BACE1 INHIBITORS

Background Art

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system and the leading cause of a progressive dementia in the elderly population. Its clinical symptoms are impairment of memory, cognition, temporal and local orientation, judgment and reasoning but also severe emotional disturbances. There are currently no treatments available which can prevent the disease or its progression or stably reverse its clinical symptoms. AD has become a major health problem in all societies with high life expectancies and also a significant economic burden for their health systems.

AD is characterized by 2 major pathologies in the central nervous system (CNS), the occurrence of amyloid plaques and neurofibrillar tangles (Hardy et al., The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science. 2002 Jul 19;297(5580):353-6, Selkoe, Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994;10:373-403). Both pathologies are also commonly observed in patients with Down's syndrome (trisomy 21), which also develop AD-like symptoms in early life. Neurofibrillar tangles are intracellular aggregates of the micro tubule-associated protein tau (MAPT). Amyloid plaques occur in the extracellular space; their principal components are Αβ-peptides. The latter are a group of proteolytic fragments derived from the β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing. The Αβ-peptides are derived from the same domain of the APP but differ at their N- and C-termini, the main species are of 40 and 42 amino-acid length. There are several lines of evidence which strongly suggest that aggregated Αβ-peptides are the essential molecules in the pathogenesis of AD: 1) amyloid plaques formed of Αβ-peptides are invariably part of the AD pathology; 2) Αβ- peptides are toxic for neurons; 3) in Familial Alzheimer's Disease (FAD) the mutations in the disease genes APP, PSN1, PSN2 lead to increased levels of Αβ-peptides and early brain amyloidosis; 4) transgenic mice which express such FAD genes develop a pathology which bears many resemblances to the human disease. Αβ-peptides are produced from APP through the sequential action of 2 proteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves first in the extracellular domain of APP approximately 28 amino acids outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP containing the TM- and the cytoplasmatic domain (ΟΤΕβ). CTFβ is the substrate for γ-secretase which cleaves at several adjacent positions within the TM to produce the Αβ peptides and the cytoplasmic fragment. The γ-secretase is a complex of at least 4 different proteins, its catalytic subunit is very likely a presenilin protein (PSEN1, PSEN2). The β-secretase (BACE1, Asp2; BACE stands for β-site APP-cleaving enzyme) is an aspartyl protease which is anchored into the membrane by a transmembrane domain (Vassar et al., Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE, Science. 1999 Oct 22;286(5440):735). It is expressed in many tissues of the human organism but its level is especially high in the CNS. Genetic ablation of the BACE1 gene in mice has clearly shown that its activity is essential for the processing of APP which leads to the generation of Αβ-peptides, in the absence of BACE1 no Αβ-peptides are produced (Luo et al., Mice deficient in BACE1, the Alzheimer's beta- secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci. 2001 Mar;4(3):231 -2, Roberds et al., BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics, Hum Mol Genet. 2001 Jun 1; 10(12): 1317-24). Mice which have been genetically engineered to express the human APP gene and which form extensive amyloid plaques and Alzheimer's disease like pathologies during aging fail to do so when β-secretase activity is reduced by genetic ablation of one of the BACE1 alleles (McConlogue et al., Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep 7;282(36):26326). It is thus presumed that inhibitors of BACE1 activity can be useful agents for therapeutic intervention in Alzheimer's disease (AD). Several patent applications have been filed describing BACE 1 inhibitors of various structures, e.g. WO2009103626, WO2010128058, WO2011020806, WO2011029803, WO2011069934, WO2011070029, WO2011138293, WO2012019966, WO2012028563, WO2012098064, WO2012104263, WO2012107371, WO2012110459, WO2012119883, WO2012126791, WO2012136603, WO2012139993, WO2012156284, WO2012163790, WO2012168164, WO2012168175, WO2013004676, WO2013041499, WO2013110622 , WO2013174781, WO2014001228, WO2014114532, WO2014150331, WO2014150340, WO2014059185 and WO2014150344. Furthermore, the formation, or formation and deposition, of β-amyloid peptides in, on or around neurological tissue (e.g., the brain) are inhibited by the present compounds, i.e. inhibition of the Αβ-production from APP or an APP fragment.

The present invention provides novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as Alzheimer's disease.

Field of the Invention

The present invention provides S-imino S-oxo iminothiazines having BACE1 inhibitory properties, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

Summary of the Invention The present invention provides a compound of formula I,

wherein the substituents and variables are as described below and in the claims, or a pharmaceutically acceptable salt thereof. The present compounds have Asp2 (β-secretase, BACEl or Memapsin-2) inhibitory activity and may therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits, particularly Alzheimer's disease.

Detailed Description of the Invention The present invention provides a compound of formula I and their pharmaceutically acceptable salts thereof, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the therapeutic and/or prophylactic treatment of diseases and disorders which are associated with inhibition of BACEl, such as Alzheimer's disease. Furthermore, the formation, or formation and deposition, of β-amyloid plaques in, on or around neurological tissue (e.g., the brain) are inhibited by the present compounds by inhibiting the Αβ production from APP or an APP fragment.

The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups. Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "Ci-6-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (iert-butyl), isopentyl, 2-ethyl-propyl (2-mefhyl-propyl), 1,2-dimethyl-propyl and the like. Particular "Ci-6-alkyl" are "Ci-3-alkyl". Specific groups are methyl and ethyl. Most specific group is methyl. The term "halogen-Ci_6-alkyl" or "Ci-6-alkyl-halogen", alone or in combination with other groups, refers to Ci-6-alkyl as defined herein, which is substituted by one or multiple halogen, particularly 1-5 halogen, more particularly 1-3 halogen. Particular halogen is fluoro. Particular "halogen-Ci-6-alkyl" is fluoro-Ci-6-alkyl and a particular "halogen-Ci-3-alkyl" is fluoro-Ci-3-alkyl. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and the like. A specific group is fluoromethyl.

The term "cyano", alone or in combination with other groups, refers to N≡C-(NC-).

The term "halogen", alone or in combination with other groups, denotes chloro (CI), iodo (I), fluoro (F) and bromo (Br). Particular "halogen" are CI, I and F. A specific group is F. The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring, in particular 5 to 8, or multiple condensed rings comprising 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms individually selected from N, O and S, in particular IN or 2N, in which group at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl, lH-benzoimidazolyl, benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, lH-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), lH-pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyridazinyl, pyridinyl (pyridyl), pyrimidinyl (pyrimidyl), pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[l]pyrindinyl and the like. Particular "heteroaryl" groups are pyridyl, pyrazinyl and imidazo[l,2-a]pyridinyl.

The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Particular "aryl" is phenyl.

The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. A specific acid is trifluoroacetic acid.

The term "amino", alone or in combination with other groups, refers to -NH ₂ .

The terms "hydroxyl" or "hydroxyl", alone or in combination with other groups, refer to -

OH. The term "C2-6-alkynyl-Ci_6-alkoxy", alone or in combination with other groups, refers to Ci-6-alkoxy as defined herein, which is substituted by one or multiple C ₂ -6-alkynyl as defined herein, in particular 1 C2-6-alkynyl.

The term "C2-6-alkynyl", alone or in combination with other groups, denotes a monovalent linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms, and comprising one, two or three triple bonds. Examples of C2-6-alkynyl include ethynyl, propynyl, and n-butynyl.

The term "Ci_6-alkoxy-Ci-6-alkyl", alone or in combination with other groups, refers to Ci- 6-alkyl as defined herein, which is substituted by one or multiple Ci-6-alkoxy, as defined herein, particularly 1 Ci-6-alkoxy. Particular "Ci-6-alkoxy-Ci_6-alkyl" is methoxy-Ci-6-alkyl. Examples are methoxymethyl, methoxyethyl and the like.

The term "C3-6-cycloalkyl" refers to a 3 to 8 membered carbon ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Particular are cycloalkyl groups having a 3, 4, 5 or 6 membered carbon ring. Specific is cyclopropyl. The term "Ci-6-alkoxy", alone or in combination with other groups, stands for an -O-Ci-6- alkyl radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy), 2-butoxy (sec- butoxy), t-butoxy (iert-butoxy), isopentyloxy (i-pentyloxy) and the like. Particular "Ci-6-alkoxy" are groups with 1 to 4 carbon atoms. Specific are ethoxy and methoxy.

The term "halogen-Ci-6-alkoxy", alone or in combination with other groups, refers to Ci_6- alkoxy as defined herein, which is substituted by one or multiple halogens, in particular fluoro. Particular "halogen-Ci-6-alkoxy" are fluoro-Ci-6-alkoxy. Specific "halogen-Ci-6-alkoxy" are CHF2-CF ₂ -CH ₂ -0-, CHF ₂ -0- and CF ₂ -0-. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. The term "inhibitor" denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein.

The term "half maximal inhibitory concentration" (IC ₅₀ ) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC ₅₀ values can be converted logarithmically to pICso values (-log IC ₅₀ ), in which higher values indicate exponentially greater potency. The IC ₅₀ value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC ₅₀ value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to pKi values (-log Ki), in which higher values indicate exponentially greater potency. "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The term "as defined herein" and "as described herein" when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any.

The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

The term "aromatic" denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught and A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof.

The invention also provides pharmaceutical compositions, methods of using, and methods of preparing the aforementioned compounds.

All separate embodiments may be combined.

One embodiment of the invention provides a compound of formula I,

wherein

n is 1, 2 or 3;

R ¹ is selected from the group consisting of

i) Ci-6-alkyl and

ii) halogen-Ci-6-alkyl;

R ² is selected from the group consisting of

i) Ci-6-alkyl, and

ii) halogen-Ci-6-alkyl;

or R ¹ and R ² form together with the C-atom they are attached to, a C ₃ -6-cycloalkyl-, wherein the C ₃ _6-cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;

R ³ is each independently selected from the group consisting of

i) hydrogen,

ii) Ci-6-alkyl, and

iii) halogen;

R ⁴ is each independently selected from the group consisting of

i) hydrogen, ii) Ci-6-alkyl, and

iii) halogen;

or wherein R ³ and R ⁴ together are -(CH ₂ ) _m -, wherein m is 2, 3, 4 or 5,

R ⁵ is hydrogen.

R ⁶ is selected from the group consisting of

i) Ci-6-alkyl, and

ii) halogen-Ci_6-alkyl;

R ⁷ is selected from the group consisting of

i) hydrogen, and

ii) halogen;

R ⁸ is selected from the group consisting of

i) aryl,

ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci-6-alkyl, halogen-Ci-6-alkoxy, Ci-6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C _2- 6-alkynyl-Ci_6-alkoxy, C ₂ _ ₆ -alkynyl, Ci- ₆ -alkyl, COOR ⁹ , wherein R ⁹ is H or Ci_6-alkyl,

CONR ¹⁰ R ⁿ , wherein R ¹⁰ is H or Ci_ ₆ -alkyl C ₃ _ ₆ -cycloalkyl and R ¹¹ is H or Ci_ ₆ -alkyl, C ₃ _ 6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci_6-alkyl and Ci_6-alkoxy, C ₃ _6-cycloalkyl-Ci_6- alkoxy and C ₃ _6-cycloalkyl-Ci_6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C _1-6 - alkyl and Ci_6-alkoxy;

iii) heteroaryl, and

iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci-6-alkyl, halogen-Ci-6-alkoxy, Ci-6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C ₂ _ 6-alkynyl-Ci_6-alkoxy, C ₂ _ ₆ -alkynyl, Ci-6-alkyl, COOR ⁹ , wherein R ⁹ is H or Ci_6-alkyl,

CONR ¹⁰ R ⁿ , wherein R ¹⁰ is H or Ci_ ₆ -alkyl C ₃ _ ₆ -cycloalkyl and R ¹¹ is H or Ci-e-alkyl, C ₃ _ 6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci_6-alkyl and Ci_6-alkoxy, C ₃ _6-cycloalkyl-Ci_6- alkoxy and C ₃ _6-cycloalkyl-Ci_6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C _1-6 - alkyl and Ci_6-alkoxy;

or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein n is 1, 2 or 3; R ¹ is selected from the group consisting of

i) Ci_6-alkyl and

ii) halogen-Ci-6-alkyl;

R ² is selected from the group consisting of

i) Ci-6-alkyl, and

ii) halogen-Ci-6-alkyl;

or R ¹ and R ² form together with the C-atom they are attached to, a C ₃ -6-cycloalkyl-, wherein the C ₃ _6-cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;

R ³ is each independently selected from the group consisting of

i) hydrogen,

ii) Ci-6-alkyl, and

iii) halogen;

R ⁴ is each independently selected from the group consisting of

i) hydrogen,

ii) Ci-6-alkyl, and

iii) halogen;

R ⁵ is hydrogen.

R ⁶ is selected from the group consisting of

i) Ci-6-alkyl, and

ii) halogen-Ci_6-alkyl;

R ⁷ is selected from the group consisting of

i) hydrogen, and

ii) halogen;

R ⁸ is selected from the group consisting of

i) aryl,

ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci-6-alkyl, halogen-Ci-6-alkoxy, Ci-6-alkoxy, Ci_6-alkoxy-Ci-6-alkyl, C ₂ - 6-alkynyl-Ci-6-alkoxy, C ₂ -6-alkynyl, Ci-6-alkyl, C ₃ _6-cycloalkyl, C ₃ _6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci-6-alkyl and Ci-6-alkoxy, C ₃ -6-cycloalkyl-Ci-6-alkoxy and C ₃ -6-cycloalkyl-Ci-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci-6-alkyl and Ci-6-alkoxy; iii) heteroaryl, and

iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci-6-alkyl, halogen-Ci-6-alkoxy, Ci-6-alkoxy, Ci_6-alkoxy-Ci-6-alkyl, C _2- 6-alkynyl-Ci-6-alkoxy, C2-6-alkynyl, Ci-6-alkyl, C ₃ _6-cycloalkyl, C ₃ _6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci-6-alkyl and Ci-6-alkoxy, C ₃ -6-cycloalkyl-Ci-6-alkoxy and C ₃ -6-cycloalkyl-Ci-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, Ci- ₆ -alkyl and Ci-6-alkoxy;

or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described herein and when n=l, then the ring configuration is cis.

A certain embodiment of the invention provides a compound of formula I as described herein, which is of formula la, wherein n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described in as described herein

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ¹ is methyl. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ² is methyl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ³ is hydrogen.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁴ is hydrogen.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ³ and R ⁴ together are -(CH ₂ ) ₂ -. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁵ is hydrogen.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁶ is methyl. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁷ is F.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is aryl substituted by 1-2 substituents individually selected from cyano and halogen. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is phenyl substituted by 1-2 substituents individually selected from cyano and CI.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is heteroaryl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C i-6-alkoxy, halogen-Ci-6-alkyl, Ci-6-alkoxy, C2-6-alkylnyl and Ci- 6-alkyl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is heteroaryl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-Ci-6-alkoxy, Ci-6-alkoxy and Ci-6-alkyl. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is lH-pyrazolyl, pyridinyl, pyrazinyl or imidazo[l,2-a]pyridinyl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-Ci-6-alkoxy, halogen-C i-6-alkyl, Ci-6-alkoxy, C2-6-alkylnyl and Ci-6-alkyl

A certain embodiment of the invention provides a compound of formula I as described herein, wherein R ⁸ is pyridinyl, pyrazinyl or imidazo[l,2-a]pyridinyl, each substituted by 1-2 substituents individually selected from cyano, halogen, halogen-Ci-6-alkoxy, Ci-6-alkoxy and Ci-6-alkyl.

A certain embodiment of the invention provides a compound of formula I as described herein wherein n is 1 or 2. A certain embodiment of the invention provides a compound of formula I as described herein wherein n is 1 or 2, R ¹ is methyl, R ² is methyl, R ³ at each occurrence is H, R ⁴ at each occurrence is H, R ⁵ is H, R ⁶ is methyl and R ⁷ is F. A certain embodiment of the invention provides a compound of formula I described herein that is selected from the group consisting of

N-(6-((3aR,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((3a^,4i?,8i?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7 -tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3a^,4«,8i?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7 -tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3aR,4«,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3aR,4^,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)pico linamide,

N-(6-((3a^,4 ?,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((3ai?,4 ?,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3aR,4«,8i?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a, 4,7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3a^,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a^,4«,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3aR,4«,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)pico linamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((3a^,4 ?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3a^,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4 ,7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide, N-(6-( (3a^?,4 i,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-(difluoromethoxy)pyrazine-2-carboxa mide,

N- (6-( (3aR,4R,SS)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-fluoropicolinamide,

N- (6-( (3aS,4#,8fl)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-cyano-3-methylpicolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-3-chloro-5-cyanopicolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-fluoro-3-methylpicolinamide,

N- (6-( (3aS,4R,SR)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-3-chloro-5-fluoropicolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-chloro-3-methylpicolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-(fluoromethoxy)picolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-(difluoromethoxy)picolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluoropropoxy)picolin amide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide,

N- (6-( (3a5,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-(difluoromethoxy)pyrazine-2-carboxa mide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-5-fluoropicolinamide,

N- (6-( (3aSAR,SR> 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-3-chloro-5-(difluoromethoxy)picolinam ide,

N- (6-( QaSARM)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-3,5-dichloropicolinamide,

N- (6-( (3aS,4R,8R)- 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-4-cyanobenzamide,

N- (6-( (3aSAR,SR> 6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isoth iazolo 1,5- a] [1,4 thiazin-4-yl -5-fluoropyridin-2-yl)-2-chloro-4-cyanobenzamide, N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a5,4R,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3a5,4R,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy) picolinamide,

N-(6-((3a5,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethox y)picolinamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide, N-(6-((3a5,4R,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine -2-carboxamide,

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyano-3-methylpicolinamide,

N-(6-((4aR,5^,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoropicolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyanopicolinamide,

N-(6-((4a^,5«,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoro^

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(2,2,3,3-tetrafluoropropoxy)- picolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-cyanopicolinamide, N-(6-((4ai?,5 ?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-

[l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-y l)-5-methoxypyrazine-2-carboxamide,

N-(6-((4aR,5«,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoro-3-methylpicolinamide

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3,5-dichloropicolinamide, N-(6-((4a^,5 i,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-fluoropicolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-chloro-3-methylpicolinamide, N-(6-((4aR,5«,9«)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-chloropicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-cliloro-5-(difluoromethoxy)- picolinamide,

N-(6-((4aR,5R,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(2,2-difluoroethoxy)pyrazine-2- carboxamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(prop-l-yn-l-yl)picolinamide, N-(6-((4aR,5i?,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a^,5ii,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a^,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a^,5i?,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4ai?,5 ?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluor opropoxy)picolinamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2J f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a#,5i?,9S)-7-amino-5,8,8-trime ^

f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide, N-(6-((4a^,5 i,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2,l- ΐ] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a^,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a#,5tf,9S)-7-amino-5,8,8-trimethyl-9-ox^

f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4ai?,5^,95 ^, )-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahyd ro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((4a5,5R,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5,5R,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a5,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a5 ^, ,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l ,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5 ^, ,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-h exahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide, N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- ΐ] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5, 8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a5,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a5 ^, ,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-h exahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((5aR,6«,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-cyano-3-methylpicolinamide,

N-(6-((5aR,6«,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluorop

N-(6-((5a^,6 i,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahyd ro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide, N-(6-((5a^,6^,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5aR,6«,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5aR,6i?,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5ai?,6 ?,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahy dro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide,

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4 ,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,105 ^, )-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahy dro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoro N-(6-((5a^,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide,

N-(6-((5a^,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a^,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoropy

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4,5, 5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-(difluoromethoxy)picolinam

N-(6-((5aR,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-y l)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5ai?,6 ?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahy dro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide,

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-cyano-3-methylpicolinamide,

N-(6-((5a5,6R,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a ₁ S ^, ,6^,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6, 9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide, N-(6-((5a5,6^,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a5,6^,10«)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoropy

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-(difluoromethoxy)picolinam

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5',6^,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide,

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy N-(6-((5a ₁ S ^, ,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9 -hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide,

N-(6-((5a5,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyri^

N-(6-((5aS,6#,10S)-8-amino-6,9,9-trimethy

[ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoropy

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluorop

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-y l)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5',6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide, N-(6-((4a^,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8 -tetrahydro-2H-spiro[[l,4]thia- zino[2,l-f][l,2]thiazine-3,l'-cyclopropan]-5-yl)-5-fluoropyr idin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H-spiro[[l,4]- thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4a^,5i?,9«)-7-amino-5,8,8-trimethyl-9-oxido-4,4a, 5,8-tetrahydro-2H-spiro[[l,4]- thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyano- picolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8 -tetrahydro-2H-spiro[[l,4]thia- zino[2,l-f][l,2]thiazine-3,l'-cyclopropan]-5-yl)-5-fluoropyr idin-2-yl)-3-chloro-5-(difluoro- methoxy)picolinamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-l-(diflu oromethyl)-lH-pyrazole-3- carboxamide, and

6-((6-((4ai?,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)c arbamoyl)nicotinic acid, or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein that is selected from the group consisting of N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- cyano-3-methylpicolinamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-cyanopicolinamide,

N-(6 ((3aR,4R,SS) 6-amino-4,7,7-trimethyl- 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoro-3-methylpicolinamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-fluoropicolinamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- chloro-3-methylpicolinamide,

N-(6 ((3aR,4R,SS) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (fluoromethoxy)picolinamide,

N-(6 ((3aR,4R,SS) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)picolinamide,

N-(6 ( 3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (2,2,3, 3-tetrafluoropropoxy)picolinamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- methoxypyrazine-2-carboxamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)pyrazine-2-carboxamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoropicolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- cyano-3-methylpicolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [l ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-cyanopicolinamide,

N-(6 ((3aSARM) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [l ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoro-3-methylpicolinamide,

N-(6 ((3aS,4R,SR) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [l ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-fluoropicolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [l ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- chloro-3-methylpicolinamide,

N-(6- ( 3aS,4RM) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [l ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (fluoromethoxy)picolinamide, N-(6-((3a5,4^,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((3a5,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide, N-(6-((3a5,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)py razine-2-carboxamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoropicolinam ide,

N-(6-((3a5,4i?,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(difluorom ethoxy)picolinamide,

N-(6-((3a5,4^,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-cyanobenzamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-2-chloro-4-cyanobenza mide,

N-(6-((4aR,5^,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyano-3-methylpicolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoropicolinamide,

N-(6-((4a^,5«,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyanopicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyrid

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl) -5-(2,2,3,3-tetrafluoropropoxy)- picolinamide,

N-(6-((4ai?,5 ?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-cyanopicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-methoxypyrazine-2-carboxamide,

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoro-3-methylpicolinamide, N-(6-((4a^,5 i,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3,5-dichloropicolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-fluoropicolinamide, N-(6-((4aR,5«,9«)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-chloro-3-methylpicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-chloropicolinamide,

N-(6-((4aR,5i?,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-(difluoromethoxy)- picolinamide,

N-(6-((4aR,5R,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8-hexahydro-

[l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-y l)-5-(2,2-difluoroethoxy)pyrazine-2- carboxamide,

N-(6-((4aR,5i?,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(prop-l-yn-l-yl)picolinamide,

N-(6-((4a^,5ii,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a^,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a^,5i?,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4ai?,5 ?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluor opropoxy)picolinamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2J f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide, N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a^,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-sp iro[[l,4]thia- zino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4a5,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8- tetrahydro-2H-spiro[[l,4]- thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4a^,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H-spiro[[l,4]- thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyano- picolinamide,

N-(6-((4a^,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8 -tetrahydro-2H-spiro[[l,4]thia- zino[2,l-f][l,2]thiazine-3,l'-cyclopropan]-5-yl)-5-fluoropyr idin-2-yl)-3-chloro-5-(difluoro- methoxy)picolinamide,

N-(6-((3a5,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-l-(diflu oromethyl)-lH-pyrazole-3- carboxamide, and

6-((6-((4aii,5 ?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl) carbamoyl)nicotinic acid, or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein that is selected from the group consisting of

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a^,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5',5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide, N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ l ,4]thiazino[2, l- ΐ] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a^,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4aS,5fl,9S)-7-anuno-5,8,8-trim^

f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a^,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2 ,4,4a,5,8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4aR,5«,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5R,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazm^ f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5, 8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a^,5«,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2 ,4,4a,5,8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4ai?,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-7-chloro-3-methylimid azo[l,2-a]pyridine-2- carboxamide, N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l ,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-7-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-7-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5, 8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-7-chloro-3-methyl imidazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4ai?,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a5,5R,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethox y)picolinamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a^,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide, N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((4aR,5«,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2 -tetrafluoropropoxy)picolinamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3a^,4i?,8i?)-6-amino-4JJ-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylp icolinamide,

N-(6-((3a5',4^,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylp icolinamide,

N-(6-((3aR,4«,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4 ,7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylp icolinamide,

N-(6-((3a5 ^, ,4R,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetra hydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylp icolinamide,

N-(6-((3a^,4 i,8i?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2 H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methyl picolinamide, N-(6-((3a5,4^,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3a^,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3aR,4«,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a^,4 ?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3aR,4«,8i?)-6-amino-4 ,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methyl picolinamide,

N-(6-((3a^,4«,8i?)-6-amino-4JJ-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)pico linamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy) picolinamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy) picolinamide,

N-(6-((3a5,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy) picolinamide,

N-(6-((3ai?,4 ?,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5 a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethox y)picolinamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethox y)picolinamide, N-(6-((3a^,4 i,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((3a5,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((3aR,4«,8«)-6-amino-4JJ-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3aR,4«,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4 ,7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3a5,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4 ,7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((3ai?,4 ?,8 ?)-6-amino-4JJ-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isot hiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((3aR,4^,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((3a5,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-33a,4J-te trahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((5a^,6i?,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluorop

N-(6-((5a5,6^,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4 ,5,5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluorop

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluorop

N-(6-((5a^,6i?,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluorop

N-(6-((5a5,6^,10 ?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2 H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4,5, 5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^ N-(6-((5aS,6R,10S 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylp icolinamide,

N-(6-((5a?,6R,10R) ^■ 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydr o-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluorop icolinamide, N-(6-((5aS,6R,10R) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluorop icolinamide,

N-(6-((5aK,6R,10S) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluorop icolinamide,

N-(6-((5aS,6R,10S> 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluorop icolinamide,

N-(6-((5a/?,6R,10R) ^■ 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydr o-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylp icolinamide,

N-(6-((5aS,6R,10R) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylp icolinamide, N-(6-((5aK,6R,10S) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylp icolinamide,

N-(6-((5aS,6R,10S> 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylp icolinamide,

N-(6-((5aR,6i?,10R) ^■ 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydr o-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)p icolinamide,

N-(6-((5aS,6R,10R) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)p icolinamide,

N-(6-((5aK,6R,10S) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)p icolinamide, N-(6-((5aS,6R,10S> 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)p icolinamide,

N-(6-((5aR,6i?,10R) ^■ 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydr o-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy )picolinamide,

N-(6-((5aS,6R,10R) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy )picolinamide,

N-(6-((5aZ?,6R,10S) 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy )picolinamide,

N-(6-((5aS,6R,10S)- 8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g] l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy )picolinamide, N-(6-((5a^,6 i,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahyd ro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5,6^,10«)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-y l)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5aR,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5',6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-y l)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5aR,6i?,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide, N-(6-((5a5,6i?,10 ?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahydro-2 H-

[l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2 -yl)-5-methoxypyrazine-2-carboxamide,

N-(6-((5a^,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H-

[l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2 -yl)-5-methoxypyrazine-2-carboxamide, and

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H-

[l,4]thiazino[2J-g][l,2] azepin-6-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carbo xamide or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein that is selected from the group consisting of N-(6-((3a^,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((3aR,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((3aR,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-fluoropico linamide,

N-(6-((3a^,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide,

N-(6-((3a^,4i?,85)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)pico linamide, N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)picolinamide,

N-(6 ((3aR,4R,SS) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (2,2,3,3-tetrafluoropropoxy)picolinamide,

N-(6 ((3aR,4R,SS) 6-amino-4,7,7-trimethyl- 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- methoxypyrazine-2-carboxamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)pyrazine-2-carboxamide,

N-(6 ((3aR,4R,8S) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoropicolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- cyano-3-methylpicolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-cyanopicolinamide,

N-(6 ((3aS,4R ) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoro-3-methylpicolinamide,

N-(6 ((3aS,4R,SR) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro-5-fluoropicolinamide,

N-(6 ((3a5,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- chloro-3-methylpicolinamide,

N-(6 ((3a5,4^,8^) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (fluoromethoxy)picolinamide,

N-(6 ((3aS,4R,8R) 6-amino-4,7,7-trimethyl- 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)picolinamide,

N-(6 ((3aS,4R,SR) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (2,2,3, 3-tetrafluoropropoxy)picolinamide,

N-(6 ((3aSARM) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- methoxypyrazine-2-carboxamide,

N-(6 ((3aS,4R,SR) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- (difluoromethoxy)pyrazine-2-carboxamide,

N-(6 ((3a5,4R,8R) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-5- fluoropicolinamide,

N-(6 ( 3aS,4R,SR) 6-amino-4,7,7-trimethyl- ^■ 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo 1 ,5- a] [ 1 ,4 ]thiazin-4-yl -5-fluoropyridin-2-yl)-3- chloro -5 - (difluoromethoxy)pic olinamide, N-(6-((3a5,4^,8 ?)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-is othiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((3a5,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-cyanobenzamide,

N-(6-((3a5,4^,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-2-chloro-4-cyanobenza mide,

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyano-3-methylpicolinamide,

N-(6-((4aR,5«,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoropicolinamide,

N-(6-((4a^,5^,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-cyanopicolinamide,

N-(6-((4ai¾,5R,9R)-7-amino-3,3-dffluoro-5 _^

[l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoro^

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(2,2,3,3-tetrafluoropropoxy)- picolinamide,

N-(6-((4a^,5 i,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-cyanopicolinamide, N-(6-((4a^,5i?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro-

[l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-y l)-5-methoxypyrazine-2-carboxamide,

N-(6-((4aR,5i?,9«)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-fluoro-3-methylpicolinamide

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3,5-dichloropicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-fluoropicolinamide,

N-(6-((4a^,5i?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyri^

N-(6-((4ai?,5 ?,9^)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-chloropicolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 3-chloro-5-(difluoromethoxy)- picolinamide, N-(6-((4aR,5R,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8-hexahydro-

[l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-y l)-5-(2,2-difluoroethoxy)pyrazine-2- carboxamide,

N-(6-((4aR,5«,9«)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)- 5-(prop-l-yn-l-yl)picolinamide,

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a^,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4ai?,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5«,9i?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4aR,5«,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methylim idazo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a^,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a^,5i?,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a ,5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluor opropoxy)picolinamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2 f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazin^ f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a^,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4ai?,5^,95 ^, )-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahyd ro-[l,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2 f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4aR,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2J f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methylim idazo[l,2-a]pyridine-2- carboxamide, N-(6-((4a^,5 i,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[ l ,4]thiazino[2, l- ΐ] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a^,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluor opropoxy)picolinamide, N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5i?,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5R,9«)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methylimid azo[l,2-a]pyridine-2- carboxamide,

N-(6-((4a5,5^,9 ?)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a5,5^,9^)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro-[ l ,4]thiazino[2, l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetrafluor opropoxy)picolinamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a ,5,8-hexahydro-[ l ,4]thiazino[2J f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicol inamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5, 8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide,

N-(6-((4a53R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5,8 -hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinam ide,

N-(6-((4a5,5i?,95)-7-amino-5,8,8-trimethyl-9-oxido-2 ,4,4a,5,8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpico linamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro-[ l ,4]thiazino[2,l- f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicol inamide,

N-(6-((4a5,5R,95)-7-amino-5,8,8-trimethyl-9-oxido-23,4,4a,5, 8-hexahydro-[ l ,4]thiazino[2,l- f] [ l ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-methylimid azo[l,2-a]pyridine-2- carboxamide, N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- ΐ] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide,

N-(6-((4a5,5^,95)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraf luoropropoxy)picolinamide,

N-(6-((5aR,6«,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H-

[l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2 -yl)-5-cyano-3-methylpicolinamide,

N-(6-((5aR,6«,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoropy

N-(6-((5aR,6i?,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide,

N-(6-((5a^,6i?,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-chloro-3-methylpicolinamide _^

N-(6-((5ai?,6 ?,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahy dro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluorop

N-(6-((5aR,6«,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a^,6i?,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H-

[l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2 -yl)-5-methoxypyrazine-2-carboxamide,

N-(6-((5a^,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-cyano-3-methylpicolinamide,

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4 ,5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5aR,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide,

N-(6-((5a^,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-chloro-3-methylpicolinamide _^ N-(6-((5ai?,6 ?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9-hexahyd ro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5aR,6i?,105')-8-amino-6,9,9-trimethyl-10-oxido-3,4,5, 5a,6,9-hexahydro-2H- [ 1 ,4]thiazino[2 J -g] [ 1 ,2] thiazepin-6-yl)-5-fluoro N-(6-((5a^,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5aR,6«,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide,

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a5,6i?,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H-

[l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2 -yl)-3-chloro-5-fluoropicolinamide,

N-(6-((5a5',6^,10^)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-chloro-3-methylpicolinamide

N-(6-((5a5,6R,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro

N-(6-((5a5,6R,10R)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a ₁ S ^, ,6^,10i?)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6, 9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-y l)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5,6^,10«)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-5-methoxypyrazine-2-carboxamide,

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5 ,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy

N-(6-((5a5,6i?,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5 a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropyridin-2-yl )-3-chloro-5-fluoropicolinamide,

N-(6-((5a5',6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4, 5,5a,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoro^

N-(6-((5a5,6R,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2J-g][l,2]thiazepin-6-yl)-5-fluoropy N-(6-((5a ₁ S ^, ,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a,6,9 -hexahydro-2H-

[l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluoropyridin- 2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide,

N-(6-((5a5,6^,105)-8-amino-6,9,9-trimethyl-10-oxido-3,4,5,5a ,6,9-hexahydro-2H- [l,4]thiazino[2,l-g][l,2]thiazepin-6-yl)-5-fluo^^

N-(6-((4aR,5«,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8 -tetrahydro-2H-spiro[[l,4]thia- zino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4a5,5R,9^)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H-spiro[[l,4]- thiazino[2,l-i [l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methyl- picolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a,5,8 -tetrahydro-2H-spiro[[l,4]- thiazino[2,l-i [l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyano- picolinamide,

N-(6-((4aR,5i?,9i?)-7-amino-5,8,8-trimethyl-9-oxido-4,4a, 5,8-tetrahydro-2H-spiro[[l,4]thia- zino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(difluo ro- methoxy)picolinamide,

N-(6-((3a5,4R,8^)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-l-(diflu oromethyl)-lH-pyrazole-3- carboxamide, and

6-((6-((4ai?,5^,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2J-i^[l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)c arbamoyl)nicotinic acid, or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I as described herein whenever prepared by a process as described herein.

A certain embodiment of the invention provides a compound of formula I as described herein for use as therapeutically active substance.

A certain embodiment of the invention provides a compound of formula I as described herein for the use as inhibitor of BACE1 activity. A certain embodiment of the invention provides a compound of formula I as described herein for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease. A certain embodiment of the invention provides a compound of formula I as described herein for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a pharmaceutical composition comprising a compound of formula I as described herein and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the use in inhibition of BACEl activity. A certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease. A certain embodiment of the invention provides a compound of formula I as described herein for the use in inhibition of BACEl activity.

A certain embodiment of the invention provides a compound of formula I as described herein for the use in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula I as described herein for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a method for the use in inhibition of BACEl activity, particularly for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β- amyloid plaques and further deposits or Alzheimer's disease, which method comprises administering compound of formula I as described herein to a human being or animal. A certain embodiment of the invention provides a method for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease, which method comprises administering a compound of formula I as described herein to a human being or animal.

Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers as well as their solvates of the compounds of formula I.

The skilled person in the art will recognize that the compounds of formula I can exist in tautomeric form

All tautomeric forms are encompassed in the present invention.

The compounds of formula I may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

Certain embodiments are the following specific forms:

In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate. The compounds of formula I can be prepared through a number of synthetic routes for example as illustrated in schemes 1-14. The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.

Key intermediate A6 can be prepared via the intermediates depicted in Scheme 1. Commercially available 2-(methylthio)acetonitrile (Al) can be alkylated using a base, such as e.g. sodium hydride, in the presence of an appropriate alkylating agent, e.g. alkyl iodide or alkyl bromide, in a suitable aprotic solvent, e.g. tetrahydrofuran, to give the corresponding intermediate A2. Alternatively, the alkylation agent can be an appropriate aldehyde, e. g. paraformaldehyde. The resulting hydroxycompounds can thereafter be transformed into the corresponding halogen compounds be methods known in the art, e.g. using suitable fluorinating agents, such as diethylaminosulfurtrifluoride, to obtain intermediates A2. The alkylations can be run stepwise, or, if R ¹ = R ² , in one pot using appropriate reagent excesses.

Scheme 1

A4 A6

Intermediate A2 can be oxidized to the corresponding sulfoxide A3 using suitable oxidation procedures known in the art, e.g. using sodium periodate, m-chloroperbenzoic acid or oxone. The following formation of the sulfoximine moiety to obtain intermediate A4 can be achieved by methods known in the art, e.g. in two steps using, e.g. catalytic amounts of dirhodiumtetraacetate, and stoichiometric amounts of diacetoxyiodosobenzene, trifluoroacetamide and magnesium oxide, followed by hydroylsis, e.g. using potassium carbonate in lower alcohols, or, alternatively, using catalytic amounts of 4,4',4"-tri-tert-butyl-2,2':6',2"- terpyridine and silver nitrate, and stoichiometric amounts of 4-nitrobenzenesulfonamide and diacetoxyiodosobenzene, and subsequent hydrolysis using thiophenol and cesium carbonate, both steps in appropriate solvents. Alternatively, intermediate A4 can be synthezised in one step using stoichiometric amounts of sodium azide in Eaton's reagent (i.e. a solution of diphosphorouspentoxide in methanesulfonic acid). Intermediate A4 can thereafter be reacted with an appropriate alkylation reagent A5 in the presence of a suitable base, e.g. sodium hydride, potassium hydride or cesium carbonate, and optionally a catalytic amount of a quaternary ammonium salt, e.g. tetra-n-butyl ammonium bromide or tetra-n-butyl ammonium iodide, in a suitable aprotic solvent, e.g. dimethoxyethane, tetrahydrofurane or acetonitrile, to give intermediate A6. The alkylation reagent A5 is a protected halo-alcohol, in which X means a leaving group, e.g. halogen, (substituted) arene- or (substituted) alkanesulfonate, preferably bromine, iodine or triflouromethanesulfonate, and PG means a protecting group, e.g. tetrahydropyranyl.

Scheme 2

Key intermediate A6 can then be reacted with sulfoximine A7 in the presence of a strong base, e.g. alkali hexamethyldisilazide, such as lithium hexamethyldisilazide, alkali diisopropylamide, such as lithium diisopropylamide, or alkyl lithium, such as n-butyl lithium, under anhydrous conditions in a suitable aprotic solvent, e.g. tetrahydrofuran or dichloromethane, to form intermediate mix-A8 as a mixture of stereoisomers (Scheme 2). The single stereoisomers can be separated at this stage by chromatography and the route as depicted in Scheme 2 and the following schemes can be followed analogously employing the separated single isomers. Alternatively, the mixture of stereoisomers can be deprotected and the sulfoxamide moiety can be cleaved to give the corresponding aminoalcohols A9 as a mixture of enantiomerically enriched diastereomers S _¾ -A9 and Ss-A9. The prefix S^ indicates the absolute configuration (Sj- for (5) and SR- for (R), respectively) at the sulfur atom. In case the protecting group PG in intermediate mix-A8 is acid labile, e.g. tetrahydropyranyl, the two cleavages mentioned above can be carried out in one step under acidic conditions, e.g. using solutions of hydrogen chloride in alcohols, such as methanol or ethanol. The two enantioenriched diastereoisomers SR-A9 and Ss-A9 can be separated by chromatography or by other means known in the art. Alternatively, the mixture of diastereoisomers can be carried through the synthesis and the respective resulting mixtures can be separated at later stages by chromatography or by other means known in the art. Scheme 3

S _fi -A1 1 S _R -A1 2

Subsequently, intermediate S _¾ -A9 can be cyclised to intermediate S _¾ -A10 using methods known in the art, e.g. using stoichiometric amounts of copper(I) salts, e.g. copper(I) chloride or copper(I) bromide, in suitable solvents, e.g. alcohols, such as ethanol, at elevated temperatures, such as 20°C to 130°C, preferably at 70°C to 90°C (Scheme 3). Alternatively, the transformation can be achieved using stoichiometric amounts of a Lewis acid, like trimethyl aluminium, in a suitable aprotic solvent, such as toluene. The amidine function in intermediate S _# -A10 is then protected by an appropriate protecting group PG to give intermediate S _¾ -A11. The protecting group PG should be stable towards basic conditions and can be, e.g. tert-butoxycarbonyl (BOC). In case PG is BOC, the transformation to intermediate S _# -A11 can be achieved using conditions known in the art, e.g. di-tert-butyl dicarbonate in the presence of a suitable base, such as sodium hydrogencarbonate, and optionally in the presence of catalytic amounts of a suitable Lewis base, e.g. 4-(dimethylamino)-pyridine, followed by addition of a suitable nucleophile, e.g. aqueous ammonia, to eliminate the excess of di-tert-butyl dicarbonate prior to concentration of the reaction mixture. Thereafter, the hydroxy group in intermediate S^-Al l is transformed into a leaving group OLG in intermediate S _¾ -A12. Suitable leaving groups include arenesulfonoyl, e.g. p-toluenesulfonoyl alkanesulfonoyl, e.g. triflourmethanesulfonoyl, or halogen, e.g. iodine.. If OLG is p-toluenesulfonoyl, the transformation to intermediate S _# -A12 can be achieved under standard conditions known in the art, using, e. g., p-toluenesulfonyl chloride in the presence of a suitable base, e. g. a tertiary amine, such as triethylamine or diisopropylethylamine, and, optionally, catalytic amounts of a suitable Lewis base, e. g. 4-(dimethylamino)-pyridine. If OLG is iodide, the transformation to intermediate S _# -A12 can be achieved under standard conditions known in the art, using, e. g., tetraalkylammonium iodide, e.g. tetra-n-butylammonium iodide, in the presence of a suitable phosphine, e. g. triphenylphosphine, and a suitable activator, such as 2,3-dichloro-5,6-dicyano- l,4-benzoquinone (DDQ), in an aprotic solvent, e.g. dichloromethane.

In analogy to the chemistry described above and in Scheme 3 for the transformation of intermediate SR-A9 into intermediate SR-A12, intermediate Ss-A9 can be transformed into intermediate S5-AI2 (Scheme 4).

Scheme 4

S _s -A1 1 S _s -A1 2

The following cyclisation step starting from intermediate Ss-A12 gives rise to two diastereoisomers S _¾ -A13 and S _¾ -A14 (Scheme 5). The two diastereoisomers can either be separated by means of chromatography or other means known in the art, or the mixture can be reacted in the follwing steps and the reaction products separated at later stages by means of chromatography, or other means known in the art. Alternatively, the mixture of diastereoisomers S _¾ -A13 and S _# -A14 can be reacted in the following steps exploiting reactivity differences. Likewise, if one of the two diastereoisomers S _¾ -A13 or Ss-A14 has a higher reactivity in the following step, this difference can be used to separate the two diastereoisomers by chromatographic means. The transformation can be achieved using a strong base, such as, e. g., lithium hexamethyldisilazide or lithium diisopropylamide, under anhydrous conditions in an aprotic solvent, e. g. tetrahydrofuran, at temperatures of -80°C to 0 °C. . In certain cases, one of the two possible diastereoisomers is strongly favoured, due to steric or thermodynamic reasons. Scheme 5

In analogy to the chemistry described above and in Scheme 5 for the transformation of intermediate SR-A12 into intermediates S _¾ -A13 and Ss-A14, intermediate S5-AI2 can be transformed into intermediates S,rA13 and S,y-A14 (Scheme 6).

Scheme 6

S .-A12 S.-A1 3 S.-A14

Next, the silyl group in intermediate SR-A13 is cleaved to give access to intermediate SR- A15 using methods known in the art, e.g. using flouride salts, such as potassium flouride in the presence of a suitable acid, e. g. acetic acid, in polar solvents, such as tetrahydrofuran and dimethylformamide, or using tetraalkylammonium flouride, e. g. tetra-n-butylammonium flouride, in an appropiate polar solvent, such as tetrahydrofuran (Scheme 7). Subsequently, intermediate S _¾ -A15 is transformed into intermediate S#-A16 using an excess of sodium azide, catalytic or stoichiometric amounts of a suitable copper(I) salt, such as copper(I) iodide, and a suitable diamino ligand, such as trans-N,N'-dimethylcyclohexane-l,2-diamine, and sub stoichiometric amounts of sodium ascorbate, in appropriate polar solvents, such as dioxane and water, at elevated temperatures, e.g. 60°C to 80°C.

Scheme 7

In analogy to the chemistry described above and in Scheme 7 for the transformation of intermediate S _# -A13 into intermediate S^-A16, intermediate Ss-A13 can be transformed into intermediate S5-AI6 (Scheme 8).

Scheme 8

S _s -A1 6

In analogy to the chemistry described above and in Scheme 7 for the transformation of intermediate S _R -A13 into intermediate S _¾ -A16, intermediate S _¾ -A14 can be transformed into intermediate S _ff -A18 (Scheme 9).

Scheme 9

S _R -A1 8

In analogy to the chemistry described above and in Scheme 7 for the transformation of intermediate S _¾ -A13 into intermediate S _¾ -A16, intermediate Ss-A14 can be transformed into intermediate S5-AI8 (Scheme 10).

Scheme 10

S _s -A1 8

Thereafter, intermediate SR-A16 is acylated to form intermediate SR-A19 by suitable amide bond forming methods known in the art using appropriate acids R ⁸ COOH, wherein R ⁸ is as defined above (Scheme 11). These methods include, as example, the reaction of intermediate SR- A16 with acid R ⁸ COOH in the presence of stoichiometric amounts of l-chloro-N,N,2-trimethyl- propenylamine and a suitable base, e. g. a tertiary amine, such as diisopropylethylamine, in an aprotic solvent, e. g. dichloromethane, at temperatures of -10°C to 30 °C. Alternatively, acid R ⁸ COOH can be transformed into the corresponding acid chloride R ⁸ COCl using methods known in the art, e. g. using oxalyl chloride or thionyl chloride in aprotic solvents, such as dichloromethane or toluene. The isolated acid chloride R ⁸ COCl can then be reacted with intermediate S _¾ -A16 in the presence of a suitable base, e.g. a tertiary amine, such as diisopropylethylamine, in an aprotic solvent, e. g. dichloromethane, at temperatures of -10°C to 30 °C to form intermediate S _R -A19. Finally, intermediate S _¾ -A19 is deprotected by methods known in the art to give access to final compounds S«-A20. If PG is BOC, the deprotection is achieved by stirring intermediate S _¾ -A19 in the presence of an excess of a strong acid, such as triflouroacetic acid or hydrogen chloride either in a suitable solvent, such as dichloromethane or tetrahydro- furan or without a solvent under neat conditions, if feasible. Subsequently, the enantiomerically enriched products of formula S _R -A20 are purified to their enantiopure form by chromatography using suitable chiral stationary phases.

S _R -A20

In analogy to the chemistry described above and in Scheme 11 for the transformation of intermediate S _# -A16 into enantiopurified final compound S«-A20, intermediate S5-AI6 can be transformed into enantiopurified final compound S5-A2O (Scheme 12).

Scheme 12

S -A1 6 S _s -A19

S _s -A20

In analogy to the chemistry described above and in Scheme 11 for the transformation of intermediate SjrA16 into enantiopurified final compound S^-A20, intermediate Sj?-A18 can be transformed into enantiopurified final compound S _R -A22 (Scheme 13).

Scheme 13

S _R -A22

In analogy to the chemistry described above and in Scheme 11 for the transformation of intermediate S _R -A16 into enantiopurified final compound Si _? -A20, intermediate S5-AI 8 can be transformed into enantiopurified final compound S^-A22 (Scheme 14).

Scheme 14

S _s -A22

The order of the synthetic steps that are depicted in the schemes 7 and 11 to obtain final compounds of formula S _¾ -A20 can be changed as appropriate. Likewise, the desilation step in Scheme 7 may be carried out, e. g., at the end of the sequence in Scheme 11. The order of the synthetic steps that are depicted in the schemes 8 and 12 to obtain final compounds of formula S5-A2O can be changed as appropriate. Likewise, the desilation step in Scheme 8 may be carried out, e. g., at the end of the sequence in Scheme 12.

The order of the synthetic steps that are depicted in the schemes 9 and 13 to obtain final compounds of formula S _# -A22 can be changed as appropriate. Likewise, the desilation step in Scheme 9 may be carried out, e. g., at the end of the sequence in Scheme 13.

The order of the synthetic steps that are depicted in the schemes 10 and 14 to obtain final compounds of formula Ss-A22 can be changed as appropriate. Likewise, the desilation step in Scheme 10 may be carried out, e. g., at the end of the sequence in Scheme 14.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a suitable solvent such as e.g. dioxane or tetrahydrofuran and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or by chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base. One possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g. M(OH) _n , wherein M = metal or ammonium cation and n = number of hydroxide anions, to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilisation. Particular salts are hydrochloride, formate and trifluoroacetate. Insofar as their preparation is not described in the examples, the compounds of formula I as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto. It will be appreciated that the compounds of general formula I in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are associated with inhibition of BACE1 activity. The compounds were investigated in accordance with the test given hereinafter.

Cellular Αβ-lowering assay:

The Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells were seeded in 96 well Microtiter plates in cell culture medium (Iscove's, plus 10% (v/v) fetal bovine serum, penicillin/streptomycin ) to about 80% confluency and the compounds were added at a 3x concentration in 1/3 volume of culture medium (final DMSO concentration was kept at 1 % v/v). After 18-20 hrs incubation at 37 °C and 5% CO ₂ in a humidified incubator, the culture supernatants were harvested for the determination of Αβ 40 concentrations using Perkin-Elmer Human Amyloid beta 1-40 (high specificity) Kit (Cat# AL275C).

In a Perkin-Elmer White Optiplate-384 (Cat# 6007290), 2ul culture supernatants were combined with 2μ1 of a 10X AlphaLISA Anti-ΙιΑβ Acceptor beads + Biotinylated Antibody Anti- Αβ 1-40 Mix ( 50 μg/mL / 5nM ). After 1 hour room temperature incubation, 16μ1 of a 1.25 X preparation of Streptavidin (SA) Donor beads (25μg/mL) were added and incubated for 30 minutes in the Dark. Light Emission at 615 nm was then recorded using En Vision- Alpha Reader. Levels of Αβ 40 in the culture supernatants were calculated as percentage of maximum signal (cells treated with 1% DMSO without inhibitor). The IC ₅₀ values were calculated using the Excel XLfit software.

Lowering of Αβ40 in Brain of Wild-Type Mice: Animals and Housing Conditions. Animals were maintained in a 12/12 h light/dark cycle, with lights starting at 6 a.m., and experiments were conducted during the light phase. Animal housing and experimental procedures were in line with ethical and legal guidelines and were authorized by local veterinary authorities. Experiment. Female C57B1/6J mice were treated with a dose of 30 mg kg of the compounds, 3-4 animals per treatment group. The test compound was dissolved in 5% EtOH, 10% Solutol, and was applied per os at 10 mL/kg. After 4 h, the animals were sacrificed and brain and plasma were collected. The brain was cut into halves and immediately frozen on dry ice. Brain was used for measurement of Αβ40 and plasma was used for determination of compound exposure. The method for Αβ40 determination in brain lysates followed the known procedure (Lanz, T. A.; Schachter, J. B. Demonstration of a common artifact in immunosorbent assays of brain extracts: development of a solidphase extraction protocol to enable measurement of amyloid-β from wild-type rodent brain. J. Neurosci. Methods 2006, 157, 71-81.). Brain tissue was homogenized in 2% DEA buffer in a Roche MagnaLyser (20", 4000 rpm) and subsequently centrifuged for 1 h at lOOOOOg. DEA was reduced to 0.2% in 50 mM NaCl and one-half of the DEA lysate was passed over an Oasis Solid phase extraction plate (Waters; cat. no. 186000679), which had been activated with MeOH and equilibrated in dH20 (1 mL each). After washes in 10% and 30% MeOH (1 mL each), the Αβ-peptides were eluted in 0.8 mL of 2% NH40H in 90% MeOH. The eluate was dried over a N2 flow, and the dried sample was reconstituted in 30 \L of AlphaLISA assay buffer. Αβ40 was determined by an AlphaLISA assay (Perkin-Elmer). In a white 96-well, half area microplate (Perkin-Elmer cat. no. 6005561), 20 \L of the reconstituted sample were mixed with 5 μΕ of biotinylated BAP-24 (specific for C-terminus of Αβ40) (Brockhaus, M.; Grunberg, J.; Rohrig, S.; Loetscher, H.; Wittenburg, N.; Baumeister, R.; Jacobsen, H.; Haass, C. Caspasemediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling. NeuroReport 1998, 9, 1481-1486.) stock = 4.4 mg/mL, f.c.5.5 μg/mL), and 5 μL· 252Q6 acceptor beads (252Q6 antibody, Invitrogen AMB0062) had been previously conjugated with AlphaLISA Acceptor beads (Perkin-Elmer cat. no. 6772002); final dilution 1:500). The mix was incubated for 1 h at RT in the dark. Then 20 μL· of Streptavin-coated Donor Beads (Perkin-Elmer cat. no. 6760002, final dilution 1: 125) were added and this final mix was incubated in the dark for another 30 min at RT before RFU was measured in an AlphaScreen Reader (Perkin-Elmer Envision 2104). The value obtained for Αβ40 in the treated animals was related to the value in the vehicle group and is given in %. Alternatively a commercial ELISA was used for Αβ40 determination (Wako ELISA: ("Human/Rat β Amyloid (40) ELISA kit Wako Π" ; cat nr. 294-64701) following the manufacture's instruction. Also here the Αβ-lowering efficacy was calculated as percentage of the vehicle group.

BACE1 Αβ40

cell act. (wt

Ex. Structure Αβ40 mice, Name

ICso brain)

[nM] [%] N-(6-((5aS,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AB [l,4]thiazino[2,l-

T s xx _r g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-cyano-3- methylpicolinamide,

N-(6-((5aR,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-cyano-3- methylpicolinamide,

N-(6-((5aS,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BB [l,4]thiazino[2,l-

' o L _c g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-cyano-3- methylpicolinamide,

N-(6-((5aR,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-fluoro-3- methylpicolinamide,

N-(6-((5aS,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AB 1 X N N J [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-fluoro-3- methylpicolinamide, N-(6-((5aR,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-fluoro-3- methylpicolinamide,

N-(6-((5aS,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BB H Ϊ I" ) [l,4]thiazino[2,l-

I o L I _c g] [ 1 ,2]thiazepin-6-yl)-5-

F

fluoropyridin-2-yl)-5-fluoro-3- methylpicolinamide,

N-(6-((5aR,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide,

N-(6-((5aS,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AB [l,4]thiazino[2,l- ci o ._ g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide,

N-(6-((5aR,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide, N-(6-((5aS,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BB [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide,

N-(6-((5aR,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-5-chloro-3- methylpicolinamide,

N-(6-((5aS,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AB [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-chloro-3- methylpicolinamide,

N-(6-((5aR,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-5-chloro-3- methylpicolinamide,

N-(6-((5aS,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BB [l,4]thiazino[2,l- XX/ g] [ 1 ,2]thiazepin-6-yl)-5- fluoropyridin-2-yl)-5-chloro-3- methylpicolinamide, N-(6-((5aR,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-5-

(fluoromethoxy)picolinamide,

N-(6-((5aS,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AB [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2- yl)- 5 -

(fluoromethoxy)picolinamide,

N-(6-((5aR,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2-yl)-5-

(fluoromethoxy)picolinamide,

N-(6-((5aS,6R,10S)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-BB [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2- yl)- 5 -

(fluoromethoxy)picolinamide,

N-(6-((5aR,6R,10R)-8-amino-

6,9,9-trimethyl-10-oxido-

3,4,5,5a,6,9-hexahydro-2H-AA [l,4]thiazino[2,l- g] [ 1 ,2]thiazepin-6-yl)-5-

fluoropyridin-2- yl)- 5 -

(difluoromethoxy)picolinamide, N-(6-((4aR,5R,9R)-7-amino-

5,8,8-trimethyl-9-oxido-4,4a,5,8- tetrahydro-2H- spiro [ [ 1 ,4] -AA 0.1 106 thiazino [2, 1 -f] [ 1 ,2] thiazine- 3 , 1 '- cyclopropan]-5-yl)-5-

fluoropyridin-2-yl)-3-chloro-5- cyanopicolinamide

N-(6-((4aR,5R,9R)-7-amino-

5,8,8-trimethyl-9-oxido-4,4a,5,8- tetrahydro-2H- spiro [ [ 1 ,4] thia-AA 15.9 117 zino[2, 1 -f] [ 1 ,2] thiazine-3, 1 '- cyclopropan]-5-yl)-5-

fluoropyridin-2-yl)-3-chloro-5-

(difluoromethoxy)picolinamide

N-(6-((3aS,4R,8R)-6-amino-

4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[ 1 ,5-AB <10 a][l,4]thiazin-4-yl)-5- fluoropyridin-2-yl)-4-chloro-l-

(difluoromethyl)- lH-pyrazole-3- carboxamide

Table 1 : Pharmacological data

Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1- 500 mg, particularly 1-100 mg, of a compound of formula I. Examples of compositions according to the invention are: Example A

Tablets of the following composition are manufactured in the usual manner:

Table 2: possible tablet composition Manufacturing Procedure

1. Mix ingredients 1 , 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

4. Add ingredient 5 and mix for three minutes; compress on a suitable

Example B-l

Capsules of the following composition are manufactured:

Table 3: possible capsule ingredient composition

Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured: ingredient mg/capsule

Compound of formula I 5

Yellow wax 8

Hydrogenated Soya bean oil 8

Partially hydrogenated plant oils 34

Soya bean oil 110 Total 165

Table 4: possible soft gelatin capsule ingredient composition ingredient mg/capsule

Gelatin 75

Glycerol 85 % 32

Karion 83 8 (dry matter)

Titan dioxide 0.4

Iron oxide yellow 1.1

Total 116.5

Table 5: possible soft gelatin capsule composition

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example C

Suppositories of the following composition are manufactured:

Table 6: possible suppository composition Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Example D

Injection solutions of the following composition are manufactured: ingredient mg/injection solution.

Compound of formula I 3 Polyethylene Glycol 400 150

acetic acid q.s. ad pH 5.0

water for injection solutions ad 1.0 ml

Table 7: possible injection solution composition

Manufacturing Procedure

The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example E

Sachets of the following composition are manufactured:

Table 8: possible sachet composition Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

Experimental Part The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

General

Analytical methods Gas chromatograms (GC) were recorded using an Agilent 6850 Series II single channel GC system. Column: Agilent HP-1, 30 m x 0.32 mm x 0.25 μπι film, SN USC174642H, PN 190917-413E; Carrier gas: Helium in constant flow mode, pressure 25 psi; nominal initial flow 7.8 mL/min, injection volume 1 μί; Inlet: Split (ratio 20:1); Detector: Temperature 300°C, hydrogen flow 30 mL/min, air flow 400 mL/min.

Oven temperature program:

HPLC (method LCMS_fglm)

Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30 mm, 1.8μιη, Part.no. 959731-902

Solvent A: Water 0.01% Formic Acid; Solvent B: acetonitrile (MeCN)

Gradients:

HPLC (method LCMS_gradient)

Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30 mm, 1.8μιη, Part.no. 959731-902

Solvent A: Water 0.01% Formic Acid; Solvent B: MeCN

Gradients:

HPLC (method 7626L05)

Column: Agilent Poroshell 120 EC-C18, 4.6x50 mm, 2.7μηι, Part.no. 699975-902

Solvent A: MeCN; Solvent B: water/MeCN 95:5 v/v; Solvent C: solution of 1 g tetra n- butylammonium hydro gensulfate in 1 L of water/MeCN 1:4 v/v.

Gradients: Time [min] Flow Rate [ml/min] %A %B %C

Initial 1.0 10 85 5

1.0 1.0 10 85 5

7.0 1.0 85 10 5

12.0 1.0 85 10 5

13.0 1.0 10 85 5

Abbreviations

The following abbreviations were used in the experimental part: THF, tetrahydrofurane; MTBE, methyl-tert-butylether; DMF, dimethylformamide; TLC, thin layer chromatography.

Intermediates Synthesis of Int-7: 2-Methyl-2-[S-methyl-N-(3-tetrahydropyran-2- yloxypropyl)sulfonimidoyl]propanenitrile

lnt-4 lnt-5 lnt-7

Step 1: 2-Methyl-2-methylsulfanyl-propanenitrile (Int-2)

Sodium hydride (24.0 g, 60% suspension in mineral oil, 600 mmol) was washed with n- heptane (3 x 100 mL) and suspended in THF (300 mL) at 0-5°C. A solution of 2- (methylthio)acetonitrile (Int-1, 20 g, 230 mmol) in THF (100 mL) was added and the resulting suspension was stirred for 15 min at 0-5°C (ice bath). Then, a solution of methyl iodide (90.8 g, 40.0 mL, 640 mmol) in THF was added over 15 min. The mixture was allowed to warm and stirred for 3 h at room temperature. After that, the reaction mixture was poured carefully onto water (200 mL) and extracted with MTBE (1 x 500 mL, 3 x 150 mL). The combined extracts were washed with saturated aqueous sodium hydrogencarbonate solution (100 mL) and brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to afford, after drying in vacuo (10 mbar, 40 °C, 45 min), the title compound as a yellow oil (23.4 g, 89%), that was used in the next step without further purification. GC (method 7626G01) t _R = 2.5 min. ^X H NMR (CDCI3, 400 MHz): δ 1.65 (s, 6 H), 2.32 (s, 3 H).

Step 2: 2-Methyl-2-methylsulfinyl-propanenitrile (Int-3) 2-Methyl-2-(methylthio)propanenitrile (Int-2, 23 g, 200 mmol) was dissolved in 1,4- dioxane (115 mL) and water (345 mL) was added. The emulsion was cooled to 0-5°C (ice bath) and sodium periodate (44.8 g, 210 mmol) was added with water (115 mL). The resulting white suspension was warmed to room temperature and stirred vigorously for 16 h. Then, the mixture was filtered, the residue washed with ethyl acetate (400 mL). After phase separation of the filtrate, the aqueous phase was saturated with sodium chloride, extracted with ethyl acetate (5 x 200 mL). The combined extracts were washed with brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to afford, after drying (50 °C, 5 mbar), the title compound as yellow oil (25 g). The crude product was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 50:50 to 0: 100) to give the title compound as yellow oil (23.3 g, 89%). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.59 (s, 3 H), 1.68 (s, 3 H), 2.74 (s, 3 H).

Step 3: 2-Methyl-2-(S-methylsulfon(trifluoracetylimidoyl))propanenit rile (Int-4)

2-Methyl-2-(methylsulfinyl)propanenitrile (Int-3, 9.8 g, 74.7 mmol) was dissolved in dichloromethane (390 mL) at 0-5°C (ice bath) and 2,2,2-trifluoroacetamide (17.0 g, 151 mmol), magnesium oxide (12.7 g, 307 mmol) and rhodium(II) acetate dimer (850 mg, 1.92 mmol) were added subsequently. Finally, a solution of iodobenzene diacetate (36.3 g, 113 mmol) in dichloromethane (98.0 mL) was added and the mixture was stirred for 1 h at 0-5°C, followed by 6 h at room temperature. Then, a second portion of rhodium(II) acetate dimer (850 mg, 1.92 mmol) was added and the suspension stirred for additional 95 h at room temperature. The reaction mixture was filtered, the residue was washed with dichloromethane (100 mL) and the combined filtrate was concentrated in vacuo to afford a dark oil as crude product. After column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 50:50) and drying in vacuo (50°C, 5 mbar) the title compound was isolated as a light yellow oil, that solidified upon standing (13.74 g, 76%). HPLC (method LCMS_fglm) t _R = 0.97 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.91 (s, 3 H), 1.91 (s, 3 H), 3.65 (s, 3 H). MS (ES-) m/z 241.1 [M-H] ,

Step 4: 2-Methyl-2-(S-methylsulfonimidoyl)propanenitrile (Int-5)

2-Methyl-2-(S-methylsulfon(trifluoracetylimidoyl))propane nitrile (Int-4, 9.90 g, 40.9 mmol) was dissolved in methanol (100 mL) at 0-5°C (ice bath). Potassium carbonate (28.2 g, 204 mmol) was added with methanol (20 mL) and the resulting suspension was stirred at room temperature for 0.5 h. The reaction mixture was diluted with MTBE (250 mL) and silica gel (25 g) was added, the mixture was stirred for 15 min. After that, it was filtered over a plug of silica gel (35 g), the residue was washed with MTBE / methanol 2: 1 (v/v, 250 mL). The combined filtrate was concentrated in vacuo to give a yellow oil. This material was again dissolved in ethyl acetate (200 mL) and filtered over a plug of silica gel (40 g), the residue was washed with ethyl acetate (200 mL). The combined filtrate was again concentrated in vacuo to afford the crude product as a yellow oil (5.98 g). The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 50:50 to 100:0) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a light yellow solid (4.54 g, 76%). GC (method 7626G01) t _R = 9.7 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.75 (s, 3 H), 1.76 (s, 3 H), 2.79 (br s, 1 H), 3.15 (s, 3 H).

Step 5: 2-Methyl-2-[S-methyl-N-(3-tetrahydropyran-2- yloxypropyl)sulfonimidoyl]propanenitrile (Int-7)

Potassium hydride (30% w/w in mineral oil, 2.2 g, 16.5 mmol) was suspended in 1 ,2- dimethoxyethane (20.0 mL) and the suspension cooled to 0-5°C (ice bath). A solution of 2- methyl-2-(methylsulfonimidoyl)propanenitrile (Int-5, 2.0 g, 13.7 mmol) in 1 ,2-dimethoxyethane (15 mL) was added dropwise over 10 min. The ice bath was removed and the mixture was stirred for 3 h at room temperature. After that, it was cooled again to 0-5°C and tetrabutylammonium bromide (235 mg, 730 μιηοΐ) followed by 2-(3-bromopropoxy)tetrahydro-2H-pyran (Int-6, 3.95 g, 3.00 mL, 17.7 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. Then, the mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate (60 mL) and diluted with ethyl acetate (180 mL). After phase separation, the aqueous phase was extraced with ethyl acetate (2 x 50 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford a yellow biphasic oil as crude product. This was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n- heptane, gradient 40:60 to 100:0) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as mixture of diastereoisomers as a colorless viscous oil (3.28 g, 83%). HPLC (method LCMS_gradient) t _R = 1.6 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.47-1.60 (m, 4 H), 1.68- 1.77 (m, 1 H), 1.76 (br s, 6 H), 1.78-1.88 (m, 3 H), 3.06 & 3.07 (2s, 3 H, dias ), 3.20-3.41 (m, 2 H), 3.45-3.54 (m, 2 H), 3.79-3.91 (m, 2 H), 4.56-4.60 (m, 1 H). MS (ES+) m/z 205.1 [M+H- (CsHgO)] .

Synthesis of Int-llA and Int-llB: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-(3-hydroxypropyl)propylsulfon imidoyl)-2- methylpropanenitrile (Int-llA) and 2-((S,2R)-2-amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-(3-hydroxypropyl)propylsulfon imidoyl)-2- methylpropanenitrile (Int-llB)

lnt-11 A lnt-1 1 B

Step 1: N-[l-(6-Bromo-3-fluoro-4-triethylsilyl-2-pyridyl)-2-[S-(l-cy ano- l-methyl- ethyl)-N-(3-tetrahydropyran-2-yloxypropyl)sulfonimidoyl]-l-m ethyl-ethyl]-2-methyl-propane-2- sulfinamide (Int-10 (mix)) 2-Methyl-2-(S-methyl-N-(3-(tetrahydro-2H-pyran-2- yloxy)propyl)sulfonimidoyl)propanenitrile (Int-8, 3.31 g, 11.5 mmol) was dissolved in THF (45 mL) and the solution was cooled to <-70°C (acetone/dry ice bath). N-Butyl lithium (1.6 M in hexanes, 7.0 mL, 11.2 mmol) was added dropwise over 10 min, and the resulting solution was stirred for 50 min at < -70°C. Then, a solution of (R,E)-N-(l-(6-bromo-3-fluoro-4-(triethylsilyl)- pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (Int-9, 3.90 g, 8.96 mmol) in THF (45.0 mL) was added over 20 min at that temperature. After 30 min stirring at <70°C, the reaction mixture was poured onto a 2M aqueous solution of ammonium chloride (75 mL) and extracted with MTBE (1 x 300 mL, 2 x 100 mL). The combined organic extracts were concentrated in vacuo to give a yellow, viscous oil (2.46 g), that was used in the following step without further purification.

Step 2: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-(3- hydroxypropyl)propylsulfonimidoyl)-2-methylpropanenitrile (Int-l lA) and 2-((S,2R)-2-amino- 2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-N-(3-hydr oxypropyl)propylsulfonimidoyl)-2- methylpropanenitrile (Int-l lB) N- [ 1 - (6-Bromo-3-fluoro-4-triethylsilyl-2-pyridyl)-2- [S- ( 1 -cyano- 1 -methyl-ethyl)-N- (3 - tetrahydropyran-2-yloxypropyl)sulfonimidoyl]- l-methyl-ethyl]-2-methyl-propane-2-sulfinamide (Int- 10 (mix), 7.40 g, 10.2 mmol) was dissolved in ethanol (74 mL) and a solution of hydrogen chloride in methanol (ca. 20% w/w, 30 g, 30 mL, 165 mmol) was added at 0-5°C (ice bath). The mixture was stirred for 30 min at room temperature. After that, it was poured onto a 2M aqueous solution of sodium carbonate (200 mL) and diluted with MTBE (300 mL). The resulting suspension was filtered, the residue was washed with MTBE (100 mL). Phases of the combined filtrate were separated, the aqueous phase was extrated with ethyl acetate (2 x 100 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford a brownish oil as crude product. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / methanol, gradient 100:0 to 90: 10) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as separated diastereomers. The first eluting, minor diastereomer (Int-l lB) was isolated as a colorless viscous oil (920 mg, 17%), the second eluting, major diastereomer (Int- l lA) was obtained as a colorless oil (3.42 g, 62%). The overall yield is 79% over two steps. Int-l lA: HPLC (method LCMS_gradient) t _R = 2.1 min. 1H NMR (CDC1 ₃ , 400 MHz): δ

0.82-0.91 (m, 6 H), 0.94- 1.01 (m, 9 H), 1.57 (d, J = 0.8 Hz, 3 H), 1.59- 1.66 (m, 2 H), 1.68 (s, 3 H), 1.72 (s, 3 H), 2.77 (br s, 3 H), 3.10-3.18 (m, 1 H), 3.24-3.31 (m, 1 H), 3.57-3.71 (m, 2 H), 3.80 (dd, / = 1.1, 13.7 Hz, 1 H), 4.08 (d, = 13.7 Hz, 1 H), 7.35 (d, J = 2.7 Hz, 1 H). MS (ES+) mJz 537.3 & 535.3 [M+H]. Int-l lB: HPLC (method LCMS_gradient) t _R = 2.1 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ

0.82-0.90 (m, 6 H), 0.93-1.00 (m, 9 H), 1.31-1.40 (m, 1 H), 1.42- 1.51 (m, 1 H), 1.62 (d, J = 1.1 Hz, 3 H), 1.71 (s, 3 H), 1.75 (s, 3 H), 2.31 (br s, 3 H), 3.05 (ddd, J = 5.5, 6.3, 11.9 Hz, 1 H), 3.26 (ddd, 7 = 5.1, 7.5, 12.4 Hz, 1 H), 3.54 (t, J = 5.9 Hz, 2 H), 3.63 (d, J = 13.7 Hz, 1 H), 4.22 (d, J = 13.4 Hz, 1 H), 7.33 (d, J = 2.7 Hz, 1 H). MS (ES+) m/z 537.3 & 535.3 [M+H] , Synthesis of Int-14A: 3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-

5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3, 6-dihydro-2H-l,4-thiazin-l- ylidene)amino)propyl 4-methylbenzenesulfonate

lnt-11 A lnt-12A

Step 1 : (lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-l-((3-hydro- xypropyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H- 1 ,4-thiazine 1-oxide (Int- 12A)

2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)py ridin-2-yl)-N-(3-hydroxypro- pyl)propylsulfonimidoyl)-2-methylpropanenitrile (Int-l lA, 3.40 g, 6.35 mmol) was dissolved in ethanol (59 mL) and copper (I) chloride (660 mg, 6.67 mmol) was added. The mixture was heated to 75-80°C and stirred for 45 min at that temperature. After that, it was cooled to 5°C (ice bath) and poured onto a mixture of brine (40 mL) and aqueous ammonia (25% w/w, 20 mL). The resulting mixture was extracted with MTBE (200 mL) and ethyl acetate (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo to give a yellow oil as crude product. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / methanol, gradient 95:5 to 85: 15) to afford, after drying in vacuo (55°C, 5 mbar), the title compound as a white solid (2.79 g, 82%). HPLC (method LCMS_gradient) t _R = 1.8 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.81-0.89 (m, 6 H), 0.92-0.99 (m, 9 H), 1.40-1.65 (m, 2 H), 1.63 (s, 3 H), 1.73 (s, 3 H), 1.78 (s, 3 H), 2.78-2.88 (m, 1 H), 3.16-3.24 (m, 1 H), 3.28-3.36 (m, 1 H), 3.39 (d, J = 14.8 Hz, 1 H), 3.41-3.49 (m, 1 H), 3.56-3.70 (m, 2 H), 3.78-3.82 (m, 1 H), 4.24 (d, J = 14.8 Hz, 1 H), 7.32 (d, J = 2.4 Hz, 1 H). MS (ES+) m/z 537.3 & 535.3 [M+H, Br] .

Step 2: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((3- hydroxypropyl)imino)-2,2,5-trimethyl-l-oxido-5,6-dihydro-2H- l,4-thiazin-3-yl)carbamate (Int- 13A) (lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-l-((3-hydroxypro- pyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H- l,4-thiazine 1-oxide (Int-12A, 2.20 g, 4.11 mmol) was dissolved in THF (22 mL) and water (4.4 mL) and Boc-anhydride (1 g, 1.06 ml, 4.58 mmol), sodium hydrogencarbonate (440 mg, 5.24 mmol) and 4-dimethylaminopyridine (26 mg, 213 μπιοΐ) were added. The mixture was stirred for 1.5 h at room temperature. After that, aqueous ammonia (25% w/w, 198 mg, 220 μΐ, 2.91 mmol) was added and the mixture was stirred for additional 30 min. The reaction mixture was then poured onto water (50 mL) and extracted with MTBE (1 x 150 mL, 1 x 50 mL). The combined extracts were dried and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 40:60 to 60:40) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a colorless gum (2.06 g, 79%). HPLC (method LCMS_gradient) tR = 3.9 min. ^X H NMR (CDCI ₃ , 400 MHz): δ 0.82-0.90 (m, 6 H), 0.93-0.99 (m, 9 H), 1.37-1.61 (m, 2 H), 1.54 (s, 9 H), 1.60 (s, 3 H), 1.63 (s, 3 H), 1.77 (s, 3 H), 2.65-2.74 (m, 2 H), 3.13-3.20 (m, 1 H), 3.54 (d, / = 15.0 Hz, 1 H), 3.57-3.69 (m, 2 H), 4.48 (d, J = 15.3 Hz, 1 H), 7.37 (d, J = 2.7 Hz, 1 H), 11.14 (br s, 1 H, exch). MS (ES+) m/z 637.4 & 635.6 [M+H, Br]. Step 3: 3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert-butoxy- carbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H- l,4-thiazin-l-ylidene)amino)propyl 4- methylbenzenesulfonate (Int-14A) tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((3-hydroxy- propyl)imino)-2,2,5-trimethyl- 1 -oxido-5,6-dihydro-2H- 1 ,4-thiazin-3-yl)carbamate (Int- 13A, 2.0 g, 3.15 mmol) was dissolved in dichloromethane (20 mL), the solution was cooled to 0-5°C (ice bath) and triethylamine (799 mg, 1.1 mL, 7.89 mmol), a solution of tosyl chloride (925 mg, 4.85 mmol) in dichloromethane (10 ml) and 4-dimethylaminopyridine (30 mg, 246 μπιοΐ) were added subsequently at that temperature. The resulting clear solution was stirred for 16 h at room temperature. Then, the reaction mixture was poured onto an aqueous saturated solution of ammonium chloride (50 mL), and, after phase separation, the aqueous phase extracted with MTBE (1 x 200 mL, 1 x 50 mL). The combined extracts were washed with sat. aqueous sodium hydrogencarbonate solution (50 mL), dried (sodium sulfate) and concentrated in vacuo to give a turbid brownish oil as crude product. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 25:75 to 40:60) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as a white solid (2.29 g, 92%). HPLC (method LCMS_gradient) t _R = 4.6 min. ^X H NMR (CDCL, 400 MHz): δ 0.81-0.89 (m, 6 H), 0.92-0.98 (m, 9 H), 1.46 (s, 3 H), 1.48- 1.69 (m, 2 H), 1.54 (s, 9 H), 1.59 (s, 3 H), 1.70 (s, 3 H), 2.44 (s, 3 H), 2.50-2.60 (m, 1 H), 2.93-3.02 (m, 1 H), 3.49 (d, = 15.0 Hz, 1 H), 3.95-4.02 (m, 2 H), 4.39 (d, J = 15.3 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 11.10 (br s, 1 H, exch). MS (ES+) m/z 791.4 & 789.6 [M+H, Br] .

Synthesis of Int-14B: 3-(((lS,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)- 5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-d ihydro-2H-l,4-thiazin-l- ylidene)amino)propyl 4-methylbenzenesulfonate

IM-13B lnt-14B

Step 1 : (lS,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-l-((3-hydro- xypropyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H- 1 ,4-thiazine 1-oxide (Int- 12B) 2-((S,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-(3-hydroxypro- pyl)propylsulfonimidoyl)-2-methylpropanenitrile (Int-l lB, 970 mg, 1.81 mmol) was dissolved in ethanol (20 mL) and copper (I) bromide (275 mg, 1.92 mmol) was added. The mixture was heated to 75-80°C and stirred for 1.5 h at that temperature. After that, it was cooled to 5°C (ice bath) and poured onto a mixture of brine (10 mL) and aqueous ammonia (25% w/w, 5 mL). The resulting mixture was extracted with MTBE (60 mL) and ethyl acetate (2 x 25 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo to give a yellow oil as crude product. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / methanol, gradient 95:5 to 70:30) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as a white foam (670 mg, 69%). HPLC (method 7626L05) t _R = 4.7 min.

Step 2: tert-Butyl ((lS,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((3-hy- droxypropyl)imino)-2,2,5-trimethyl- 1 -oxido-5,6-dihydro-2H- 1 ,4-thiazin-3-yl)carbamate (Int- 13B)

(lS,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyri din-2-yl)-l-((3-hydroxy- propyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H-l,4-thiazine 1-oxide (Int- 12B, 670 mg, 1.25 mmol) was dissolved in THF (8 mL) and water (1.7 mL) and Boc-anhydride (350 mg, 372 μΐ, 1.6 mmol), sodium hydrogencarbonate (135 mg, 1.61 mmol) and 4-dimethylaminopyridine (8 mg, 65 μηιοΐ) were added. The mixture was stirred for 2 h at room temperature. After that, aqueous ammonia (25% w/w, 54 mg, 60 μΐ, 0.79 mmol) was added and the mixture was stirred for additional 30 min. The reaction mixture was then poured onto water (15 mL) and extracted with MTBE (1 x 40 mL, 1 x 20 mL). The combined extracts were washed with brine (10 mL), dried (sodium sulfate) and concentrated in vacuo (50°C, 5 mbar) to afford the title compound as a light brown gum (770 mg, 97% yield), that was used in the next step without further purification. HPLC (method 7626L05) t _R = 8.6 min. Step 3: 3-(((lS,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert-butoxy- carbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H- l,4-thiazin-l-ylidene)amino)propyl 4- methylbenzenesulfonate (Int- 14B ) tert-Butyl ((lS,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((3-hydroxy- propyl)imino)-2,2,5-trimethyl- 1 -oxido-5,6-dihydro-2H- 1 ,4-thiazin-3-yl)carbamate (Int- 13B, 1.22 g, 1.92 mmol) was dissolved in dichloromethane (12 mL), the solution was cooled to 0-5°C (ice bath) and triethylamine (486 mg, 670 μΕ, 4.81 mmol), a solution of tosyl chloride (560 mg, 2.94 mmol) in dichloromethane (6 ml) and 4-dimethylaminopyridine (15 mg, 123 μιηοΐ) were added subsequently at that temperature. The resulting clear solution was stirred for 16 h at room temperature. Then, the reaction mixture was poured onto an aqueous saturated solution of ammonium chloride (25 mL), and, after phase separation, the aqueous phase extracted with MTBE (1 x 100 mL, 1 x 50 mL). The combined extracts were washed with sat. aqueous sodium hydrogencarbonate solution (25 mL), dried (sodium sulfate) and concentrated in vacuo to give a turbid brownish oil as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 25:75 to 50:50) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a light brown gum (1.25 g, 83% yield). HPLC (method 7626L05) t _R = 11.1 min. Synthesis of Int-15AA and Int-15AB: tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoro-

4-(triethylsilyl)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2, 3,4,4a,5,8-hexahydro-[l,4]thia- zino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-15AA) and tert-butyl ((4aS,5R,9R)-5-(6-bromo- 3-fluoro-4-(triethylsilyl)pyridin-2-yl)-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-15AB)

lnt-14A lnt-15AA lnt-15AB

3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin- 2-yl)-5-((tert-butoxycarbonyl)- arnino)-3,6,6-trimethyl- l-oxido-3,6-dihydro-2H-l,4-thiazin- l-ylidene)amino)propyl 4-methyl- benzenesulfonate (Int-14A, 2.28 g, 2.89 mmol) was dissolved in THF (50 mL) and the solution was cooled to <-70°C (acetone / dry ice bath). A solution of LHMDS in THF (1.0 M, 7.6 ml, 7.6 mmol) was added over 10 min at that temperature. Then, the resulting clear, yellow solution was allowed to warm to 0-5°C (ice bath) and stirred for 1.5 h at that temperature. The reaction mixture was poured onto a 2 M aqueous ammonium chloride solution (50 mL) and extracted with MTBE (1 x 150 mL, 1 x 50 mL). The combined extracts were washed with brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 30:70 to 60:40) to afford, after drying in vacuo (55°C, 5 mbar), the title compounds as separated diastereoisomers. The first eluting diastereoisomer (Int- 15AA) was isolated as a white foam (800 mg, 45%) and the second eluting diastereoisomer (Int- 15AB) was obtained as a white foam (670 mg, 37%). Int-15AA: HPLC (method LCMS_gradient) t _R = 4.4 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ

0.82-0.91 (m, 6 H), 0.94- 1.00 (m, 9 H), 1.48 (s, 9 H), 1.77 (s, 3 H), 1.79 (s, 3 H), 1.81-2.01 (m, 2 H), 1.91 (d, J = 1.3 Hz, 3 H), 2.07-2.14 (m, 1 H), 2.38 (dddd, / = 3.0, 12.9, 13.2, 13.2 Hz, 1 H), 3.36-3.44 (m, 1 H), 3.62 (ddd, / = 3.5, 12.7, 12.7 Hz, 1 H), 4.17 (dd, / = 3.4, 12.5 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 11.37 (br s, 1 H, exch). MS (ES+) m/z 619.3 & 617.6 [M+H, Br]. Int-15AB: HPLC (method LCMS_gradient) t _R = 4.2 min. 1H NMR (CDC1 ₃ , 400 MHz): δ

0.83-0.91 (m, 6 H), 0.93-0.99 (m, 9 H), 1.49-1.69 (m, 2 H), 1.59 (s, 9 H), 1.71-1.82 (m, 2 H), 1.78 (s, 3 H), 1.89 (s, 3 H), 2.02 (d, J = 0.8 Hz, 3 H), 3.37-3.47 (m, 1 H), 3.56-3.70 (m, 2 H), 7.45 (d, J = 2.7 Hz, 1 H), 11.82 (br s, 1 H, exch). MS (ES+) m/z 619.3 & 617.6 [M+H, Br].

Synthesis of Int-15BA and Int-15BB: tert-Butyl ((4aR,5R,9S)-5-(6-bromo-3-fluoro- 4-(triethylsilyl)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4 ,4a,5,8-hexahydro-[l,4]thia- zino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-15BA) and tert-butyl ((4aS,5R,9S)-5-(6-bromo- 3-fluoro-4-(triethylsilyl)pyridin-2-yl)-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-15BB)

lnt-14B lnt-15BA lnt-15BB

3-(((lS,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin- 2-yl)-5-((tert-butoxycarbonyl)- amino)-3,6,6-trimethyl- l-oxido-3,6-dihydro-2H-l,4-thiazin- l-ylidene)amino)propyl 4-methyl- benzenesulfonate (Int- 14B, 1.25 g, 1.58 mmol) was dissolved in THF (28 mL) and the solution was cooled to <-70°C (acetone / dry ice bath). A solution of LHMDS in THF (1.0 M, 4.2 ml, 4.2 mmol) was added over 10 min at that temperature. Then, the resulting clear, yellow solution was allowed to warm to 0-5°C (ice bath) and stirred for 2.5 h at that temperature. The reaction mixture was poured onto a 2 M aqueous ammonium chloride solution (50 mL) and extracted with MTBE (1 x 100 mL, 1 x 50 mL). The combined extracts were washed with brine (30 mL), dried (sodium sulfate) and concentrated in vacuo to give a yellow foam as crude product (1.06 g). The crude product contained two diastereoisomers in a ratio of ca. 7:3 (Int-15BA / Int-15BB, by HPLC) and was used in the following step without further purification. Int-15BA: HPLC (method LCMS_gradient) t _R = 4.1 min. MS (ES+) m/z 619.3 & 617.3

[M+H, Br] ,

Int-15BB: HPLC (method LCMS_gradient) t _R = 4.3 min. MS (ES+) m/z 619.3 & 617.3 [M+H, Br] ,

Synthesis of Int-17AA: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7- yl)carbamate

lnt-15AA lnt-16AA lnt-17AA

Step h tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 16AA) tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, l-fj [ 1 ,2]fhiazin-7-yl)carbamate (Int- 15AA, 780 mg, 1.26 mmol) was dissolved in THF (9.6 mL) and DMF (2.4 mL). Acetic acid (157 mg, 150 μΐ, 2.62 mmol) and potassium fluoride (150 mg, 2.58 mmol) were added at room temperature and the resulting fine suspension was stirred for 2 h at that temperature. After that, it was poured upon a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and extracted with MTBE (1 x 80 mL, 1 x 40 mL). The combined extracts were washed with brine (20 mL), dried (sodium sulfate) and concentrated in vacuo to give a white foam as crude product (650 mg). The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a white solid (550 mg, 86%). HPLC (method LCMS_gradient) t _R = 2.8 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.77 (s, 3 H), 1.81 (s, 3 H), 1.82-1.95 (m, 2 H), 1.92 (d, J = 1.6 Hz, 3 H), 1.95-2.05 (m, 1 H), 2.38 (dddd, /= 3.5, 12.4, 12.6, 13.4 Hz, 1 H), 3.36- 3.43 (m, 1 H), 3.61 (ddd, = 3.5, 12.5, 12.5 Hz, 1 H), 4.08-4.14 (m, 1 H), 7.38 (dd, / = 8.3, 10.8 Hz, 1 H), 7.51 (dd, 7 = 3.1, 8.5 Hz, 1 H), 11.23 (br s, 1 H, exch). MS (ES+) m/z 505.3 & 503.4 [M+H, Br], Step 2: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 17AA) tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-7-yl )carbamate (Int-16AA, 300 mg, 596 μπιοΐ) was dissolved in 1,4-dioxane (5 mL) and water (1.7 mL) and sodium azide (400 mg, 6.15 mmol) was added. Copper (I) iodide (63 mg, 331 μιηοΐ), sodium ascorbate (33 mg, 167 μιηοΐ) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (72.2 mg, 80 μΐ, 507 μιηοΐ) were added subsequently and the dark blue mixture was stirred for 1 h at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured onto a saturated aqueous solution of sodium hydrogencarbonate (20 mL). It was extracted with ethyl acetate (1 x 60 mL, 1 x 30 mL), the combined extracts were dried over sodium sulfate and silica gel (2 g) was added to the solution. After filtration, the filtrate was concentrated in vacuo to give a green solid as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n- heptane, gradient 80:20 to 100:0) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as an off-white solid (150 mg, 57%). HPLC (method LCMS_gradient) IR = 2.2 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.76 (s, 3 H), 1.79-1.95 (m, 2 H), 1.82 (s, 3 H), 1.87 (d, J = 1.9 Hz, 3 H), 2.01-2.08 (m, 1 H), 2.35 (dddd, = 3.8, 12.6, 13.2, 13.2 Hz, 1 H), 3.34- 3.42 (m, 1 H), 3.61 (ddd, / = 3.9, 12.4, 12.4 Hz, 1 H), 4.09-4.16 (m, 1 H), 4.38 (s, 2 H), 6.47 (dd, J = 2.4, 8.9 Hz, 1 H), 7.24 (dd, J = 8.7, 11.1 Hz, 1 H), 11.12 (br s, 1 H, exch). MS (ES+) m/z 440.3 [M+H].

Synthesis of Int-17AB: tert-Butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2^,4,4a,5,8-hexahydro-[l,4]thiazino[ 2 -fl[l,2]thiazm

yl)carbamate

lnt-15AB lnt-16AB lnt-17AB

Step 1 : tert-Butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int-16AB) tert-Butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8-trime- thyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f] [l,2]thiazin-7-yl)carbamate (Int- 15AB, 650 mg, 1.05 mmol) was dissolved in THF (8 mL) and DMF (2 mL). Acetic acid (131 mg, 125 μΐ, 2.18 mmol) and potassium fluoride (125 mg, 2.15 mmol) were added at room temperature and the resulting fine suspension was stirred for 2h at that temperature. After that, it was poured upon a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and extracted with MTBE (1 x 60 mL, 1 x 30 mL). The combined extracts were washed with brine (15 mL), dried (sodium sulfate) and concentrated in vacuo to give a white solid as crude product. The crude was suspended in MTBE (10 mL) and stirred for 10 min at room temperature. N-Heptane (10 mL) was added, the precipitate was filtered, washed with n-heptane (10 mL) and dried in vacuo (50°C, 5 mbar) to afford the title compound as white powder (410 mg, 77%). HPLC (method LCMS_gradient) t _R = 2.6 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.58 (s, 9 H), 1.59-1.70 (m, 2 H), 1.72-1.82 (m, 2 H), 1.79 (s, 3 H), 1.90 (s, 3 H), 2.03 (d, / = 1.1 Hz, 3 H), 3.38-3.48 (m, 1 H), 3.54-3.61 (m, 1 H), 3.63-3.70 (m, 1 H), 7.39 (dd, / = 8.5, 10.5 Hz, 1 H), 7.55 (dd, / = 3.1, 8.5 Hz, 1 H), 11.86 (br s, 1 H, exch). MS (ES+) m/z 505.3 & 503.4 [M+H, Br].

Step 2: tert-Butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 17AB) tert-Butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-16AB, 180 mg, 358 μηιοΐ) was dissolved in 1,4-dioxane (3 mL) and water (1 mL) and sodium azide (240 mg, 3.69 mmol) was added. Copper (I) iodide (38 mg, 200 μιηοΐ), sodium ascorbate (20 mg, 101 μιηοΐ) and trans-N,N'-dimethyl- 1,2-cyclohexanediamine (45.1 mg, 50 μΐ, 317 μιτιοΓ) were added subsequently and the dark blue mixture was stirred for 1 h at 70°C. After that, a second portion of sodium azide (120 mg, 1.85 mmol), and a suspension of copper (I) iodide (38 mg, 200 μπιοΐ), sodium ascorbate (20 mg, 101 μιηοΐ) and trans-N,N'-dimethyl- 1,2-cyclohexanediamine (45.1 mg, 50 μΐ, 317 μπιοΐ) in dioxane (0.5 mL) were added and the mixture was stirred for additional 45 min at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL). It was extracted with ethyl acetate (1 x 60 mL, 1 x 30 mL), the combined extracts were dried over sodium sulfate and silica gel (2 g) was added to the solution. After filtration, the filtrate was concentrated in vacuo to give a green sticky solid as crude product (200 mg). The crude was purified by column chromatography (silica gel, 50 g, eluting with dichloromethane / methanol, gradient 99: 1 to 95:5) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as an off-white solid (140 mg, 89%). HPLC (method LCMS_gradient) t _R = 1.8 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.56 (s, 9 H), 1.62-1.84 (m, 4 H), 1.79 (s, 3 H), 1.89 (s, 3 H), 1.98 (d, J = 0.8 Hz, 3 H), 3.35-3.45 (m, 1 H), 3.56-3.69 (m, 2 H), 4.57 (s, 2 H), 6.48 (dd, J = 2.4, 8.9 Hz, 1 H), 7.26 (dd, J = 8.6, 10.5 Hz, 1 H), 12.07 (br s, 1 H, exch). MS (ES+) mJz 440.3 [M+H].

Synthesis of Int-17BA: tert-Butyl ((4aR,5R,9S)-5-(6-amino-3-fluoropyridin-2-yl)- 5,8,8 rimethyl-9-oxido-2,3,4,4a,5^

yl)carbamate

lnt-15BB

Step 1 : tert-Butyl ((4aR,5R,9S)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 16BA) A mixture of tert-butyl ((4aR,5R,9S)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate and tert-butyl ((4aS,5R,9S)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 15BA/Int- 15BB ca. 7:3, 1.00 g, 1.62 mmol) was dissolved in THF (12 mL) and DMF (3 mL). Acetic acid (315 mg, 300 μΐ, 5.24 mmol) and potassium fluoride (300 mg, 5.16 mmol) were added at room temperature and the resulting fine suspension was stirred for 2 h at that temperature. After that, it was poured upon a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and extracted with MTBE (1 x 100 mL, 1 x 50 mL). The combined extracts were washed with brine (25 mL), dried (sodium sulfate) and concentrated in vacuo to give a yellow viscous oil as crude product. The reaction control by HPLC and tic showed that only Int-15BA was converted to the desilated product, the other diastereomer (Int- 15BB) did not react. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to afford, after drying in vacuo (50°C, 5 mbar), desilated compound (Int-16BA) as white foam (460 mg, 56% yield). The remaining starting material was also isolated as pure Int-15BB as yellow oil (210 mg, 21%).

Int-16BA: HPLC (method LCMS_gradient) t _R = 2.6 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.44 (s, 3 H), 1.55 (s, 9 H), 1.77 (s, 3 H), 1.85 (s, 3 H), 1.87- 1.95 (m, 2 H), 2.12-2.24 (m, 1 H), 2.51-2.59 (m, 1 H), 3.49-3.57 (m, 1 H), 3.63-3.72 (m, 2 H), 7.25 (dd, / = 8.5, 10.6 Hz, 1 H), 7.40 (dd, / = 3.1, 8.5 Hz, 1 H), 10.69 (br s, 1 H, exch). MS (ES+) m/z 505.3 & 503.4 [M+H, Br].

Step 2: tert-Butyl ((4aR,5R,9S)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 17BA) tert-Butyl ((4aR,5R,9S)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-

2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-16BA, 450 mg, 894 μιτιοΐ) was dissolved in 1,4-dioxane (7.5 mL) and water (2.5 mL) and sodium azide (600 mg, 9.23 mmol) was added. Copper (I) iodide (90 mg, 473 μιηοΐ), sodium ascorbate (45 mg, 227 μπιοΐ) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (108 mg, 120 μΐ, 761 μπιοΐ) were added subsequently and the dark blue mixture was stirred for 1 h at 70°C. After that, a second portion of sodium azide (200 mg, 3.08 mmol), copper (I) iodide (45 mg, 236 μπιοΐ), sodium ascorbate (25 mg, 126 μιηοΐ) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (60 μΐ, 380 μιηοΐ) were added and the mixture was stirred for additional 20 min at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured onto a saturated aqueous solution of sodium hydrogencarbonate (25 mL). It was extracted with ethyl acetate (1 x 100 mL, 1 x 50 mL), the combined extracts were dried over sodium sulfate and silica gel (4 g) was added to the solution. After filtration, the filtrate was concentrated in vacuo to give a green sticky solid as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 80:20 to 100:0) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as a white solid (290 mg, 74%). HPLC (method LCMS_gradient) t _R = 2.0 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.34 (s, 3 H), 1.54 (s, 9 H), 1.73 (s, 3 H), 1.79 (s, 3 H), 1.81-1.92 (m, 2 H), 2.15-2.26 (m, 1 H), 2.47-2.57 (m, 1 H), 3.40 (ddd, = 5.0, 8.6, 13.3 Hz, 1 H), 3.64 (ddd, = 4.8, 4.8, 13.2 Hz, 1 H), 3.98 (dd, .7 = 4.8, 10.2 Hz, 1 H), 4.31 (s, 2 H), 6.38 (dd, = 2.4, 8.6 Hz, 1 H), 7.15 (dd, J = 8.7, 10.9 Hz, 1 H), 10.47 (br s, 1 H, exch). MS (ES+) m/z 440.4 [M+H].

Synthesis of Int-9: (7?, )-N-(l-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)ethylidene)-2-methylpropane-2-sulfinamide

lnt-19 lnt-20 lnt-21 lnt-9

Step 1 : 2-Bromo-5-fluoro-4-(triethylsilyl)pyridine (lnt-20)

To a solution of diisopropylamine (130 g, 183 mL, 1.28 mol) in tetrahydrofuran (1500 mL) was added 1.6 M n-butyllithium in tetrahydrofuran (800 mL, 1.28 mol) at -20 °C. The reaction mixture was allowed to warm to 0 °C and stirred for additional 30 minutes. A solution consisting of 2-bromo-5-fluoropyridine (lnt-19, 205 g, 1.16 mol) in tetrahydrofuran (200 mL) was added at -70 °C. After 60 minutes triethylchlorosilane (193 g, 217 mL, 1.28 mol) was added drop wise in 30 minutes. Stirring was continued for 1 h at -70 °C and then allowed to warm to - 30 °C. The reaction mixture was poured onto a mixture of 1 M aqueous hydrogen chloride solution (1000 mL) and 13-% aqueous ammonium chloride solution. The layers were separated. The aqueous layer was extracted with tert-butyl methyl ether (2000 mL). The combined organic layers were washed with one 1500-mL portion of water and concentrated in vacuo to give the crude title compound (345 g, quantitative) as orange oil, which was used in the next step without further purification. MS (ES+) m/z 290.1 & 292.1 [M+H, Br].

Step 2: l-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethanone (lnt-21) To a solution of diisopropylamine (160 g, 225 mL, 1.55 mol) in tetrahydrofuran (2200 mL) was added 1.6 M n-butyllithium in tetrahydrofuran (950 mL, 1.52 mol) at -20 °C. The reaction mixture was allowed to warm to 0 °C and stirred for additional 30 minutes. A solution of 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (338 g, 1.16 mol) in tetrahydrofuran (300 mL) was added drop wise in 30 minutes at -70 °C. After 80 minutes N,N-dimethylacetamide (107 g, 115 mL, 1.22 mol) was added drop wise in 10 minutes. The cooling bath was removed and the reaction mixture was poured onto a mixture of 25-% aqueous hydrogen chloride solution (255 g, 227 mL, 1.75 mol), 10-% aqueous sodium chloride solution (2500 mL). The layers were separated. The aqueous layer was extracted with tert-butyl methyl ether (2500 mL). The combined organic layers were concentrated in vacuo to give the crude title compound (392 g, quantitative) as dark brown viscous oil, which was used in the next step without further purification. MS (ES+) m/z 332.1 & 334.1 [M+H, Br] , Step 3: (^,£)-N-(l-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl) ethylidene)-2-methyl- propane-2-sulfinamide (Int-9)

To a mixture of l-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethanone (200 g, 512 mmol) and (i?)-2-methylpropane-2-sulfinamide (77.5 g, 640 mmol) in ethyl acetate (2000 mL) was added titanium (IV) ethoxide (187 g, 171 mL, 819 mmol). The reaction mixture was heated at 60 °C and stirred over night. The heating bath was removed and the excess of titanium (IV) ethoxide was quenched by addition of water (24.0 g, 24 mL, 1.33 mol) at 40 °C. The solids were removed by filtration and washed with two 500-mL portions of water. The filtrate was washed with one 1000-mL portion of 5-% aqueous hydrogen chloride solution and one 5-% aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo. Purification by flash-chromatography with n-heptane/efhyl acetate as eluent gave the title compound as brown viscous oil. MS (ES+) m/z 435.2 & 437.2 [M+H, Br] ,

Synthesis of Int-24BB: tert-Butyl ((4aS,5R,9S)-5-(6-amino-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-5,8,84rimethyl-9-ox

f] [l,2]thiazin-7-yl)carbamate

lnt-15BB lnt-24BB tert-Butyl ((4aS,5R,9S)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8-trime- thyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int-15BB, 210 mg, 340 μιηοΐ) was dissolved in 1,4-dioxane (4 mL) and water (1 mL) and sodium azide (225 mg, 3.46 mmol) was added. Copper (I) iodide (35 mg, 184 μιηοΐ), sodium ascorbate (17.5 mg, 88.3 μηιοΐ) and trans-N,N'-dimethyl- 1 ,2-cyclohexanediamine (45.1 mg, 50 μΐ, 317 μηιοΐ) were added subsequently and the dark blue mixture was stirred for 1 h at 70°C. After that, it was cooled to room temperature and second portions of sodium azide (225 mg, 3.46 mmol), copper (I) iodide (40 mg, 210 μιηοΐ), sodium ascorbate (20 mg, 101 μιηοΐ) and trans-N,N'-dimefhyl- l,2- cyclohexanediamine (60 μΐ, 380 μηιοΐ) were added and the mixture was stirred for additional 1 h min at 70°C. After that, it was cooled to room temperature and third portions of sodium azide (225 mg, 3.46 mmol), copper (I) iodide (40 mg, 210 μιηοΐ), sodium ascorbate (20 mg, 101 μπιοΐ) and trans-N,N'-dimethyl- 1 ,2-cyclohexanediamine (60 μΐ, 380 μιηοΐ) were added and the mixture was stirred for additional 1 h min at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured onto a saturated aqueous solution of sodium hydrogencarbonate (25 mL). It was extracted with ethyl acetate (1 x 100 mL, 1 x 50 mL), the combined extracts were dried over sodium sulfate and silica gel (4 g) was added to the solution. After filtration, the filtrate was concentrated in vacuo to give a green solid as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 80:20 to 100:0) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as a brown oil (50 mg, 27%). HPLC (method LCMS_gradient) t _R = 3.4 min. MS (ES+) m/z 554.5 [M+H] . Synthesis of Int-31: 2-Methyl-2-[S-methyl-N-(2-tetrahydropyran-2- yloxyethyl)sulfonimidoyl]propanenitrile

lnt-5 Int-31

A suspension of potassium hydride (30% suspension in mineral oil, 54.7 g, 410.4 mmol) in DME (200.0 mL) was cooled to 0-5 °C (ice bath). Then a solution of 2-methyl-2- (methylsulfonimidoyl)propanenitrile (Int-5, 30.0 g, 205.2 mmol) in DME (100.0 mL) was added dropwise to the mixture. After that, the mixture was allowed to warm to 23°C and stirred for 3 h. Then tetra-n-butylammonium bromide (3.3 g, 10.26 mmol) and 2-(2-bromoethoxy)tetrahydro- pyran (Int-30, 85.8 g, 410.4 mmol) in DME (100.0 mL) was added to the reaction mixture. The mixture was stirred at 23 °C for 16 h. After complete consumption of starting material had been detected by tic, the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (500 mL) and diluted with ethyl acetate (300 mL). After phase separation, the aqueous phase was extracted with ethyl acetate (2 x 200 mL), the combined organic extracts were dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 50:50) to give the title compound as yellow oil (45.0 g, 80% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.46-1.61 (m, 4 H), 1.67- 1.86 (m, 2 H), 1.76 (s, 6 H), 3.09 & 3.10 (2s, 3 H, diast), 3.31-3.54 (m, 4 H), 3.77-3.91 (m, 2 H), 4.60-4.64 (m, 1 H).

Synthesis of Int-33 (mix): 2-((2R)-2-Amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-(2-hydroxyethyl)propylsulfoni midoyl)-2-methylpropanenitrile

lnt-33 (mix)

Step 1 : (R)-N-((2R)-2-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-l-(2-cyano-N-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)propan-2-ylsulfonimidoy l)propan-2-yl)-2-methylpropane- 2-sulfinamide (Int-32 (mix)) To a solution of 2-methyl-2-[S-methyl-N-(2-tetrahydropyran-2-yloxyethyl)sulfo n- imidoyl]propanenitrile (Int-31, 8.0 g, 29.16 mmol) in THF (120.0 mL) was added n-BuLi (11.6 mL, 29.16 mmol, 2.5 N) at -70 °C over 10 min, the mixture was stirred at -70 °C for 1 h. Then a solution of (R,E)-N-(l-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)e thylidene)-2-methyl- propane-2-sulfinamide (Int-9, 12.7 g, 29.16 mmol) in THF (30.0 mL) was added to the reaction mixture over 10 min. Then the mixture was stirred at -70 °C for 4 h. The reaction mixture was quenched by addition of an aqueous saturated solution of ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate. After filtration, the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 50:50) to give the title compound (5.0 g, 24% yield) as a yellow oil and as a mixture of diastereoisomers.

Step 2: 2-((2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-N-(2- hydroxyethyl)propylsulfonimidoyl)-2-methylpropanenitrile (lnt-33 (mix))

To a solution of (R)-N-((2R)-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-l-(2- cyano-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)propan-2-yls ulfonimidoyl)propan-2-yl)-2- methylpropane-2-sulfinamide (Int-32 (mix), 25.0 g, 35.2 mmol) in methanol (200 mL) was added a solution of hydrogen chloride in methanol (4 N, 40.0 mL) at 0 °C. The reaction mixture was stirred for 1 h at 15 °C. After that, the reaction mixture was basified by addition of an aqueous solution of sodium carbonate (2 M) until pH 8-9, and extrated with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, eluting with ethyl acetate) to afford the title compound (16.3 g, 75% yield) as a yellow solid and as mixture of diastereoisomers. Synthesis of Int-35A & Int-35B: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-

(triethylsilyl)pyridin-2-yl)-l-((2-hydroxyethyl)imino)-2, 2,5-trimethyl-l-oxido-5,6-dihydro 2H-l,4-thiazin-3-yl)carbamate (Int-35A) and tert-butyl ((lS,5R)-5-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-l-((2-hydroxyethyl)imino)-2,2,5 -trimethyl-l-oxido-5,6-dihydro- 2H-l,4-thiazin-3-yl)carbamate (Int-35B)

lnt-35A lnt-35B

Step 1: (3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)- l-((2- hydroxyethyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H-l,4-thiaz ine 1-oxide (Int-34 (mix))

To a suspension of 2-((2R)-2-amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)- N-(2-hydroxyethyl)propylsulfonimidoyl)-2-methylpropanenitril e (Int-33 (mix), 15.0 g, 28.7 mmol) in ethanol (200 mL) was added copper(I) chloride (3.13 g, 31.6 mmol). Then, the mixture was stirred at 70 °C for 2 h. The reaction mixture was poured into a mixture of brine (100 mL) and aqueous ammonia (100 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL), the combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude product as a yellow gum which was used for the next step without further purification (15 g).

Step 2: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((2- hydroxyethyl)imino)-2,2,5-trimethyl- l-oxido-5,6-dihydro-2H-l,4-thiazin-3-yl)carbamate (Int- 35A) and tert-butyl ((lS,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((2- hydroxyethyl)imino)-2,2,5-trimethyl- l-oxido-5,6-dihydro-2H-l,4-thiazin-3-yl)carb (Int- 35B)

To a suspension of (3R)-5-amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-l- ((2-hydroxyethyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H-l,4-t hiazine 1-oxide (Int-34 (mix), crude from preceeding step, 30.0 g, 57.2 mmol) in tetrahydrofuran (400 mL) and water (80 mL), solid sodium hydrogencarbonate (6.3 g, 74.7 mmol), followed by Boc-anhydride (13.8 g, 63.3 mmol) and 4-(dimethylamino)-pyridine (351 mg, 2.8 mmol) were added. The mixture was stirred at 15 °C for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 25:75) to yield the title compounds as separated diastereoisomers. The first eluting diastereoisomer (Int-35A) was isolated as a yellow solid (9.0 g, 25%) and the second eluting diastereoisomer (Int-35B) was obtained as a yellow gum (11.0 g, 31%). The combined yield was 56% over 2 steps. Int-35A: ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.82-0.90 (m, 6 H), 0.93-1.00 (m, 9 H), 1.55 (s,

9 H), 1.64 (s, 3 H), 1.79 (s, 3 H), 1.83 (s, 3 H), 2.12 (t, J = 6.3 Hz, 1 H), 2.67 (ddd, J = 3.5, 6.0, 12.5 Hz, 1 H), 3.09 (ddd, J = 3.5, 6.8, 12.5 Hz, 1 H), 3.24-3.34 (m, 1 H), 3.37-3.46 (m, 1 H), 3.60 (d, J = 15.1 Hz, 1 H), 4.49 (d, J = 15.1 Hz, 1 H), 7.36 (d, J = 2.5 Hz, 1 H), 11.11 (s, 1 H).

Int-35B: ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.80-0.90 (m, 6 H), 0.91- 1.00 (m, 9 H), 1.53 (s, 9 H), 1.66 (s, 3 H), 1.73 (s, 3 H), 1.85 (s, 3 H), 2.39-2.47 (m, 1 H), 3.29-3.33 (m, 2 H), 3.58 (d, J = 15.3 Hz, 1 H), 3.62-3.68 (m, 2 H), 4.31 (d, J = 15.1 Hz, 1 H), 7.36 (d, 7 = 2.5 Hz, 1 H), 11.16 (s, 1 H).

Synthesis of Int-37AB: tert-Butyl ((3aS,4R,8R)-4-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate

lnt-35A lnt-36A

Step 1 : 2-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert- butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H - l,4-thiazin-l- ylidene)amino)ethyl 4-methylbenzenesulfonate (Int-36A) To a solution of tert-butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-

((2-hydroxyethyl)imino)-2,2,5-trimethyl-l-oxido-5,6-dihyd ro-2H-l,4-thiazin-3-yl)carbamate (Int-35A, 9.0 g, 14.5 mmol) in dichloromethane (150 mL) was added tosyl chloride (3.3 g, 17.4 mmol), triethylamine (2.9 g, 29.0 mmol) and 4-(dimethylamino)-pyridine (88.5 mg, 0.73 mmol) at 0 °C. The resulting mixture was stirred at 15 °C for 16 h. After that, the mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 25:75) to yield the title compound as a yellow solid (10.5 g, 95%). ¹ H NMR (CDC1 ₃ , 400 MHz): δ 0.81-0.90 (m, 6 H), 0.92- 1.00 (m, 9 H), 1.54 (s, 9 H), 1.59 (s, 3 H), 1.82 (s, 3 H), 2.44 (s, 3 H), 2.86-2.94 (m, 1 H), 3.16-3.24 (m, 1 H), 3.50 (d, / = 15.1 Hz, 1 H), 3.70-3.78 (m, 1 H), 3.82-3.89 (m, 1 H), 4.46 (d, J - 15.1 Hz, 1 H), 7.33 (d, J - 8.0 Hz, 2 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 2 H), 11.14 (s, 1 H).

Step 2: tert-Butyl ((3aS,4R,8R)-4-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 37AB) To a solution of 2-(((lR,3R)-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert- butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H - l,4-thiazin-l-ylidene)amino)- ethyl 4-methylbenzenesulfonate (Int-36A, 8.5 g, 10.9 mmol) in dry THF (150 mL) a solution of lithium hexamefhyldisilazide (LHMDS) in THF (1 M, 32.7 mL, 32.7 mmol) was added dropwise at -70 °C over 5 min. Then, the yellow solution was allowed to warm to 0 °C (ice bath) and stirred for 2 h. After that, the reaction mixture was poured into an aqueous saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give the crude product (6.48 g) as single diastereoisomer, which was used in the next step without further purification. 1H NMR (CDC1 ₃ , 400 MHz): δ 0.84-0.91 (m, 6 H), 0.93-0.99 (m, 9 H), 1.57 (s, 9 H), 1.70-1.80 (m, 1 H), 1.83 (s, 3 H), 1.91-2.01 (m, 1 H), 1.95 (s, 3 H), 2.11 (s, 3 H), 3.54 (dd, J - 7.5, 10.5 Hz, 1 H), 3.69 (ddd, J = 5.0, 10.5, 10.5 Hz, 1 H), 4.24 (ddd, J = 2.5, 7.3, 12.0 Hz, 1 H), 7.47 (d, J = 2.5 Hz, 1 H), 12.09 (s, 1 H).

Synthesis of Int-37BA: tert-Butyl ((3aR,4R,8S)-4-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate

lnt-35B lnt-36B lnt-37BA Step 1 : 2-(((lS,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert- butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H - l,4-thiazin-l- ylidene)amino)ethyl 4-methylbenzenesulfonate (Int-36B)

To a solution of tert-butyl ((lS,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l- ((2-hydroxyethyl)imino)-2,2,5-trimethyl-l-oxido-5,6-dihydro- 2H-l,4-thiazin-3-yl)carbamate (Int-35B, 11.0 g, 17.7 mmol) in dichloromethane (150 mL) was added tosyl chloride (4.0 g, 21.2 mmol), triethylamine (3.6 g, 35.4 mmol) and 4-(dimethylamino)-pyridine (107.9 mg, 0.89 mmol) at 0 °C. The resulting mixture was stirred at 15 °C for 16 h. After that, the mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 25:75) to yield the title compound as a yellow solid (13.0 g, 95%). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.81-0.91 (m, 6 H), 0.92- 1.00 (m, 9 H), 1.54 (s, 9 H), 1.59 (s, 3 H), 1.64 (s, 3 H), 1.82 (s, 3 H), 2.45 (s, 3 H), 3.30-3.43 (m, 2 H), 3.47 (d, = 15.1 Hz, 1 H), 4.03-4.13 (m, 2 H), 4.24 (d, J = 15.1 Hz, 1 H), 7.34-7.38 (m, 3 H), 7.80 (d, J = 8.3 Hz, 2 H), 11.15 (s, 1 H).

Step 2: tert-Butyl ((3aR,4R,8S)-4-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 37BA)

To a solution of 2-(((lS,3R)-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert- butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H - l,4-thiazin-l- ylidene)amino)ethyl 4-methylbenzenesulfonate (Int-36B, 11.0 g, 14.2 mmol) in dry THF (150 mL) a solution of lithium hexamethyldisilazide (LHMDS) in THF (1 M, 42.6 mL, 42.6 mmol) was added dropwise at -70 °C over 5 min. Then, the yellow solution was allowed to warm to 0 °C (ice bath) and stirred for 2 h. After that, the reaction mixture was poured into an aqueous saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give the crude product (6.77 g) as single diastereoisomer, which was used in the next step without further purification.

Synthesis of Int-39AB: tert-Butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3^a,4 -tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6- yl)carbamate

lnt-37AB lnt-38AB lnt-39AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-bromo-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8-oxido- 3,3a,4,7-tetrahydro-2H-isothiazolo[ 1 ,5-a] [ 1 ,4]thiazin-6-yl)carbamate (Int-38 AB)

To a suspension of tert-butyl ((3aS,4R,8R)-4-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin- 2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothia zolo[l,5-a][l,4]thiazin-6- yl)carbamate (Int-37AB, 6.0 g, crude from preceeding step, ca. 9.94 mmol) in THF (60 mL) and DMF (10 mL) was added potassium fluoride (1.15 g, 19.8 mmol) and acetic acid (1.18 g, 19.8 mmol) at 16 C, the mixture was stirred at 30 °C for 3 h. The reaction mixture was diluted with aqueous sodium hydrogencarbonate solution (100 mL), extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (100 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give a crude product. The crude was suspended in a mixture of ethyl acetate (15 mL) and petroleum ether (60 mL) and stirred for 30 min at 15 °C. The precipitate was filtered off, washed with a mixture of ethyl acetate / petroleum ether (1 :5 v/v, 30 mL) and dried in vacuo to afford the title compound as a yellow solid (4.87 g, 85% over 2 steps). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.59 (s, 9 H), 1.61-1.65 (m, 1 H), 1.85 (s, 3 H), 1.96 (s, 3 H), 2.01-2.09 (m, 1 H), 2.14 (s, 3 H), 3.56 (dd, J - 7.7, 10.6 Hz, 1 H), 3.70 (dd, ./ = 4.9, 10.6 Hz, 1 H), 4.24 (ddd, / = 2.5, 7.1, 12.1 Hz, 1 H), 7.42 (dd, J = 8.5, 10.5 Hz, 1 H), 7.57 (dd, J = 3.3, 8.5 Hz, 1 H), 12.13 (s, 1 H).

Step 2: tert-Butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8- oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin- 6-yl)carbamate (Int-39AB)

To a mixture of tert-butyl ((3aS,4R,8R)-4-(6-bromo-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 38AB, 3.0 g, 6.13 mmol) in dioxane (30.0 mL) and water (10.0 mL) was added copper(I) iodide (1.27 g, 6.7 mmol), sodium ascorbate (0.73 g, 3.7 mmol), sodium azide (6.0 g, 92.0 mmol) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (1.57 g, 11.03 mmol). Then the dark blue mixture was stirred for 1 h at 70°C. The reaction mixture was diluted with aqueous sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 2: 1) to yield, after drying in vacuo, the title compound as yellow solid (2.3 g, 89% yield). ^l R NMR (CDC1 ₃ , 400 MHz): δ 1.53-1.63 (m, 1 H), 1.57 (s, 9 H), 1.84 (s, 3 H), 1.95 (s, 3 H), 2.06-2.15 (m, 1 H), 2.09 (s, 3 H), 3.53 (dd, / = 7.6, 10.6 Hz, 1 H), 3.68 (ddd, J = 4.8, 10.5, 10.5 Hz, 1 H), 4.25 (ddd, J = 1.9, 7.0, 12.2 Hz, 1 H), 4.60 (s, 2 H), 6.50 (dd, = 2.5, 8.8 Hz, 1 H), 7.28 (dd, 7 = 8.9, 10.5 Hz, 1 H), 12.29 (s, 1 H).

Synthesis of Int-39BA: tert-Butyl ((3aR,4R,8S)-4-(6-amino-3-nuoropyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6- yl)carbamate

lnt-37BA lnt-38BA lnt-39BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-bromo-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8-oxido- 3,3a,4,7-tetrahydro-2H-isothiazolo[ 1 ,5-a] [ 1 ,4]thiazin-6-yl)carbamate (Int-38BA)

To a suspension of tert-butyl ((3aR,4R,8S)-4-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin- 2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothia zolo[l,5-a][l,4]thiazin-6- yl)carbamate (Int-37BA, 6.0 g, crude from preceeding step, ca. 9.94 mmol) in THF (60 mL) and DMF (10 mL) was added potassium fluoride (1.15 g, 19.8 mmol) and acetic acid (1.18 g, 19.8 mmol) at 16 C, the mixture was stirred at 30 °C for 3 h. The reaction mixture was diluted with aqueous sodium hydrogencarbonate solution (100 mL), extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (100 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give a crude product. The crude was suspended in a mixture of ethyl acetate (15 mL) and petroleum ether (60 mL) and stirred for 30 min at 15 °C. The precipitate was filtered off, washed with a mixture of ethyl acetate / petroleum ether (1 :5 v/v, 30 mL) and dried in vacuo to afford the title compound as a yellow solid (4.12 g, 68% over 2 steps). 1H NMR (CDC1 ₃ , 400 MHz): δ 0.91 (s, 3 H), 1.55 (s, 9 H), 1.72 (s. 3 H), 1.75 (s, 3 H), 2.07-2.19 (m, 1 H), 2.54-2.62 (m, 1 H), 3.71-3.85 (m, 2 H), 5.07 (dd, = 7.2, 10.9 Hz, 1 H), 7.36 (dd, J = 8.5, 10.3 Hz, 1 H), 7.53 (dd, J = 3.0, 8.5 Hz, 1 H), 10.99 (s, 1 H).

Step 2: tert-Butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8- oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin- 6-yl)carbamate (Int-39BA) To a mixture of tert-butyl ((3aR,4R,8S)-4-(6-bromo-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 38BA, 5.5 g, 11.2 mmol) in dioxane (100.0 mL) and water (30.0 mL) was added copper(I) iodide (2.3 g, 12.3 mmol), sodium ascorbate (1.3 g, 6.7 mmol), sodium azide (11.0 g, 168.0 mmol) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (2.88 g, 20.23 mmol). Then the dark blue mixture was stirred for 1 h at 70°C. The reaction mixture was diluted with aqueous sodium hydrogencarbonate solution (200 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 2: 1) to yield, after drying in vacuo, the title compound as yellow solid (4.5 g, 94% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 0.93 (s, 3 H), 1.52 (s, 9 H), 1.66 (s, 3 H), 1.73 (s, 3 H), 2.03-2.15 (m, 1 H), 2.47-2.57 (m, 1 H), 3.69-3.79 (m, 2 H), 4.54 (s, 2 H), 5.16 (dd, J = 7.2, 10.9 Hz, 1 H), 6.46 (dd, 7 = 2.3, 8.8 Hz, 1 H), 7.20 (dd, / = 8.8, 10.8 Hz, 1 H), 10.90 (s, 1 H).

Synthesis of Int-43: 2-(N-(2,2-Difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)- S- methylsulfonimidoyl)-2-methylpropanenitrile

Step 1: 2,2-Difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propan- l-ol (Int-41)

2,2-Difluoropropane-l,3-diol (1.00 g, 8.92 mmol) was suspended in cyclohexane (50 mL), 2,3-dihydropyrane (2.48 g, 2.7 ml, 29.5 mmol) followed by an aqueous solution of sodium hydrogensulfate (5 mol/L, 1.8 mL, 9 mmol) were added and the biphasic mixture was stirred for 90 min at 30°C. After that, solid sodium carbonate (8 g, 75.5 mmol) was added, the reaction mixture diluted by addition of tert-butylmethylether (20 mL) and stirred for 30 min at room temperature. It was filtered and the filtrate was concentrated in vacuo (55°C / 5 mbar). The crude product was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 40:60) to give, after drying in vacuo (50°C, 5 mbar), the title compound as colorless oil (1.2 g, 69%). ^! H NMR (CDC1 ₃ , 400 MHz): δ 1.49-1.65 (m, 4 H), 1.72-1.88 (m, 2 H), 2.58 (dd, = 7.1, 7.7 Hz, 1 H), 3.51-3.59 (m, 1 H), 3.74-4.07 (m, 5 H), 4.62- 4.66 (m, 1 H).

Step 2: 2,2-Difluoro-3-hydroxypropyl trifluoromethanesulfonate (Int-42)

2,2-Difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol (Int-41, 1.20 g, 6.12 mmol) was dissolved in dichloromethane (15 mL) and the solution was cooled to 0-5°C (ice bath). Pyridine (685 mg, 700 μΐ, 8.65 mmol) followed by a solution of trifluoromethanesulfonic anhydride (2 g, 1.2 ml, 6.96 mmol) in dichloromethane (2 mL) were added over 15 min. The reaction mixture was stirred for 45 min. After that, it was poured into an aqueous saturated solution of sodium hydrogencarbonate (50 mL) and extracted with tert-butylmethylether (1 x 100 mL, 1 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (sodium sulfate) and concentrated in vacuo to give a brown oil as crude product. The crude product was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 2:98 to 10:90) to afford, after drying in vacuo (40°C, 5 mbar) the title compound as viscous, colorless oil (1.54 g, 77%). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.48- 1.68 (m, 4 H), 1.69- 1,86 (m, 2 H), 3.52-3.60 (m, 1 H), 3.68-3.84 (m, 2 H), 4.02 (ddd, J = 10.7, 11.5, 14.5 Hz, 1 H), 4.63-4.76 (m, 3 H).

Step 3: 2-(N-(2,2-Difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)- S-methylsulfon- imidoyl)-2-methylpropanenitrile (Int-43)

Potassium hydride (30% w/w in mineral oil, 700 mg, 5.24 mmol) was suspended in 1,2- dimethoxyethane (12 mL) and the suspension cooled to 0-5°C (ice bath). A solution of 2- methyl-2-(methylsulfonimidoyl)propanenitrile (Int-5, 650 mg, 4.45 mmol) in 1,2- dimethoxyethane (5 mL) was added dropwise over 5 min. The ice bath was removed and the mixture was stirred for 30 min at room temperature. After that, it was cooled again to 0-5°C and tetrabutylammonium bromide (80 mg, 248 μπιοΐ) followed by a solution of 2,2-difluoro-3- hydroxypropyl trifluoromethanesulfonate (Int-42, 1.53 g, 4.66 mmol) in 1 ,2-dimethoxyethane (5 mL) were added. The reaction mixture was stirred for 16 h at room temperature. Then, the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and diluted with tert-butylmethylether (60 mL). After phase separation, the aqueous phase was extraced with tert-butylmethylether (2 x 30 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford the crude product. This was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 40:60 to 60:40) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as mixture of diastereoisomers as a light yellow viscous oil (980 mg, 68%). HPLC (method LCMS_gradient) t _R = 2.0 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.49- 1.87 (m, 6 H), 1.78 (s, 6 H), 3.11 & 3.12 (2s, 3 H, diast.), 3.50-3.77 (m, 4 H), 3.83-4.03 (m, 2 H), 4.72 (t, / = 3.2 Hz, 1 H). MS (ES+) m/z 241.1 [M+H-(C ₅ H ₈ 0)] .

Synthesis of Int-45A and Int-45B: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-(2,2-difluoro-3-hydroxypropyl )propylsulfonimidoyl)-2- methylpropanenitrile (Int-45A) and 2-((S,2R)-2-amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-(2,2-difluoro-3-hydroxypropyl )propylsulfonimidoyl)-2- methylpropanenitrile (Int-45B)

lnt-45A lnt-45B

Step 1 : N-(2-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-l-(2-c yano-N-(2,2- difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)propan-2-yl sulfonimidoyl)propan-2-yl)-2- methylpropane-2-sulfinamide (Int-44 (mix)) 2-(N-(2,2-Difluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)- S-methylsulfonimidoyl)- 2-methylpropanenitrile (Int-43, 960 mg, 2.96 mmol) was dissolved in THF (8 mL) and the solution was cooled to <-70°C (acetone/dry ice bath). N-Butyl lithium (1.6 M in hexanes, 1.8 mL, 2.88 mmol) was added dropwise over 10 min, and the resulting solution was stirred for 50 min at < -70°C. Then, a solution of (R,E)-N-(l-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)e thyl- idene)-2-methylpropane-2-sulfinamide (Int-9, 1.0 g, 2.3 mmol) in THF (6.0 mL) was added over 5 min at that temperature. After 30 min stirring at < -70°C, the reaction was not complete by tic and HLPC. A solution of lithium hexamethyldisilazide in THF (1 M, 2.9 mL, 2.9 mmol) was added over 5 min and the reaction mixture was stirred for further 15 min at < -70°C. After that, it was poured into a 2M aqueous solution of ammonium chloride (20 mL) and extracted with tert- butylmethylether (1 x 80 mL, 1 x 40 mL). The combined organic extracts were concentrated in vacuo to give a yellow, viscous oil (2.1 g), that was used in the following step without further purification.

Step 2: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-(2,2- difluoro-3-hydroxypropyl)propylsulfonimidoyl)-2-methylpropan enitrile (Int-45A) and 2-((S,2R)- 2-amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-N -(2,2-difluoro-3- hydroxypropyl)propylsulfonimidoyl)-2-methylpropanenitrile (Int-45B)

N-(2-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-l-( 2-cyano-N-(2,2-difluoro-3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)propan-2-ylsulfonimido yl)propan-2-yl)-2-methyl- propane-2-sulfinamide (Int-44 (mix), 2.10 g, 2.76 mmol) was dissolved in ethanol (21 mL) and a solution of hydrogen chloride in methanol (ca. 20% w/w, 8.5 g, 8.5 mL, 46.6 mmol) was added at 0-5°C (ice bath). The mixture was stirred for 30 min at room temperature. After that, it was poured onto a 2M aqueous solution of sodium carbonate (100 mL) and diluted with MTBE (150 mL). The resulting suspension was filtered, the residue was washed with MTBE (50 mL). Phases of the combined filtrate were separated, the aqueous phase was extrated with ethyl acetate (2 x 50 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford a brownish oil as crude product. The crude was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / methanol, gradient 100:0 to 90: 10) to yield, after drying in vacuo (40°C, 5 mbar), the title compound Int-45A as single diastereomer and as a colorless oil 600 mg, 39% over two steps). HPLC (method LCMS_gradient) t _R = 2.2 min. ^l H NMR (CDC1 ₃ , 400 MHz): δ 0.82-0.90 (m, 6 H), 0.94-1.00 (m, 9 H), 1.59 (s, 3 H), 1.72 (s, 3 H), 1.73 (s, 3 H), 2.86 (br s, 3 H), 3.46 (ddd, J = 10.1, 13.0, 13.0 Hz, 1 H), 3.60 (ddd, J = 9.1, 13.4, 19.1 Hz, 1 H), 3.75-3.85 (m, 3 H), 4.25 (d, J = 13.7 Hz, 1 H), 7.36 (d, / = 2.7 Hz, 1 H). MS (ES+) mJz 573.1 & 571.2 [M+H, Br]. The minor diastereomer Int-45B was not isolated.

Synthesis of Int-48A: 3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)- 5-((tert-butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-d ihydro-2H-l,4-thiazin-l- ylidene)amino)-2,2-difluoropropyl trifluoromethanesulfonate

Step 1 : (lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-l-((2,2- difluoro-3-hydroxypropyl)imino)-3,6,6-trimethyl-3,6-dihydro- 2H- 1 ,4-thiazine 1-oxide (Int-46A)

2-(2-amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2 -yl)-N-(2,2-difluoro-3- hydroxypropyl)propylsulfonimidoyl)-2-methylpropanenitrile (Int-45A, 600 mg, 1.05 mmol) was dissolved in ethanol (9 mL) and copper (I) bromide (160 mg, 1.12 mmol) was added. The mixture was heated to 75-80°C and stirred for 45 min at that temperature. After that, it was cooled to 5°C (ice bath) and poured into a mixture of brine (10 mL) and aqueous ammonia (25% w/w, 5 mL). The resulting mixture was extracted with MTBE (60 mL) and ethyl acetate (2 x 25 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo to give a yellow oil as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / methanol, gradient 95:5 to 85: 15) to yield, after drying in vacuo (60°C, 5 mbar), the title compound as a white foam (490 mg, 82%). HPLC (method LCMS_gradient) t _R = 2.1 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.80-0.90 (m, 6 H), 0.93-1.00 (m, 9 H), 1.65 (s, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 2.96-3.09 (m, 1 H), 3.40 (d, / = 15.0 Hz, 1 H), 3.40-3.52 (m, 1 H), 3.64-3.80 (m, 2 H), 4.30 (d, / = 14.8 Hz, 1 H), 7.33 (d, ./ = 2.4 Hz, 1 H). MS (ES+) m/z 573.1 & 571.2 [M+H, Br] . Step 2: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((2,2- difluoro-3-hydroxypropyl)imino)-2,2,5-trimethyl-l-oxido-5,6- dihydro-2H-l,4-thiazin-3- yl)carbamate (Int-47A)

(lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyri din-2-yl)-l-((2,2-difluoro-3- hydroxypropyl)imino)-3,6,6-trimethyl-3,6-dihydro-2H-l,4-thia zine 1-oxide (Int-46A, 490 mg, 857 μιηοΐ) was dissolved in THF (5 mL) and water (1 mL) and Boc-anhydride (280 mg, 298 μί, 1.28 mmol), sodium hydrogencarbonate (100 mg, 1.19 mmol) and 4-dimethylaminopyridine (5 mg, 41 μιηοΐ) were added. The mixture was stirred for 3.75 h at room temperature. After that, aqueous ammonia (25% w/w, 90 mg, 100 ^L, 1.32 mmol) was added and the mixture was stirred for additional 30 min. The reaction mixture was then poured onto water (10 mL) and extracted with MTBE (1 x 80 mL, 1 x 40 mL). The combined extracts were dried and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100 g, eluting with ethyl acetate / n-heptane, gradient 40:60 to 60:40) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as a white foam (520 mg, 90%). HPLC (method LCMS_gradient) t _R = 4.1 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 0.82-0.90 (m, 6 H), 0.93-0.99 (m, 9 H), 1.54 (s, 9 H), 1.64 (s, 3 H), 1.78 (s, 3 H), 1.83 (s, 3 H), 2.66 (t, - 7.5 Hz, 1 H), 2.86 (ddd, / = 10.5, 13.2, 13.2 Hz, 1 H), 3.42 (ddd, / = 8.9, 13.4, 18.5 Hz, 1 H), 3.57 (d, / = 15.3 Hz, 1 H), 3.60-3.80 (m, 2 H), 4.56 (d, / = 15.0 Hz, 1 H), 7.38 (d, J = 2.7 Hz, 1 H), 11.15 (s, 1 H). MS (ES+) m/z 673.2 & 671.2 [M+H, Br] ,

Step 3: 3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-y l)-5-((tert- butoxycarbonyl)amino)-3,6,6-trimethyl-l-oxido-3,6-dihydro-2H - l,4-thiazin-l-ylidene)amino)- 2,2-difluoropropyl trifluoromethanesulfonate (Int-48A) tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-((2,2-difluoro-3- hydroxypropyl)imino)-2,2,5-trimethyl-l-oxido-5,6-dihydro-2H- l,4-thiazin-3-yl)carbamate (Int- 47A, 2.05 g, 3.05 mmol) was dissolved in dichloromethane (25 mL), the solution was cooled to 0-5°C (ice bath) and pyridine (302 mg, 309 μΐ _^ , 3.82 mmol) and a solution of triflic anhydride (947 mg, 3.36 mmol) in dichloromethane (8 ml) were added subsequently at that temperature. The resulting yellow solution was stirred for 30 min at 0-5°C. After that, an aqueous solution of sodium hydrogencarbonate (5%, 100 mL) was added and the pH of the aqueous phase was verified to be 8-9. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 60 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give the crude product. The crude was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 30:70) to afford, after drying in vacuo (40°C, 5 mbar), the title compound as a light yellow foam (2.15 g, 88%). HPLC (method LCMS_fglm) t _R = 1.86 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.81-0.91 (m, 6 H), 0.93-1.01 (m, 9 H), 1.55 (s, 9 H), 1.62 (s, 3 H), 1.78 (s, 3 H), 1.83 (s, 3 H), 3.07 (ddd, J = 9.9, 13.9, 13.9 Hz, 1 H), 3.44 (ddd, 7 = 9.5, 13.5, 17.1 Hz, 1 H), 3.57 (d, J = 15.1 Hz, 1 H), 4.46- 4.56 (m, 2 H), 4.56 (d, J = 15.1 Hz, 1 H), 7.39 (d, .7 = 2.6 Hz, 1 H), 11.20 (s, 1 H). MS (ES+) m/z 803.2 & 805.2 [M+H, Br] ,

Synthesis of Int-49AA and Int-49AB: tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3- fluoro-4-(triethylsilyl)pyridin-2-yl)-3,3-difluoro-5,8,8-tri methyl-9-oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-49AA) and tert-butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl>^

9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f][l,2]thia zin-7-yl)carbamate (Int-49AB)

lnt-48A lnt-49AA lnt-49AB

3-(((lR,3R)-3-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin- 2-yl)-5-((tert-butoxycarbonyl)amino)- 3,6,6-trimethyl-l-oxido-3,6-dihydro-2H- l,4-thiazin- l-ylidene)amino)-2,2-difluoropropyl trifluoromethanesulfonate (Int-48A, 2.13 g, 2.65 mmol) was dissolved in THF (25 mL) under anhydrous conditions and the solution was cooled to <-70°C (acetone / dry ice bath). A solution of LHMDS in THF (1.0 M, 6.89 ml, 6.89 mmol) was added over 15 min and stirred for 15 min at that temperature. Then, the resulting clear, yellow solution was allowed to warm to -20°C (ice / ethanol bath) and stirred for 90 min at that temperature TLC showed complete conversion. The reaction was stopped by addition of a saturated aqeuous solution of ammonium chloride (60 mL) and, after phase separation, the aqueous phase was extracted with ethyl acetate (2 x 60 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 35:65) to yield, after drying in vacuo (55°C, 5 mbar), the title compound Int- 49AA as single diastereoisomer and as colorless viscous oil (1.57 g, 91%). HPLC (method LCMS_gradient) t _R = 4.5 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.83-0.91 (m, 6 H), 0.94-1.00 (m, 9 H), 1.47 (s, 9 H), 1.79 (s, 3 H), 1.82 (s, 3 H), 1.93 (br s, 3 H), 2.55-2.77 (m, 2 H), 3.63-3.86 (m, 2 H), 4.50-4.57 (m, 1 H), 7.45 (d, / = 2.7 Hz, 1 H), 11.45 (s, 1 H). MS (ES+) mJz 555.1 & 553.1 [M+H-C02-CH2=CMe2, Br] . The minor diastereomer was not isolated.

Synthesis of Int-51AA: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)- 3,3-difluoro-5,8,84rimethyl-9-oxido-2,3,4,4a^

7-yl)carbamate

lnt-49AA lnt-50AA lnt-51

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 50AA) tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-3,3-difluoro-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-49AA, 170 mg, 260 μmol) was dissolved in THF (4 mL) and DMF (1 mL). Acetic acid (52.5 mg, 50 μΐ, 873 μηιοΐ) and potassium fluoride (50 mg, 861 μιηοΐ) were added at room temperature and the resulting fine suspension was stirred for 2.5 h at that temperature. After that, it was poured into a saturated aqueous solution of sodium hydro gencarbonate (10 mL) and extracted with MTBE (1 x 60 mL, 1 x 30 mL). The combined extracts were washed with brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was treated with o- xylene (8 mL) and concentrated again in vacuo to give a yellow viscous oil as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 40:60) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as a white foam (130 mg, 93%). HPLC (method LCMS_gradient) t _R = 3.1 min. ^l R NMR (CDC1 ₃ , 400 MHz): δ 1.49 (s, 9 H), 1.80 (s, 3 H), 1.82 (s, 3 H), 1.93 (d, J = 1.1 Hz, 3 H), 2.49-2.60 (m, 1 H), 2.61-2.78 (m, 1 H), 3.63-3.86 (m, 2 H), 4.45-4.51 (m, 1 H), 7.41 (dd, / = 8.6, 10.7 Hz, 1 H), 7.54 (dd, J = 3.1, 8.5 Hz, 1 H), 11.31 (s, 1 H). MS (ES+) m/z 541.1 & 539.1 [M+H, Br] .

Step 2: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 51AA) tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int-50AA, 120 mg, 222 μιηοΐ) was dissolved in 1,4-dioxane (3 mL) and water (1 mL) and sodium azide (200 mg, 3.08 mmol) was added. Copper (I) iodide (30 mg, 158 μηιοΐ), sodium ascorbate (15 mg, 76 μιηοΐ) and trans-N,N'-dimethyl- 1,2-cyclohexanediamine (36.1 mg, 40 μΐ, 254 μιηοΐ) were added subsequently and the dark blue mixture was stirred for 1 h at 70°C. Since the conversion was not complete, further portions of sodium azide (100 mg, 1.54 mmol), copper (I) iodide (30 mg, 158 μηιοΐ), sodium ascorbate (15 mg, 76 μηιοΐ) and trans-N,N'-dimethyl- 1,2-cyclohexanediamine (36.1 mg, 40 μΐ, 254 μιηοΐ) were added subsequently and the mixture was stirred at 70°C for further 30 min. Then, the reaction mixture was allowed to cool to room temperature and poured into a saturated aqueous solution of sodium hydrogencarbonate (10 mL). It was extracted with ethyl acetate (1 x 50 mL, 2 x 30 mL), the combined extracts were washed with a mixture of brine (10 mL) and ammonia (25% w/w, 1 mL), dried over sodium sulfate and silica gel (2 g) was added to the solution. After filtration, the filtrate was concentrated in vacuo to give a yellow solid as crude product. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 30:70 to 50:50) to afford, after drying in vacuo (55°C, 5 mbar), the title compound as a white solid (70 mg, 66%). HPLC (method LCMS_gradient) t _R = 2.6 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.49 (s, 9 H), 1.78 (s, 3 H), 1.80 (s, 3 H), 1.87 (d, / = 1.6 Hz, 3 H), 2.58-2.75 (m, 2 H), 3.62-3.86 (m, 2 H), 4.41 (s, 2 H), 4.59-4.65 (m, 1 H), 6.49 (dd, J = 2.6, 8.6 Hz, 1 H), 7.28 (dd, J = 8.7, 10.9 Hz, 1 H), 11.23 (s, 1 H). MS (ES+) mJz 476.2 [M+H].

Synthesis of Int-51AAp: Enantiopure tert-Butyl ((4aR,5R,9R)-5-(6-amino-3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-7-yl)carbamate

lnt-51 AA lnt-51 AAp lnt-51 AAq

Enantiomeric purification of tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-51AA, 1.68 g, 3.53 mmol) was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane/ethanol 90/10, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (Int-51AAp, 979 mg, 58%), and the opposite (+) -rotating enantiomer as a white solid (Int-51AAq, 366 mg, 22%).

Synthesis of Int-55: 2-Methyl-2-(S-methyl-N-((l-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)cyclopropyl)methyl)sulfonimidoyl)propanenitril e

lnt-54 lnt-55

Step 1: (l-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methan ol (Int-53)

Cyclopropane- 1, 1-diyldimethanol (16.0 g, 157 mmol) was suspended in toluene (312 mL) at 30 °C, 2,3-dihydropyrane (43.6 g, 47.0 ml, 519 mmol) followed by an aqueous solution of sodium hydrogensulfate (5 mol/L, 31.6 mL, 158 mmol) were added and the biphasic mixture was stirred for lh at 30°C. After that, solid sodium carbonate (140 g, 1.33 mol) was added, the resulting suspension was stirred for 30 min at room temperature and filtered. The precipitate was washed with toluene (4 x 125 mL), and the combined filtrates were concentrated in vacuo (40°C / 5 mbar). The crude product was purified by column chromatography (silica gel, 330 g, eluting with tert-butylmethyl ether / n-heptane, gradient 20:80 to 35:65) to give, after drying in vacuo (40°C, 5 mbar), the title compound as light yellow liquid (21.1 g, 72%). 1H NMR (CDC1 ₃ , 300 MHz): δ 0.48-0.58 (m, 4 H), 1.51- 1.64 (m, 4 H), 1.72- 1.78 (m, 1 H), 1.79-1.87 (m, 1 H), 2.63 (br s, 1 H), 3.40 (d, J = 10.3 Hz, 1 H), 3.49-3.55 (m, 1 H), 3.51 (d, J = 11.3 Hz, 1 H), 3.63 (d, J = 11.2 Hz, 1 H), 3.76 (d, J = 10.2 Hz, 1 H), 3.87-3.92 (m, 1 H), 4.61-4.63 (m, 1 H). Step 2: 2-((l-(Iodomethyl)cyclopropyl)methoxy)tetrahydro-2H-pyran (lnt-54)

2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (6.67 g, 29.4 mmol) was dissolved in dichloromethane (200 mL) and triphenyl phosphine (7.71 g, 29.4 mmol) was added. The brown suspension was cooled to 0-5°C (ice bath) and tetra-n-butylammonium iodide (10.9 g, 29.4 mmol) was added in one portion, followed by a solution of (l-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)cyclopropyl)methanol (Int-53, 5.21 g, 28 mmol) in dichloromethane (50 mL). The reaction mixture was stirred for 15 min at 0-5°C and for 1 h at room temperature. After that, it was concentrated in vacuo and purified directly by column chromatography (silica gel, 220 g, eluting with ethyl acetate / n-heptane, gradient 2:98 to 15:85) to afford, after drying in vacuo (40°C, 5 mbar) the title compound as colorless liquid (6.0 g, 72%). ^l H NMR (CDC1 ₃ , 600 MHz): δ 0.60-0.72 (m, 4 H), 0.83-0.98 (m, 2 H), 1.48- 1.91 (m, 6 H), 3.29 (d, AB, / = 9.9 Hz, 1 H), 3.38-3.45 (m, 2 H), 3.49-3.57 (m, 1 H), 3.62 (d, AB, / = 10.5 Hz, 1 H), 3.85-3.94 (m, 1 H), 4.64-4.68 (m, 1 H).

Step 3: 2-Methyl-2-(S-methyl-N-((l-(((tetrahydro-2H-pyran-2-yl)oxy)m ethyl)cyclo- propyl)methyl)sulfonimidoyl)propanenitrile (lnt-55) Potassium hydride (30% w/w in mineral oil, 758 mg, 5.67 mmol) was suspended in tetrahydrofuran (5 mL) and the suspension cooled to 0-5 °C (ice bath). A solution of 2-methyl-2- (methylsulfonimidoyl)propanenitrile (Int-5, 829 mg, 5.67 mmol) in tetrahydrofuran (3 mL) was added dropwise over 5 min. The mixture was stirred for 15 min at 0-5 °C and for 90 min at room temperature. After that, it was cooled again to 0-5°C and tetrabutylammonium bromide (45.1 mg, 140 μιτιοΐ) followed by a solution of 2-((l-(iodomethyl)cyclopropyl)methoxy)tetrahydro-2H- pyran (Int-54, 829 mg, 2.8 mmol) in tetrahydrofuran (3 mL) were added. The reaction mixture was stirred for 14 h at room temperature, followed by 24 h at 65°C (reflux). After cooling to room temperature, the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (5% m/m, 40 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford the crude product. This was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 25:75 to 75:25) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as mixture of diastereoisomers as a yellow viscous oil (404 mg, 46%). ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.43-0.58 (m, 4 H), 1.48-1.65 (m, 4 H), 1.68- 1.91 (m, 2 H), 1.76 (s, 6 H), 3.08 (2s, 3 H, diast.), 3.10-3.54 (m, 4 H), 3.60 (dd, J = 6.0, 10.2 Hz, 1 H), 3.84-3.93 (m, 1 H), 4.61-4.66 (m, 1 H). MS (ES+) mJz 315.2 [M+H].

Synthesis of Int-57A and Int-57B: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-((l-(hydroxymethyl)cyclopropy l)methyl)propylsulfonimi- doyl)-2-methylpropanenitrile (Int-57A) and 2-((S,2R)-2-amino-2-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-N-((l-(hydroxymethyl)cyclopropy l)methyl)propylsulfon- imidoyl)-2-methylpropanenitrile (Int-57B)

lnt-57A lnt-57B

Step 1 : N-(2-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-l-(2-c yano-N-((l- (((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropyl)methyl)pr opan-2-ylsulfonimidoyl)propan- 2-yl)-2-methylpropane-2-sulfinamide (Int-56 (mix)) 2-Methyl-2-(S-methyl-N-((l-(((tetrahydro-2H-pyran-2-yl)oxy)m ethyl)cyclopropyl)- methyl)sulfonimidoyl)propanenitrile (Int-55, 2.34 g, 7.44 mmol) was dissolved in THF (40 mL) and the solution was cooled to <-70°C (acetone/dry ice bath). N-Butyl lithium (1.6 M in hexanes, 4.65 mL, 7.44 mmol) was added dropwise over 10 min, and the resulting solution was stirred for 1 h at < -70°C. Then, a solution of (R,E)-N-(l-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)ethylidene)-2-methylpropane-2-sulfinamide (Int-9, 2.7 g, 6.2 mmol) in THF (20 mL) was added over 20 min at that temperature. After 90 min stirring at < -70°C, a saturated aqueous solution of ammonium chloride (100 mL) was added and the mixture was allowed to warm to room temperature. Then, it was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give a yellow, viscous oil (6.08 g), that was used in the following step without further purification.

Step 2: 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-((l- (hydroxymethyl)cyclopropyl)methyl)propylsulfonimidoyl)-2-met hylpropanenitrile (Int-57A) and 2-((S,2R)-2-amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-((l-(hydroxymethyl)- cyclopropyl)methyl)propylsulfonimidoyl)-2-methylpropanenitri le (Int-57B)

N-(2-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-l-( 2-cyano-N-((l-(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)cyclopropyl)methyl)propan-2-ylsulfo nimidoyl)propan-2-yl)-2- methylpropane-2-sulfinamide (Int-56 (mix), 6.08 g, 6.2 mmol) was dissolved in ethanol (25 mL) and a solution of hydrogen chloride in methanol (ca. 20% w/w, 41.9 g, 45.6 mL, 676 mmol) was added at 0-5°C (ice bath). The mixture was stirred for 40 min at 0-5°C. After that, an aqueous solution of sodium carbonate (10% m/m, 300 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford a yellow oil as crude product. The crude was purified by column chromatography (silica gel, 120 g, eluting with ethyl acetate / methanol, gradient 100:0 to 90: 10) to yield, after drying in vacuo (40°C, 5 mbar), the title compound Int- 57A as single diastereomer ans as light yellow solid (1.8 g, 52% over 2 steps). The minor diastereomer Int-57B was not isolated. Int-57A: ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.30-0.50 (m, 4 H), 0.81-0.93 (m, 6 H), 0.94-1.03 (m, 9 H), 1.56 (s, 3 H), 1.67 (s, 3 H), 1.72 (s, 3 H), 2.77 (br s, 3 H), 3.01 (d, AB, J = 12.5 Hz, 1 H), 3.14 (d, AB, J = 12.3 Hz, 1 H), 3.42 (d, AB, / = 11.5 Hz, 1 H), 3.51 (d, AB, J - 11.5 Hz, 1 H), 3.77 (dd, AB, / = 1.2, 13.5 Hz, 1 H), 4.13 (d, AB, J = 13.5 Hz, 1 H), 7.36 (d, J = 2.6 Hz, 1 H). MS (ES+) m/z 563.2 & 561.2 [M+H, Br] .

Synthesis of Int-60A: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4- (triethylsilyl)pyridin-2-yl)-l-(((l-(iodomethyl)cyclopropyl) methyl)imino)-2,2,5-trimethyl-l- oxido-5,6-dihydro-2H-l,4-thiazin-3-yl)carbamate

lnt-59A lnt-60A

Step 1: (lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin -2-yl)-l-(((l- (hydroxymethyl)cyclopropyl)methyl)imino)-3,6,6-trimethyl-3,6 -dihydro-2H- 1 ,4-thiazine 1-oxide (Int-58A) 2-((R,2R)-2-Amino-2-(6-bromo-3-fluoro-4-(triethylsilyl)pyrid in-2-yl)-N-((l-(hydroxy- methyl)cyclopropyl)methyl)propylsulfonimidoyl)-2-methylpropa nenitrile (Int-57A, 1.8 g, 3.2 mmol) was dissolved in ethanol (30 mL) and copper (I) bromide (460 mg, 3.2 mmol) was added. The mixture was heated to 85°C and stirred for 90 min at that temperature. After that, it was cooled to room temperature and poured into a mixture of brine (100 mL) and aqueous ammonia (32% w/w, 40 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo to give a light yellow foam as crude product. The crude was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / 2N ammonia in methanol, gradient 98:2 to 90: 10) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white foam (1.4 g, 78%). 1H NMR (CDC1 ₃ , 300 MHz): δ 0.25-0.49 (m, 4 H), 0.81-0.92 (m, 6 H), 0.93- 1.02 (m, 9 H), 1.66 (s, 3 H), 1.72 (s, 3 H), 1.77 (s, 3 H), 2.80 (br s, 1 H), 3.02 (d, / = 11.9 Hz, 1 H), 3.18-3.51 (m, 4 H), 4.20 (d, J = 14.7 Hz, 1 H), 7.33 (d, J = 2.4 Hz, 1 H). MS (ES+) m/z 563.2 & 561.2 [M+H, Br] .

Step 2: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-(((l- (hydroxymethyl)cyclopropyl)methyl)imino)-2,2,5-trimethyl-l-o xido-5,6-dihydro-2H-l,4- thiazin-3-yl)carbamate (Int-59A)

(lR,3R)-5-Amino-3-(6-bromo-3-fluoro-4-(triethylsilyl)pyri din-2-yl)-l-(((l-(hydroxy- methyl)cyclopropyl)methyl)imino)-3,6,6-trimethyl-3,6-dihydro -2H-l,4-thiazine 1-oxide (Int- 58A, 1.4 mg, 2.49 mmol) was dissolved in THF (30 mL) and water (6 mL) and Boc-anhydride (816 mg, 3.74 mmol), sodium hydrogencarbonate (293 mg, 3.49 mmol) and 4- dimethylaminopyridine (15.2 mg, 125 μηιοΐ) were added. The mixture was stirred for 90 min at room temperature. After that, aqueous ammonia (25% w/w, 255 mg, 324 μΐ _^ , 3.74 mmol) was added and the mixture was stirred for additional 10 min. The reaction mixture was then diluted with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 24 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 50:50) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white foam (1.52 g, 92%). HPLC (method LCMS_fglm) t _R = 1.70 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.21-0.46 (m, 4 H), 0.80-0.92 (m, 6 H), 0.93- 1.03 (m, 9 H), 1.54 (s, 9 H), 1.65 (s, 3 H), 1.77 (s, 3 H), 1.85 (s, 3 H), 2.61 (d, J = 12.5 Hz, 1 H), 2.94 (dd, J = 5.7, 6.3 Hz, 1 H), 3.01 (d, = 12.5 Hz, 1 H), 3.35 (dd, J = 6.4, 11.3 Hz, 1 H), 3.54 (d, / = 15.1 Hz, 1 H), 4.45 (d, J = 15.1 Hz, 1 H), 7.38 (d, J = 2.4 Hz, 1 H). MS (ES+) m/z 663.2 & 661.2 [M+H, Br] ,

Step 3: tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-(((l- (iodomethyl)cyclopropyl)methyl)imino)-2,2,5-trimethyl-l-oxid o-5,6-dihydro-2H-l,4-thiazin-3- yl)carbamate (Int-60A)

2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (626 mg, 2.76 mmol) was dissolved in dichloromethane (25 mL) and triphenyl phosphine (723 mg, 2.76 mmol) was added. The brown suspension was cooled to 0-5°C (ice bath) and tetra-n-butylammonium iodide (1.02 g, 2.76 mmol) was added in one portion, followed by a solution of tert-butyl ((lR,5R)-5-(6-bromo-3- fluoro-4-(triethylsilyl)pyridin-2-yl)-l-(((l-(hydroxymethyl) cyclopropyl)methyl)imino)-2,2,5- trimethyl-l-oxido-5,6-dihydro-2H-l,4-thiazin-3-yl)carbamate (Int-59A, 1.52 g, 2.3 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 15 min at 0-5°C and for 1 h at room temperature. After that, it was concentrated in vacuo and purified directly by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 30:70) to afford, after drying in vacuo (40°C, 5 mbar) the title compound as colorless oil (1.36 g, 73%). HPLC (method LCMS_gradient) t _R = 4.8 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.40-0.50 (m, 2 H), 0.63-0.79 (m, 2 H), 0.81-0.92 (m, 6 H), 0.93- 1.02 (m, 9 H), 1.56 (s, 9 H), 1.63 (s, 3 H), 1.77 (s, 3 H), 1.82 (s, 3 H), 2.55 (d, J = 12.3 Hz, 1 H), 2.91 (d, J = 12.5 Hz, 1 H), 3.15 (d, AB, J = 9.7 Hz, 1 H), 3.26 (d, AB, / = 9.7 Hz, 1 H), 3.57 (d, = 15.1 Hz, 1 H), 4.41 (d, / = 14.9 Hz, 1 H), 7.38 (d, J = 2.6 Hz, 1 H), 11.15 (s, 1 H). MS (ES+) m/z 771.4 & 773.4 [M+H, Br] .

Synthesis of Int-61AA and Int-61AB: tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3- fluoro-4-(triethylsilyl)pyridin-2-yl)-5,8,8-trimethyl-9-oxid o-4,4a,5,8-tetrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3,l'-cyclopropan]-7- yl)carbamate (Int-61AA) and tert-butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8-trimethyl-9- oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]thiazino[2,l-f][l,2] thiazine-3,l'-cyclopropan]-7- yl)carbamate (Int-61AB)

lnt-60A lnt-61 AA lnt-61 AB tert-Butyl ((lR,5R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)- l-(((l- (iodomethyl)cyclopropyl)methyl)imino)-2,2,5-trimethyl-l-oxid o-5,6-dihydro-2H-l,4-tM yl)carbamate (Int-60A, 1.36 g, 1.76 mmol) was dissolved in THF (20 mL) under anhydrous conditions and the solution was cooled to <-70°C (acetone / dry ice bath). A solution of LHMDS in THF (1.0 M, 4.58 ml, 4.58 mmol) was added over 15 min and stirred for 45 min at that temperature. Then, the resulting clear, yellow solution was allowed to warm to -20°C (ice / ethanol bath) and stirred for 45 min at that temperature TLC showed complete conversion. The reaction was stopped by addition of a saturated aqeuous solution of ammonium chloride (80 mL) and, after phase separation, the aqueous phase was extracted with ethyl acetate (2 x 80 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 50:50) to yield, after drying in vacuo (40°C, 5 mbar), the title compounds Int- 61AA (first eluting, 608 mg, 54%, white waxy solid) and Int-61AB (second eluting, 408 mg, 36%, colorless viscous oil) as separated diastereoisomers.

Int-61AA: HPLC (method LCMS_gradient) t _R = 4.55 min. MS (ES+) m/z 643.3 & 645.3 [M+H, Br] .

Int-61AB: HPLC (method LCMS_gradient) t _R = 4.31 min. MS (ES+) m/z 643.4 & 645.4 [M+H, Br] . Synthesis of Int-63AA and Int-63AB: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3- fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahy dro-2H-spiro[[l,4]thiazino[2,l- f][l,2]thiazine-3,l'-cyclopropan]-7-yl)carbamate (Int-63AA) and tert-butyl ((4aS,5R,9R)-5- (6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-4,4a, 5,8-tetrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3,l'-cyclopropan]-7- yl)carbamate (Int-63AB)

lnt-62AB lnt-63AB

Step 1: tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 4,4a,5,8-tetrahydro-2H-spiro[[ 1 ,4]thiazino[2,l-f] [ 1 ,2]thiazine-3, l'-cyclopropan]-7-yl)carbamate (Int-62AA) and tert-butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-4,4a,5,8-tetrahydro-2H-spko[[l,4]thiazino[2, l-f] [l,2]thiazine-3, -cyclopropan]-7- yl)carbamate (Int-62AA)

Note: It was noticed, that during this reaction epimerisation at C4a occurs (AB to AA). Therefore, it was decided to carry on a mixture of Int-61AA and Int-61AB in step 1 and separate the diastereomers afterwards. tert-Butyl ((4aRS,5R,9R)-5-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2 -yl)-5,8,8- trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]thiazino [2,l-f] [l,2]thiazine-3, - cyclopropan]-7-yl)carbamate (Int-61AA & Int-61AB, 1016 mg, 1.58 mmol) was dissolved in THF (24 mL) and DMF (6 mL). Acetic acid (319 mg, 304 μΐ, 5.3 mmol) and potassium fluoride (304 mg, 5.23 mmol) were added at room temperature and the resulting fine suspension was stirred for 3 h at that temperature. After that, an aqueous solution of sodium hydrogencarbonate (5% m/m, 120 mL) was added and the mixture was extracted with tert-butylmethyl ether (2 x 150 mL). The combined extracts were washed with brine (2 x 100 mL), dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 40 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 90: 10) to yield, after drying in vacuo (40°C, 5 mbar), the title compounds Int-62AA (first eluting, 532 mg, 64%, white solid) and Int- 62AB (second eluting, 246 mg, 29%, white solid) as separated diastereoisomers.

Int-62AA: HPLC (method LCMS_gradient) t _R = 3.1 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.37-0.55 (m, 2 H), 0.62-0.75 (m, 2 H), 1.29- 1.40 (m, 1 H), 1.50 (s, 9 H), 1.80 (2s, 6 H), 1.89 (s, 3 H), 2.52 (d, J = 13.1 Hz, 1 H), 2.76-2.90 (m, 1 H), 4.06 (d, / = 12.7 Hz, 1 H), 4.54-4.64 (m, 1 H), 7.36-7.46 (m, 1 H), 7.47-7.55 (m, 1 H), 11.33 (s, 1 H). MS (ES+) m/z 529.3 & 531.3 [M+H, Br].

Int-62AB: HPLC (method LCMS_gradient) t _R = 2.8 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.24-0.46 (m, 3 H), 0.60-0.76 (m, 2 H), 1.59 (s, 9 H), 1.80 (s, 3 H), 1.94 (s, 3 H), 2.03 (d, J = 0.8 Hz, 3 H), 2.27-2.39 (m, 1 H), 2.79 (dd, J = 1.9, 13.4 Hz, 1 H), 3.81-3.91 (m, 2 H), 7.38 (dd, J = 8.5, 10.5 Hz, 1 H), 7.54 (dd, / = 3.2, 8.5 Hz, 1 H), 11.86 (s, 1 H). MS (ES+) mJz 529.3 & 531.3 [M+H, Br] ,

Step 2a: tert-Butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-4,4a,5,8-tetrahydro-2H-spko[[l,4]thiazino[2, l-f] [l,2]thiazine-3, -cyclopropan]-7- yl)carbamate (Int-63AA) tert-Butyl ((4aR,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 4,4a,5,8-tetrahydro-2H-spiro[[ 1 ,4]thiazino[2,l-f] [ 1 ,2]thiazine-3, l'-cyclopropan]-7-yl)carbamate (Int-62AA, 527 mg, 995 μmol) was dissolved in 1,4-dioxane (14 mL) and water (4.5 mL) and sodium azide (893 mg, 13.7 mmol) were added. Copper (I) iodide (134 mg, 705 μηιοΐ), sodium ascorbate (67 mg, 338 μιηοΐ) and trans-N,N'-dimethyl- 1 ,2-cyclohexanediamine (161 mg, 181 μΐ, 1.13 mmol) were added subsequently and the dark green mixture was stirred for 75 min at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of sodium hydrogencarbonate (5% m/m, 120 mL). It was extracted with ethyl acetate (1 x 120 mL), the combined extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give a yellow solid as crude product. The crude was purified by column chromatography (silica gel, 24 g, eluting with ethyl acetate / n-heptane, gradient 35:65 to 100:0) to afford, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (305 mg, 66%). HPLC (method LCMS_gradient) t _R = 2.5 min. ^! H NMR (CDC1 ₃ , 300 MHz): δ 0.31- 0.42 (m, 2 H), 0.44-0.50 (m, 1 H), 0.60-0.67 (m, 2 H), 1.17-1.26 (m, 1 H), 1.49 (s, 9 H), 1.79 (s, 3 H), 1.83 (s, 3 H), 1.86 (d, = 1.6 Hz, 3 H), 2.48 (dd, J = 2.1, 13.0 Hz, 1 H), 2.74-2.86 (m, 1 H), 4.03 (dd, = 1.2, 12.9 Hz, 1 H), 4.35 (br s, 2 H), 4.46 (dd, / = 3.4, 12.3 Hz, 1 H), 6.47 (dd, J = 2.5, 8.0 Hz, 1 H), 7.26 (dd, / = 8.7, 11.1 Hz, 1 H), 11.16 (s, 1 H). MS (ES+) m/z 466.3 [M+H].

Step 2b: tert-Butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]thiazino[2, l-f] [l,2]thiazine-3,r-cyclopropan]-7- yl)carbamate (Int-63AB) tert-Butyl ((4aS,5R,9R)-5-(6-bromo-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 4,4a,5,8-tetrahydro-2H-spiro[[l,4]thiazino[2,l-f] [l,2]thiazine-3,r-cyclopropan]-7-yl)carbamate (Int-62AB, 240 mg, 453 μιηοΐ) was dissolved in 1,4-dioxane (15 mL) and water (2.5 mL) and sodium azide (407 mg, 6.26 mmol) were added. Copper (I) iodide (61 mg, 321 μιηοΐ), sodium ascorbate (30 mg, 154 μιηοΐ) and trans-N,N'-dimethyl-l,2-cyclohexanediamine (74 mg, 83 μΐ, 0.52 mmol) were added subsequently and the dark green mixture was stirred for 75 min at 70°C. Then, the reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of sodium hydrogencarbonate (5% m/m, 120 mL), stirred for 5 min. A suspension was formed, which was filtered, and washed with water (4 x 10 mL). The precipitate was dissolved in tetrahydrofuran (50 mL), dried (sodium sulfate) and concentrated in vacuo give a yellow green solid as crude product. The crude was purified by column chromatography (silica gel, 24 g, eluting with dichloromethane / 2N ammonia in methanol, gradient 99: 1 to 95:5) to afford, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (123 mg, 58%). HPLC (method LCMS_gradient) t _R = 2.13 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.24-0.33 (m, 1 H), 0.35-0.44 (m, 2 H), 0.64-0.84 (m, 2 H), 1.57 (s, 9 H), 1.80 (s, 3 H), 1.93 (s, 3 H), 1.98 (m, 3 H), 2.18-2.30 (m, 1 H), 2.78 (dd, / = 1.8, 13.5 Hz, 1 H), 3.79-3.92 (m, 2 H), 7.57 (s, 2 H), 6.47 (dd, J = 2.5, 8.8 Hz, 1 H), 7.24 (dd, / = 8.7, 10.5 Hz, 1 H), 12.07 (s, 1 H). MS (ES+) m/z 466.3 [M+H].

Examples

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2^-i1[l,2]thiazin-5-yl)-5-fluoropy

(1AA)

lnt-17AA lnt-18AA 1AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate

(Int- 18AA) 5-Cyano-3-methylpicolinic acid (200 mg, 1.23 mmol) was suspended in dichloromethane

(4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (203 mg, 140 μί,, 1.6 mmol) as well as a drop of a mixture of dimethylformamide and dichloromethane (2: 1, v/v) were added. The mixture was stirred for 1.5 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with n-heptane (3 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (220 mg, 99%). After that, tert- butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8-hexa- hydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int- 17AA, 150 mg, 341 μηιοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N- diisopropylethylamine (75.5 mg, 100 μΐ, 584 μιηοΐ) was added, followed by a solution of 5- cyano-3-methylpicolinoyl chloride (vide supra, 80 mg, 443 μιηοΐ) in dichloromethane (2.5 mL). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, the mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and extracted with dichloromethane (1 x 50 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was triturated with ethyl acetate (100 mL), and filtered over a plug silica gel (10 g), that was washed with ethyl acetate (50 mL). The combined filtrate was concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a yellow solid (190 mg, 95%). HPLC (method LCMS_gradient) t _R = 3.1 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.47 (s, 9 H), 1.79 (s, 3 H), 1.82- 2.02 (m, 3 H), 1.84 (s, 3 H), 1.95 (s, 3 H), 2.34-2.46 (m, 1 H), 2.86 (s, 3 H), 3.36-3.42 (m, 1 H), 3.57-3.66 (m, 1 H), 4.04-4.10 (m, 1 H), 7.57 (dd, / = 8.9, 10.7 Hz, 1 H), 7.96-7.99 (m, 1 H), 8.41 (dd, = 3.1, 9.0 Hz, 1 H), 8.79 (d, / = 1.3 Hz, 1 H), 10.41 (br s, 1 H, exch), 11.23 (br s, 1 H, exch). MS (ES+) m/z 484.3 [M+H-C0 ₂ tBu] .

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-i^[l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methy lpicolinamide (1AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int- 18AA, 180 mg, 308 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2.66 g, 1.8 mL, 23.4 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (20 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product, which was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μιη, isocratic, (n-heptane + 0.2% triethylamine) / (ethanol + 0.1% triethylamine) 60/40, flow 1.0 mL/min) to yield the title compound as a white powder (79 mg, 53%). For transfer purpose, the material was dissolved in dichloromethane (2 mL) and MTBE (8 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.4 min. ^l U NMR (CDCL, 400 MHz): δ 1.65-1.90 (m, 3 H), 1.72 (s, 3 H), 1.82 (s, 3 H), 1.85 (s, 3 H), 2.25-2.42 (m, 1 H), 2.87 (s, 3 H), 3.36 (br d, J - 12.4 Hz, 1 H), 3.52-3.68 (m, 1 H), 3.80 (br d, J = 12.1 Hz, 1 H), 4.36 (br s, 2 H, exch), 7.47 (dd, 7 = 9.8, 9.8 Hz, 1 H), 7.97 (s, 1 H), 8.31 (dd, 7 = 2.4, 8.6 Hz, 1 H), 8.79 (s, 1 H), 10.38 (br s, 1 H, exch). MS (ES+) m/z 484.3 [M+H].

N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoro^

(1AB)

lnt-17AB lnt-18AB 1AB

Step 1 : tert-Butyl ((4aS,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazm^

(Int- 18AB)

5-Cyano-3-methylpicolinic acid (85 mg, 524 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension cooled to 0-5°C (ice bath) and l-chloro-N,N,2-trimethylpropenylamine (140 mg, 140 μΐ, 1.05 mmol) was added. After 30 min stirring at 0°C, a solution of tert-butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-17AB, 150 mg, 341 μιηοΐ) and N,N- diisopropylethylamine (148 mg, 200 μL, 1.15 mmol) in dichloromethane (3 mL) was added over 5 min at -5°C. The reaction mixture was stirred at 0-5°C for 15 min and allowed to warm to room temperature. Then, the mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and extracted with dichloromethane (1 x 50 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was triturated with ethyl acetate (100 mL), and filtered over a plug silica gel (10 g), that was washed with ethyl acetate (50 mL). The combined filtrate was concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with dichloromethane / methanol, gradient 99: 1 to 95:5) to yield, after drying in vacuo (50°C, 5 mbar), a yellow sticky solid. This material was suspended in a mixture of MTBE (3 mL) and n-heptane (2 mL), the precipitate was filtered, washed with a mixture of MTBE / n-heptane (1:3 v/v, 4 mL) and dried in vacuo (50°C, 5 mbar) to afford the title compound as an off-white solid (50 mg, 25%). HPLC (method LCMS_gradient) t _R = 3.0 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.62-1.71 (m, 2 H), 1.65 (s, 9 H), 1.74-1.84 (m, 2 H), 1.82 (s, 3 H), 1.91 (s, 3 H), 2.04 (s, 3 H), 2.88 (s, 3 H), 3.36-3.46 (m, 1 H), 3.62-3.71 (m, 2 H), 7.59 (dd, / = 9.0, 10.0 Hz, 1 H), 7.98-8.00 (m, 1 H), 8.47 (dd, / = 3.2, 8.9 Hz, 1 H), 8.71 (d, = 1.3 Hz, 1 H), 10.76 (br s, 1 H, exch), 12.40 (br s, 1 H, exch). MS (ES+) m/z 584.4 [M+H]. Step 2: N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-

[l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methy lpicolinamide (1AB) tert-Butyl ((4aS,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f [l,2]thiazin-7-yl)carbamate (Int- 18AB, 50 mg, 85.7 μπιοΐ) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (740 mg, 500 μΐ _^ , 6.49 mmol) was added. The solution was stirred for 2h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (30 mL), saturated aqueous sodium hydrogencarbonate solution (10 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (3 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product, which was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.1% triethylamine) 50/50, flow 1.0 mL/min) to yield the title compound as a white powder (16 mg, 39%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (3 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.3 min. ^J H NMR (CDC1 ₃ , 400 MHz): δ 1.65-2.06 (m, 4 H), 1.70 (s, 3 H), 1.86 (s, 3 H), 1.92 (s, 3 H), 2.87 (s, 3 H), 3.45-3.54 (m, 1 H), 3.56-3.64 (m, 1 H), 3.66-3.74 (m, 1 H), 7.55 (dd, / = 9.1, 10.0 Hz, 1 H), 7.98 (s, 1 H), 8.42 (dd, / = 3.0, 8.9 Hz, 1 H), 8.80 (s, 1 H), 10.59 (br s, 1 H, exch). MS (ES+) m/z 484.3 [M+H].

N-(6-((4aR,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoro^

(1BA)

lnt-17BA lnt-18BA 1 BA

Step 1 : tert-Butyl ((4aR,5R,9S)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate

(Int- 18BA)

5-Cyano-3-methylpicolinic acid (100 mg, 617 μηιοΐ) was suspended in dichloromethane (2 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (102 mg, 70 μL·, 0.8 mmol) as well as a drop of a mixture of dimethylformamide and dichloromethane (1 :3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with n-heptane (2 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (110 mg). After that, tert-butyl ((4aR,5R,9S)-5-(6-armno-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-17AB, 150 mg, 341 μπιοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (75.5 mg, 100 μΐ, 584 μιηοΐ) was added, followed by a solution of 5-cyano-3-methylpicolinoyl chloride (vide supra, 80 mg, 443 μιηοΐ) in dichloromethane (2.5 mL). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, the mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and extracted with dichloromethane (1 x 50 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a yellow solid (135 mg, 68% yield). HPLC (method LCMS_gradient) t _R = 3.0 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.34 (s, 3 H), 1.56 (s, 9 H), 1.79 (s, 3 H), 1.82 (s, 3 H), 1.86-1.97 (m, 2 H), 2.16-2.29 (m, 1 H), 2.53-2.62 (m, 1 H), 2.85 (s, 3 H), 3.52 (ddd, J = 5.6, 7.9, 13.6 Hz, 1 H), 3.67 (ddd, / = 4.6, 4.6, 13.4 Hz, 1 H), 3.98 (dd, / = 4.7, 10.6 Hz, 1 H), 7.48 (dd, / = 9.0, 10.6 Hz, 1 H), 7.96 (dd, / = 0.8, 1.9 Hz, 1 H), 8.36 (dd, / = 3.0, 8.9 Hz, 1 H), 8.74-8.77 (m, 1 H), 10.31 (br s, 1 H, exch), 10.78 (br s, 1 H, exch). MS (ES+) m z 584.4 [M+H] ,

Step 2: N-(6-((4aR,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methy lpicolinamide (1BA) tert-Butyl ((4aR,5R,9S)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbam (Int- 18BA, 130 mg, 223 μηιοΐ) was dissolved in dichloromethane (7 mL) and trifluoroacetic acid (1.92 g, 1.3 mL, 16.9 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (20 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (ReprosilChiral-NR, 250*4.6 mm*5 μιη, isocratic, (n-heptane / (ethanol + 0.1% ammonium acetate) 60/40, flow 1.0 mL/min) to yield the title compound as a off white powder (89 mg, 83%). For transfer purpose, the material was dissolved in dichloromethane (2 mL) and MTBE (8 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.2 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.55 (s, 3 H), 1.88-1.99 (m, 2 H), 1.99 (s, 3 H), 2.01 (s, 3 H), 2.07 (s, 3 H), 2.08-2.20 (m, 1 H), 2.61-2.70 (m, 1 H), 2.73 (s, 3 H), 3.42-3.54 (m, 2 H), 3.66-3.74 (m, 1 H), 7.51 (dd, / = 9.0, 10.1 Hz, 1 H), 7.70-7.74 (m, 1 H), 8.08 (dd, / = 3.0, 8.6 Hz, 1 H), 8.77 (d, J = 1.3 Hz, 1 H), 10.30 (br s, 1 H, exch). MS (ES+) m/z 484.3 [M+H]. N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2,l-i][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl) -5-methoxypyrazine-2- carboxamide (2AA)

Step 1: tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate

(Int-22AA)

5-Methoxypyrazine-2-carboxylic acid (100 mg, 649 μιηοΐ) was suspended in dichloromethane (2 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (218 mg, 150 μΐ, 1.71 mmol) as well as a drop of a mixture of dimethylformamide and dichloromethane (1 :3, v/v) were added. The mixture was stirred for 1.5 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (2 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-mefhoxypyrazine-2-carboxylic acid chloride as red oil (110 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3- fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hex ahydro-[l,4]thiazino[2,l- f] [l,2]thiazin-7-yl)carbamate (Int- 17AA, 100 mg, 228 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (75.5 mg, 100 μΐ, 584 μπιοΐ) was added, followed by a solution of 5- methoxypyrazine-2-carboxylic acid chloride (vide supra, 50 mg, 290 μιηοΐ) in dichloromethane (1 mL). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, ethanol (100 μΐ) was added, the mixture was stirred for 15 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a yellow solid (120 mg, 92% yield). HPLC (method LCMS_gradient) t _R = 3.0 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.79 (s, 3 H), 1.82-2.04 (m, 3 H), 1.85 (s, 3 H), 1.95 (s, 3 H), 2.40 (dddd, J = 3.8, 12.6, 12.6, 12.6 Hz, 1 H), 3.36-3.44 (m, 1 H), 3.58-3.66 (m, 1 H), 4.05-4.11 (m, 1 H), 4.09 (s, 3 H), 7.57 (dd, / = 9.0, 10.9 Hz, 1 H), 8.23 (d, J = 1.3 Hz, 1 H), 8.44 (dd, J = 3.0, 8.9 Hz, 1 H), 9.04 (d, / = 1.3 Hz, 1 H), 9.94 (br s, 1 H), 11.24 (br s, 1 H, exch). MS (ES+) m/z 576.4 [M+H] .

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazi ne-2-carboxamide

(2AA) tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2- yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thia zino[2, l-f][l,2]thiazin-7- yl)carbamate (Int-22AA, 120 mg, 208 μηιοΐ) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1.78 g, 1.2 mL, 15.6 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.1% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the title compound as a white powder (48 mg, 48%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (4 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.4 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.72-1.94 (m, 3 H), 1.84 (s, 3 H), 1.92 (2s, 6 H), 2.27-2.41 (m, 1 H), 3.33-3.41 (m, 1 H), 3.53-3.63 (m, 1 H), 3.80 (dd, J = 3.2, 12.6 Hz, 1 H), 4.09 (s, 3 H), 7.53 (dd, J = 8.9, 10.9 Hz, 1 H), 8.22 (d, J = 1.1 Hz, 1 H), 8.41 (dd, J = 3.0, 8.9 Hz, 1 H), 9.03 (d, J = 1.1 Hz, 1 H), 9.96 (br s, 1 H). MS (ES+) m/z 476.3 [M+H] . N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2 -i][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazin e-2- carboxamide (2AB)

lnt-17AB lnt-22AB 2AB

Step 1: tert-Butyl ((4aS,5R,9R)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro

(Int-22AB)

5-Methoxypyrazine-2-carboxylic acid (200 mg, 1.3 mmol) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (435 mg, 300 μΐ, 3.43 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (2 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-methoxypyrazine-2-carboxylic acid chloride as red oil (229 mg). After that, tert-butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f][l,2]thiazi n-7-yl)carbamate (Int-17AB, 70 mg, 159 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (53 mg, 70 μΐ, 409 μπιοΐ) was added, followed by a solution of 5- methoxypyrazine-2-carboxylic acid chloride (vide supra, 100 mg, 579 μιηοΐ) in dichloromethane (1.3 mL). The reaction mixture was stirred at room temperature for 4 h. Then, ethanol (200 μΐ) was added, the mixture was stirred for 30 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a white solid (90 mg, 98% yield). HPLC (method LCMS_gradient) t _R = 2.9 min. ^X H NMR (CDCI3, 400 MHz): δ 1.62-1.88 (m, 4 H), 1.66 (s, 9 H), 1.82 (s, 3 H), 1.91 (s, 3 H), 2.04 (s, 3 H), 3.36-3.45 (m, 1 H), 3.62-3.71 (m, 2 H), 4.09 (s, 3 H), 7.59 (dd, / = 9.0, 10.1 Hz, 1 H), 8.14 (d, J = 1.3 Hz, 1 H), 8.48 (dd, = 3.0, 8.9 Hz, 1 H), 9.06 (d, J = 1.3 Hz, 1 H), 10.36 (br s, 1 H), 12.49 (br s, 1 H). MS (ES+) m/z 576.3 [M+H]. Step 2: N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazi ne-2-carboxamide (2AB) tert-Butyl ((4aS,5R,9R)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbam

(Int-22AB, 85 mg, 148 μηιοΐ) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (740 mg, 500 μί, 6.5 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak IE, 250*4.6 mm*5 μηι, isocratic, (isopropanol + 0.1% triethylamine) / dichloromethane 90/10, flow 0.7 mL/min) to yield the title compound as a white powder (29 mg, 41%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (4 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.3 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.64-2.01 (m, 4 H), 1.71 (s, 3 H), 1.86 (s, 3 H), 1.93 (s, 3 H), 3.41-3.53 (m, 1 H), 3.54-3.63 (m, 1 H), 3.64-3.74 (m, 1 H), 4.09 (s, 3 H), 7.55 (dd, / = 9.4, 9.9 Hz, 1 H), 8.23 (s, 1 H), 8.44 (dd, J = 3.0, 8.9 Hz, 1 H), 9.03 (s, 1 H), 10.19 (br s, 1 H). MS (ES+) m/z 476.2 [M+H].

N-(6-((4aR,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl) -5-methoxypyrazine-2- carboxamide (2BA)

lnt-17BA lnt-22BA

Step 1: tert-Butyl ((4aR,5R,9S)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate

(Int-22BA) tert-Butyl ((4aR,5R,9S)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int- 17BA, 70 mg, 159 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (53 mg, 70 μΐ, 409 μιτιοΐ) was added, followed by a solution of 5- methoxypyrazine-2-carboxylic acid chloride (for preparation see example 2AB, 40 mg, 232 μιηοΐ) in dichloromethane (1.3 mL). The reaction mixture was stirred at room temperature for 3 h. Then, ethanol (200 μΐ) was added, the mixture was stirred for 30 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 80:20 to 100:0) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a yellow foam (80 mg, 87% yield). HPLC (method LCMS_gradient) t _R = 2.9 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.34 (s, 3 H), 1.57 (s, 9 H), 1.79 (s, 3 H), 1.82 (s, 3 H), 1.86- 1.95 (m, 2 H), 2.18-2.30 (m, 1 H), 2.53-2.62 (m, 1 H), 3.51 (ddd, / = 5.4, 8.1, 13.4 Hz, 1 H), 3.66 (ddd, J = 4.6, 4.6, 13.2 Hz, 1 H), 3.97 (dd, J = 4.7, 10.3 Hz, 1 H), 4.08 (s, 3 H), 7.48 (dd, / = 8.9, 10.5 Hz, 1 H), 8.18 (d, / = 1.3 Hz, 1 H), 8.39 (dd, / = 3.1, 9.0 Hz, 1 H), 9.02 (d, J = 1.3 Hz, 1 H), 9.86 (br s, 1 H), 10.80 (br s, 1 H). MS (ES+) mJz 576.3 [M+H].

Step 2: N-(6-((4aR,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazi ne-2-carboxamide (2BA) tert-Butyl ((4aR,5R,9S)-5-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int-22BA, 80 mg, 139 μιηοΐ) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (740 mg, 500 μΐ _^ , 6.5 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Reprosil Chiral NR, 250*4.6 mm*8 μιη, isocratic, n-heptane / (ethanol + 0.1% triethylamine) 50/50, flow 1.0 niL/min) to yield the title compound as a white powder (30 mg, 45%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (5 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.2 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.39 (s, 3 H), 1.74 (s, 3 H), 1.79 (s, 3 H), 1.81-1.98 (m, 2 H), 2.06-2.18 (m, 1 H), 2.49-2.59 (m, 1 H), 3.48 (ddd, J = 4.6, 9.1, 13.5 Hz, 1 H), 3.67 (ddd, J = 4.7, 4.7, 13.4 Hz, 1 H), 3.90 (dd, J = 4.7, 10.3 Hz, 1 H), 4.07 (s, 3 H), 7.45 (dd, / = 8.9, 10.8 Hz, 1 H), 8.19 (d, J = 1.3 Hz, 1 H), 8.32 (dd, J = 3.0, 8.9 Hz, 1 H), 9.01 (d, / = 1.1 Hz, 1 H), 9.94 (br s, 1 H). MS (ES+) m/z 476.3 [M+H] ,

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyri (3AA)

lnt-17AA lnt-23AA 3AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3,5-dichloropicolinamido)-3-fluoropyridin -2-yl)-5,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 23AA) 3,5-Dichloropicolinic acid (200 mg, 1.04 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (363 mg, 250 μΐ, 2.86 mmol,) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1.5 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 3,5-dichloropicolinoyl chloride as yellow solid (110 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-7-yl)carbamate (Int-17AA, 100 mg, 228 μπιοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N- diisopropylethylamine (75.5 mg, 100 μΐ, 584 μιηοΐ) was added, followed by a solution of 3,5- dichloropicolinoyl chloride (vide supra, 60 mg, 285 μιηοΐ) in dichloromethane (1.2 mL).The reaction mixture was stirred at 0-5°C for 1.5 h. Then, ethanol (100 μΐ) was added, the mixture was stirred for 45 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a light yellow foam (140 mg, 99% yield). HPLC (method LCMS_gradient) t _R = 3.2 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.79 (s, 3 H), 1.81-2.02 (m, 3 H), 1.85 (s, 3 H), 1.95 (s, 3 H), 2.40 (dddd, J = 3.8, 12.6, 12.6, 12.6 Hz, 1 H), 3.36-3.43 (m, 1 H), 3.58-3.66 (m, 1 H), 4.08 (dd, J = 3.2, 12.4 Hz, 1 H), 7.57 (dd, .7 = 8.9, 10.7 Hz, 1 H), 7.95 (d, 7 = 2.1 Hz, 1 H), 8.44 (dd, / = 3.1, 9.0 Hz, 1 H), 8.57 (d, J = 1.9 Hz, 1 H), 10.16 (br s, 1 H, exch), 11.23 (br s, 1 H, exch). MS (ES+) m/z 613.3, 615.3 & 617.3 [M+H, 2 CI] .

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropic olinamide (3AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3,5-dichloropicolinamido)-3-fluoropyridin -2-yl)-5,8,8-tri- methyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f][l ,2]thiazin-7-yl)carbamate (Int- 23AA, 140 mg, 228 μπιοΐ) was dissolved in dichloromethane (6 mL)and trifluoroacetic acid (1.78 g, 1.2 mL, 15.6 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.1% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the title compound as a white powder (61 mg, 52%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (4 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.6 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.73-1.88 (m, 3 H), 1.81 (s, 3 H), 1.89 (s, 3 H), 1.90 (s, 3 H), 2.27-2.42 (m, 1 H), 3.37 (b d, J = 12.6 Hz, 1 H), 3.52-3.65 (m, 1 H), 3.79 (dd, / = 3.1, 12.6 Hz, 1 H), 7.51 (dd, / = 8.9, 10.7 Hz, 1 H), 7.93 (d, / = 1.9 Hz, 1 H), 8.39 (dd, J = 3.0, 8.7 Hz, 1 H), 8.56 (d, J = 1.9 Hz, 1 H), 10.17 (br s, 1 H). MS (ES+) m/z 513.2, 515.3 & 517.3 [M+H, 2 CI]. N-(6-((4aS,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyri^

(IBB)

lnt-24BB lnt-25BB 1 BB

Step 1 : tert-Butyl ((4aS,5R,9S)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoro-4- (triethyl- silyl)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hex ahydro-[l,4]thiazino[2,l- f] [ 1 ,2]fhiazin-7-yl)carbamate (Int-25BB)

5-Cyano-3-methylpicolinic acid (100 mg, 617 μηιοΐ) was suspended in dichloromethane (2 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (145 mg, 100 μΕ, 1.14 mmol) as well as a drop of a mixture of dimethylformamide and dichloromethane (1 :3, v/v) were added. The mixture was stirred for 1.5 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with n-heptane (2 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (110 mg). After that,tert-butyl ((4aS,5R,9S)-5-(6-amino-3-fluoro-4-(triethylsilyl)pyridin-2- yl)-5,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-24BB, 40 mg, 72 μιηοΐ) was dissolved in dichloromethane (3 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (37.7 mg, 50 μΐ, 292 μιηοΐ) was added, followed by a solution of 5- cyano-3-methylpicolinoyl chloride (vide supra, 21.3 mg, 118 μιηοΐ) in dichloromethane (2.5 mL). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, ethanol (50 μΐ) was added, the mixture was stirred for 15 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude (66 mg) was used in the next step without further purification. HPLC (method 7626L05) tR = 9.7 min. Step 2: N-(6-((4aS,5R,9S)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-

[l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methy lpicolinamide (IBB) tert-Butyl ((4aS,5R,9S)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoro-4- (triethylsilyl)- pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-25BB, 66 mg, 72 μιηοΐ) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (740 mg, 0.5 mL, 6.5 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (10 mL), and saturated aqueous sodium hydrogencarbonate solution (5 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 5 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue (70 mg) was dissolved in THF (2 mL) and DMF (0.5 mL). Acetic acid (21 mg, 20 μΐ, 349 μηιοΐ) and potassium fluoride (20 mg, 344 μιηοΐ) were added at room temperature and the resulting mixture was stirred for 2 h at that temperature, followed by 18 h at 60°C. Then, it was cooled to room temperature and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.0 M, 150 μΐ, 150 μηιοΐ) was added and the mixture was stirred for 4 h at 50°C. After that, it was poured upon a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted with MTBE (1 x 20 mL, 1 x 10 mL). The combined extracts were washed with brine (10 mL), dried (sodium sulfate) and concentrated in vacuo to give a brown viscous oil as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.1% ammonium acetate) 70/30, flow 1.0 mL/min) to yield the title compound as a off white powder (15 mg, 43% overall yield). For transfer purpose, the material was dissolved in dichloromethane (2 mL) and MTBE (8 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.4 min. ^X H NMR (CDC1 ₃ , 400 MHz, major rotamer): δ 1.81- 1.96 (m, 2 H), 1.92 (s, 3 H), 2.00 (s, 3 H), 2.01 (s, 3 H), 2.08-2.21 (m, 1 H), 2.55-2.64 (m, 1 H), 2.88 (s, 3 H), 3.27-3.37 (m, 2 H), 3.49 (dd, / = 3.4, 12.8 Hz, 1 H), 7.50 (dd, J = 9.1, 11.0 Hz, 1 H), 7.96 (d, = 1.1 Hz, 1 H), 8.34 (dd, / = 2.8, 9.0 Hz, 1 H), 8.80 (d, / = 1.3 Hz, 1 H), 10.31 (br s, 1 H, exch). MS (ES+) m/z 484.3 [M+H] ,

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropy

(4AA)

lnt-17AA lnt-26AA 4AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-fluoro-3-methylpicolinam

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazm^

(Int-26AA)

5-Fluoro-3-methylpicolinic acid (200 mg, 1.29 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (435 mg, 300 μΐ, 3.43 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-fluoro-3-methylpicolinoyl chloride as dark brown oil (220 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l- 9-oxido-2,3 ,4,4a,5 ,8-hexahydro- [ 1 ,4] thiazino [2, 1 -f] [ 1 ,2] thiazin-7-yl)carbamate (Int- 17 A A, 100 mg, 228 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (75.5 mg, 100 μΐ, 584 μιηοΐ) was added, followed by a solution of 5-fluoro-3-methylpicolinoyl chloride (vide supra, 50 mg, 288 μιηοΐ) in dichloromethane (1 mL). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, ethanol (100 μΐ) was added, the mixture was stirred for 45 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as a white foam (115 mg, 88% yield). HPLC (method LCMS_gradient) t _R = 3.2 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.79 (s, 3 H), 1.80-2.01 (m, 3 H), 1.85 (s, 3 H), 1.96 (d, J = 1.2 Hz, 3 H), 2.31-2.48 (m, 1 H), 2.83 (s, 3 H), 3.35-3.45 (m, 1 H), 3.56-3.68 (m, 1 H), 4.07-4.14 (m, 1 H), 7.40 (ddd, J = 0.6, 2.7, 8.8 Hz, 1 H), 7.55 (dd, J = 8.9, 10.9 Hz, 1 H), 8.38 (d, J = 2.6 Hz, 1 H), 8.41 (dd, / = 3.0, 8.9 Hz, 1 H), 10.41 (br s, 1 H), 11.23 (br s, 1 H, exch). MS (ES+) m/z 577.3 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-meth ylpicolinamide (4AA) tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-fluoro-3-methylpicolinamido)py ridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-26AA, 110 mg, 191 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.48 g, 1.0 mL, 13.0 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.1% triethyl- amine) 75/25, flow 1.0 mL/min) to yield the title compound as a white powder (39 mg, 43%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (4 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.5 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.71-1.90 (m, 3 H), 1.75 (s, 3 H), 1.85 (s, 3 H), 1.87 (s, 3 H), 2.26-2.41 (m, 1 H), 2.83 (s, 3 H), 3.32-3.40 (m, 1 H), 3.55-3.64 (m, 1 H), 3.81 (dd, / = 3.4, 12.8 Hz, 1 H), 7.39 (dd, J = 2.4, 8.9 Hz, 1 H), 7.46 (dd, J = 8.9, 11.0 Hz, 1 H), 8.33 (dd, / = 3.0, 8.9 Hz, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 10.38 (br s, 1 H). MS (ES+) m/z 477.3 [M+H] , N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyri

a]pyridine-2-carboxamide (6AA)

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(6-chloro-3-methylimidazo[l,2-a]pyridine-2 -carboxamido)- 3-fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-h exahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-7-yl)carbamate (Int-27AA)

6-Chloro-3-methylimidazo[l,2-a]pyridine-2-carboxylic acid (300 mg, 1.42 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (435 mg, 300 μΐ, 3.43 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-fluoro-3-methylpicolinoyl chloride as brown solid (360 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int- 17AA, 100 mg, 228 μπιοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (113 mg, 150 μΐ, 876 μιηοΐ) was added, followed by a solution of 6-chloro-3-methylimidazo[l,2-a]pyridine-2-carbonyl chloride (vide supra, 80 mg, 349 μιηοΐ) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1.5 h. Then, ethanol (200 μΐ) was added, the mixture was stirred for 30 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, 80:20, v/v) to afford, after drying in vacuo (50°C, 5 mbar), the title compound as white solid (130 mg, 90% yield). HPLC (method LCMS_gradient) t _R = 3.4 min. ¾ NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.75-2.01 (m, 3 H), 1.79 (s, 3 H), 1.85 (s, 3 H), 1.96 (2s, 3 H, rotamers), 2.31-2.48 (m, 1 H), 2.88 (s, 3 H), 3.36-3.45 (m, 1 H), 3.57-3.69 (m, 1 H), 4.06-4.14 (m, 1 H), 7.28 (dd, / = 1.8, 9.7 Hz, 1 H), 7.54 (dd, J = 8.9, 10.9 Hz, 1 H), 7.61 (dd, J = 0.9, 9.6 Hz, 1 H), 7.99-8.02 (m, 1 H), 8.43 (dd, 7 = 3.0, 8.9 Hz, 1 H), 9.81 (br s, 1 H), 11.23 (br s, 1 H, exch). MS (ES+) m/z 632.3 [M+H] .

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-6-chloro-3-meth ylimidazo[l,2- a]pyridine-2-carboxamide (6AA) tert-Butyl ((4aR,5R,9R)-5-(6-(6-chloro-3-methylimidazo[ 1 ,2-a]pyridine-2- carboxamido)-3-fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-2 ,3,4,4a,5,8-hexahydro-

[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-27AA, 130 mg, 206 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.48 g, 1.0 mL, 13.0 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.1% triethylamine) 50/50, flow 1.0 mL/min) to yield the title compound as a white powder (61 mg, 56%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (5 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.64-1.89 (m, 3 H), 1.73 (s, 3 H), 1.83 (s, 3 H), 1.86 (s, 3 H), 2.26-2.40 (m, 1 H), 2.88 (s, 3 H), 3.31-3.40 (m, 1 H), 3.55-3.66 (m, 1 H), 3.81 (dd, / = 3.1, 12.7 Hz, 1 H), 7.27 (dd, J = 1.9, 9.7 Hz, 1 H), 7.45 (dd, / = 8.9, 11.0 Hz, 1 H), 7.60 (d, = 9.7 Hz, 1 H), 7.99-8.02 (m, 1 H), 8.33 (dd, = 3.0, 8.9 Hz, 1 H), 9.79 (br s, 1 H). MS (ES+) m/z 532.3 [M+H] .

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2^-f1[l,2]thiazin-5-yl)-5-fluoropyri

(7AA)

lnt-17AA lnt-28AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbam

(Int-28AA) 5-(Difluoromethoxy)picolinic acid (300 mg, 1.59 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (508 mg, 350 μΐ, 4.0 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-(difluoromethoxy)picolinoyl chloride as dark green oil (330 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9- oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2,l-f][l,2]thiazi n-7-yl)carbamate (Int- 17AA, 100 mg, 228 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (75.5 mg, 100 μΐ, 584 μιηοΐ) was added, followed by a solution of 5- (difluoromethoxy)picolinoyl chloride (vide supra, 65 mg, 313 μιηοΐ) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1.5 h. Then, ethanol (200 μΐ) was added, the mixture was stirred for 30 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n- heptane, gradient 60:40 to 80:20, v/v) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as white solid (135 mg, 97% yield). HPLC (method LCMS_gradient) t _R = 3.1 min. 'H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.79 (s, 3 H), 1.81-2.04 (m, 3 H), 1.85 (s, 3 H), 1.96 (br s, 3 H), 2.34-2.47 (m, 1 H), 3.37-3.44 (m, 1 H), 3.58-3.67 (m, 1 H), 4.10 (dd, J = 3.5, 12.4 Hz, 1 H), 6.67 (t, = 71.7 Hz, 1 H), 7.58 (dd, / = 9.0, 10.9 Hz, 1 H), 7.70 (dd, = 2.7, 8.6 Hz, 1 H), 8.34 (d, J = 8.9 Hz, 1 H), 8.45 (dd, J = 3.0, 8.9 Hz, 1 H), 8.55 (d, / = 2.4 Hz, 1 H), 10.26 (s, 1 H), 11.25 (br s, 1 H, exch). MS (ES+) m/z 611.3 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluorometh oxy)picolinamide (7AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]miazino[ 2,l-f [l,2]thiazin-7-yl)carbamate (Int-28AA, 130 mg, 213 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifhioroacetic acid (1.48 g, 1.0 mL, 13.0 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25 °C, 5 mbar). The residue, a colorless viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.1% triethyl- amine) 70/30, flow 1.0 mL/min) to yield the title compound as a white powder (73 mg, 67%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (5 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.5 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.67-1.87 (m, 3 H), 1.73 (s, 3 H), 1.84 (s, 3 H), 1.86 (s, 3 H), 2.27-2.41 (m, 1 H), 3.32-3.40 (m, 1 H), 3.55-3.65 (m, 1 H), 3.81 (dd, / = 3.2, 12.6 Hz, 1 H), 6.66 (t, J = 11.1 Hz, 1 H), 7.48 (dd, / = 8.9, 11.0 Hz, 1 H), 7.69 (dd, J = 2.7, 8.6 Hz, 1 H), 8.31-8.38 (m, 2 H), 8.54 (d, .7 = 2.4 Hz, 1 H), 10.24 (s, 1 H). MS (ES+) m/z 511.3 [M+H],

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4 a,5,8-hexahydro- [l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl) -5-(2,2,3,3- tetrafluoropropoxy)picolinamide (8AA)

lnt-17AA lnt-29AA 8AA

Step 1: tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-(2,2,3,3-tetrafluoropropoxy)pi colinamido)- pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2,l-f][l,2]thiazin-7- yl)carbamate (Int-29AA)

5-(2,2,3,3-Tetrafluoropropoxy)picolinic acid (200 mg, 790 μιτιοΐ) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (290 mg, 200 μΐ, 2.28 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo at 40°C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-(2,2,3,3-tetrafluoropropoxy)picolinoyl chloride as yellow, turbid oil (210 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2- yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thia zino[2,l-f][l,2]thiazin-7- yl)carbamate (Int-17AA, 70 mg, 159 μιηοΐ) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (52.9 mg, 70 μΐ, 409 μπιοΐ) was added, followed by a solution of 5-(2,2,3,3-tetrafluoropropoxy)picolinoyl chloride (vide supra, 60 mg, 221 μηιοΐ) in dichloromethane (1.3 mL). The reaction mixture was stirred at room temperature for 1.5 h. Then, ethanol (200 μΐ) was added, the mixture was stirred for 30 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20, v/v) to yield, after drying in vacuo (55°C, 5 mbar), the title compound as white solid (100 mg, 93% yield). HPLC (method LCMS_gradient) t _R = 3.3 min. 1H NMR (CDC1 ₃ , 400 MHz): δ 1.48 (s, 9 H), 1.79 (s, 3 H), 1.80-2.06 (m, 3 H), 1.85 (s, 3 H), 1.96 (br s, 3 H), 2.41 (dddd, / = 3.2, 12.1, 12.6, 12.9 Hz, 1 H), 3.37-3.44 (m, 1 H), 3.63 (ddd, / = 3.8, 12.1, 12.9 Hz, 1 H), 4.10 (dd, J = 3.5, 12.4 Hz, 1 H), 4.52 (br t, / = 11.8 Hz, 2 H), 6.07 (tt, / = 4.0, 53.0 Hz, 1 H), 7.44 (dd, J = 2.8, 8.7 Hz, 1 H), 7.57 (dd, / - 8.9, 10.8 Hz, 1 H), 8.30 (dd, J = 0.5, 8.6 Hz, 1 H), 8.41 (d, / = 2.4 Hz, 1 H), 8.45 (dd, J = 3.1, 9.0 Hz, 1 H), 10.23 (s, 1 H), 11.24 (br s, 1 H). MS (ES+) mJz 675.4 [M+H]. Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-

[l,4]thiazino[2, l-f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetr afluoropropoxy)pico- linamide (8AA) tert-Butyl ((4aR,5R,9R)-5-(3-fluoro-6-(5-(2,2,3,3- tetrafluoropropoxy)picolinamido)pyridin-2-yl)-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (M-29AA, 100 mg, 148 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.48 g, 1.0 mL, 13.0 mmol) was added. The solution was stirred for 1 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a colorless viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (40°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD-H, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.1% tnethylamine) 70/30, flow 1.0 mL/min) to yield the title compound as a white powder (62 mg, 73%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and MTBE (5 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.8 min. ^l H NMR (CDC1 ₃ , 400 MHz): δ 1.71-1.95 (m, 3 H), 1.74 (s, 3 H), 1.85 (s, 3 H), 1.87 (s, 3 H), 2.28-2.42 (m, 1 H), 3.32-3.41 (m, 1 H), 3.54- 3.66 (m, 1 H), 3.78-3.86 (m, 1 H), 4.51 (t, / = 11.8 Hz, 2 H), 6.07 (tt, / = 4.0, 53.0 Hz, 1 H), 7.42 (dd, J = 2.7, 8.6 Hz, 1 H), 7.47 (dd, / = 9.1, 11.0 Hz, 1 H), 8.29 (d, = 8.6 Hz, 1 H), 8.35 (dd, J = 3.0, 8.9 Hz, 1 H), 8.40 (d, J = 2.7 Hz, 1 H), 10.21 (s, 1 H). MS (ES+) m/z 575.2 [M+H]. N-(6-((3aS,4R,8R)-6-Aniino-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -cyano-3-methylpicolinamide

(9AB)

lnt-39AB lnt-64AB 9AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-64AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 100.0 mg, 0.24 mmol) in THF (5.0 mL) was added 5-cyano-3-methylpicolinic acid (76.2 mg, 0.48 mmol), followed by T3P (763.2 mg, 1.2 mmol, 50% in ethyl acetate), and diisopropylethylamine (182.8 mg, 1.44 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 2: 1) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 75% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.50-1.65 (m, 1 H), 1.67 (s, 9 H), 1.87 (s, 3 H), 1.99 (s, 3 H), 2.06-2.20 (m, 1 H), 2.16 (s, 3 H), 2.89 (s, 3 H), 3.56 (dd, / = 7.5, 10.5 Hz, 1 H), 3.71 (ddd, J = 4.9, 10.5, 10.5 Hz, 1 H), 4.26-4.35 (m, 1 H), 7.62 (dd, J = 8.8, 10.3 Hz, 1 H), 8.00 (s, 1 H), 8.51 (dd, J = 3.0, 8.8 Hz, 1 H), 8.72 (s, 1 H), 10.78 (s, 1 H), 12.53 (s, 1 H). MS (ES+) m/z 570.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -cyano-3-methylpicolinamide (9AB) tert-Butyl ((3aS,4R,8R)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate

(Int-64AB, 100 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1.48 g, 1.0 mL, 13.0 mmol) was added. The solution was stirred for 4 h at room temperature. The reaction mixture was basified with saturated aqueous sodium hydrogencarbonate solution to pH=7~8, extracted with dichloromethane (2 x 10 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) twice to give a product. The product was diluted with water (20.0 mL) and acetonitrile (10 mL), the solution was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give the title compound as a white solid (38 mg, 46% yield). H NMR (CDCI ₃ , 400 MHz): δ 1.62-1.75 (m, 1 H), 1.87 (s, 3 H), 1.97 (s, 3 H), 2.06-2.17 (m, 1 H), 2.10 (s, 3 H), 2.84 (s, 3 H), 3.54 (dd, / = 7.8, 10.5 Hz, 1 H), 3.72 (ddd, J = 5.3, 10.5, 10.5 Hz, 1 H), 4.24-4.33 (m, 1 H), 7.61 (dd, J = 9.0, 10.3 Hz, 1 H), 7.96 (s, 1 H), 8.48 (dd, J = 3.3, 9.0 Hz, 1 H), 8.79 (s, 1 H), 10.86 (s, 1 H). MS (ES+) m/z 470.2 [M+H].

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -cyano-3-methylpicolinamide (9BA)

IM-39BA lnt-64BA 9BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-64BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150.0 mg, 0.35 mmol) in THF (20 mL) was added 5-cyano-3-methylpicolinic acid (85.9 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (266.7 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 2: 1) to yield, after drying in vacuo, the title compound as a yellow solid (120 mg, 60% yield). ^X H NMR (CDCI ₃ , 400 MHz): δ 0.85 (s, 3 H), 1.50-1.57 (m, 9 H), 1.68- 1.75 (m, 6 H), 2.08-2.21 (m, 1 H), 2.50-2.63 (m, 1 H), 2.80-2.89 (m, 3 H), 3.73-3.89 (m, 2 H), 5.19 (dd, = 7.1, 11.1 Hz, 1 H), 7.55 (dd, J = 9.1, 10.2 Hz, 1 H), 7.91-8.00 (m, 1 H), 8.37-8.49 (m, 1 H), 8.78 (d, / = 1.4 Hz, 1 H), 10.48 (s, 1 H), 11.03 (br s, 1 H). MS (ES+) m/z 570.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothiazolo- [l,5-a] [l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpic olinamide (9BA)

tert-Butyl ((3aR,4R,8S)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate

(Int-64BA, 120 mg, 0.21 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (6 mL). Zinc dibromide (142 mg, 0.63 mmol) was added and the solution was stirred for 18 h at 35°C. After that, the reaction mixture was diluted with saturated aqueous sodium hydrogen- carbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (55 mg, 57% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.99 (s, 3 H), 1.85 (2s, 6 H), 2.15-2.32 (m, 1 H), 2.60-2.71 (m, 1 H), 2.86 (s, 3 H), 3.73-3.88 (m, 2 H), 5.14-5.23 (m, 1 H), 7.62 (dd, / = 9.4, 9.4 Hz, 1 H), 7.97 (s, 1 H), 8.48 (dd, / = 3.0, 9.0 Hz, 1 H), 8.82 (d, J = 1.5 Hz, 1 H), 10.53 (s, 1 H). MS (ES+) m/z 470.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoro-3-methylpicolinamide (10AB)

lnt-39AB lnt-66AB 10AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-fluoro-3-methylpicolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-66AB) To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-fluoro-3-methylpicolinic acid (82 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (130 mg, 66% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.50-1.59 (m, 1 H), 1.66 (s, 9 H), 1.86 (s, 3 H), 1.97 (s, 3 H), 2.06-2.12 (m, 1 H), 2.14 (s, 3 H), 2.84 (s, 3 H), 3.54 (dd, J = 7.7, 10.7 Hz, 1 H), 3.69 (ddd, J = 4.8, 10.7, 10.7 Hz, 1 H), 4.30 (ddd, / = 2.1, 7.1, 12.0 Hz, 1 H), 7.40 (dd, J = 2.1, 8.9 Hz, 1 H), 7.58 (dd, = 9.1, 10.0 Hz, 1 H), 8.31 (d, J = 2.6 Hz, 1 H), 8.49 (dd, / = 3.1, 8.9 Hz, 1 H), 10.78 (s, 1 H), 12.54 (s, 1 H). MS (ES+) m/z 563.2 [M+H]. Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoro-3-methylpicolinamide (10AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-fluoro-3-methylpicolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-66AB, 130 mg, 0.23 mmol) was dissolved in acetonitrile (20 mL) and zinc dibromide (155 mg, 0.69 mmol) was added. Then, dichloromethane (5 mL) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (37 mg, 34% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.65- 1.79 (m, 1 H), 1.80 (s, 3 H), 1.93 (s, 3 H), 2.05-2.12 (m, 1 H), 2.06 (s, 3 H), 2.82 (s, 3 H), 3.52 (dd, J = 7.6, 10.5 Hz, 1 H), 3.71 (ddd, J = 5.2, 10.5, 10.5 Hz, 1 H), 4.25 (ddd, J = 2.0, 7.0, 12.3 Hz, 1 H), 7.40 (dd, = 2.3, 8.8 Hz, 1 H), 7.56 (dd, / = 9.0, 10.3 Hz, 1 H), 8.38 (d, / = 2.8 Hz, 1 H), 8.45 (dd, J = 3.1, 8.9 Hz, 1 H), 10.62 (s, 1 H). MS (ES+) mJz 463.2 [M+H].

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoro-3-methylpicolinamide (10BA)

lnt-39BA lnt-66BA 10BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-fluoro-3-methylpicolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-66BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-fluoro-3-methylpicolinic acid (82 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (130 mg, 66% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.81-0.91 (m, 3 H), 1.49-1.59 (m, 9 H), 1.67- 1.76 (m, 6 H), 2.08-2.22 (m, 1 H), 2.52-2.64 (m, 1 H), 2.76-2.87 (m, 3 H), 3.71-3.87 (m, 2 H), 5.21 (dd, / = 7.1, 11.0 Hz, 1 H), 7.37 (dd, / = 2.3, 8.8 Hz, 1 H), 7.48-7.57 (m, 1 H), 8.37 (d, / = 2.5 Hz, 1 H), 8.44 (dd, / = 3.0, 8.9 Hz, 1 H), 10.46 (s, 1 H), 11.00 (br s, 1 H). MS (ES+) mJz 563.2 [M+H] . Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoro-3-methylpicolinam (10BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-fluoro-3-methylpicolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-66BA, 130 mg, 0.23 mmol) was dissolved in acetonitrile (20 mL) and zinc dibromide (155 mg, 0.69 mmol) was added. Then, dichloromethane (5 mL) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (50 mg, 47% yield). ^X H NMR (d4-MeOH, 400 MHz): δ 0.98 (s, 3 H), 1.77 (s, 3 H), 1.82 (s, 3 H), 2.16-2.28 (m, 1 H), 2.72-2.81 (m, 1 H), 2.77 (s, 3 H), 3.65-3.72 (m, 1 H), 3.78 (ddd, 7 = 4.8, 10.5, 10.5 Hz, 1 H), 5.37 (dd, 7 = 7.1, 11.4 Hz, 1 H), 7.65 (dd, 7 = 2.3, 9.5 Hz, 1 H), 7.83 (dd, 7 = 9.0, 10.8 Hz, 1 H), 8.43 (d, 7 = 2.3 Hz, 1 H), 8.48 (dd, 7 = 3.3, 9.0 Hz, 1 H). MS (ES+) mJz 463.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-fluoropicolinamide (11AB)

lnt-39AB lnt-67AB 11 AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-67AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 3-chloro-5-fluoropicolinic acid (92.8 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 60 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (120 mg, 58% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.53-1.59 (m, 1 H), 1.64 (s, 9 H), 1.86 (s, 3 H), 1.97 (s, 3 H), 2.06-2.12 (m, 1 H), 2.14 (s, 3 H), 3.50-3.58 (m, 1 H), 3.64-3.76 (m, 1 H), 4.29 (ddd, / = 2.0, 7.2, 12.0 Hz, 1 H), 7.60 (dd, / = 9.1, 10.0 Hz, 1 H), 7.70 (dd, / = 2.5, 7.7 Hz, 1 H), 8.41 (d, / = 2.0 Hz, 1 H), 8.52 (dd, / = 3.0, 8.9 Hz, 1 H), 10.43- 10.63 (m, 1 H), 12.53 (s, 1 H). MS (ES+) mJz 583.1 [M+H] ,

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isotmazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoro (11AB) tert-Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-67AB, 120 mg, 0.20 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (5 mL). Then, zinc dibromide (135 mg, 0.60 mmol) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (24 mg, 24% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.63- 1.79 (m, 1 H), 1.80 (s, 3 H), 1.93 (s, 3 H), 2.06-2.12 (m, 1 H), 2.06 (s, 3 H), 3.52 (dd, / = 7.8, 10.5 Hz, 1 H), 3.71 (ddd, J = 5.1, 10.5, 10.5 Hz, 1 H), 4.25 (ddd, J = 2.0, 7.1, 12.4 Hz, 1 H), 7.58 (dd, J = 9.0, 10.3 Hz, 1 H), 7.69 (dd, J = 2.4, 7.7 Hz, 1 H), 8.46-8.52 (m, 2 H), 10.38 (s, 1 H). MS (ES+) m/z 483.1 [M+H] . N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-isothia- zolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro -5-fluoropicolinamide (11BA)

lnt-39BA lnt-67BA 11 BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-67BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 3-chloro-5-fluoropicolinic acid (92.8 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 60 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (120 mg, 58% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.85 (s, 3 H), 1.54 (s, 9 H), 1.73 (s, 6 H), 2.08-2.22 (m, 1 H), 2.52-2.63 (m, 1 H), 3.70-3.87 (m, 2 H), 5.19 (dd, 7 = 7.1, 11.1 Hz, 1 H), 7.54 (dd, J = 9.1, 10.2 Hz, 1 H), 7.67 (dd, 7 = 2.4, 7.7 Hz, 1 H), 8.42-8.51 (m, 2 H), 10.21 (s, 1 H), 11.03 (br s, 1 H). MS (ES+) m/z 583.1 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-fluoropicolinamide (11BA) tert-Butyl ((3aR,4R,8S)-4-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-67BA, 120 mg, 0.20 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (5 mL). Then, zinc dibromide (135 mg, 0.60 mmol) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (25.0 mg, 24% yield). H NMR (d4-MeOH, 400 MHz): δ 1.07 (s, 3 H), 1.91 (s, 3 H), 1.92 (s, 3 H), 2.40-2.52 (m, 1 H), 2.85-2.93 (m, 1 H), 3.78-3.86 (m, 1 H), 3.87-3.96 (m, 1 H), 5.81 (dd, 7 = 7.5, 11.5 Hz, 1 H), 7.92 (dd, 7 = 9.0, 10.5 Hz, 1 H), 8.03 (dd, 7 = 2.5, 8.3 Hz, 1 H), 8.49 (dd, 7 = 2.9, 8.9 Hz, 1 H), 8.58 (d, 7 = 2.5 Hz, 1 H). MS (ES+) m/z 483.2 [M+H] .

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -chloro-3-methylpicolinamide (12AB)

lnt-39AB lnt-68AB 12AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-68AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-chloro-3-methylpicolinic acid (92.8 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). MS (ES+) m/z 579.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]fhiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide ( 12AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-68AB, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (32 mg, 40% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.66-1.79 (m, 1 H), 1.81 (s, 3 H), 1.94 (s, 3 H), 2.04-2.13 (m, 1 H), 2.06 (s, 3 H), 2.80 (s, 3 H), 3.53 (dd, / = 7.5, 10.5 Hz, 1 H), 3.72 (ddd, / = 5.0, 10.5, 10.5 Hz, 1 H), 4.26 (ddd, J = 2.2, 7.2, 12.4 Hz, 1 H), 7.57 (dd, J = 9.0, 10.3 Hz, 1 H), 7.68-7.70 (m, 1 H), 8.44-8.50 (m, 2 H), 10.64 (s, 1 H). MS (ES+) m/z 479.2 [M+H].

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -chloro-3-methylpicolinamide (12BA)

lnt-39BA lnt-68BA 12BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-68BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-chloro-3-methylpicolinic acid (92.4 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). MS (ES+) m/z 579.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]fhiazin-4-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpico linamide ( 12BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-68BA, 100 mg, 0.23 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (21.3 mg, 26% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.82 (s, 3 H), 1.67 (s, 3 H), 1.69 (s, 3 H), 2.11-2.24 (m, 1 H), 2.51-2.60 (m, 1 H), 2.79 (s, 3 H), 3.66-3.73 (m, 1 H), 3.76-3.84 (m, 1 H), 5.13 (dd, J = 7.0, 10.8 Hz, 1 H), 7.49 (dd, = 9.4, 9.4 Hz, 1 H), 7.66 (d, J = 2.0 Hz, 1 H), 8.37 (dd, J = 2.3, 8.8 Hz, 1 H), 8.49 (d, J = 2.3 Hz, 1 H), 10.48 (s, 1 H). MS (ES+) m/z 479.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(fluoromethoxy)picolinamide (13AB)

lnt-39AB lnt-69AB 13AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-(fluoromethoxy)picolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-69AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(fluoromethoxy)picolinic acid (90.6 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (0.1 g, 50% yield). MS (ES+) m/z 579.2 [M+H] .

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(fluoromethoxy)picolinamide (13AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-(fluoromethoxy)picolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-69AB, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (20 mg, 25% yield). ^X H NMR (d6-DMSO, 400 MHz): δ 1.67-1.81 (m, 1 H), 1.95 (s, 3 H), 1.97 (s, 3 H), 2.03 (s, 3 H), 2.12-2.21 (m, 1 H), 3.36-3.44 (m, 1 H), 3.58-3.67 (m, 1 H), 4.89-5.00 (m, 1 H), 6.06 (d, J = 53.2 Hz, 2 H), 7.82 (dd, J = 2.8, 8.8 Hz, 1 H), 8.06 (dd, / = 9.3, 10.3 Hz, 1 H), 8.23 (d, J = 8.8 Hz, 1 H), 8.44 (dd, / = 2.8, 9.0 Hz, 1 H), 8.50 (d, 7 = 2.8 Hz, 1 H), 10.17 (s, 1 H), 11.04 (s, 1 H), 11.10 (s, 1 H), 11.43 (s, 1 H). MS (ES+) m/z 479.2 [M+H] .

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(fluoromethoxy)picolinamide (13BA)

lnt-39BA lnt-69BA 13BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-(fluoromethoxy)picolinamido)py ridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-69BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(fluoromethoxy)picolinic acid (90.6 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70°C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (0.1 g, 50% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.51-1.60 (m, 12 H), 1.73 (2s, 6 H), 2.06-2.23 (m, 1 H), 2.59 (ddd, 7 = 5.7, 11.3, 11.3 Hz, 1 H), 3.67-3.89 (m, 2 H), 5.21 (dd, J = 7.2, 10.8 Hz, 1 H), 5.82 (d, J = 52.0 Hz, 2 H), 7.46-7.66 (m, 2 H), 8.28 (d, / = 8.5 Hz, 1 H), 8.43-8.53 (m, 2 H), 10.36 (s, 1 H), 11.02 (s, 1 H). MS (ES+) m/z 579.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(fluoromethoxy)picolinamide (13BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-(fluoromethoxy)picolinamido)py ridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate (Int-69BA, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (56.0 mg, 69% yield). ^! H NMR (CDC1 ₃ , 400 MHz): δ 0.90 (s, 3 H), 1.75 (s, 3 H), 1.76 (s, 3 H), 2.13-2.26 (m, 1 H), 2.56-2.64 (m, 1 H), 3.69-3.77 (m, 1 H), 3.82 (ddd, J = 4.9, 10.5, 10.5 Hz, 1 H), 5.17 (dd, J = 7.3, 11.3 Hz, 1 H), 5.82 (d, J = 53.2 Hz, 2 H), 7.51-7.61 (m, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 8.45 (dd, J = 3.0, 9.0 Hz, 1 H), 8.50 (d, J = 2.5 Hz, 1 H), 10.37 (s, 1 H). MS (ES+) m/z 479.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(difluoromethoxy)picolinamide (14AB)

lnt-39AB lnt-70AB 14AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate

(Int-70AB) To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(difluoromethoxy)picolinic acid (100 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 60 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (120 mg, 57% yield). MS (ES+) m/z 597.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide (14AB) tert-Butyl ((3aS,4R,8R)-4-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate (Int-70AB, 120 mg, 0.20 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (5 mL). Then, zinc dibromide (135 mg, 0.60 mmol) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (19 mg, 19% yield). ^X H NMR (d6-DMSO, 400 MHz): δ 1.58-1.68 (m, 1 H), 1.62 (s, 3 H), 1.73 (s, 3 H), 1.91 (s, 3 H), 2.04-2.13 (m, 1 H), 3.24-3.31 (m, 1 H), 3.45-3.54 (m, 1 H), 3.92-4.04 (m, 1 H), 7.53 (t, J = 72.8 Hz, 1 H), 7.86-7.94 (m, 1 H), 7.95 (dd, J = 2.8, 8.5 Hz, 1 H), 8.26-8.32 (m, 2 H), 8.30 (d, J = 8.5 Hz, 1 H), 8.66-8.68 (m, 1 H), 10.84 (s, 1 H). MS (ES+) m/z 497.2 [M+H].

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(difluoromethoxy)picolinamide (14BA)

lnt-39BA lnt-70BA 14BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbam (Int-70BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(difluoromethoxy)picolinic acid (100 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 60 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (120 mg, 57% yield). ^X H NMR (CDCI ₃ , 400 MHz): δ 1.68 (s, 9 H), 1.86 (s, 3 H), 1.98 (s, 3 H), 2.15 (s, 3 H), 3.55 (dd, / = 7.5, 10.7 Hz, 1 H), 3.70 (ddd, = 4.7, 10.7, 10.7 Hz, 1 H), 4.25-4.33 (m, 1 H), 6.46-6.86 (m, 1 H), 7.61 (dd, / = 9.0, 10.0 Hz, 1 H), 7.70 (dd, J = 2.6, 8.7 Hz, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.46- 8.52 (m, 2 H), 10.69 (s, 1 H), 12.63 (s, 1 H). MS (ES+) m/z 597.1 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)pi colinamide (14BA) tert-Butyl ((3aR,4R,8S)-4-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate (Int-70BA, 120 mg, 0.20 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (5 mL). Then, zinc dibromide (135 mg, 0.60 mmol) was added and the resulting solution was stirred for 18 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (55.0 mg, 55% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.95 (s, 3 H), 1.80 (s, 3 H), 1.83 (s, 3 H), 2.13-2.28 (m, 1 H), 2.57-2.67 (m, 1 H), 3.70-3.88 (m, 2 H), 5.19 (dd, 7 = 7.2, 11.4 Hz, 1 H), 6.67 (t, = 71.9 Hz, 1 H), 7.59 (dd, / = 9.5, 9.5 Hz, 1 H), 7.68 (dd, / = 2.5, 8.5 Hz, 1 H), 8.32 (d, J = 8.8 Hz, 1 H), 8.48 (dd, / = 2.9, 8.9 Hz, 1 H), 8.55 (d, J = 2.5 Hz, 1 H), 10.37 (s, 1 H). MS (ES+) m/z 497.1 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahyd]

isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl )-5-(2,2,3,3- tetrafluoropropoxy)picolinamide (15AB)

lnt-39AB lnt-71 AB 15AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-(2,2,3,3-tetrafluoropropoxy)pi colinamido)- pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5-a] [l,4]thiazin-6 yl)carbamate (Int-71AB) To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(2,2,3,3-tetrafluoropropoxy)picolinic acid (134 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 18 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1:2) to yield, after drying in vacuo, the purified product. The pure title compound was obtained by stirring this material in petroleum ether (10 mL) and dichloromethane (2 mL) at 15 °C for 1 h. The suspension was filtered, and dried in vacuo to give the title compound as white solid (80 mg, 34% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.51-1.57 (m, 1 H), 1.69 (s, 9 H), 1.86 (s, 3 H), 1.98 (s, 3 H), 2.09 (d, J = 1.2 Hz, 1 H), 2.15 (s, 3 H), 3.49-3.59 (m, 1 H), 3.64-3.75 (m, 1 H), 4.31 (d, J = 6.8 Hz, 1 H), 4.50 (t, J = 11.8 Hz, 2 H), 5.89-6.26 (m, 1 H), 7.43 (d, J = 8.3 Hz, 1 H), 7.60 (dd, / = 9.5 Hz, 1 H), 8.32 (d, / = 2.6 Hz, 2 H), 8.44-8.59 (m, 1 H), 10.38- 10.71 (m, 1 H), 12.38- 12.74 (m, 1 H). MS (ES+) m/z 661.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H-iso- thiazolo[l,5-a] [l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraflu oropropoxy)picolin- amide (15AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-(2,2,3,3- tetrafluoropropoxy)picolinamido)pyridin-2-yl)-4,7,7-trimethy l-8-oxido-3,3a,4,7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-71AB, 70 mg, 0.1 mmol) was dissolved in acetonitrile (10 mL) and dichloromethane (5 mL). Then, zinc dibromide (67.5 mg, 0.3 mmol) was added and the resulting solution was stirred for 16 h at 35°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (17 mg, 29% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.65-1.81 (m, 1 H), 1.81 (s, 3 H), 1.94 (s, 3 H), 2.05-2.14 (m, 1 H), 2.07 (s, 3 H), 3.49-3.57 (m, 1 H), 3.67-3.77 (m, 1 H), 4.21-4.30 (m, 1 H), 4.52 (t, / = 11.8 Hz, 2 H), 6.09 (tt, / = 4.0, 52.8 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.58 (dd, = 9.5, 10.0 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 8.40 (s, 1 H), 8.49 (dd, J = 2.8, 8.8 Hz, 1 H), 10.45 (s, 1 H). MS (ES+) mJz 561.1 [M+H] .

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(2,2,3,3- tetrafluoropropoxy)picolinamide (15BA)

lnt-39BA lnt-71 BA 15BA Step 1 : tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-(2,2,3,3-tetrafluoropropoxy)pi colinamido)- pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5-a] [l,4]thiazin-6- yl)carbamate (Int-71BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(2,2,3,3-tetrafluoropropoxy)picolinic acid (134 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 43% yield). MS (ES+) m/z 661.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]miazin-4-yl)-5-fluoropyridin-2-yl)-5- (2,2,3,3-tetrafluoropropoxy)picolin- amide (15BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-(2,2,3,3- tetrafluoropropoxy)picolinamido)pyridin-2-yl)-4,7,7-trimethy l-8-oxido-3,3a,4,7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-71BA, 100 mg, 0.16 mmol) was dissolved in acetonitrile (15 mL) and dichloromethane (8 mL). Then, zinc dibromide (111 mg, 0.5 mmol) was added and the resulting solution was stirred for 18 h at 35°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (19.6 mg, 23% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.00 (s, 3 H), 1.85 (2s, 6 H), 2.17-2.30 (m, 1 H), 2.60-2.71 (m, 1 H), 3.74- 3.89 (m, 2 H), 4.52 (t, J = 11.8 Hz, 2 H), 5.23 (dd, J = 7.2, 11.4 Hz, 1 H), 6.08 (tt, / = 4.3, 52.9 Hz, 1 H), 7.43 (dd, J = 2.8, 8.8 Hz, 1 H), 7.60 (dd, J = 9.3, 9.8 Hz, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.41 (d, = 2.8 Hz, 1 H), 8.51 (dd, J - 2.7, 8.9 Hz, 1 H), 10.36 (s, 1 H). MS (ES+) m/z 561.1 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -methoxypyrazine-2-carboxamide (16AB)

Step 1: tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-72AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-methoxypyrazine-2-carboxylic acid (90 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.62-2.20 (m, 24 H), 4.05-4.14 (m, 4 H), 4.28 (dd, = 6.8, 10.4 Hz, 1 H), 7.54-7.65 (m, 1 H), 8.12 (s, 1 H), 8.48 (dd, J = 2.9, 8.9 Hz, 1 H), 9.03 (s, 1 H), 10.37 (s, 1 H), 12.60 (s, 1 H). MS (ES+) m/z 562.2 [M+H]. Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide (16AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbam (Int-72AB, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Zinc dibromide (100 mg, 0.45 mmol) was added and the solution was stirred for 16 h at 40°C. After that, the reaction mixture was diluted with saturated aqueous sodium hydrogen- carbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a yellow solid as product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (23 mg, 28% yield). ^X H NMR (CDCI3, 400 MHz): δ 1.65-1.78 (m, 1 H), 1.81 (s, 3 H), 1.93 (s, 3 H), 2.04-2.13 (m, 1 H), 2.06 (s, 3 H), 3.52 (dd, 7 = 7.7, 10.7 Hz, 1 H), 3.71 (ddd, / = 5.0, 10.5, 10.5 Hz, 1 H), 4.09 (s, 3 H), 4.25 (ddd, / = 2.0, 6.8, 12.1 Hz, 1 H), 7.59 (dd, J - 8.9, 10.4 Hz, 1 H), 8.23 (d, J - 1.3 Hz, 1 H), 8.48 (dd, 7 = 3.1, 8.9 Hz, 1 H), 9.03 (d, J = 1.2 Hz, 1 H), 10.19 (s, 1 H). MS (ES+) m z 462.2 [M+H] . N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -methoxypyrazine-2-carboxamide (16BA)

lnt-39BA lnt-72BA 16BA

Step 1: tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-72BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-methoxypyrazine-2-carboxylic acid (90 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.87 (s, 3 H), 1.52-1.60 (m, 9 H), 1.73 (2s, 6 H), 2.09-2.21 (m, 1 H), 2.54-2.62 (m, 1 H), 3.72- 3.87 (m, 2 H), 4.08 (s, 3 H), 5.19 (dd, / = 7.2, 10.9 Hz, 1 H), 7.48-7.60 (m, 1 H), 8.21 (d, / = 1.4 Hz, 1 H), 8.47 (dd, / = 3.0, 8.9 Hz, 1 H), 9.02 (d, J = 1.3 Hz, 1 H), 10.04 (s, 1 H), 11.02 (s, 1 H). MS (ES+) m/z 562.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-c arboxamide (16BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-methoxypyrazine-2-carboxamido) pyridin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-72BA, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Zinc dibromide (100 mg, 0.45 mmol) was added and the solution was stirred for 16 h at 40°C. After that, the reaction mixture was diluted with saturated aqueous sodium hydrogen- carbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a yellow solid as product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (15 mg, 18% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.82 (s, 3 H), 1.68 (s, 3 H), 1.70 (s, 3 H), 2.11-2.24 (m, 1 H), 2.52-2.60 (m, 1 H), 3.67-3.74 (m, 1 H), 3.80 (ddd, / = 4.7, 10.5, 10.5 Hz, 1 H), 4.08 (s, 3 H), 5.11 (dd, 7 = 7.3, 11.3 Hz, 1 H), 7.51 (dd, J = 9.0, 10.3 Hz, 1 H), 8.23 (d, J = 1.0 Hz, 1 H), 8.40 (dd, = 2.9, 8.9 Hz, 1 H), 9.02 (d, / = 1.3 Hz, 1 H), 10.06 (br s, 1 H). MS (ES+) m/z 462.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-cyanopicolinamide (25AB)

lnt-39AB lnt-65AB 25AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-65AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150.0 mg, 0.35 mmol) in THF (15 mL) was added 5-cyano-3-chloropicolinic acid (96.5 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (266.7 mg, 2.1 mmol). The reaction was stirred at 70 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (105 mg, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.61- 1.70 (m, 10 H), 1.87 (s, 3 H), 1.98 (s, 3 H), 2.10-2.31 (m, 1 H), 2.15 (s, 3 H), 3.50-3.60 (m, 1 H), 3.66-3.76 (m, 1 H), 4.28-4.35 (m, 1 H), 7.59-7.68 (m, 1 H), 8.23 (s, 1 H), 8.49-8.56 (m, 1 H), 8.73-8.78 (m, 1 H), 10.40-10.57 (m, 1 H), 12.41-12.62 (m, 1 H). MS (ES+) m/z 590.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-cyanopicolinamide (25 AB) tert-Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-65AB, 100 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (194 mg, 1.7 mmol) was added. The solution was stirred for 4 h at room temperature. The reaction mixture was basified with saturated aqueous sodium hydrogencarbonate solution to pH=7~8, extracted with dichloromethane (2 x 10 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (CI 8, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (18 mg, 22% yield). ^! H NMR (CDCI ₃ , 400 MHz): δ 1.51-1.67 (m, 1 H), 1.79 (s, 3 H), 2.07 (s, 3 H), 2.17-2.26 (m, 1 H), 2.19 (s, 3 H), 3.56-3.64 (m, 1 H), 3.67-3.77 (m, 1 H), 4.31-4.40 (m, 1 H), 7.68 (dd, / = 9.5, 9.5 Hz, 1 H), 8.13 (s, 1 H), 8.57 (dd, / = 2.8, 9.0 Hz, 1 H), 8.87 (d, / = 1.3 Hz, 1 H), 11.46 (s, 1 H). MS (ES+) m/z 490.2 [M+H]. N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-cyanopicolinamide (25BA)

lnt-39BA lnt-65BA 25BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2-yl)- 4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l ,5-a][l,4]thiazin-6-yl)carbamate (Int-65BA)

To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150.0 mg, 0.35 mmol) in THF (20 mL) was added 5-cyano-3-chloropicolinic acid (96.5 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (222.2 mg, 1.75 mmol). The reaction was stirred at 70 °C for 16 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.84 (s, 3 H), 1.54 (s, 9 H), 1.73 (2s, 6 H), 2.09 - 2.22 (m, 1 H), 2.48 - 2.64 (m, 1 H), 3.70-3.88 (m, 2 H), 5.11-5.21 (m, 1 H), 7.52-7.64 (m, 1 H), 8.11-8.23 (m, 1 H), 8.37- 8.52 (m, 1 H), 8.72- 8.91 (m, 1 H), 10.03-10.26 (m, 1 H), 10.88-11.12 (m, 1 H). MS (ES+) m/z 590.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 -chloro-5-cyanopicolinamide (25BA) tert-Butyl ((3aR,4R,8S)-4-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate (Int-65BA, 100 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and zinc dibromide (115 mg, 0.51 mmol) was added. Then, dichloromethane (6 mL) was added and the resulting solution was stirred for 18 h at 35°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with dichloromethane (2 x 20 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane / methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (16 mg, 19% yield). 1H NMR (CDCI ₃ , 400 MHz): δ 0.96 (s, 3 H), 1.83 (s, 3 H), 1.84 (s, 3 H), 2.17-2.29 (m, 1 H), 2.59-2.69 (m, 1 H), 3.73-3.86 (m, 2 H), 5.10 (dd, / = 7.1, 11.2 Hz, 1 H), 7.63 (dd, / = 9.4, 9.4 Hz, 1 H), 8.20 (d, / = 1.8 Hz, 1 H), 8.49 (dd, J = 2.9, 8.9 Hz, 1 H), 8.88 (d, J = 1.5 Hz, 1 H), 10.25 (br s, 1 H). MS (ES+) m/z 490.2 [M+H] ,

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(difluoromethoxy)pyrazine-2- carboxamide (26AB)

lnt-39AB lnt-73AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(5-(difluoromethoxy)pyrazine-2-carboxamido )-3-fluoro- pyridin-2-yl)-4,7 ,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5- a] [l,4]thiazin-6- yl)carbamate (Int-73AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(difluoromefhoxy)pyrazine-2- carboxylic acid (150 mg, 0.78 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (0.1 g, 50% yield). MS (ES+) m/z 598.2 [M+H] .

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)py razine-2- carboxamide (26 AB) tert-Butyl ((3aS,4R,8R)-4-(6-(5-(difluoromethoxy)pyrazine-2-carboxamido )-3- fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahy dro-2H-isothiazolo[l,5- a] [l,4]thiazin-6-yl)carbamate (Int-73AB, 100 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (32 mg, 38% yield). 1H NMR (d6-DMSO, 400 MHz): δ 1.54- 1.67 (m, 1 H), 1.62 (s, 3 H), 1.73 (s, 3 H), 1.91 (s, 3 H), 2.05-2.14 (m, 1 H), 3.23-3.31 (m, 1 H), 3.44-3.53 (m, 1 H), 3.90-4.06 (m, 1 H), 7.82 (t, / = 71.3 Hz, 1 H), 7.86-7.95 (m, 1 H), 8.21-8.32 (m, 2 H), 8.71-8.75 (m, 1 H), 9.04 (d, 7 = 1.3 Hz, 1 H), 10.87 (br s, 1 H). MS (ES+) m/z 498.2 [M+H] . N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -(difluoromethoxy)pyrazine-2- carboxamide (26BA)

lnt-39BA lnt-73BA 26BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(6-(5-(difluoromethoxy)pyrazine-2-carboxamido )-3-fluoro- pyridin-2-yl)-4,7,7-trimemyl-8-oxido-3,3a,4,7-tetrahy

yl)carbamate (Int-73BA) To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-(difluoromefhoxy)pyrazine-2- carboxylic acid (150 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydro gencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (0.1 g, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.86 (s, 3 H), 1.54 (s, 9 H), 1.70 - 1.77 (m, 6 H), 2.06-2.22 (m, 1 H), 2.58 (ddd, / = 5.7, 11.1, 11.1 Hz, 1 H), 3.70-3.89 (m, 2 H), 5.17 (dd, / = 7.2, 11.2 Hz, 1 H), 7.32-7.70 (m, 2 H), 8.39 (d, J = 1.3 Hz, 1 H), 8.46 (dd, = 3.0, 8.9 Hz, 1 H), 9.03-9.10 (m, 1 H), 10.01 (s, 1 H), 11.04 (br s, 1 H). MS (ES+) mJz 598.2 [M+H].

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)py razine-2- carboxamide (26BA) tert-Butyl ((3aR,4R,8S)-4-(6-(5-(difluoromethoxy)pyrazine-2-carboxamido )-3- fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahy dro-2H-isothiazolo[l,5- a] [l,4]thiazin-6-yl)carbamate (Int-73BA, 100 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Then, zinc dibromide (100 mg, 0.45 mmol) was added and the resulting solution was stirred for 16 h at 40°C. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give the title compound as a white solid (33.0 mg, 38% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.01 (s, 3 H), 1.88 (2s, 6 H), 2.17-2.31 (m, 1 H), 2.60-2.71 (m, 1 H), 3.74-3.89 (m, 2 H), 5.19 (dd, 7 = 7.2, 11.3 Hz, 1 H), 7.52 (t, / = 71.3 Hz, 1 H), 7.66 (dd, J = 9.4, 9.4 Hz, 1 H), 8.42 (s, 1 H), 8.49-8.55 (m, 1 H), 9.09 (s, 1 H), 10.06 (s, 1 H). MS (ES+) m/z 498.3 [M+H]. N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoropicolinamide (27AB)

lnt-39AB lnt-74AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-fluoropicolinamido)pyridin-2-y l)-4,7,7- trimethyl-8-oxido-3 a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carb amate (Int- 74AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 150.0 mg, 0.35 mmol) in THF (20 mL) was added 5-fluoropicolinic acid (80 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1 : 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). 1H NMR (CDC1 ₃ , 400 MHz): δ 1.68 (s, 9 H), 1.87 (s, 3 H), 1.98 (s, 3 H), 2.06-2.19 (m, 4 H), 3.44-3.59 (m, 11 H), 3.68 (d, J = 13.2 Hz, 1 H), 4.24-4.36 (m, 1 H), 7.58-7.66 (m, 2 H), 8.37 (dd, J = 4.5, 8.7 Hz, 1 H), 8.45 (d, J = 2.6 Hz, 1 H), 8.51 (dd, / = 3.0, 8.9 Hz, 1 H), 10.64 (s, 1 H), 12.48-12.70 (m, 1 H). MS (ES+) m/z 549.1 [M+H] . Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoropicolinamide (27 AB) tert-Butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-fluoropicolinamido)pyridin-2-y l)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 74AB, 100 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Zinc dibromide (100 mg, 0.45 mmol) was added and the solution was stirred for 16 h at 40°C. After that, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a yellow solid as product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (23 mg, 28% yield). ^l H NMR (CDC1 ₃ , 400 MHz): δ 1.62-1.81 (m, 1 H), 1.80 (s, 3 H), 1.93 (s, 3 H), 2.05-2.13 (m, 1 H), 2.06 (s, 3 H), 3.52 (dd, / = 7.8, 10.5 Hz, 1 H), 3.71 (ddd, J = 5.3, 10.5, 10.5 Hz, 1 H), 4.24 (ddd, J = 1.8, 7.0, 12.3 Hz, 1 H), 7.59 (dd, J = 9.0, 10.3 Hz, 1 H), 7.63 (ddd, / = 2.8, 8.3, 8.3 Hz, 1 H), 8.34 (dd, / = 4.5, 8.8 Hz, 1 H), 8.48 (dd, / = 3.2, 8.9 Hz, 1 H), 8.53 (d, J = 2.5 Hz, 1 H), 10.46 (s, 1 H). MS (ES+) m/z 449.1 [M+H].

N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoropicolinamide (27BA)

lnt-39BA lnt-74BA

Step 1 : tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-fluoropicolinamido)pyridin-2-y l)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 74BA) To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added 5-fluoropicolinic acid (80 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 °C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1 : 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). ^X H NMR (CDC1 ₃ , 400 MHz): δ 0.75-0.93 (m, 3 H), 1.49-1.63 (m, 9 H), 1.70- 1.83 (m, 6 H), 2.06-2.23 (m, 1 H), 2.52-2.66 (m, 1 H), 3.74-3.91 (m, 2 H), 5.23 (dd, J = 13, 11.2 Hz, 1 H), 7.51-7.69 (m, 2 H), 8.35 (dd, J = 4.5, 8.7 Hz, 1 H), 8.44-8.58 (m, 2 H), 10.35 (s, 1 H), 11.05 (s, 1H). MS (ES+) m/z 549.1 [M+H] .

Step 2: N-(6-((3aR,4R,8S)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-5 -fluoropicolinamide (27BA) tert-Butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-fluoropicolinamido)pyridin-2-y l)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 74BA, 100 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL) and dichloromethane (1 mL). Zinc dibromide (100 mg, 0.45 mmol) was added and the solution was stirred for 16 h at 40°C. After that, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (dichloromethane/ methanol 10: 1, UV) to give a yellow solid as product. The product was repurified by preparative HPLC (C18, eluting with 0.05% ammonia / acetonitrile), followed by lyophilization to give the title compound as a white solid (24 mg, 30% yield). ^l ¥l NMR (CDC1 ₃ , 400 MHz): δ 0.82 (s, 3 H), 1.67 (s, 3 H), 1.70 (s, 3 H), 2.10-2.24 (m, 1 H), 2.51- 2.60 (m, 1 H), 3.67-3.74 (m, 1 H), 3.81 (ddd, J = 4.8, 10.5, 10.5 Hz, 1 H), 5.12 (dd, / = 7.3, 11.3 Hz, 1 H), 7.51 (dd, / = 9.0, 10.3 Hz, 1 H), 7.61 (ddd, / = 2.8, 8.2, 8.2 Hz, 1 H), 8.33 (dd, = 4.5, 8.8 Hz, 1 H), 8.40 (dd, / = 2.9, 8.9 Hz, 1 H), 8.53 (d, J = 2.5 Hz, 1 H), 10.33 (s, 1 H). MS (ES+) m/z 449.1 [M+H] .

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahyd]

isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl )-3-chloro-5- (difluoromethoxy)picolinamide (28AB)

lnt-39AB lnt-75AB 28AB

Step 1: tert- Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3-fluoro- pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H -isothiazolo[l,5-a] [l,4]thiazin-6- yl)carbamate (Int-75AB)

3-Chloro-5-(difluoromethoxy)picolinic acid (78 mg, 353 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (62 mg, 494 μηιοΐ) as well as dimethylformamide (0.242 M in toluene, 36 μί, 9 μηιοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3-chloro-5-(difluoromethoxy)picolinoyl chloride as yellow oil (85 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8-oxido- 3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a] [l,4]thiazin-6-yl)carbamate (Int-39AB, 100 mg, 235 μιτιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (60.7 mg, 82.1 μL·, 470 μιηοΐ) was added, followed by a solution of 3-chloro-5-(difluoromethoxy)picolinoyl chloride (vide supra, 85 mg, 353 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 45 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 100:0) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a light orange solid (90 mg, 61% yield). HPLC (method LCMS_fglm) t _R = 1.36 min. MS (ES+) m/z 631.3 [M+H] . Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(difluorom ethoxy)picolin- amide (28AB) tert-Butyl ((3aS,4R,8R)-4-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3- fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahy dro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate (Int-75AB, 90 mg, 143 μηιοΐ) was dissolved in dichloromethane (10 mL) and trifluoro acetic acid (268 mg, 181 μί, 2.35 mmol) was added. The solution was stirred for 16 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 8 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 24 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 6:94) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white foam (70 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 60/40, flow 1.0 niL/min) to yield the desired second eluting enantiomer as an off-white powder (48 mg, 62%), and the opposite first eluting enantiomer as an off white powder (12 mg, 15%). HPLC (method LCMS_gradient) tR = 1.4 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.59- 1.76 (m, 1 H), 1.91 (s, 3 H), 2.01 (s, 3 H), 2.10- 2.20 (m, 1 H), 2.14 (s, 3 H), 3.55 (dd, 7 = 7.7, 10.7 Hz, 1 H), 3.72 (ddd, 7 = 5.1, 10.7, 10.7 Hz, 1 H), 4.30 (ddd, 7 = 1.9, 7.2, 12.2 Hz, 1 H), 6.68 (t, 7 = 71.3 Hz, 1 H), 7.60 (dd, 7 = 8.9, 10.3 Hz, 1 H), 7.69 (d, 7 = 2.4 Hz, 1 H), 8.11 (br s, 2 H), 8.50 (d, 7 = 2.4 Hz, 1 H), 8.54 (dd, 7 = 3.0, 8.9 Hz, 1 H), 11.21 (s, 1 H). MS (ES+) m/z 531.3 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 ,5-dichloropicolinamide (29AB)

lnt-39AB lnt-76AB 29AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(3,5-dichloropicolinamido)-3-fluoropyridin -2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 76AB)

3,5-Dichloropicolinic acid (68 mg, 353 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (62 mg, 494 μιιιοΐ) as well as dimethylformamide (0.242 M in toluene, 36 μί, 9 μιηοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3,5- dichloropicolinoyl chloride as light yellow oil (74 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethy l-8-oxido-3,3a,4,7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-39AB, 100 mg, 235 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (61 mg, 82 μΐ _^ , 470 μηιοΐ) was added, followed by a solution of 3,5-dichloropicolinoyl chloride (vide supra, 74 mg, 353 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 60 min at 0-5 °C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 24 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 100:0) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a light purple solid (75 mg, 53% yield). HPLC (method LCMS_fglm) t _R = 1.41 min. MS (ES+) m/z 599.2 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-3 ,5-dichloropicolinamide (29 AB) tert-Butyl ((3aS,4R,8R)-4-(6-(3,5-dichloropicolinamido)-3-fluoropyridin -2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 76AB, 75 mg, 125 μιτιοΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (268 mg, 181 μί, 2.35 mmol) was added. The solution was stirred for 16 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 8 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 6:94) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white foam (67 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 70/30, flow 1.0 mL/min) to yield the desired second eluting enantiomer as an off-white powder (49 mg, 79%), and the opposite first eluting enantiomer as an off white powder (12 mg, 19%). HPLC (method LCMS_gradient) t _R = 1.4 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.59-1.78 (m, 1 H), 1.89 (s, 3 H), 1.99 (s, 3 H), 2.08-2.19 (m, 1 H), 2.12 (s, 3 H), 3.54 (dd, / = 7.8, 10.6 Hz, 1 H), 3.72 (ddd, / = 5.0, 10.6, 10.6 Hz, 1 H), 4.29 (ddd, / = 1.9, 7.2, 12.2 Hz, 1 H), 5.83 (br s, 2 H), 7.60 (dd, = 9.0, 10.2 Hz, 1 H), 7.91 (d, / = 2.0 Hz, 1 H), 8.52 (dd, J = 2.9, 9.0 Hz, 1 H), 8.56 (d, J = 2.0 Hz, 1 H), 11.00 (s, 1 H). MS (ES+) m/z 499.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4 -cyanobenzamide (30AB)

lnt-39AB lnt-77AB 30AB

Step 1 : tert-Butyl ((3aS,4R,8R)-4-(6-(4-cyanobenzamido)-3-fluoropyridin-2-yl)-4 ,7,7-trimethyl- 8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazi n-6-yl)carbamate (Int-77AB) To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 100 mg, 0.23 mmol) in dichloromethane (2.3 mL) was added 4-cyanobenzoic acid (86.4 mg, 0.59 mmol), followed by T3P (0.70 mL, 1.2 mmol, 50% in ethyl acetate), and diisopropylethylamine (0.25 mL, 1.4 mmol). The reaction was stirred in a sealed vial at 60 °C for 20 h. After that, the reaction was stopped by addition of aqueous ammonia solution (25% m/m, 0.2 mL), and stirred for 1 h at room temperature. The mixture was diluted with aqueous sodium hydrogencarbonate solution (1 M, 20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 100:0) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a yellow solid (0.033 g, 25% yield). MS (ES+) m/z 555 [M+H].

Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1 ,5-a] [ 1 ,4] thiazin-4-yl)-5-fluoropyridin-2-yl)-4-cyanobenzamide (30AB) To a solution of tert-butyl ((3aS,4R,8R)-4-(6-(4-cyanobenzamido)-3-fluoropyridin-2-yl)-

4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazol o[l,5-a][l,4]thiazin-6-yl)carbamate (Int-77AB, 0.033 g, 0.060 mmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.092 mL, 1.19 mmol) at room temperature. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo and the residue was purified by preparative HPLC (CI 8, eluting with water / acetonitrile / triethylamine) to give the title compound as an off-white solid (3 mg, 11% yield). 1H NMR (CDC1 ₃ , 300 MHz): δ 1.55-1.73 (m, 1 H), 1.99 (s, 3 H), 2.09 (s, 3 H), 2.15-2.28 (m, 1 H), 2.20 (s, 3 H), 3.55-3.65 (m, 1 H), 3.67-3.79 (m, 1 H), 4.34- 4.44 (m, 1 H), 7.66 (dd, J = 9.2, 10.2 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 2 H), 8.23 (d, J = 8.3 Hz, 2 H), 8.57 (dd, J = 3.2, 9.1 Hz, 1 H), 11.10 (s, 1 H). MS (ES+) m/z 455 [M+H] , N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-2 -chloro-4-cyanobenzamide (31AB)

lnt-39AB lnt-78AB 31 AB

Step 1: tert-Butyl ((3aS,4R,8R)-4-(6-(2-chloro-4-cyanobenzamido)-3-fluoropyridi n-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 78AB)

To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][ l,4]thiazin-6-yl)carbamate (Int- 39AB, 100 mg, 0.23 mmol) in tetrahydrofuran (2.4 mL) was added 2-chloro-4-cyanobenzoic acid (107 mg, 0.59 mmol), followed by T3P (0.70 mL, 1.2 mmol, 50% in ethyl acetate), and diisopropylethylamine (0.25 mL, 1.4 mmol). The reaction was stirred in a sealed vial at 60 °C for 20 h. After that, the reaction was stopped by addition of aqueous ammonia solution (25% m/m, 0.2 mL), and stirred for 1 h at room temperature. The mixture was diluted with aqueous sodium hydrogencarbonate solution (1 M, 20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 100:0) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a yellow solid (0.035 g, 25% yield). MS (ES+) mJz 589 [M+H]. Step 2: N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-2 -chloro-4-cyanobenzamide (31AB)

To a solution tert-butyl ((3aS,4R,8R)-4-(6-(2-chloro-4-cyanobenzamido)-3- fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahy dro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate (Int-78AB, 0.035 g, 0.059 mmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.092 mL, 1.19 mmol) at room temperature. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo and the residue was purified by preparative HPLC (CI 8, eluting with water / acetonitrile / triethylamine) to give the title compound as an off-white solid (9 mg, 31% yield). ^l B NMR (CDC1 ₃ , 300 MHz): δ 1.52- 1.70 (m, 1 H), 1.94 (s, 3 H), 2.05 (s, 3 H), 2.17-2.29 (m, 1 H), 2.19 (s, 3 H), 3.60 (dd, / = 7.7, 10.9 Hz, 1 H), 3.74 (ddd, J = 5.0, 10.7, 10.7 Hz, 1 H), 4.40 (ddd, 7 = 1.5, 7.2, 11.8 Hz, 1 H), 7.60-7.71 (m, 3 H), 7.74-7.77 (m, 1 H), 8.58 (dd, / = 3.2, 9.0 Hz, 1 H), 10.78 (s, 1 H), 11.17 (s, 1 H), 11.88 (br s, 1 H). MS (ES+) m/z 489 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-cyano-3- methylpicolinamide (32AA)

lnt-51 AA lnt-79AA 32AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-79AA)

5-Cyano-3-methylpicolinic acid (195 mg, 1.2 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (203 mg, 140 μί, 1.6 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1:3, v/v) were added. The mixture was stirred for 1.75 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with n-heptane (3 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (220 mg, 99%). After that, tert- butyl ((4aR,5R,9R)-5-(6-armno-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 70 mg, 147 μηιοΐ) was dissolved in dichloromethane (3 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (37.7 mg, 50 μί, 292 μιηοΐ) was added, followed by a solution of 5- cyano-3-methylpicolinoyl chloride (vide supra, 35 mg, 194 μιηοΐ) in dichloromethane (650 μί). The reaction mixture was stirred at 0-5°C for 1.5 h. Then, ethanol (100 μί) was added, the mixture was stirred for 30 min at room temperature, and the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted with dichloromethane (1 x 40 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 80 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 40:60) to yield, after drying in vacuo (50°C, 5 mbar), the title compound as a white solid (90 mg, 99%). HPLC (method LCMS_gradient) t _R = 3.4 min. 1H NMR (CDCI ₃ , 400 MHz): δ 1.49 (s, 9 H), 1.81 (s, 3 H), 1.83 (s, 3 H), 1.95 (s, 3 H), 2.52-2.82 (m,

2 H), 2.87 (s, 3 H), 3.64-3.88 (m, 2 H), 4.56-4.62 (m, 1 H), 7.62 (dd, J = 9.0, 10.6 Hz, 1 H), 7.97- 7.99 (m, 1 H), 8.45 (dd, / = 3.1, 9.0 Hz, 1 H), 8.79-8.81 (m, 1 H), 10.50 (s, 1 H), 11.36 (s, 1 H). MS (ES+) m/z 620.2 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpic olin- amide (32AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7-yl)- carbamate (Int-79AA, 90 mg, 145 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.33 g, 900 μL·, 11.7 mmol) was added. The solution was stirred for 0.5 h at room temperature. After that, it was concentrated in vacuo (25°C, 5 mbar). The residue, a brown viscous oil, was dissolved in dichloromethane (40 mL), and saturated aqueous sodium hydrogencarbonate solution (15 mL) was added. After stirring for 5 min, phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL), MTBE (5 mL) was added and again concentrated in vacuo to give, after drying in vacuo (50°C, 5 mbar), an off white solid as crude product. The crude was purified by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 70/30, flow 1.0 mL/min) to yield the desired (-)-rotating enantiomer as a white solid (49.8 mg, 66%), and the opposite (-i-)-rotating enantiomer as a white solid (24.2 mg, 32%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert- butylmethyl ether (3 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. ^X H NMR (CDC1 ₃ , 400 MHz): δ 1.89 (s, 3 H), 1.91 (s, 3 H), 1.96 (s,

3 H), 2.22-2.39 (m, 1 H), 2.57-2.79 (m, 1 H), 2.87 (s, 3 H), 3.57-3.85 (m, 2 H), 4.07-4.15 (m, 1 H), 7.09 (br s, 2 H, exch), 7.56 (dd, J = 9.0, 10.8 Hz, 1 H), 7.97-8.00 (m, 1 H), 8.43 (dd, / = 3.0, 8.9 Hz, 1 H), 8.79 (d, J = 1.6 Hz, 1 H), 10.46 (s, 1 H). MS (ES+) m/z 520.1 [M+H] ,

N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2 -f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoropicolm^ (33AA)

lnt-51 AA lnt-80AA

Step 1 : tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-fluoropicolinamid o)pyridin-2-yl)-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbama

(Int-80AA) 5-Fluoropicolinic acid (47.6 mg, 337 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (56.9 mg, 39.3 μί, 449 μπιοΐ) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 2 h at room temperature. A second portion of oxalyl chloride (28.7 mg, 19.8 μΐ _^ , 226 μιηοΐ) was added and the mixture was stirred for additional 1 h at room temperature to drive the reaction to completion. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-fluoropicolinoyl chloride as red oil (52.1 mg, 97%). After that, tert-butyl ((4aR,5R,9R)- 5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethy l-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 115 mg, 242 μιηοΐ) was dissolved in dichloromethane (6 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (61.9 mg, 83.6 μL·, 479 μιηοΐ) was added, followed by a solution of 5-fluoropicolinoyl chloride (vide supra, 52.1 mg, 326 μιηοΐ) in dichloromethane (5 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 14 h at room temperature. Then, methanol (2 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 35:65) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (100 mg, 69%). HPLC (method LCMS_gradient) t _R = 3.4 min. MS (ES+) m/z 599.2 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoropicolinamid e (33AA) tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-fluoropicolinamid o)pyridin-2-yl)- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f [l,2]thiazin-7-yl)carbamate (Int-80AA, 99 mg, 165 μηιοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (378 mg, 254 μΐ _^ , 3.30 mmol) was added. The solution was stirred for 4 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white foam (80 mg, 96%). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired (-)-rotating enantiomer as a white solid (51 mg, 61 %), and the opposite (+) -rotating enantiomer as a white solid (18.3 mg, 22%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert- butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.80 (s, 3 H), 1.85 (2s, 6 H), 2.29- 2.44 (m, 1 H), 2.57-2.79 (m, 1 H), 3.58-3.88 (m, 2 H), 4.16-4.27 (m, 1 H), 7.52 (dd, = 9.0, 10.8 Hz, 1 H), 7.63 (ddd, / = 2.6, 8.3, 8.3 Hz, 1 H), 8.31-8.46 (m, 2 H), 8.54 (d, / = 2.6 Hz, 1 H), 10.26 (s, 1 H). MS (ES+) m/z 499.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-cyanopicolm^ (34AA)

lnt-51 AA lnt-81 AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyanopicolinamido)-3-fluoropyridin-2-yl )-3,3-difluoro- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int-81AA)

5-Cyanopicolinic acid (60 mg, 405 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (86.1 mg, 59.4 μΐ _^ , 679 μιηοΐ) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 18 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-cyanopicolinoyl chloride as red oil (52 mg, 77%). After that, tert-butyl ((4aR,5R,9R)-5- (6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl- 9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 110 mg, 231 μπιοΐ) was dissolved in dichloromethane (6 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (59.2 mg, 80 μΐ _^ , 458 μηιοΐ) was added, followed by a solution of 5-fluoropicolinoyl chloride (vide supra, 52 mg, 312 μιηοΐ) in dichloromethane (5 mL). The reaction mixture was stirred for 45 min at 0-5 °C. Then, methanol (2 mL) was added, the mixture was stirred for 15 min at room temperature, and the mixture was concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 20:80 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (140 mg, 96%). HPLC (method LCMS_gradient) t _R = 3.2 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.50 (s, 9 H), 1.82 (s, 3 H), 1.84 (s, 3 H), 1.97 (s, 3 H), 2.52-2.85 (m, 2 H), 3.64-3.92 (m, 2 H), 4.54-4.65 (m, 1 H), 7.66 (dd, / = 9.0, 10.6 Hz, 1 H), 8.25 (dd, J = 2.0, 8.3 Hz, 1 H), 8.46 (dd, / = 0.7, 8.2 Hz, 1 H), 8.50 (dd, = 3.1, 9.0 Hz, 1 H), 8.97-9.00 (m, 1 H), 10.33 (s, 1 H), 11.38 (s, 1 H). MS (ES+) m/z 606.2 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide (34AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyanopicolinamido)-3-fluoropyridin-2-yl )-3,3-difluoro-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate (Int-81AA, 137 mg, 226 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (516 mg, 349 μί, 4.52 mmol) was added. The solution was stirred for 90 min at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 8 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (100 mg, 94%). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μπι, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 70/30, flow 1.0 mL/min) to yield the desired (-)-rotating enantiomer as a white solid (68 mg, 59%), and the opposite (+)-rotating enantiomer as a white solid (15 mg, 13%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert- butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.83 (s, 3 H), 1.88 (s, 3 H), 1.89 (s, 3 H), 2.26-2.41 (m, 1 H), 2.57-2.80 (m, 1 H), 3.58-3.78 (m, 2 H), 4.11-4.21 (m, 1 H), 5.55 (br s, 2 H, exch), 7.56 (dd, / = 8.9, 10.9 Hz, 1 H), 8.24 (dd, J = 2.0, 8.1 Hz, 1 H), 8.40-8.48 (m, 2 H), 8.95-9.00 (m, 1 H), 10.29 (s, 1 H). MS (ES+) m/z 506.1 [M+H]. N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-oxid o-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5- (difluoromethoxy)picolinamide (35AA)

lnt-51 AA lnt-82AA 35AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)- 3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-82AA) 5-(Difluoromethoxy)picolinic acid (76.6 mg, 405 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (68.4 mg, 47.2 μL, 539 μιτιοΐ) as well as dimethylformamide (0.25 M in toluene, 40.5 μί, 10 μπιοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-(difluoromethoxy)picolinoyl chloride as green oil (72 mg, 86%). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 51AA, 110 mg, 231 μπιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (59.8 mg, 80.8 μΐ _^ , 463 μπιοΐ) was added, followed by a solution of 5-(difluoromethoxy)picolinoyl chloride (vide supra, 72 mg, 347 μπιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 45 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 20 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 70:30) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a waxy solid (173 mg), which was used in the next step without further purification. HPLC (method LCMS_fglm) t _R = 1.50 min. MS (ES+) m/z 647.5 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy) - picolinamide (35AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-(difluoromethoxy)picolinamido)-3-fluoro pyridin-2-yl)- 3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-82AA, 173 mg, see preceeding step, 231 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (528 mg, 356 μL·, 4.63 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (121 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (66 mg, 52% over 2 steps), and the opposite (+) -rotating enantiomer as a white solid (22 mg, 17%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.8 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.86 (s, 3 H), 1.90 (2s, 6 H), 2.27-2.42 (m, 1 H), 2.56-2.80 (m, 1 H), 3.58-3.86 (m, 2 H), 4.11- 4.21 (m, 1 H), 5.41 (br s, 2 H, exch), 6.67 (t, / = 71.8 Hz, 1 H), 7.54 (dd, / = 9.1, 10.7 Hz, 1 H), 7.70 (dd, / = 2.5, 8.6 Hz, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 8.43 (dd, J = 3.0, 8.9 Hz, 1 H), 8.55 (d, J = 24 Hz, 1 H), 10.29 (s, 1 H). MS (ES+) m/z 547.1 [M+H] .

N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-(2,2,3,3- tetrafluoropropoxy)picolinamide (36 AA)

lnt-51 AA lnt-83AA 36 AA

Step 1: tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-(2,2,3,3-tetraflu oropropoxy)- picolinamido)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-7-yl)carbamate (Int-83AA) 5-(2,2,3,3-Tetrafluoropropoxy)picolinic acid (103 mg, 405 μιτιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (68.4 mg, 47.2 μL·, 539 μιηοΐ) as well as dimethylformamide (0.25 M in toluene, 40.5 μί, 10 μπιοΐ) were added. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-(2,2,3,3-tetrafluoropropoxy)picolinoyl chloride as orange oil (94.2 mg, 86%). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 51AA, 110 mg, 231 μηιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (59.8 mg, 80.8 μΐ _^ , 463 μπιοΐ) was added, followed by a solution of 5-(2,2,3,3-tetrafluoropropoxy)picolinoyl chloride (vide supra, 94.2 mg, 347 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 20 g, eluting with ethyl acetate / n-heptane, gradient 5:95 to 70:30) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white foam (173 mg), which was used in the next step without further purification. HPLC (method LCMS_fglm) t _R = 1.53 min. MS (ES+) m/z 711.3 [M+H] , Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2,3,3-tetraflu oro- propoxy)picolinamide (36AA) tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-(2,2,3,3-tetraflu oropropoxy)- picolinamido)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a, 5,8-hexahydro-[l,4]thiazino[2,l- f] [l,2]thiazin-7-yl)carbamate (Int-83AA, 173 mg, see preceeding step, 231 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (528 mg, 356 μί, 4.63 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0- 5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (127 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (85 mg, 60% over 2 steps), and the opposite (+)-rotating enantiomer as a white solid (26 mg, 18%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) tR = 2.1 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.82 (s, 3 H), 1.87 (2s, 6 H), 2.28-2.44 (m, 1 H), 2.56-2.80 (m, 1 H), 3.57-3.88 (m, 2 H), 4.02 (br s, 2 H), 4.14-4.25 (m, 1 H), 4.52 (t, J = 11.8 Hz, 1 H), 6.08 (tt, J = 4.2, 53.1 Hz, 1 H), 7.44 (dd, J = 2.8, 8.7 Hz, 1 H), 7.52 (dd, / = 9.0, 10.8 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.37-8.44 (m, 2 H), 10.26 (s, 1 H). MS (ES+) m/z 611.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2 -f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5- cyanopicolinamide (37 AA)

lnt-51 AA lnt-84AA 37AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2- yl)-33-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahyd ro-[l,4]thiazino[2, l-f][l,2]thia 7-yl)carbamate (Int-84AA)

3-Chloro-5-cyanopicolinic acid (73.9 mg, 405 μπιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (68.4 mg, 47.2 μL·, 539 μιηοΐ) as well as dimethylformamide (0.25 M in toluene, 40.5 μΐ _^ , 10 μιηοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 3-chloro-5-cyanopicolinoyl chloride as brown oil (69.7 mg, 86%). After that, tert-butyl ((4aR,5R,9R)-5-(6-armno-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 110 mg, 231 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (59.8 mg, 80.8 μL·, 463 μιηοΐ) was added, followed by a solution of 3-chloro-5-cyanopicolinoyl chloride (vide supra, 69.7 mg, 347 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 60:40) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (141 mg, 95%). HPLC (method LCMS_fglm) t _R = 1.44 min. MS (ES+) m/z 640.1 [M+H] , Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopic olin- amide (37AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-84AA, 141 mg, 220 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (528 mg, 356 μL·, 4.63 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (110 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 70/30, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (66 mg, 56%), and the opposite (+) -rotating enantiomer as a white solid (22 mg, 19%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.83 (s, 3 H), 1.86 (s, 3 H), 1.87 (s, 3 H), 2.27-2.42 (m, 1 H), 2.56-2.79 (m, 1 H), 3.58-3.87 (m, 2 H), 4.12-4.22 (m, 1 H), 4.67 (br s, 2 H), 7.55 (dd, / = 8.9, 10.7 Hz, 1 H), 8.21 (d, J = 1.6 Hz, 1 H), 8.41 (dd, 7 = 3.0, 8.9 Hz, 1 H), 8.86 (d, J = 1.8 Hz, 1 H), 10.15 (s, 1 H). MS (ES+) m/z 540.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fl^

carboxamide (38AA)

lnt-51 AA lnt-85AA 38AA

Step 1: tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-methoxypyrazine-2 - carboxamido)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [ 1 ,2]thiazin-7-yl)carbamate (Int-85AA)

5-Methoxypyrazine-2-carboxylic acid (62.4 mg, 405 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (68.4 mg, 47.2 μL, 539 μιηοΐ) as well as dimethylformamide (0.25 M in toluene, 40.5 μί, 10 μπιοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo, the residue was treated with toluene (5 mL) and again concentrated and dried in vacuo (40°C, 5 mbar) to afford 5-methoxypyrazine-2-carbonyl chloride as brown oil (59.9 mg, 86%). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 51AA, 110 mg, 231 μπιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (59.8 mg, 80.8 μΐ _^ , 463 μπιοΐ) was added, followed by a solution of 5-methoxypyrazine-2-carbonyl chloride (vide supra, 59.9 mg, 347 μιτιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 70:30) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white foam (131 mg, 93%). HPLC (method LCMS_fglm) t _R = 1.49 min. MS (ES+) m/z 612.2 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2 - carboxamide (38AA) tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-methoxypyrazine-2 - carboxamido)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5 ,8-hexahydro-[l,4]thiazino[2,l- f] [l,2]thiazin-7-yl)carbamate (Int-85AA, 131 mg, 214 μηιοΐ) was dissolved in dichloromethane (5 mL) and trifluoro acetic acid (528 mg, 356 μL·, 4.63 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (110 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (75 mg, 68%), and the opposite (+)-rotating enantiomer as a white solid (20 mg, 18%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 50°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.6 min. ^l U NMR (CDC1 ₃ , 300 MHz): δ 1.80 (s, 3 H), 1.85 (2s, 6 H), 2.28-2.43 (m, 1 H), 2.55-2.79 (m, 1 H), 3.57-3.87 (m, 2 H), 4.09 (s, 3 H), 4.11 (br s, 2 H), 4.15-4.25 (m, 1 H), 7.51 (dd, / = 9.1, 10.9 Hz, 1 H), 8.23 (d, J = 1.2 Hz, 1 H), 8.40 (dd, / = 3.0, 8.9 Hz, 1 H), 9.04 (d, / = 1.2 Hz, 1 H), 9.97 (s, 1 H). MS (ES+) m/z 512.2 [M+H]. N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5^8-trimethyl-9-oxido- 2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-fluoro-3- methylpicolinamide (39AA)

lnt-51 AA lnt-86AA 39AA

Step 1 : tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-fluoro-3-methylpi colinamido)- pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-86AA)

5-Fluoro-3-methylpicolinic acid (57.4 mg, 370 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (62.5 mg, 43.1 492 μιηοΐ) as well as dimethylformamide (0.25 M in toluene, 37 μί, 9.2 μιηοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-fluoro-3-methylpicolinoyl chloride as brown oil (50.4 mg, 78%). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AA, 92 mg, 193 μιτιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and Ν,Ν-diisopropylethylamine (50 mg, 67.6 μΐ _^ , 387 μιηοΐ) was added, followed by a solution of 5- fluoro-3-methylpicolinoyl chloride (vide supra, 50.4 mg, 290 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (118 mg, quant.). HPLC (method LCMS_fglm) t _R = 1.56 min. MS (ES+) m/z 613.2 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-fluoro-3-methylpi colin- amide (39AA) tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-fluoro-3-methylpi colinamido)- pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-86AA, 118 mg, 193 μπιοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (441 mg, 298 μL·, 3.87 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with ethyl acetate (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (60 mg). Enantiomeric purification was performed by chiral preparative HPLC (Reprosil Chiral NR, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired (-)-rotating first eluting enantiomer as a white solid (32 mg, 32%), and the opposite (+) -rotating enantiomer as a white solid (7 mg, 7%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.7 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.80 (s, 3 H), 1.86 (2s, 6 H), 2.29-2.44 (m, 1 H), 2.56-2.78 (m, 1 H), 2.84 (s, 3 H), 3.58-3.87 (m, 2 H), 4.15-4.24 (m, 1 H), 4.42 (br s, 2 H), 7.36-7.43 (m, 1 H), 7.50 (dd, / = 9.1, 10.9 Hz, 1 H), 8.34-8.41 (m, 2 H), 10.43 (s, 1 H). MS (ES+) m/z 513.2 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-3,5- dichloropicolinamide (40AA)

lnt-51 AAp lnt-87AA 40AA

Step 1: tert-Butyl ((4aR,5R,9R)-5-(6-(3,5-dichloropicolinam

difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexa

yl)carbamate (Int-87AA) 3,5-Dichloropicolinic acid (46.1 mg, 240 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (42.6 mg, 29.4 μL·, 336 μπιοΐ) as well as dimethylformamide (0.137 M in toluene, 43.8 μΐ _^ , 6 μπιοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3,5-dichloropicolinoyl chloride as yellow oil (50.6 mg, quant.). After that, tert- butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 μL·, 320 μιηοΐ) was added, followed by a solution of 3,5-dichloropicolinoyl chloride (vide supra, 50.6 mg, 240 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (115 mg), which was used in the next step without further purification. HPLC (method LCMS_fglm) t _R = 1.56 min. MS (ES+) m/z 649.1 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolin amide (40AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3,5-dichloropicolinamido)-3-fluoropyridin -2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-87AA, 115 mg, see preceeding step, 168 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (384 mg, 259 3.36 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (85 mg, 92% over 2 steps). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.7 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.78 (s, 3 H), 1.83 (2s, 6 H), 2.30-2.47 (m, 1 H), 2.54-2.79 (m, 1 H), 3.57-3.88 (m, 2 H), 4.17-4.30 (m, 1 H), 4.41 (br s, 2 H), 7.50 (dd, J = 9.3, 10.3 Hz, 1 H), 7.94 (s, 1 H), 8.34-8.43 (m, 1 H), 8.57 (d, J - 1.0 Hz, 1 H), 10.17 (s, 1 H). MS (ES+) m/z 549.0 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydiO-[l,4]tWazino[2 -f][lj2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide (41AA)

lnt-51 AAp lnt-88AA 41 AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-88AA) 3-Chloro-5-fluoropicolinic acid (42.1 mg, 240 μηιοΐ) was suspended in dichloromethane

(3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (42.6 mg, 29.4 μL·, 336 μιηοΐ) as well as dimethylformamide (0.137 M in toluene, 43.8 μΐ _^ , 6 μιηοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3-chloro-5-fluoropicolinoyl chloride as brown oil (49 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido-

2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 μί, 320 μπιοΐ) was added, followed by a solution of 3-chloro-5-fluoropicolinoyl chloride (vide supra, 49 mg, 240 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (110 mg), which was used in the next step without further purification. HPLC (method LCMS_gradient) t _R = 3.4 min. MS (ES+) m/z 633.1 [M+H]. Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5- fluoropicolinamide (41 A A) tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-fluoropicolinamido)-3-fluoropy ridin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thi

yl)carbamate (Int-88AA, 110 mg, see preceeding step, 168 μηιοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (384 mg, 259 μL, 3.36 mmol) was added. The solution was stirred for 2 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormefhane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as off-white powder (85 mg, 95% over 2 steps). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) tR = 1.5 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.78 (s, 3 H), 1.83 (2s, 6 H), 2.31-2.46 (m, 1 H), 2.55-2.78 (m, 1 H), 3.58-3.88 (m, 2 H), 4.18-4.29 (m, 1 H), 4.41 (br s, 2 H), 7.50 (dd, J = 8.9, 10.9 Hz, 1 H), 7.68 (dd, J = 2.4, 7.9 Hz, 1 H), 8.38 (dd, J = 3.0, 8.9 Hz, 1 H), 8.50 (d, J = 1.8 Hz, 1 H), 10.15 (s, 1 H). MS (ES+) m/z 533.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-chloro-3- methylpicolinamide (42AA)

lnt-51 AAp lnt-89AA 42AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-chloro-3-methylpicolinamido)-3-fluoropy ridin-2-yl)-3,3- difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4 ]thiazino[2,l-f] [l,2]thiazin-7- yl)carbamate (Int-89AA)

5-Chloro-3-methylpicolinic acid (42.1 mg, 240 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (42.6 mg, 29.4 μL·, 336 μπιοΐ) as well as dimethylformamide (0.137 M in toluene, 43.8 μί, 6 μπιοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-chloro-3-methylpicolinoyl chloride as brown oil (48 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μmol) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 μL·, 320 μιηοΐ) was added, followed by a solution of 5-chloro-3-methylpicolinoyl chloride (vide supra, 50.6 mg, 240 μπιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 90 min at room temperature. Then, an aqueous solution of sodium carbonate (10%, 15 mL) was added, the mixture was stirred for 10 min at room temperature. After phase separation, the aqueous layer was extracted the dichloromethane (2 x 10 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (61 mg, 58%). HPLC (method LCMS_gradient) t _R = 3.86 min. MS (ES+) m/z 629.2 [M+H] .

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-chloro-3- methylpicolinamide (42AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-chloro-3-methylpicolinamido)-3-fluoropy ridin-2-yl)- 3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-89AA, 61 mg, 97 μηιοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (192 mg, 130 μL·, 1.68 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (49 mg, 95%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmethyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.95 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.79 (s, 3 H), 1.84 (2s, 6 H), 2.31-2.46 (m, 1 H), 2.56-2.78 (m, 1 H), 2.81 (s, 3 H), 3.58-3.87 (m, 2 H), 4.18-4.28 (m, 1 H), 4.44 (br s, 2 H), 7.48 (dd, / = 8.9, 10.9 Hz, 1 H), 7.65-7.70 (m, 1 H), 8.35 (dd, J = 3.0, 8.9 Hz, 1 H), 8.49 (d, / = 1.8 Hz, 1 H), 10.44 (s, 1 H). MS (ES+) m/z 529.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2 -f][l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-chloropicolina mide (43AA)

lnt-51 AAp lnt-90AA 43AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-chloropicolinamido)-3-fluoropyridin-2-y l)-3,3-difluoro-

5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiaz ino[2,l-f][l,2]thiazin-7-yl)carbamate

(Int-90AA) 5-Chloropicolinic acid (75.6 mg, 480 μηιοΐ) was suspended in dichloromethane (6 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (85.2 mg, 58.8 μί, 672 μπιοΐ) as well as dimethylformamide (0.137 M in toluene, 87.6 μΐ _^ , 12 μπιοΐ) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-chloropicolinoyl chloride as yellow oil (88.8 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido-

2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (82.6 mg, 111.6 μL, 640 μιηοΐ) was added, followed by a solution of 5-chloropicolinoyl chloride (vide supra, 88.8 mg, 480 μιηοΐ) in dichloromethane (6 mL). The reaction mixture was stirred for 15 min at 0-5°C, followed by 3 h at room temperature. Then, an aqueous solution of sodium carbonate (10%, 15 mL) was added, the mixture was stirred for 10 min at room temperature. After phase separation, the aqueous layer was extracted the dichloromethane (2 x 10 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (110 mg), that was used in the next step without further purification. HPLC (method LCMS_gradient) t _R = 3.6 min. MS (ES+) m/z 615.1 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamid e (43AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-chloropicolinamido)-3-fluoropyridin-2-y l)-3,3-difluoro- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int-90AA, 110 mg, see preceeding step, 168 μιηοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (384 mg, 259 μί, 3.36 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), and aqueous ammonia (8% m/m, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 5 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 10:90) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (75 mg, 87% over 2 steps). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmefhyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.8 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.79 (s, 3 H), 1.84 (2s, 6 H), 2.30-2.45 (m, 1 H), 2.56-2.79 (m, 1 H), 3.58-3.88 (m, 2 H), 4.17-4.28 (m, 1 H), 4.43 (br s, 2 H), 7.51 (dd, / = 8.9, 10.9 Hz, 1 H), 7.91 (dd, / = 2.3, 8.4 Hz, 1 H), 8.27 (dd, J - 0.6, 8.5 Hz, 1 H), 8.39 (dd, J = 3.0, 8.9 Hz, 1 H), 8.65 (dd, J = 0.6, 2.4 Hz, 1 H), 10.26 (s, 1 H). MS (ES+) mJz 515.1 [M+H] .

6-((6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9 -oxido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)carbamoyl)iiicotiiiic acid (44AA)

Step 1 : tert-Butyl 6-((6-((4aR,5R,9R)-7-((tert-butoxycarbonyl)amino)-3,3-difluo ro-5,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin- 2-yl)carbamoyl)nicotinate (Int-91 A A)

5-(tert-Butoxycarbonyl)picolinic acid (70.4 mg, 315 μιηοΐ) was suspended in dichloromethane (5 mL), the suspension cooled to - 10-0°C (ethanol / ice bath) and 1-chloro- N,N,2-trimethylpropenylamine (98.3 mg, 736 μηιοΐ) was added. After 60 min stirring at - 10-0°C, a solution of tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-7-yl)carbamate (Int- 51AAp, 100 mg, 210 μιηοΐ) and N,N-diisopropylethylamine (136 mg, 184 μί, 1.05 mmol) in dichloromethane (3 mL) was added over 5 min at -4°C. The reaction mixture was stirred at 0- 5°C for 30 min and allowed to warm to room temperature. Then, an aqueous solution of sodium carbonate ( 10%, 15 mL) was added, the mixture was stirred for 10 min at room temperature. After phase separation, the aqueous layer was extracted the dichloromethane (2 x 20 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 30:70) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (140 mg, 98%). HPLC (method LCMS_gradient) t _R = 4.0 min. ^! H NMR (CDC1 ₃ , 300 MHz): δ 1.50 (s, 9 H), 1.65 (s, 9 H), 1.83 (s, 3 H), 1.84 (s, 3 H), 1.97 (s, 3 H), 2.53-2.85 (m, 2 H), 3.65-3.92 (m, 2 H), 4.56-4.65 (m, 1 H), 7.64 (dd, J = 9.0, 10.7 Hz, 1 H), 8.36 (d, / = 8.1 Hz, 1 H), 8.45-8.55 (m, 2 H), 9.20-9.24 (m, 1 H), 10.51 (s, 1 H), 11.37 (s, 1 H). MS (ES+) m/z 681.3 [M+H].

Step 2: 6-((6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-ox ido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)carbamoyl)nicotinic acid (44 AA) tert-Butyl 6-((6-((4aR,5R,9R)-7-((tert-butoxycarbonyl)amino)-3,3-difluo ro-5,8,8- trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[ 1 ,4]thiazino[2, 1-f] [ 1 ,2]thiazin-5-yl)-5-fluoropyridin- 2-yl)carbamoyl)nicotinate (Int-91AA, 140 mg, 206 μιηοΐ) was dissolved in dichloromethane (7 mL) and trifluoroacetic acid (703 mg, 475 μL·, 6.17 mmol) was added. The solution was stirred for 42 h at room temperature. After that, the mixture was concentrated in water, the foamy residue was redissolved in water (5 mL). Aqueous sodium hydroxide solution (1M) was added until the pH was adjusted to 11. Then, acetic acid was added until the pH was 5. The formed precipitate was filtered off and washed thoroughly and subsequently with water, acetonitrile, and diethyl ether to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (86 mg, 80%). HPLC (method LCMS_gradient) t _R = 1.4 min. ^X H NMR (d6-DMSO, 300 MHz): δ 1.69 (s, 3 H), 1.71 (s, 3 H), 1.74 (s, 3 H), 2.38-2.42 (m, 1 H), 2.55-2.80 (m, 1 H), 3.42 (br s, 2 H), 3.46-3.70 (m, 2 H), 4.04-4.12 (m, 1 H), 6.83 (br s, 1 H), 7.85 (dd, J = 8.9, 11.5 Hz, 1 H), 8.20- 8.30 (m, 2 H), 8.47 (dd, = 2.0, 8.1 Hz, 1 H), 9.14-9.17 (m, 1 H), 10.51 (s, 1 H). MS (ES+) m/z 525.1 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-o xido-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-3-chloro-5- (difluoromethoxy)picolinamide (45AA)

lnt-51 AAp lnt-92AA 45AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro-[l,4]thiazino- [2, l-f] [l,2]thiazin-7-yl)carbamate (Int-92AA)

3-Chloro-5-(difluoromethoxy)picolinic acid (56.3 mg, 252 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (44.8 mg, 30.9 μΐ _^ , 353 μηιοΐ) as well as dimethylformamide (0.242 M in toluene, 26 μΐ _^ , 6.3 μηιοΐ) were added. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3-chloro-5-(difluoromethoxy)picolinoyl chloride as red oil (58.4 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro- 5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[l,4]thiazino [2,l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μπιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 μΐ _^ , 320 μιηοΐ) was added, followed by a solution of 3-chloro-5-(difluoromethoxy)picolinoyl chloride (vide supra, 58.4 mg, 252 μπιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 45 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 35:65) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (109 mg, 95%). HPLC (method LCMS_fglm) t _R = 1.49 min. MS (ES+) mJz 681.3 [M+H]. Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(difluor o- methoxy)picolinamide (45 AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro-[l,4]thiazino- [2, l-f] [l,2]thiazin-7-yl)carbamate (Int-92AA, 109 mg, 160 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (384 mg, 259 μί, 3.36 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 5:95) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (91 mg, 98%). For transfer purpose, the material was dissolved in dichloromethane (1 mL) and tert-butylmefhyl ether (3 mL) and concentrated and dried in vacuo at 40°C / 5 mbar. HPLC (method LCMS_gradient) t _R = 1.6 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 1.78 (s, 3 H), 1.82 (s, 3 H), 1.83 (s, 3 H), 2.31-2.46 (m, 1 H), 2.55-2.78 (m, 1 H), 3.58-3.87 (m, 2 H), 4.18-4.29 (m, 1 H), 4.40 (br s, 2 H), 6.68 (t, / = 71.2 Hz, 1 H), 7.50 (dd, / = 8.9, 10.9 Hz, 1 H), 7.71 (d, J = 2.2 Hz, 1 H), 8.39 (dd, .7 = 3.0, 8.9 Hz, 1 H), 8.49 (d, 7 = 2.4 Hz, 1 H), 10.19 (s, 1 H). MS (ES+) m/z 581.2 [M+H] . N-(6-((4aR,5R,9R)-7-Amino-3,3-dinuoro-5,8,8-trimethyl-9-oxid o-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f][l,2]thiazin-5-yl)-5-fluoropyr idin-2-yl)-5-(2,2- difluoroethoxy)pyrazine-2-carboxamide (46AA)

lnt-51AAp lnt-93AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-(2,2-difluoroethoxy)pyrazine-2-carboxam ido)-3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro-[l,4]thiazino- [2, 1 -f] [ 1 ,2] thiazin-7-yl)carbamate (Int-93 A A) 5-(2,2-Difluoroethoxy)pyrazine-2-carboxylic acid (51.4 mg, 252 μιηοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5 °C (ice bath) and oxalyl chloride (44.8 mg, 30.9 μί, 353 μιηοΐ) as well as dimethylformamide (0.242 M in toluene, 26 μL, 6.3 μιηοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-(2,2-difluoroethoxy)pyrazine-2-carboxylic acid chloride as yellow oil (56.1 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 μL, 320 μπιοΐ) was added, followed by a solution of 5-(2,2- difluoroethoxy)pyrazine-2-carboxylic acid chloride (vide supra, 56.1 mg, 252 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 75 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 35:65) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (104 mg, 94%). HPLC (method LCMS_fglm) t _R = 1.49 min. MS (ES+) m/z 662.3 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(2,2-difluoroetho xy)- pyrazine-2-carboxamide (46AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-(2,2-difluoroethoxy)pyrazine-2-carboxam ido)-3- fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3 ,4,4a,5,8-hexahydro- [l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-93AA, 104 mg, 157 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (384 mg, 259 μί, 3.36 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 5:95) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (88 mg, 99%). HPLC (method LCMS_gradient) t _R = 1.7 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.79 (s, 3 H), 1.83 (s, 3 H), 1.84 (s, 3 H), 2.29-2.44 (m, 1 H), 2.55-2.79 (m, 1 H), 3.57-3.87 (m, 2 H), 4.16-4.27 (m, 1 H), 4.41 (br s, 2 H), 4.68 (dt, 7 = 4.0, 13.3 Hz, 2 H), 6.18 (tt, J = 4.0, 55.0 Hz, 1 H), 7.51 (dd, 7 = 9.0, 10.8 Hz, 1 H), 8.34 (d, J = 1.4 Hz, 1 H), 8.38 (dd, J - 3.0, 8.9 Hz, 1 H), 9.04 (d, J = 1.2 Hz, 1 H), 9.94 (s, 1 H). MS (ES+) m/z 562.3 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9- oxido-2,3,4,4a,5,8- hexahydiO-[l,4]tWazino[2 -f][lj2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(prop-l-yn-l- yl)picolinamide (47AA)

lnt-51AAp Int-

Step 1 : tert-Butyl ((4aR,5R,9R)-3,3-difiuoro-5-(3-fluoro-6-(5-(prop-l-yn-l-yl)p icolinamido)- pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro -[l,4]thiazino[2, l-f] [l,2]thiazin-7- yl)carbamate (Int-94AA) 5-(Prop- l-yn- l-yl)picolinic acid (30.5 mg, 189 μιτιοΐ) was suspended in dichloromethane

(3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (33.6 mg, 23.2 μL·, 265 μπιοΐ) as well as dimethylformamide (0.242 M in toluene, 19.5 μί, 4.7 μηιοΐ) were added. The mixture was stirred for 3 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-(prop-l-yn- l-yl)picolinoyl chloride as yellow oil (34 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5 ,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 60 mg, 126 μιτιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (31 mg, 41.9 μί, 240 μιτιοΐ) was added, followed by a solution of 5- (prop-l-yn-l-yl)picolinoyl chloride (vide supra, 34 mg, 189 μηιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 75 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 35:65) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (85 mg), that was used in the next without further purification. HPLC (method LCMS_fglm) t _R = 1.57 min. MS (ES+) m/z 619.3 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-3,3-difluoro-5,8,8-trimethyl-9-oxi do-2,3,4,4a,5,8- hexahydro-[l,4]thiazino[2,l-f] [l,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-(prop-l-yn-l-yl)p icolin- amide (47 AA) tert-Butyl ((4aR,5R,9R)-3,3-difluoro-5-(3-fluoro-6-(5-(prop-l-yn-l- yl)picolinamido)pyridin-2-yl)-5,8,8-trimethyl-9-oxido-2,3,4, 4a,5,8-hexahydro-[l,4]thiazino[2, l f] [l,2]thiazin-7-yl)carbamate (Int-94AA, 85 mg, see preceeding step, 126 μη οΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (288 mg, 194 μΐ _^ , 2.52 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0- 5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 7:93) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (61 mg, 93% over 2 steps). HPLC (method LCMS_gradient) t _R = 1.9 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.79 (s, 3 H), 1.84 (2s, 6 H), 2.14 (s, 3 H), 2.29-2.45 (m, 1 H), 2.56-2.79 (m, 1 H), 3.58-3.88 (m, 2 H), 4.16-4.26 (m, 1 H), 4.41 (br s, 2 H), 7.50 (dd, / = 8.9, 10.9 Hz, 1 H), 7.88 (dd, / = 1.9, 8.2 Hz, 1 H), 8.22 (d, J = 8.1 Hz, 1 H), 8.40 (dd, J = 3.0, 8.9 Hz, 1 H), 8.66 (d, J = 1.4 Hz, 1 H), 10.35 (s, 1 H). MS (ES+) m/z 519.3 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5, 8-tetrahydro-2H- spiro[[l,4]thiazino[2 -fl[l,2]thiazine-3,l'-cyclopropan]-5-yl)-5-fluoropyridin-2-y l)-5- cyano-3-methylpicolinamide (48AA)

lnt-63AA lnt-95AA 48AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]th iazino[2,l-f][l,2]thiazine-3,l'- cyclopropan]-7-yl)carbamate (Int-95AA)

5-Cyano-3-methylpicolinic acid (52.2 mg, 322 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (57.2 mg, 39.5 μL·, 451 μιηοΐ) as well as dimethylformamide (0.242 M in toluene, 33 μί, 8.0 μιηοΐ) were added. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (58.2 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-4,4a,5,8- tetrahydro-2H-spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, l'-cyclopropan]-7-yl)carbamate (Int- 63AA, 100 mg, 215 μπιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (55.5 mg, 75 μί, 430 μιηοΐ) was added, followed by a solution of 5-cyano-3-methylpicolinoyl chloride (vide supra, 58.2 mg, 322 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 45 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 60:40) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (137 mg), that was used in the next step without further purification. HPLC (method LCMS_fglm) t _R = 1.45 min. MS (ES+) m/z 610.3 [M+H].

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3,r-cyclopropan]-5-y l)-5-fluoropyridin-2-yl)-5-cyano-3- methylpicolinamide (48AA) tert-Butyl ((4aR,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]th iazino[2,l-f][l,2]thiazine-3,l'- cyclopropan]-7-yl)carbamate (Int-95AA, 137 mg, 215 μιτιοΐ, see preceding step) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (490 mg, 331 μL·, 4.3 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0- 5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 7:93) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white powder (100 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 60/40, flow 1.0 mL/min) to yield the desired major, first eluting enantiomer as a white solid (58 mg, 52% over 2 steps), and the opposite, minor enantiomer as a white solid (28 mg, 25%). HPLC (method LCMS_gradient) t _R = 1.6 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.07-0.17 (m, 1 H), 0.26-0.35 (m, 1 H), 0.39-0.48 (m, 1 H), 0.53-0.62 (m, 1 H), 0.89-0.99 (m, 1 H), 1.83 (s, 3 H), 1.90 (s, 3 H), 1.92 (s, 3 H), 2.46 (dd, J = 1.8, 13.1 Hz, 1 H), 2.80 (dd, J = 13.2, 13.2 Hz, 1 H), 2.87 (s, 3 H), 3.96-4.08 (m, 2 H), 5.15 (br s, 2 H), 7.52 (dd, J = 8.9, 10.9 Hz, 1 H), 7.96-7.99 (m, 1 H), 8.35 (dd, / = 3.0, 8.9 Hz, 1 H), 8.78-8.81 (m, 1 H), 10.43 (s, 1 H). MS (ES+) m/z 510.3 [M+H] ,

N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5, 8-tetrahydro-2H- spiro[[l,4]thiazino[2 -f][l,2]thiazine-3,l' yclopropan]-5-yl)-5-fluoropyridin-2-yl)-5- cyano-3-methylpicolinamide (48AB)

lnt-63AB lnt-95AB 48AB

Step 1 : tert-Butyl ((4aS,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)- 5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]th iazino[2,l-f][l,2]thiazine-3 cyclopropan]-7-yl)carbamate (Int-95AB)

5-Cyano-3-methylpicolinic acid (51.1 mg, 377 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (67 mg, 46 μΐ _^ , 528 μιηοΐ) as well as dimethylformamide (0.242 M in toluene, 39 μL·, 9.4 μιηοΐ) were added. The mixture was stirred for 15 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 5-cyano-3-methylpicolinoyl chloride as red oil (68.1 mg, quant.). After that, tert- butyl ((4aS,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-4,4a,5,8- tetrahydro-2H-spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-7-yl)carbamate (Int- 63AB, 117 mg, 251 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (65 mg, 88 μL·, 503 μιηοΐ) was added, followed by a solution of 5-cyano-3-methylpicolinoyl chloride (vide supra, 68.1 mg, 377 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 90 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature. The resulting suspension was filtered, the precipitate was washed with dichloromethane (3 x 5 mL) and dried to give the first crop of the title compound. The combined filtrate was concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 1 :99 to 3:97) to yield, after drying in vacuo (40°C, 5 mbar), the second crop of the title compound. Both crops were combined to give the title compound as a light brown solid (141 mg, 92%). HPLC (method LCMS_fglm) t _R = 1.40 min. MS (ES+) m/z 610.3 [M+H].

Step 2: N-(6-((4aS,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-5-cyano-3- methylpicolinamide (48AB) tert-Butyl ((4aS,5R,9R)-5-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyr idin-2-yl)-

5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4 ]thiazino[2,l-f][l,2]thiazine-3,l'- cyclopropan]-7-yl)carbamate (Int-95AB, 141 mg, 231 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifhioro acetic acid (573 mg, 387 μL, 5.0 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 2:98 to 7:93) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (110 mg). Enantiomeric purification was performed by chiral preparative HPLC (Reprosil Chiral NR, 250*4.6 mm*5 μιη, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 60/40, flow 1.0 niL/min) to yield the desired (-i-)-rotating second eluting enantiomer as a light brown solid (68 mg, 57%), and the opposite (-)-rotating first eluting enantiomer as a light brown solid (22 mg, 18%). HPLC (method LCMS_gradient) t _R = 0.86 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.29-0.49 (m, 3 H), 0.69-0.83 (m, 2 H), 1.81 (s, 3 H), 1.93 (s, 3 H), 1.98 (s, 3 H), 2.40 (dd, J = 13.9, 13.9 Hz, 1 H), 2.79-2.86 (m, 1 H), 2.83 (s, 3 H), 3.83-3.92 (m, 2 H), 6.17 (br s, 2 H), 7.55 (dd, / = 9.1, 10.3 Hz, 1 H), 7.95-7.98 (m, 1 H), 8.44 (dd, J = 3.0, 8.9 Hz, 1 H), 8.80 (d, J = 1.4 Hz, 1 H), 11.00 (s, 1 H). MS (ES+) m/z 510.2 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5, 8-tetrahydro-2H- spiro[[l,4]thiazino[2 -f][l,2]thiazine-3,l' yclopropan]-5-yl)-5-fluoropyridin-2-yl)-3- chloro-5-cyanopicolinamide (49AA)

lnt-63AA lnt-96AA 49AA

Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-cyanopicolinamido)-3-fluoropyr idin-2- yl)-5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l, 4]thiazino[2,l-f][l,2]thiazine-3, l'- cyclopropan]-7-yl)carbamate (Int-96AA)

3-Chloro-5-cyanopicolinic acid (58.8 mg, 322 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (57.2 mg, 39.5 μL·, 451 μιηοΐ) as well as dimethylformamide (0.242 M in toluene, 33 iL, 8 μιηοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3-chloro-5-cyanopicolinoyl chloride as brown oil (64.8 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethy l-9-oxido-4,4a,5,8- tetrahydro-2H-spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-7-yl)carbamate (Int- 63AA, 100 mg, 215 μπιοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0- 5°C (ice bath) and N,N-diisopropylethylamine (55.5 mg, 75 μΐ _^ , 430 μιηοΐ) was added, followed by a solution of 3-chloro-5-cyanopicolinoyl chloride (vide supra, 64.8 mg, 322 μιηοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 45 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 70:30) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a light yellow solid (137 mg, 99%). HPLC (method LCMS_fglm) t _R = 1.38 min. MS (ES+) m/z 630.3 [M+H] . Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5- cyanopicolinamide (49 AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-cyanopicolinam

5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spko[[l,4] miazino[2,l-fl

cyclopropan]-7-yl)carbamate (Int-96AA, 137 mg, 214 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifluoro acetic acid (490 mg, 331 μί, 4.3 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0-5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11-12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 8:92) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (97 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μηι, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 60/40, flow 1.0 mL/min) to yield the desired first eluting enantiomer as an off-white solid (67 mg, 58%), and the opposite second eluting enantiomer as a light brown solid (26 mg, 22%). HPLC (method LCMS_gradient) tR =

I.5 min. ^X H NMR (CDC1 ₃ , 300 MHz): δ 0.02-0.10 (m, 1 H), 0.27-0.36 (m, 1 H), 0.40-0.49 (m, 1 H), 0.51-0.60 (m, 1 H), 0.84-0.96 (m, 1 H), 1.87 (s, 3 H), 1.91 (s, 3 H), 1.95 (s, 3 H), 2.42-2.51 (m, 1 H), 2.80 (dd, J = 13.2, 13.2 Hz, 1 H), 3.92-4.02 (m, 2 H), 4.62 (br s, 2 H), 7.57 (dd, J = 9.0,

I I .0 Hz, 1 H), 8.21 (d, J = 1.8 Hz, 1 H), 8.41 (dd, J = 3.0, 8.9 Hz, 1 H), 8.85 (d, 7 = 1.8 Hz, 1 H), 10.16 (s, 1 H). MS (ES+) m/z 530.3 [M+H].

N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5, 8-tetrahydro-2H- spiro[[l,4]thiazino[2 -i][l,2]thiazine-3,l'-cyclopropan]-5-yl)-5-fluoropyridin-2-y l)-3- chloro-5-(difluoromethoxy)picolinamide (50AA)

lnt-63AA lnt-97AA 50AA Step 1 : tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3- fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahy dro-2H-spiro[[l,4]thiazino[2, l- f] [ 1 ,2]thiazine-3, l'-cyclopropan]-7-yl)carbamate (Int-97AA)

3-Chloro-5-(difluoromethoxy)picolinic acid (72 mg, 322 μηιοΐ) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (57.2 mg, 39.5 μί, 451 μπιοΐ) as well as dimethylformamide (0.242 M in toluene, 33 μΐ _^ , 8 μπιοΐ) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) to afford 3-chloro-5-(difluoromethoxy)picolinoyl chloride as yellow oil (78 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8- trimethyl-9-oxido-4,4a,5,8-tetrahydro-2H-spiro[[l,4]thiazino [2,l-f] [l,2]thiazine-3, - cyclopropan]-7-yl)carbamate (Int-63AA, 100 mg, 215 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (55.5 mg, 75 μΐ _^ , 430 μπιοΐ) was added, followed by a solution of 3-chloro-5-(difluoromethoxy)picolinoyl chloride (vide supra, 78 mg, 322 μπιοΐ) in dichloromethane (3 mL). The reaction mixture was stirred for 45 min at 0-5°C. Then, methanol (5 mL) was added, the mixture was stirred for 15 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 60:40) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (137 mg, 95%). HPLC (method LCMS_fglm) t _R = 1.48 min. MS (ES+) mJz 671.3 [M+H] ,

Step 2: N-(6-((4aR,5R,9R)-7-Amino-5,8,8-trimethyl-9-oxido-4,4a,5,8-t etrahydro-2H- spiro[[l,4]thiazino[2,l-f][l,2]thiazine-3, -cyclopropan]-5-yl)-5-fluoropyridin-2-yl)-3-chloro-5- (difluoromethoxy)picolinamide (50AA) tert-Butyl ((4aR,5R,9R)-5-(6-(3-chloro-5-(difluoromethoxy)picolinamido) -3- fluoropyridin-2-yl)-5,8,8-trimethyl-9-oxido-4,4a,5,8-tetrahy dro-2H-spiro[[l,4]thiazino[2, l- f] [l,2]thiazine-3,l'-cyclopropan]-7-yl)carbamate (Int-97AA, 137 mg, 204 μιηοΐ) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (490 mg, 331 μL·, 4.3 mmol) was added. The solution was stirred for 17 h at room temperature. After that, the mixture was cooled to 0- 5°C (ice bath), water (20 mL) and aqueous ammonia (2 M, 6 mL) was added cautiously upon stirring, until the pH of the aqueous layer was 11- 12. After phase separation, the aqueous layer was extracted with dichloromethane (2 x 50 mL), the combined extracts were dried (sodium sulfate) and concentrated in vacuo The residue was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 0: 100 to 8:92) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (108 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μπι, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 60/40, flow 1.0 mL/min) to yield the desired first eluting enantiomer as an off-white solid (80 mg, 69%), and the opposite second eluting enantiomer as a light brown solid (25 mg, 21%). HPLC (method LCMS_gradient) t _R = 1.8 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 0.06-0.16 (m, 1 H), 0.26-0.36 (m, 1 H), 0.39-0.47 (m, 1 H), 0.52-0.61 (m, 1 H), 0.89-0.98 (m, 1 H), 1.83 (s, 3 H), 1.90 (s, 3 H), 1.92 (s, 3 H), 2.42- 2.49 (m, 1 H), 2.79 (dd, = 13.3, 13.3 Hz, 1 H), 3.96-4.06 (m, 2 H), 5.67 (br s, 2 H), 6.68 (t, J = 71.1 Hz, 1 H), 7.52 (dd, J = 8.9, 10.9 Hz, 1 H), 7.72 (d, = 2.4 Hz, 1 H), 8.39 (dd, / = 3.0, 8.9 Hz, 1 H), 8.48 (d, J = 2.2 Hz, 1 H), 10.19 (s, 1 H). MS (ES+) m/z 571.2 [M+H].

N-(6-((3aS,4R,8R)-6-Amino-4,7,7-trimethyl-8-oxido-3,3a,4, 7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4 -chloro-l-(difluoromethyl)-lH pyrazole-3-carboxamide (51AB)

lnt-39AB lnt-98AB 51 AB

Step 1: tert-Butyl ((3aS,4R,8R)-4-(6-(4-chloro- l-(difluorometliyl)- lH-pyrazole-3-carboxamido)-

3-fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-te trahydro-2H-isothiazolo[l,5- a] [ 1 ,4]thiazin-6-yl)carbamate (Int-98AB)

4-Chloro- l-(difluoromethyl)-lH-pyrazole-3-carboxylic acid (111 mg, 565 μιηοΐ) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5°C (ice bath) and oxalyl chloride (100 mg, 791 μιηοΐ) as well as dimethylformamide (0.308 M in toluene, 76 μΐ _^ , 23 μιηοΐ) were added. The mixture was stirred for 3.5 h at room temperature. Then, it was concentrated in vacuo (40°C, 5 mbar) and dried azeotropically by addition of toluene (5 mL) followed by concentration in vacuo to afford 4-chloro-l-(difluoromethyl)-lH-pyrazole-3-carbonyl chloride as light yellow oil (121 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin- 2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothia zolo[l,5-a][l,4]thiazin-6- yl)carbamate (Int-39AB, 100 mg, 235 μιηοΐ) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5°C (ice bath) and N,N-diisopropylethylamine (46 mg, 62 μL, 353 μπιοΐ) and 4-(dimethylamino)pyridine (2.9 mg, 23.5 μιτιοΐ) were added, followed by a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 61 mg, 282 μιηοΐ) in dichloromethane (5 mL). The reaction mixture was stirred for 75 min at room temperature. Then, additional portions of N,N-diisopropylethylamine (46 mg, 62 μL, 353 μιτιοΐ) and a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 60 mg, 280 μιηοΐ) in dichloromethane (5 mL) were added, the mixture was stirred for 16 h at room temperature. After that, a third portion of N,N-diisopropylethylamine (46 mg, 62 μί, 353 μπιοΐ) and a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 61 mg, 282 μιηοΐ) in dichloromethane (5 mL) were added, the mixture was stirred for a further 1 h at room temperature. Aqueous sodium carbonate solution (10% m/m, 25 mL) was added, the aqueous phase was extracted with dichloromethane (2 x 25 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 24 g, eluting with ethyl acetate / dichloromethane, gradient 35:65 to 100:0) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as an off-white solid (71 mg, 50% yield). HPLC (method LCMS_fglm) t _R = 1.31 min. MS (ES+) m/z 604.4 [M+H] . Step 2: N-(6-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-t etrahydro-2H- isothiazolo[ 1,5-a] [ 1 ,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro- l-(difluoromethyl)- 1H- pyrazole-3-carboxamide (51AB) tert-Butyl ((3aS,4R,8R)-4-(6-(4-chloro- l-(difluoromethyl)-lH-pyrazole-3-carboxamido)- 3-fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetra hydro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate (Int-98AB, 71 mg, 118 μηιοΐ) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (268 mg, 181 μL·, 2.35 mmol) was added. The solution was stirred for 18 h at room temperature. After that, the mixture was concentrated in vacuo, the residue was redissolved in methanol (5 mL), aqueous ammonia (25% m/m, 200 μΕ) was added, stirred for 5 min at room temperature, and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with 2 M ammonia in methanol / dichlormethane, gradient 1:99 to 6:94) to yield, after drying in vacuo (40°C, 5 mbar), the title compound as a white solid (60 mg). Enantiomeric purification was performed by chiral preparative HPLC (Chiralpak AD, 250*4.6 mm*5 μπι, isocratic, n-heptane / (ethanol + 0.01% ammonium acetate) 80/20, flow 1.0 mL/min) to yield the desired second eluting enantiomer as an off-white powder (40 mg, 67%), and the opposite first eluting enantiomer as an off white powder (10 mg, 17%). HPLC (method LCMS_gradient) t _R = 1.4 min. 1H NMR (CDC1 ₃ , 300 MHz): δ 1.62- 1.78 (m, 1 H), 1.80 (s, 3 H), 1.93 (s, 3 H), 2.03-2.14 (m, 1 H), 2.06 (s, 3 H), 3.52 (dd, 7 = 7.5, 10.5 Hz, 1 H), 3.71 (ddd, / = 5.0, 10.6, 10.6 Hz, 1 H), 4.23 (ddd, J = 2.1, 7.1, 12.4 Hz, 1 H), 7.24 (t, / = 59.8 Hz, 1 H), 7.58 (dd, J = 8.9, 10.3 Hz, 1 H), 7.97 (s, 1 H), 8.43 (dd, J = 3.0, 8.9 Hz, 1 H), 9.35 (s, 1 H). MS (ES+) m/z 504.3 [M+H].

Examples 2BB, 3AB, 3BA, 3BB, 4AB, 4BA, 4BB, 5AA, 5AB, 5BA, 5BB, 6AB, 6BA, 6BB, 7AB, 7BA, 7BB, 8AB, 8BA, 8BB, 17AB, 17BA, 17BB, 18AA, 18AB, 18BA, 18BB, 19AA, 19AB, 19BA, 20AA, 20AB, 20BA, 20BB, 21AA, 21AB, 21BA, 21BB, 22AA, 22AB, 22BA, 22BB, 23AA, 23AB, 23BA, 23BB, 24AA, 24AB, 24BA and 24BB can analogously be synthesized.