hydrogenation continued at 4 bar and room temperature for 16 h. The catalyst was filtered, washed with MeOH and the filtrate evaporated in vacuo. The reaction was once again dissolved in MeOH, 20% Pd(OH) 2 /C (250 mg, 0.36) added and hydrogenation continued for 3 days. The catalyst was filtered, washed with MeOH and the filtrate evaporated in vacuo to afford tert-butyl (2-(hexylamino)ethyl)carbamate (2.38 g, 102%) as a colorless oil.

[00327] 1H NMR (500 MHz, CDCl3) δ 0.89 (t, 3H), 1.22 - 1.36 (m, 6H), 1.41 - 1.53 (m, 11H), 2.61 (t, 2H), 2.75 (t, 2H), 3.19 - 3.28 (m, 2H), 4.97 (bs, 1H). Step 3 (9H-fluoren-9-yl)methyl (2-((tert-butoxycarbonyl)amino)ethyl)(hexyl)carbamate

[00328] To an ice-bath cooled solution of tert-butyl (2-(hexylamino)ethyl)carbamate (2.38 g, 9.74 mmol) in DCM (40 mL) was added DIPEA (1.79 mL , 10.2 mmol) and (9H-fluoren-9-yl)methylcarbonochloridate (2.65 g, 10.2 mmol). The reaction was stirred with cooling for 10 min and then at room temperature for 1 h. Water (20 mL) was added, stirred and the layers separated. The aqueous phase was extracted with DCM (2x20ml). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a 100 g Biotage® KP-SIL column. A gradient of 5 - 30% EtOAc in heptane over 9 CV followed by 30% EtOAc in heptane over 3 CV was used as the mobile phase. The product was collected using the wavelength 264 nm. The collected fractions were evaporated in vacuo to afford (9H-fluoren-9-yl)methyl (2-((tert-butoxycarbonyl)amino)ethyl)(hexyl)carbamate (3.70 g, 81%) as a colorless oil .

[00329] LC/MS: m/z: 467.4 [M+H]

[00330] 1.43 (s, 9H), 2.78 - 2.87 (m, 1H), 2.95 - 3.08 (m, 2H), 3.11 - 3.36 (m, 3H) , 4.18 - 4.26 (m, 1H), 4.49 - 4.63 (m, 2H), 4.89 (bs, 1H), 7.3 - 7.36 (m, 2H), 7 .41 (t, 2H), 7.59 (d, 2H), 7.77 (d, 2H). Step 4(9H-Fluoren-9-yl)methyl(2-aminoethyl)(hexyl)carbamate hydrochloride

[00331] Acetyl chloride (2.84 mL, 40.0 mmol) was added dropwise to an ice-bath cooled flask of MeOH (10 mL, 247 mmol) and stirred for 5 min. This solution was then added to (9H-fluoren-9-yl)methyl (2-((tert-butoxycarbonyl)amino)ethyl)(hexyl)carbamate (3.7 g, 7.93 mmol) and the reaction stirred at room temperature for 2.5 h. The solvent was concentrated in vacuo to afford (9H-fluoren-9-yl)methyl (2-aminoethyl)(hexyl)carbamate hydrochloride (2.92 g, 91%) as a white solid.

[00332] LC/MS: m/z: 367.3 [M+H]+

[00333] 1H NMR (400 MHz, DMSO-d6) δ 0.82 - 0.97 (m, 4H), 0.99 - 1.51 (m, 7H), 2.68 - 2.88 (m, 3H), 3.23 - 3.39 (m, 3H), 4.23 - 4.4 (m, 2H), 4.52 (d, 1H), 7.29 - 7.37 (m, 2H) , 7.37 - 7.46 (m, 2H), 7.64 (d, 2H), 7.83 - 8.09 (m, 5H). Intermediate D (3-(3,5-diamino-6- (S)-tert-butyl chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl)carbamoyl)phenethyl)carbamate Step 1 Methyl 4-(2-hydroxyethyl)benzoate

[00334] 4-(2-Hydroxyethyl)benzoic acid (2.41 g, 14.5 mmol) was dissolved in MeOH (5 mL) and H 2 SO 4 (0.06 mL, 1.13 mmol) added. The reaction was heated in a microwave at 120 °C for 1 h and was then evaporated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with 8% NaHCO 3 (aq) (150 mL), brine (50 mL), dried with a phase separator and evaporated in vacuo to give 4-(2-hydroxyethyl) methyl benzoate (2.41 g, 92%) as a pale oil.

[00335] LC/MS: m/z: 181.0 [M+H]+

[00336] 1H NMR (500 MHz, CDCl3) δ 2.94 (t, 2H), 3.88 - 3.94 (m, 5H), 7.32 (d, 2H), 7.97 - 8.02 (m, 2H). Step 2 Methyl 4-(2-Oxoethyl)benzoate

[00337] Methyl 4-(2-hydroxyethyl)benzoate (2.41 g, 13.37 mmol) was dissolved in DCM (50 mL) and Dess-Martin periodinane (6.24 g, 14.7 mmol) added. The reaction was stirred at room temperature for 2 h and was then quenched by addition of 15% Na 2 S 2 O 3 /NaHCO 3 3:2 (aq) (50 mL) and stirred vigorously for 30 min. The phases were separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a 100 g Biotage® KP-SIL column. A gradient of 5 - 40% EtOAc in heptane over 9 CV followed by 50% EtOAc in heptane over 3 CV was used as the mobile phase. The product was collected using the wavelength 245 nm. The product was collected and evaporated in vacuo to afford methyl 4-(2-oxoethyl)benzoate (0.880 g, 36.9%) as a yellow solid.

[00338] 1H NMR (500 MHz, CDCl3) δ 3.78 (d, 2H), 3.93 (s, 3H), 7.29 - 7.34 (m, 2H), 8.03 - 8.09 (m, 2H), 9.79 (t, 1H). Step 3 (S) 4-(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)ethyl)benzoate - methyl

[00339] (R)-3,5-Diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (Intermediate A, 2.00 g, 5.56 mmol ), methyl 4-(2-oxoethyl)benzoate (1.09 g, 6.12 mmol) and DIPEA (0.971 mL, 5.56 mmol) were dissolved in MeOH (4 mL) and stirred at room temperature for 30 min . Sodium cyanoborohydride (1.05 g, 16.7 mmol) and acetic acid (0.318 mL, 5.56 mmol) were then added and the reaction stirred at room temperature for 3 h. The reaction was quenched by addition of 8% NaHCO3 (aq). The reaction was diluted with EtOAc (100 mL), stirred for 30 min and the layers separated. The aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (50ml), dried with a phase separator and evaporated in vacuo. The residue was dissolved in DCM (20 mL) and BOC2O (1.290 mL, 5.56 mmol) added. The mixture was stirred at room temperature for 5.5 h and was then concentrated in vacuo. The residue was purified by automated flash chromatography on a 100 g Biotage® KP-SIL column. A gradient of 10 - 80% EtOAc in heptane over 10 CV was used as the mobile phase. The product was collected using the wavelength 270 nm. The product peak was collected and evaporated in vacuo to yield 4-(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl) (S)-methyl)amino)ethyl)benzoate (1.84 g, 54%) as a pale solid.

[00340] LC/MS: m/z: 611.4 [M+H]+

[00341] 1H NMR (500 MHz, DMSO-d6) δ 1.36 (d, 9H), 2.15 - 2.26 (m, 4H), 2.45 - 2.49 (m, 2H), 2 .75 (t, 2H), 2.93 (dd, 1H), 3.01 - 3.4 (m, 5H), 3.84 (s, 3H), 6.97 (bs, 2H), 7, 05 - 7.17 (m, 4H), 7.21 (d, 2H), 7.82 (d, 2H), 7.85 - 7.94 (m, 1H). Step 4 Acid (S)-4 -(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine -2-carboxamido)-2-(2-methylbenzyl)propyl)amino)ethyl)benzoyl

[00342] 4-(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)ethyl)benzoate (S )-methyl (1.84 g, 2.56 mmol) was dissolved in MeOH (20 mL) and sodium hydroxide (3.37 mL, 12.8 mmol) added. The reaction was stirred at room temperature for 3 days. The solvent (MeOH) was then concentrated in vacuo. Water (50 mL) and MeTHF (50 mL) were added and the pH adjusted to ~2 with 3M HCl (aq). The phases were separated and the aqueous phase extracted with L-MeTHF (50 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo to yield (S)-4-(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2) acid). -carboxamido)-2-(2-methylbenzyl)propyl)amino)ethyl)benzoic acid (1.53 g, 100%) as a pale solid.

[00343] LC/MS: m/z: 597.4 [M+H]+

[00344] 1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 9H), 2.21 (d, 4H), 2.38 - 2.49 (m, 2H), 2.73 (t , 2H), 2.83 - 3.43 (m, 6H), 6.84 - 7.26 (m, 8H), 7.78 - 7.98 (m, 3H), 12.80 (bs, 1H ).Step 5 4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl)carbamoyl)phenethyl(3-(3,5-diamino-6-chloropyrazine- (S)-tert-butyl 2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate

[00345] (S)-4-(2-((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)ethyl acid )benzoic acid (1.24 g, 1.77 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.623 g, 1.94 mmol) and DIPEA (1.54 mL, 8.83 mmol) were dissolved in DCM (30 mL) and stirred at room temperature for 5 min before addition of (2-aminoethyl)(hexyl) hydrochloride (9H-fluoren-9-yl)methyl carbamate (Intermediate C, 0.95 g, 2.12 mmol). The reaction was stirred for 2.5 h. The reaction was washed with 8% NaHCO 3 (aq) (150 mL). The aqueous phase was extracted with DCM (150 ml). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a 100 g Biotage® KP-SIL column. A gradient of 20 - 80% EtOAc in heptane over 9 CV followed by 80% EtOAc in heptane over 3 CV was used as the mobile phase. The product was collected and evaporated in vacuo to yield 4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl)carbamoyl)phenethyl(3-(3,5- (S)-tert-butyl diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (1.56 g, 93%) as a pale solid.

[00346] LC/MS: m/z: 945.6 [M+H]+

[00347] 1H NMR (500 MHz, DMSO-d6) δ 0.82 (t, 3H), 0.87 - 0.97 (m, 2H), 1 - 1.27 (m, 5H), 1.33 (s, 9H), 1.38 - 1.47 (m, 1H), 2.15 - 2.27 (m, 4H), 2.45 (dd, 1H), 2.69 (s, 2H), 2.81 - 2.89 (m, 1H), 2.9 - 3 (m, 1H), 3.01 - 3.41 (m, 11H), 4.15 - 4.27 (m, 2H), 4.48 (d, 1H), 6.96 (bs, 2H), 7.05 - 7.18 (m, 6H), 7.30 (t, 2H), 7.39 (t, 2H), 7 .55 - 7.65 (m, 2H), 7.71 (dd, 2H), 7.8 - 7.97 (m, 3H), 8.37 - 8.51 (m, 1H). Step 6 (S )- tert-butyl

[00348] 4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl) carbamoyl)phenethyl(3-(3,5-diamino-6-chloropyrazine-2) (S)-tert-butyl-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (1.59 g, 1.68 mmol) was dissolved in THF (15 mL) and piperidine (1.67 mL, 16 .8 mmol) added. The reaction was stirred at room temperature for 3 h and was then concentrated in vacuo. The residue was purified by automated flash chromatography on a 100 g Biotage® KP-SIL column. A gradient of 4 - 8% (2M ammonia in MeOH) in DCM over 5 CV followed by 8% (2M ammonia in MeOH) in DCM over 10 CV was used as the mobile phase. The product was collected and evaporated in vacuo to give (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl) (S)-tert-butyl carbamoyl)phenethyl)carbamate (1.03 g, 85%) as a pale solid.

[00349] LC/MS: m/z: 723.6 [M+H]+

[00350] 1H NMR (500 MHz, DMSO-d6) δ 0.84 (t, 3H), 1.19 - 1.44 (m, 17H), 2.15 - 2.29 (m, 4H), 2 .45 (dd, 1H), 2.54 (t, 2H), 2.65 - 2.75 (m, 4H), 2.94 (dd, 1H), 3.02 - 3.18 (m, 2H ), 3.18 - 3.3 (m, 3H), 3.3 - 3.4 (m, 4H), 6.97 (bs, 2H), 7.05 - 7.2 (m, 7H), 7.73 (d, 2H), 7.79 - 7.97 (m, 1H), 8.32 (t, 1H). Intermediate E (S-(S) (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(S )-tert-butyl Step 1 (S)-methyl 4-((( tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzoate

[00351] (R)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (Intermediate A, 2.17 g, 6.22 mmol ), methyl 4-formylbenzoate (1.12 g, 6.84 mmol) and DIPEA (1.09 mL, 6.22 mmol) were dissolved in MeOH (15 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.782 g, 12.4 mmol) and acetic acid (0.392 mL, 6.84 mmol) were then added and the reaction stirred at room temperature for 3 hours. When monitoring by LCMS analysis showed incomplete conversion, methyl 4-formylbenzoate (200 mg, 1.22 mmol) was added and stirring was continued for 3 hours. Then again methyl 4-formylbenzoate (200 mg, 1.22 mmol) and sodium cyanoborohydride (200 mg, 3.18 mmol) were added and stirring was continued for 18 hours. The reaction was quenched by addition of 8% NaHCO3 (aq). The solvent was concentrated in vacuo. The residue was dissolved in EtOAc (250 mL) and 8% NaHCO 3 (aq) 250 mL), stirred and the phases separated. The aqueous phase was extracted with EtOAc (250 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The residue was dissolved in DCM (50 mL), BOC2O (1.63 g, 7.46 mmol) added and the reaction stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and was then purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20 to 80% EtOAc in Heptane over 12 CV was used as the mobile phase. The product was collected using the wavelength of 265 nm. The product peak was evaporated in vacuo to yield 4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl (S)-methyl benzoate (2.85 g, 77%) as a solid.

[00352] LC/MS: m/z: 597.5 [M+H]+

[00353] 1H NMR (500 MHz, DMSO-d6) δ 1.36 (d, 9H), 2.21 (s, 3H), 2.24 - 2.38 (m, 1H), 2.45 - 2 .57 (m, 2H), 2.95 - 3.3 (m, 4H), 3.83 (s, 3H), 4.33 - 4.51 (m, 2H), 6.97 (bs, 2H ), 7.04 - 7.17 (m, 4H), 7.22 (d, 2H), 7.76 - 7.96 (m, 3H). Step 2 (S)-4-((( tert -butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzoyl

[00354] (S)- 4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzoate Methyl (2.85 g, 4.77 mmol) was dissolved, MeOH (40 mL) and sodium hydroxide, 3.8 M (6.28 mL, 23.9 mmol) added. The reaction was stirred at room temperature for 24 hours and the solvent (MeOH) was then concentrated in vacuo. Water (75 mL) and MeTHF (75 mL) were added and the pH adjusted to ~2 with 3M HCl (aq). The phases were separated and the aqueous phase extracted with MeTHF (75 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo to yield (S)-4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-acid) 2-(2-methylbenzyl)propyl)amino)methyl)benzoic acid (2.75 g, 99%) as a solid.

[00355] LC/MS: m/z: 583.4 [M+H]+

[00356] 1H NMR (500 MHz, DMSO-d6) δ 1.32 - 1.42 (m, 9H), 2.20 (s, 3H), 2.24 - 2.38 (m, 1H), 2 .5 - 2.55 (m, 2H), 2.92 - 3.36 (m, 4H), 4.27 -4.54 (m, 2H), 6.97 (bs, 2H), 7.03 - 7.17 (m, 4H), 7.19 (d, 2H), 7.78 - 8 (m, 3H), 12.85 (bs, 1H).Step 3 4-((2-((( (9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl)carbamoyl)benzyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl )(S)-tert-butyl carbamate

[00357] (S)-4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzoic acid (1.61 g, 2.76 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.975 g, 3.04 mmol) and DIPEA (2.41 mL, 13.8 mmol) were dissolved in DCM (150 mL) and stirred at room temperature for 5 min before addition of (2-aminoethyl)(hexyl)carbamate hydrochloride (9H-fluoren-9-yl)methyl (Intermediate C, 1.48 g, 3.31 mmol). The reaction was stirred for 1.5 h. The reaction was washed with 8% NaHCO 3 (aq) (100 mL). The aqueous phase was extracted with DCM (100ml). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20 to 80% EtOAc in Heptane over 12 CV followed by 80% EtOAc in Heptane over 3 CV was used as the mobile phase. The product was collected and evaporated in vacuo to yield 4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl) carbamoyl)benzyl(3-(3,5- (S)-tert-butyl diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (2.38 g, 93%) as a pale solid.

[00358] LC/MS: m/z: 931.5 [M+H]+

[00359] 1H NMR (500 MHz, DMSO-d6) δ 0.82 (t, 3H), 0.86 - 0.96 (m, 1H), 0.99 - 1.27 (m, 6H), 1 .27 - 1.48 (m, 10H), 2.19 (s, 3H), 2.23 - 2.35 (m, 1H), 2.45 - 2.54 (m, 2H), 2.8 - 2.9 (m, 1H), 2.9 - 3.05 (m, 1H), 3.05 - 3.38 (m, 8H), 4.16 - 4.32 (m, 3H), 4 .39 - 4.56 (m, 2H), 6.97 (bs, 2H), 7.02 - 7.18 (m, 6H), 7.30 (t, 2H), 7.39 (t, 2H ), 7.60 (t, 2H), 7.64 - 7.76 (m, 2H), 7.78 - 7.99 (m, 3H), 8.37 - 8.52 (m, 1H). Step 4 (S-(S )- tert-butyl

[00360] 4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)(hexyl)amino)ethyl) carbamoyl)benzyl(3-(3,5-diamino-6-chloropyrazine-2) (S)-tert-Butyl-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (2.38 g, 2.55 mmol) was dissolved in THF (25 mL) and piperidine (2.53 mL, 25 .6 mmol) added. The reaction was stirred at room temperature for 20 hours. The solvent was evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 2.5 to 8% (2 M ammonia in MeOH) in DCM over 9 CV followed by 8% (2 M ammonia in MeOH) in DCM over 3 CV were used as the mobile phase. The product was collected and evaporated in vacuo to give (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl) (S)-tert-butyl carbamoyl)benzyl)carbamate (1.60 g, 88%) as a pale solid.

[00361] LC/MS: m/z: 709.5 [M+H]+

[00362] 1H NMR (500 MHz, DMSO-d6) δ 0.84 (t, 3H), 1.17 - 1.31 (m, 6H), 1.31 - 1.45 (m, 11H), 2 .20 (s, 3H), 2.24 - 2.37 (m, 1H), 2.51 - 2.57 (m, 3H), 2.68 (t, 2H), 2.91 - 3.06 (m, 1H), 3.06 - 3.4 (m, 6H), 4.23 - 4.36 (m, 1H), 4.4 - 4.53 (m, 1H), 6.97 (bs , 2H), 7.04 - 7.19 (m, 6H), 7.72 (d, 2H), 7.79 - 7.98 (m, 1H), 8.28 - 8.35 (m, 1H Intermediate F (9H-fluoren-9-yl)methyl (3-(4-formylpiperidin-1-yl)-3-oxopropyl)carbamate Step 1: (9H-fluoren-9-yl)methyl 3-(4-(hydroxymethyl)piperidin-1-yl)-3-oxopropylcarbamate

[00363] To a stirred solution of piperidin-4-ylmethanol (200 mg, 1.74 mmol), 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (541 mg, 1.74 mmol ) and HATU (660 mg, 1.74 mmol) in dry DMF (5 mL) was added DIPEA (0.910 mL, 5.21 mmol). The yellow mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with 15% aqueous NaCl solution (50 mL) and 30% aqueous NaCl solution (50 mL). Solvents were evaporated and the residue was purified by preparative HPLC. After freeze drying the residue was redissolved in DCM and heptane was added. Evaporation gave the title compound as a colorless solid (378mg, 53%).

[00364] LC/MS: m/z: 409 [M+H]+

[00365] 1H NMR (500 MHz, DMSO) d 0.88 - 1.09 (m, 2H), 1.51 - 1.73 (m, 3H), 2.44 (t, 2H), 2.47 - 2.52 (m, 1H + DMSO peak), 2.93 (t, 1H), 3.18 (dd, 2H), 3.23 (d, 2H), 3.80 (d, 1H), 4 .20 (t, 1H), 4.29 (d, 2H), 4.37 (d, 1H), 7.21 (t, 1H), 7.33 (dt, 2H), 7.41 (t, 2H), 7.68 (d, 2H), 7.89 (d, 2H). Step 2 (9H-fluoren-9-yl)methyl 3-(4-formylpiperidin-1-yl)-3-oxopropyl)carbamate

[00366] To a solution of (9H-fluoren-9-yl)methyl 3-(4-(hydroxymethyl)piperidin-1-yl)-3-oxopropylcarbamate (362 mg, 0.89 mmol) in DCM (5 mL ) was added solid Dess-Martin Periodinane (413 mg, 0.97 mmol). The resulting suspension was stirred at room temperature for 2.5 hours. To the reaction mixture was added 10% Na2S2O3 (3 mL), 10% NaHCO3 (3 mL) and DCM (2 mL), the mixture was stirred vigorously for 10 minutes and allowed to settle. The layers were separated and the water phase containing insoluble salts was extracted repeatedly with DCM. The combined organic phases were dried over MgSO4, filtered and the solvents were evaporated to leave the crude product (440 mg) which was used without further purification.

[00367] LC/MS: m/z: 407 [M+H]+ Intermediate G (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4 (R)-tert-butyl-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate Step 1 (R)-allyl (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate

[00368] (3,5-diamino-6-chloropyrazin-2-yl)(1H-imidazol-1-yl)methanone, (858 mg, 3.59 mmol) and (3-amino-2-(2-methylbenzyl) (R)-allyl)propyl)carbamate (Intermediate A, Step 5) (990 mg, 3.77 mmol) were suspended in NMP (15 mL) and heated to 100°C for 4 hours. The reaction mixture was allowed to cool to room temperature. EtOAc (50 mL) and water (50 mL) were added, stirred and the layers separated. The aqueous phase was extracted with EtOAc (2x50 mL). The combined organic phases were washed with 0.1M HCl (aq) (50 mL), water (2x50 mL), brine (50 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20 to 80% EtOAc in Heptane over 9 CV was used as the mobile phase. The product was collected using the wavelength 270 nm. The collected fractions were pooled and evaporated in vacuo to yield (R)-allyl (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (714 mg, 45.9%) as a pale solid.

[00369] 1H NMR (500 MHz, DMSO-d ) δ 1.9 - 2.02 (m, 1H), 2.23 (s, 3H), 2.41 - 2.55 (m, 2H), 2 .91 - 3.09 (m, 2H), 3.12 - 3.23 (m, 2H), 4.48 (d, 2H), 5.17 (d, 1H), 5.24 - 5.32 (m, 1H), 5.85 - 5.96 (m, 1H), 6.97 (bs, 2H), 7.04 - 7.15 (m, 3H), 7.21 - 7.25 (m , 1H), 7.28 (t, 1H), 8.00 (t, 1H).

[00370] LC/MS: m/z 433.3 [M+H]+ Step 2 (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6- chloropyrazine-2-carboxamide

[00371] (R)-allyl (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate (694 mg, 1.60 mmol), 1, 3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (688 mg, 4.41 mmol), palladium(II) acetate (14.4 mg, 0.06 mmol) and triphenylphosphine (50, 5 mg, 0.19 mmol) was dissolved in DCM (7 mL) and heated to 35 °C for 1.5 h. A suspension formed. DCM (50 mL) and 5% Na 2 CO 3 (aq) (50 mL) were added and the mixture stirred for 15 min. The phases were separated and the aqueous phase extracted with DCM (50ml). The combined organic phases were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm 250 x 50 ID mm) using a gradient of 5 to 45% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 ml/min. Compounds were detected by UV at 270 nm. The product fractions were collected and freeze-dried to yield 586 mg of the acetic acid salt. The salt was stirred in EtOAc (50 mL) and 5% Na 2 CO 3 (aq) for 15 min and the phases were then separated. The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo to yield (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine- 2-carboxamide (411 mg, 73.5%) as a light yellow solid. Chiral purity: 60% ee, determined with chiral SFC column: ChiralPak IC (150 x 4.6mm), particle size 3 μm, mobile phase: 20% MeOH/DEA 100:0.5 in CO2, (120 bar ), flow rate 4 mL/min.

[00372] 1H NMR (500 MHz, DMSO-d6) δ 1.73 (bs, 2H), 2.01 - 2.12(m, 1H), 2.50 (s, 3H), 2.64 - 2 .73 (m, 2H), 2.76 - 2.86 (m, 2H), 3.4 - 3.53 (m, 2H), 7.19 (bs, 2H), 7.28 - 7.41 (m, 4H), 8.39 (t, 1H).

[00373] LC/MS: m/z 349.2 [M+H]+ Step 3 (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)carbamate from (R)-tert-butyl (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (1.19 g, 3.41 mmol), BOC2O (0.871 mL , 3.75 mmol) and DIPEA (0.596 mL, 3.41 mmol) were dissolved in DCM (100 mL) and stirred at room temperature for 18 hours. The reaction mixture was washed with 0.1 M HCl (aq), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 30 to 70% EtOAc in Heptane over 9 CV followed by 70% EtOAc in Heptane over 3 CV was used as the mobile phase. The product was collected using the wavelength 268 nm. The product was evaporated in vacuo to afford (1.150g, 75%) as a pale solid.

[00374] The enantiomer was purified using preparative chiral HPLC (Column: ChiralPak AY (250 x 20 mm), particle size 20 μm, mobile phase: Heptane/EtOH/TEA 20 / 80:0.1, flow rate 120 m /min). The first eluting compound was collected to yield 866 mg, chiral purity: 98.6% ee. Optical rotation [a]D = -6 (acetonitrile, c=1).

[00375] 1H NMR (500 MHz, DMSO-d6) δ 1.38 (d, 9H), 1.88 - 2 (m, 1H), 2.23 (s, 3H), 2.39 - 2.49 (m, 2H), 2.83 - 2.93 (m, 1H), 2.93 - 3.03 (m, 1H), 3.09 - 3.23 (m, 2H), 6.89 (t , 1H), 6.97 (bs, 2H), 7.04 - 7.15 (m, 3H), 7.22 (d, 1H), 8.01 (t, 1H).

[00376] LC/MS: m/z 449.2 [M+H]+ Step 4 (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6- chloropyrazine-2-carboxamide

[00377] Acetyl chloride (1.422 mL, 20 mmol) was added dropwise to an ice-bath chilled flask of MeOH (5 mL, 123.59 mmol). The mixture was stirred for 5 min and then added to a vial of (R)-tert-butyl(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl ) carbamate (866 mg, 1.93 mmol). The reaction was stirred at room temperature for 45 min and was then evaporated in vacuo. The residue was stirred in EtOAc (125 mL) and 8% NaHCO 3 (aq) (125 mL) for 15 min. The phases were separated and the aqueous phase extracted with EtOAc (3x125 mL). The combined organic phases were dried with Na 2 SO 4 (s), filtered and evaporated in vacuo to yield (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine- 2-carboxamide (459 mg, 68.2%) as a pale solid. Chiral purity: 99% ee, determined with chiral SFC column: Lux C4 (150 x 4.6 mm), particle size 3 μm, mobile phase: 35% EtOH/NH3 100:0.5 in CO2, (120 bar ), flow rate 4 mL/min. Optical rotation [a ]20 = -45.9 (CHCh, c=1).

[00378] 1H NMR (500 MHz, DMSO-d ) δ 1.57 (bs, 2H), 1.78 - 1.88 (m, 1H), 2.26 (s, 3H), 2.39 - 2 .48 (m, 2H), 2.52 - 2.62 (m, 2H), 3.18 - 3.28 (m, 2H), 6.95 (bs, 2H), 7.04 - 7.17 (m, 4H), 8.14 (t, 1H).

[00379] LC/MS: m/z 349.2 [M+H]+ Step 5 (2-(4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2- (R)-(9H-fluoren-9-yl)methyl carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzamido)ethyl)(hexyl)carbamate

[00380] (S)-3,5-diamino-N-(3-amino-2-(2-methylbenzyl)propyl)-6-chloropyrazine-2-carboxamide (215 mg, 0.62 mmol), (2- (9H-fluoren-9-yl)methyl (4-formylbenzamido)ethyl)(hexyl)carbamate (Intermediate H) (293 mg, 0.59 mmol) and DIPEA (0.103 mL, 0.59 mmol) were dissolved in MeOH (5 mL) and stirred at room temperature for 1.5 h. Sodium cyanoborohydride (38.8mg, 0.62mmol) and acetic acid (0.101ml, 1.76mmol) were then added and stirring continued for 3 hours. The reaction was quenched by addition of 8% NaHCO3 (aq). DCM (25 mL) and 8% NaHCO 3 (aq) (25 mL) were added, stirred and the layers separated. The aqueous phase was extracted with DCM (25ml). The combined organic phases were dried with a phase separator and evaporated in vacuo.

[00381] The residue and BOC2O (0.150 mL, 0.65 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The product was purified by automated flash chromatography on a Biotage® KP-SIL 50 g column. A gradient of 50 to 100% EtOAc in Heptane over 9CV was used as the mobile phase. The product was collected using the wavelength 265 nm. The product fractions were evaporated in vacuo to give (2-(4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl (R)-(9H-fluoren-9-yl)methyl)(Amino)methyl)benzamido)ethyl)(hexyl)carbamate (511 mg, 93%) as a colorless film.

[00382] 1H NMR (500 MHz, DMSO-d6) δ 0.82 (t, 3H), 0.87 - 0.96 (m, 1H), 0.99 - 1.26 (m, 6H), 1 .27 - 1.5 (m, 10H), 2.19 (s, 3H), 2.23 - 2.35 (m, 1H), 2.8 - 2.9 (m, 1H), 2.9 - 3.04 (m, 1H), 3.05 - 3.39 (m, 10H), 4.16 - 4.32 (m, 3H), 4.39 - 4.57 (m, 2H), 6 .88 - 7.18 (m, 8H), 7.30 (t, 2H), 7.39 (t, 2H), 7.55 - 7.76 (m, 4H), 7.77 - 7.99 (m, 3H), 8.37 - 8.52 (m, 1H).

[00383] LC/MS: m/z 931.4 [M+H]+ Step 6 (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)( (R)-tert-butyl 4-((2-(hexylamino)ethyl)carbamoyl)benzyl)carbamate

[00384] (2-(4-(((tert-butoxycarbonyl)(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)amino)methyl)benzamido) (R)-(9H-fluoren-9-yl)methyl ethyl)(hexyl)carbamate (511 mg, 0.55 mmol) was dissolved in THF (5 mL) and piperidine (0.543 mL, 5.49 mmol) added . The reaction was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 50 g column. A gradient of 2.5 - 8% (2 M ammonia in MeOH) in DCM over 9 CV followed by 8 % (2 M ammonia in MeOH) in DCM over 3 CV was used as the mobile phase. The product was collected and evaporated in vacuo to give (3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propyl)(4-((2-(hexylamino)ethyl) (R)-tert-butyl carbamoyl)benzyl)carbamate (326 mg, 84%) as a pale solid.

[00385] 1H NMR (500 MHz, DMSO-d6) δ 0.84 (t, 3H), 1.12 - 1.45 (m, 17H), 2.20 (s, 3H), 2.24 - 2 .36 (m, 1H), 2.51 - 2.58 (m, 2H), 2.69 (t, 2H), 2.92 - 3.05 (m, 1H), 3.05 - 3.4 (m, 7H), 4.22 - 4.37 (m, 1H), 4.38 - 4.54 (m, 1H), 6.97 (bs, 2H), 7.03 - 7.18 (m , 6H), 7.72 (d, 2H), 7.79 - 7.98 (m, 1H), 8.28 - 8.35 (m, 1H).

[00386] LC/MS: m/z 709.4 [M+H]+ Intermediate H (9H-fluoren-9-yl)methyl (2-(4-formylbenzamido)ethyl)(hexyl)carbamate

[00387] 4-Formylbenzoic acid (0.81 g, 5.40 mmol) and 4-methylmorpholine (1.424 mL, 12.95 mmol) were dissolved in THF (10 mL) and cooled with an ice bath. Isobutyl carbonochlorhydrate (0.700 mL, 5.40 mmol) was added dropwise, the mixture stirred for 30 min and (9H-fluoren-9-yl)methyl (2-aminoethyl)(hexyl)carbamate hydrochloride (Intermediate C ) (1.739 g, 4.32 mmol) is added. The reaction was stirred at room temperature for 2.5 h. The resulting suspension was extracted between EtOAc (50 mL) and water (50 mL). The organic phase was washed with 5% citric acid (2x50 mL), 10% Na 2 CO 3 (aq) (50 mL), brine (50 mL), dried with Na 2 SO 4 (s), filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20 to 80% EtOAc in Heptane over 9 CV followed by 80% EtOAc in Heptane over 3 CV was used as the mobile phase. The product was collected using the wavelength 260 nm. The product peaks were evaporated in vacuo to afford (9H-fluoren-9-yl)methyl (2-(4-formylbenzamido)ethyl)(hexyl)carbamate (1.690 g, 79%) as a white solid.

[00388] 1H NMR (500 MHz, CDCl3) δ 0.82 - 0.95 (m, 3H), 1.08 - 1.46 (m, 8H), 3.02 - 3.21 (m, 3H) , 3.48 - 3.64 (m, 3H), 4.16 - 4.25 (m, 1H), 4.51 - 4.74 (m, 2H), 7.2 - 7.42 (m, 5H), 7.5 - 7.67 (m, 3H), 7.75 (d, 2H), 7.93 (q, 3H), 10.06 (s, 1H).

[00389] LC/MS: m/z 499.5 [M+H]+ Intermediate I 4-formyl-N-(2-(hexyl((2S,3R,4R)-2,3,4,5-tetra -hydroxypentyl)amino)ethyl)benzamide Step 1 tert-butyl 2-(hexylamino)ethylcarbamate

[00390] To a 10 L flange flask was charged hexylamine (1020 mL, 7.76 mol), Na2CO3 (206 g, 1.94 mol) and MeCN (2560 mL). The mixture was heated to 70 °C for 1 h. To the mixture was charged a solution of tert-butyl 2-bromoethylcarbamate (371.3 g, 289.6 g active, 1.29 mol) in MeCN (740 ml) slowly over 1% h. The reaction was stirred at 70°C overnight. The reaction was cooled to 50oC and concentrated in vacuo. To the stirred residue was charged water (2100 ml) and EtOAc (4200 ml). The layers were separated and the organic phases were washed with water (3 x 2100 ml). The organic phases were concentrated in vacuo and sequentially azeotroped with water (3 x 870 ml) and EtOH (3 x 870 ml) to give 368.6 g (315.8 g active, quantitative yield) of stage 1 as a clear oil.

[00391] 1H-NMR(270 MHz, CDClβ.) δ 4.95 (1H, br s), 3.29 - 3.19 (m, 2H), 2.71 (t, 2H), 2.58 ( t, 2H), 1.50 - 1.40 (br. m, 11H), 1.35 - 1.23 (m, 6H), 0.89 (t, 3H).

[00392] LC/MS: m/z 245 [M+H]+ Step 2 tert- tert-2,3,4,5-tetrahydroxypentyl)amino)ethylcarbamate butyl

[00393] To a 10 L flange flask was charged D-xylose (124.3 g, 0.83 mol), tert-butyl 2-(hexylamino)ethylcarbamate (step 1, 181.8 g, 155.8 active g, 0.49 mol), EtOH (5000 ml) and DIPEA (110.8 ml, 0.64 mol). The mixture was heated to 35°C for 1 h until dissolved. To the solution was charged AcOH (36.5 mL, 0.64 mol) and the resulting mixture stirred at 35 °C for 15 min. To this was charged NaCNBH3 (56.1 g, 0.89 mol) portionwise over 5 min at 35°C. No exotherms or gas evolution observed. The reaction was stirred at 35°C overnight. To this was charged NaCNBH 3 (8.0 g, 0.13 mol) and stirred at 35°C for 3 hours. The reaction was allowed to cool to room temperature overnight. To the mixture was charged saturated aqueous NaHCO 3 (1600 mL) for 10 min, a slightly exothermic reaction was observed. The mixture was stirred at room temperature over the weekend. EtOH was removed in vacuo and combined with a second batch of the same scale (181.8 g stage 1) during preparation. To the mixture was charged NaCl (311 g). The organic phases were extracted with 10% MeOH/DCM (3 x 3000 ml) and the combined organic phases were concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 7 kg), packed, loaded and eluted with 5% MeOH/DCM + 0.2% 7N NH3 in MeOH (35 L), 50% MeOH/DCM + 0.2% 7N NH3 in MeOH (75 L), then rinsing with 65% MeOH/DCM + 0.2% 7N NH3 in MeOH (20 L). Product containing fractions were combined, evaporated in vacuo and azeotroped with MeOH (2 x 500 mL) to afford 387 g (366 g actives, 76%) of the subtitle compound as a yellow gum.

[00394] 1H-NMR(270 MHz, DMSO-d6) δ 6.80 (br.s, 1H), 4.80 - 4.30 (br.m, 3H), 4.22 - 4.05 (br. m, 1H), 3.74 - 3.60 (br. m, 1H), 3.59 - 3.48 (m, 1H), 3.47 - 3.20 (m, 6H), 3.08 - 2.87 (br.m, 2H), 2.70 - 2.45 (br.m, 3H), 1.51 - 1.35 (m, 10H), 1.32 - 1.16 (m, 7H), 0.85 (t, 3H).

[00395] LC/MS: m/z 401 [M+H]+ Step 3 (2R,3R,4S)-5-((2-aminoethyl)(hexyl)amino)pentane-1,2,3,4- tetraol

[00396] To a solution of tert-butyl 2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethylcarbamate (step 2, 365 g, 345 g of actives , 0.91 mol) in MeOH (520 ml) at room temperature was charged 4M HCl in dioxane (1710 ml, 6.84 mol) over 30 minutes, maintaining a temperature < 31°C. The reaction was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo to provide 485.1 g (306 g active, 95%) of the subtitle compound as a purple black tar.

[00397] 1H-NMR(270 MHz, DMSO-d6) δ 8.41 (br. s, 3H), 4.20 - 3.00 (br. m, 16H), 1.77 - 1.62 (br. .m, 2H), 1.37 - 1.17 (br.m, 6H), 0.87 (br.t, 3H).

[00398] MS ES: m/z 279 [M+H]+ Step 4 4-formyl-N-(2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)benzamide

[00399] To a 5 L flange flask was charged 4-formylbenzoic acid (107.6 g, 0.72 mol) and DMF (1400 ml) at room temperature. To this was charged 4-methylmorpholine (255.5 ml, 2.3 mol). The mixture was cooled to -15 °C for 5 min. To this was charged isobutyl chloroformate (93.4 ml, 0.71 mol) over 15 min, maintaining a reaction temperature < -10 °C. The reaction was stirred at -10°C to -15°C for 1 hour. In a separate vial, (2R,3R,4S)-5-((2-aminoethyl)(hexyl)amino)pentane-1,2,3,4-tetraol (step 3, 383.9 g, 245.7 g actives, 0.71 mol) was dissolved in DMF (1400 ml) and 4-methylmorpholine (123 ml, 1.1 mol) at 45oC for 1 hour. The mixed anhydride mixture was charged to step 3 containing the mixture for 15 min, maintaining a reaction temperature < -5°C. The resulting mixture was allowed to warm to room temperature overnight. To the reaction mixture was charged saturated aqueous NaHCO 3 (2500 ml) slowly over 30 min. The resulting mixture was concentrated in vacuo. To the residue was charged saturated aqueous NaHCO 3 (1200 ml) and stirred with DCM (4900 ml) for 10 min at RT. The layers were separated and the aqueous was extracted with 13% MeOH/DCM (2870 ml). The combined organic phases were washed with saturated aqueous NaHCO 3 (1200 ml) and concentrated in vacuo to give 395.3 g. The residue was combined with 10 g of crude material recovered from an intermediate scale reaction and purified by chromatography [SiO 2 , 3 kg; loaded and packed with 5% MeOH/DCM; eluted with 5% MeOH/DCM (30 L), 10% MeOH/DCM (20 L), 20% MeOH/DCM (10 L), 30% MeOH/DCM (30 L), 40% MeOH /DCM (20 L) and 100% MeOH (80 L)]. Product fractions were combined (100 L) and concentrated in vacuo to provide 138.4 g (112 g active, 39% yield) of the subtitle compound. 1H NMR indicated 81.4% w/w activity with approximately 5.5% formylbenzamide impurity remaining. HPLC-MS analysis indicated 97.4% purity. Mixed fractions (20 L) were combined and concentrated in vacuo to provide 46 g of material that was 74.5% pure by HPLC. This was repurified by chromatography (SiO 2 , 600 g), eluting with 10% to 30% MeOH/DCM (18 L). Product fractions were combined and concentrated in vacuo to provide an additional 21.0 g (20.3 g actives, 44%) of the subtitle compound.

[00400] 1H-NMR (270 MHz, DMSO-d6): δ 10.08 (s, 1H), 8.60 (t, 1H), 8.02 (d, 2H), 7.97 (d, 2H ), 4.70 - 4.20 (br. m, 4H), 3.66 - 3.52 (m, 2H), 3.46 - 3.34 (m, 8H), 2.65 - 2.58 (m, 2H), 2.51 - 2.44 (m, 2H), 1.40 - 1.28 (br. m, 2H), 1.19 - 1.08 (m, 6H), 0.79 (t, 3H).

[00401] LC/MS: m/z 411 [M+H]+

Enzymatic demeterization of 2-(2-methylbenzyl)propane-1,3-diamine.

[00402] The enzymatic desimetrization of 2-(2-methylbenzyl)propane-1,3-diamine was investigated using diallylcarbonate and a range of immobilized lipases.

[00403] Evaluation of immobilized lipase: To a solution of 2-(2-methylbenzyl)propane-1,3-diamine (0.60 g, 3.37 mmol) in 1,4-dioxane (30 mL) was added diallylcarbonate (0.507 mL, 3.53 mmol). 1.0 ml aliquots of this solution were added to 10 ml screw cap test tubes containing the enzymes (0.02 g) described in Table 1. The tubes were shaken at 500 rpm/30°C for 3 days. Each tube was sampled and analyzed by Reversed Phase HPLC (4.6 x 50 mm Thermoquest Hypercarb, UV detection at 260 nm) and chiral HPLC (4.6 x 250 mm Chiralpak IC3, UV detection at 260 nm).

[00404] Six of the analyzed lipases showed more than 20% conversion after 3 days (Table 1). 1Conversion to mono-allyl carbamate is reported in HPLC area %. 2 R/S ratios are indicated in area% of R enantiomer divided by area% of S enantiomer of chiral HPLC.Table 1.

[00405] Solvent Evaluation with Amano Lipase PS-IM: A solvent evaluation with Amano Lipase PS-IM was performed on 20 relative volumes of the solvents with 1.1 equivalent of diallylcarbonate, 1 mass equivalent of Amano PS-IM and 0, 1 g of 2-(2-methylbenzyl)propane-1,3-diamine. After 6 days at 30 °C the experiments were sampled using the same methods as described for lipase assessment (Table 2). 2-(2-Methylbenzyl)propane-1,3-diamine was not very soluble in non-polar solvents such as methyl t-butyl ether, heptanes and cyclohexane. Addition of THF to each of the solvents, however, allowed the diamine to dissolve and the above mentioned 1:1 solvent mixtures were tested. The results suggested that 2-MeTHF provided the best enantioselectivity despite some background reaction. In order to minimize base carboxylation in 2-MeTHF, a gram-scale experiment was performed at 30 oC with excess Amano lipase PS-IM (3 mass equivalents of immobilized phase, 1.2 equivalents of diallylcarbonate, 20 vol of 2 -MeTHF). The reaction proceeded to completion within 3 days and after preparation, crude (R)-monoallylcarbamate 1-(R) was isolated with 85% ee. Conversion of the crude product to the corresponding D-tartrate salt in ethanol increased the enantiomeric excess to 91.0% (58% of total diamine production). 1Conversion to mono-allyl carbamate is reported in HPLC area %.2 R/S ratios are reported in area% of R enantiomer divided by area% of S enantiomer of chiral HPLC.Table 2

Sodium channel ENaC Ussing chamber test

[00406] Differentiated primary human bronchial epithelial cells at the air-liquid interface (ALI) on permeable snapwell supports (MatTek Corporation, MA, USA, cat no. AIR-100-SNP) were maintained in ALI culture in a humidified incubator at 37° C and 5% CO2. Basolateral medium (MatTek Corporation, MA, USA cat no. AIR-100-MM-ASY) was changed every second day. Mucus or liquid formed on the apical side was gently aspirated every second day to maintain cell viability and performance.

[00407] The transepithelial voltage between the luminal/apical and basolateral membrane was measured in the Ussing chamber consisting of in-house manufactured Ussing chambers, vertical, DVC-1000 V/C clamps with preamplifiers (World Precision Instruments), electrode kits (EK1 , World Precision Instruments), Power Lab with Chart5 software, water bath with external circulation and carbon dioxide gas distribution and regulation system. Electrodes used in the setup were manually fused using 4% agarose in 0.9% sterile NaCl, as per the manufacturer's recommendation.

[00408] The Ussing chambers were sampled with an empty Snapwell membrane (Costar 3407) and electrodes contained in Kreb buffer (SIGMA-ALDRICH cat no. K3753) for one hour at 37°C in the presence of 95% oxygen and 5% of carbon dioxide. After this Equilibration Step the system was compensated for fluid resistance and input lag.

[00409] Before the experiment the ALI cultures were evaluated for Trans Epithelial Electrical Resistance (TEER) with the EndOhm device (World Precision Instruments), cells exhibiting a resistance between 400-600 Ohms were used.

[00410] The equilibrated chambers were resampled with a Snapwell containing ALI cells and after 20 minutes of stabilization cumulative doses of compounds were added to the apical side of the membrane. After the final dose 10 µM Benzamil was added to reach the maximum.

[00411] All test compounds, including the reference compound, were diluted from stocks to 10 mM in 100% DMSO and added to opaque 96-well plates (Greiner, Cat No. 651201). Dilution series of 12 doses were prepared in DMSO, starting with 3 µM followed by 10-fold dilution steps.

[00412] The Chart5 software for Windows was used to measure the short circuit current value after each compound addition. Data were transferred to Excel and analyzed using IDBS XLfit® 5.2 (ID Business Solutions Ltd). The molar concentration of test or reference compound producing 50% inhibition (IC50 curve) was derived by fitting the data to a 4-parameter logistic function of the form: y = (A+((BA)/(1+(((10AC)/ x)AD)))) AO the base plateau of the curve, that is, the final minimum y-value B The top of the curve plateau, that is, the final maximum y-value C the log10x value at a y-value of 50%. D Hill slope factor. x The known x values. Table 1 shows the pIC50 values for examples 1 to 14. TABLE 1

Intestinal Mucosal Permeation Estimated using Cacus-2 Cell Monolayer

[00413] Caco-2 cells are grown in Dulbecco's Modified Eagle's Medium (DMEM) in 96-well Transwell polycarbonate membrane inserts for 15 days until confluence and differentiation is achieved. After evaluating the integrity by measuring the electrical resistance between the monolayer cells are washed twice with HBSS (25 mM HEPES, pH 7.4) and incubated at 37 oC for 30 min.

[00414] Stock solutions of test compounds in DMSO are diluted with HBSS (containing 100 μM Lucifer Yellow) to reach a final concentration of 10 μM; all incubations are performed in duplicate. To determine the rate of drug transport in an apical to basolateral direction (A to B) 100 µL of test compound solutions are added to the apical compartment of the Transwell insert. The basolateral compartment is loaded with 300 µL of HBSS.

[00415] For determination of basolateral to apical transport (B to A) the basolateral compartment is loaded with 300 μL of test compound solution and 100 μL of HBSS is added to the apical compartment.

[00416] After incubating the plate at 37 oC for 2 h, 50 μL from each compartment are removed and transferred to 96-well plates for fluorescence measurement in a suitable plate reader at 485 nm of excitation and 530 nm of emission to monitor the monolayer integrity. For test compound permeability analysis 3 volumes of cold methanol are added to each buffer sample and the samples are centrifuged at 4°C for 15 minutes. A 5 µL aliquot of the supernatant is used for LC/MS/MS analysis.

[00417] The evident permeability (Papp, in units of cm/s) can be calculated using the following equation

[00418] where VA is the volume (in mL) in the acceptor cavity (0.3 mL for apical to basolateral), Area is the surface area of the membrane (0.143 cm2 for HTS Transwell-96 Well Permeable Supports) and time is the total transport time in s.

[00419] The evident patency in the apical to basolateral direction (A to B Mean Papp,1E-6.cm/s) was measured for each of the examples 1 to 16. No evident patency could be detected for any of the examples in the direction apical to basolateral. Compounds that exhibit low permeability may be more desirable for delivery of ENaC inhibitors via inhaled administration.

[00420] The above description of illustrative embodiments is intended only to familiarize others skilled in the art with the Applicant's invention, its principles, and its practical application, so that others skilled in the art can easily adapt and apply the invention in its numerous forms , as they can be better adapted to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the illustrative embodiments described in this report, and can be modified variously. Furthermore, it should be appreciated that various aspects of the invention which are, for the sake of clarity, described in the context of separate embodiments, may also be combined to form a single embodiment. Rather, various aspects of the invention which are, for brevity's sake, described in the context of a single embodiment, may also be combined to form sub-combinations thereof.

Claims (9)

1. Compound characterized by the fact that it has formula (I): wherein: R1 is selected from hydrogen or C1-4 alkyl; m is 1 or 2; A is selected from phenyl or heterocyclyl; X is selected from -C(=O)-, -C(=O)-NR4- or -OC(=O)-NR5-; n is 2 or 3; R2 is selected from hydrogen or C1-8 alkyl; R3 is C5-6 alkyl-OH, wherein said C5-6 alkyl group is also substituted by an additional 3 or 4 -OH groups; and R4 and R5 are independently selected from hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 is C1-4 alkyl and R4 and R5 are both hydrogen. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, characterized in that A is phenyl. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)-NR4-. 5. Compound according to any one of claims 1 to 4, characterized in that: R1 is C1-4 alkyl; m is 1; A is phenyl; X is -C(=O)-NH-; n is 2; R2 is C1-8 alkyl; and R3 is selected from the following: with the pharmaceutically acceptable salt thereof. 6. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that R2 is n-hexyl. 7. Compound according to claim 1, characterized in that it is selected from: 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-(((1- (3-(((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)propanoyl)piperidin-4-yl)methyl)amino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(2-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6-penta -hydroxyhexyl)amino)ethylcarbamoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-penta -hydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino )propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(4-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6-penta -hydroxyhexyl)amino)butanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-2-(2-methylbenzyl)-3-((1-(3-((2S,3R,4R,5R)-2,3,4 ,5,6-pentahydroxyhexylamino)propanoyl)piperidin-4-yl)methylamino)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((1-(3-(hexyl((2R,3R,4R,5R)-2,3,4,5,6-penta -hydroxyhexyl)amino)propanoyl)piperidin-4-yl)methylamino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2R,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 4-(((R)-3-(3,5-diamino-6-chloropyrazine-2-carboxamido)-2-(2-methylbenzyl)propylamino)methyl)phenyl-2-(hexyl((2S,3R,4R ,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethylcarbamate; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6- pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl) amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof. 8. Compound according to claim 1, characterized in that it is: 3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R) ,4R)-2,3,4,5-tetrahydroxypentyl)amino)ethyl)carbamoyl)benzyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide, having the formula (Ia) : or a pharmaceutically acceptable salt thereof. 9. Combination characterized by the fact that it comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 8, and one or more agents selected from the list comprising: • a beta agonist -adrenoceptor; • a muscarinic receptor antagonist • a joint muscarinic receptor antagonist and beta-adrenoceptor agonist; • a Toll-like receptor agonist (such as a TLR7 or TLR9 agonist); • an adenosine antagonist; • a glucocorticoid receptor agonist (steroidal or non-steroidal); • an antagonist of p38; • an antagonist of IKK2; • an antagonist of PDE4; • a modulator of chemokine receptor function (such as a CCR1, CCR2B, CCR5, CXCR2 or CXCR3 receptor antagonist); • an antagonist of CRTh2; or • an osmolyte, such as hypertonic saline.