WO2016001266A1

WO2016001266A1 - Fluoro-[1,3]oxazines as bace1 inhibitors

Info

Publication number: WO2016001266A1
Application number: PCT/EP2015/064913
Authority: WO
Inventors: Wolfgang Guba; Wolfgang Haap; Ulrike Obst Sander; Jens-Uwe Peters; Thomas Woltering
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.; Siena Biotech S.P.A.
Priority date: 2014-07-04
Filing date: 2015-07-01
Publication date: 2016-01-07

Abstract

The present invention provides a compound of formula I having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

Description

FLUORO-[l,3]OXAZINES AS 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 1 2

et al. and Selkoe ). 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 microtubule-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 ^ΤΡβ). 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 (PSENl, PSEN2). The β-secretase (BACEl, 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. ). It is expressed in many tissues of the human organism but its level is especially high in the CNS. Genetic ablation of the BACEl 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 BACEl no Αβ-peptides are produced (Luo et al ⁴ and Roberds et al.⁵). 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 BACEl alleles (McConlogue et al.⁶). It is thus presumed that inhibitors of BACEl activity can be useful agents for therapeutic intervention in Alzheimer' s disease (AD).

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. Inhibitors of BACEl can in addition be used to treat the following diseases:

7 8

IBM (inclusion body myositis) (Vattemi G. et al. ), Down' s Syndrome (Barbiero L. et al. ), Wilson' s Disease (Sugimoto I. et al.⁹), Whipple's disease (Desnues B. et al.¹⁰), Spinocerebellar Ataxia 1 and Spinocerebellar Ataxia 7 (Gatchel J.R. et al.¹¹ Dermatomyositis (Greenberg S.A. et a/⁷² and Greenberg S.A. et al.¹³), Kaposi Sarcoma (Lagos D. et al.¹⁴), Glioblastoma multiforme¹⁵, Rheumatoid arthritis (Ungethuem U. et al.¹⁶), Amyotrophic lateral sclerosis (Koistinen H. et al.¹⁷

18 19 20 and Li Q.X. et al. ), Huntington's Disease (Kim Y.J. et al. and Hodges A. et al. ), Multiple

21 22

Mieloma (Kihara Y. et al. ), Malignant melanoma (Talantov D. et al. ) Sjogren syndrome

23 24

(Basset C. et al. ), Lupus erythematosus (Grewal P.K. et al. ), Macrophagic myofasciitis,

25 juvenile idiopathic arthritis, granulomatous arthritis, Breast cancer (Hedlund M. et al. and Kondoh K. et al. ²⁶ ), Gastrointestinal diseases (Hoffmeister A. et al. ²⁷ ),

28

Autoimmune/inflammatory diseases (Woodard-Grice A.V. et al. ), Rheumatoid Arthritis

29 30

(Toegel S. et al. ), Inflammatory reactions (Lichtenthaler S.F. et al. ), Arterial Thrombosis

31

(Merten M. et al. ), Cardiovascular diseases such as Myocardial infarction and stroke (Maugeri

32 33

N. et al. and Graves disease (Kiljanski J. et al. ). WO2013110622, WO2012168175, WO2012168164, WO2012156284, WO2013142613 and PCT/EP2014/050645³⁴ describe certain oxazines as BACEl and/or BACE2 inhibitors. 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. Furthermore the use of compounds of formula I in the treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease and Wilson's Disease. The novel compounds of formula I have improved pharmacological properties.

Field of the Invention

The present invention provides fluoro-[l,3]oxazines 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, BACE1 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 its 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.

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 (ie/t-butyl), isopentyl,

2- ethyl -propyl (2-methyl -butyl), 1,2-dimethyl -propyl and the like. Particular "Ci_6-alkyl" are "Ci_

3- alkyl". Examples are methyl and ethyl. A specific group is methyl (CH₃).

The term "halogen-Ci-6-alkyl", alone or in combination with other groups, refers to C_1-6- 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. Specific groups are CF₃ and CHF₂.

The term "-0-halogen-Ci_6-alkyl", alone or in combination with other groups, refers to"halogen-Ci_6-alkyl" as defined herein linked via -0-, for example, but not limited to, groups like -0-CH₂-CF₃ and -0-CH₂-CHF_2.

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

The term "halogen", alone or in combination with other groups, denotes chloro (CI), iodo (I), fluoro (F) and bromo (Br). Particular "halogen" is Br and CI. A specific group is Br.

The term "heteroaromatic ring", 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, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[l]pyrindinyl and the like.

The term "5-membered heteroaromatic ring", alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 5-membered ring and containing 1, 2 or 3 heteroatoms, in particular 2 heteroatoms, individually selected from N, O and S, in particular N and O, for example, but not limited to, groups like isoxazolyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, thiazolyl and triazolyl. Particular "5-membered heteroaromatic ring" are groups containing 2 heteroatoms, in particular N and O or 2N, for example, but not limited to, isoxazolyl and pyrazolyl. Specific groups are isoxazol-3-yl, isoxazol-5-yl and pyrazol-l-yl.

The term "6-membered heteroaromatic ring", alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 6-membered ring and containing 1, 2 or 3 heteroatoms individually selected from N, O and S, in particular N, for example, but not limited to, groups like pyridinyl, pyrazinyl and pyrimidinyl.

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 "-0-C₂-6-alkynyl", alone or in combination with other groups, refers to"C_2-6- alkynyl" as defined herein linked via -0-, for example, but not limited to, a group -0-CH₂-C≡C- CH₃.

The term "Ci-6-alkoxy", alone or in combination with other groups, refers to"Ci_6-alkyl" as defined herein linked via -0-, for example, but not limited to, a group -0-CH₃. The term "-0-Ci_6-alkoxy", alone or in combination with other groups, refers to"C_1-6- alkoxy" as defined herein linked via -0-, for example, but not limited to, a group -0-CH₂-0- CH₃.

The term "halogen-Ci-6-alkoxy", alone or in combination with other groups, refers to"C_1-6- alkoxy" as defined herein substituted by a halogen as defined herein. Particular groups are fluoro-Ci_6-alkoxy, for example, but not limited to, a group -0-CHF₂.

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. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid, in particular trifluoroacetic acid. 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" (IC₅₀) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC₅₀ values can be converted logarithmically to pIC₅o values (-log IC₅₀), in which higher values indicate exponentially greater potency. The IC₅₀ value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC₅₀ value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation 35. 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 "protecting group" denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" (here also P¹) denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-fluorenylmethoxycarbonyl (FMOC), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, iert-butoxycarbonyl (BOC), and trifluoro acetyl. Further examples of these groups are found in several books. . The term "protected amino group" refers to an amino group substituted by an amino-protecting groups. Particular amino-protecting groups are ie/t-butoxycarbonyl group and dimethoxytrityl.

The term "leaving group" denotes the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include halogen, in particular bromo, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, and acyloxy.

The term "aromatic" denotes the conventional idea of aromaticity as defined in the literature 37

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 Het is a 5-membered heteroaromatic ring containing 2 heteroatoms,

Het is a 5-membered or a 6-membered heteroaromatic ring unsubstituted or substituted by one or two R¹,

R¹ is each individually selected from the group consisting of Ci_6-alkoxy, cyano, halogen, halogen-Ci_₆-alkoxy; halogen-C_1-6-alkyl, HO-Ci_₆-alkyl-0-, N(R²,R³), -0-Ci_₆-alkoxy, -0- (CH₂)i_4-0-Ci_6-alkoxy, -0-C₂_6-alkynyl, -0-halogen-Ci_6-alkyl, -S-Ci_6-alkyl and Ci_6-alkyl;

R is selected from the group consisting of H and C_1-6-alkyl;

R is selected from the group consisting of H, halogen-C_1-6-alkyl, Ci_6-alkoxy and C_1-6-alkyl; or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention relates to a compound of formula I as described herein, wherein

Het¹ is a 5-membered heteroaromatic ring containing 2 heteroatoms,

Het is a 5-membered or a 6-membered heteroaromatic ring unsubstituted or substituted by R , R¹ is each individually selected from the group consisting of Ci-6-alkoxy, cyano, halogen,

2

halogen-Ci-6-alkoxy; halogen-Ci-6-alkyl, N(R ,R ), -0-C_1-6-alkoxy, -0-C_2-6-alkynyl, -O-halogen- Ci-6-alkyl and C_1-6-alkyl;

R is selected from the group consisting of H and C_1-6-alkyl;

R is selected from the group consisting of H, halogen-Ci-6-alkyl and C_1-6-alkyl; or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention relates to a compound of formula I as described herein that is of formula la

wherein Het 1 and Het 2 are as defined as herein. A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het¹ is selected from the group consisting of 1,2-oxazolyl, lH-pyrazolyl, isoxazolyl and pyrazolyl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het¹ is selected from the group consisting of isoxazolyl and pyrazolyl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het¹ is selected from the group consisting of isoxazol-3-yl, isoxazol-5-yl and pyrazol-l-yl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het¹ is isoxazolyl.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het is selected from the group consisting of lH-pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each individually substituted by one or two R¹ as defined herein. A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het is selected from the group consisting of isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each individually substituted by one R¹ as defined herein.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het is pyrimidinyl, substituted by one R as defined herein. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R¹ is selected from the group consisting of 2-(2-ethoxyethoxy)ethoxy, 2- (difluoromethoxy)ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, Br, -CH₂CHF₂, -CHF₂, CI, CN, F, CH₃, -N(H,CH₂CHF₂), -N(H,CH₂CH₂), -N(H,CH₂), -N(CH₃,methoxyethyl), -0-CH₂-C≡C- CH₃, -0-CH₂-CF₃, -0-CH₂-CH₂OH, -OCH₂CHF₂, -OCHF₂, -OCH₂CH₃, -OCH₃, -SCH₃. A certain embodiment of the invention provides a compound of formula I as described herein, wherein R¹ is selected from the group consisting of Br, CH₃ CF₃, CI, CN, -0-CH₂-C≡C- CH₃, -0-CH₃, -0-CH₂-CF₃, -0-CHF₂, -0-CH₂-CHF₂ and -CHF₂.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het -R is selected from the group consisting of l-(difluoromethyl)pyrazol-3-yl, 3-(5-but-2-ynoxy-2-pyridyl), 3-methylisothiazol-5-yl, 5-(2,2,2-trifluoroethoxy)-2-pyridyl, 5-(2,2- dif uoroethoxy)pyrazin-2-yl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(trifluoromethyl)-2-pyridyl,

5- bromopyrimidin-2-yl, 5-chloro-2-pyridyl, 5-cyano-2-pyridyl, 5-methoxypyrazin-2-yl and 6- (difluoromethyl)pyridin-2-yl.

A certain embodiment of the invention relates to a compound of formula I as described herein wherein Het¹ is selected from the group consisting of 1,2-oxazolyl, lH-pyrazolyl, isoxazolyl and pyrazolyl and Het is selected from the group consisting of lH-pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each Het individually substituted by one or two R¹ as defined herein.

A certain embodiment of the invention relates to a compound of formula I as described herein wherein Het¹ is selected from the group consisting of 1,2-oxazolyl, lH-pyrazolyl, isoxazolyl and pyrazolyl and Het is selected from the group consisting of lH-pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each Het individually substituted by one or two R¹ selected from the group consisting of 2-(2-ethoxyethoxy)ethoxy, 2- (difluoromethoxy)ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, Br, -CH₂CHF₂, -CHF₂, CI, CN, F, CH₃, -N(H,CH₂CHF₂), -N(H,CH₂CH₂), -N(H,CH₂), -N(CH₃,methoxyethyl), -0-CH₂-C≡C- CH₃, -0-CH₂-CF₃, -0-CH₂-CH₂OH, -OCH₂CHF₂, -OCHF₂, -OCH₂CH₃, -OCH₃ and -SCH_3.

A certain embodiment of the invention provides a compound of formula I as described herein, wherein Het -R is selected from the group consisting of 5-methoxypyrimidin-2-yl and 5- cyanopyrimidin-2-yl. A certain embodiment of the invention provides a compound of formula I as described herein, which is selected from the group consisting of

6- [5-[3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-4-yl]-4-fluoro- phenyl]isoxazol-3-yl]pyridine-3-carbonitrile,

(4S,6S )-4-(2-fluoi -5-( I -(5-methoxypyrazin-2-yl }- 1 H-pyrazol-4-yl iphenyl l-4-methy!-6- (trifluoromethyl)-5,6-dihydro-4H- 1 J-oxazin-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l ,3-oxazin-2-amine,

(4S,6S)-4-(2-fluoro-5-(3-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( tri fl uoromethyl )-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate, ( 4S )S )-4-( 2-n uotO-5-( 3-( 5-( methyl thio )pyrimidin-2-yl )isoxazol-5-yl (phenyl )-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifhioromethyl )-5.6-di ydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl )-5,6-dihydro-4H- 1 ,3-oxazin-2 amine,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-y^

(triHuoromethyl )-5,6-dihydro-4H- 1„3-oxazm-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- l ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H- l,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(l-(2,2-difluoroethyl)- l H-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-

6-(trifluoiOmethyl)-5,6-diliydiO-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(l-(difluoromethyl)-l H-pyrazol-4-yl)isoxazol-5-yl)-2-fluorophenyl)-4

(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(4-chloro-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-rnethyl-6- ( trifluorornethyl )-5,6-dihydro-4I 1- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-((2,2-difluoroethyl)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluoropheny methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-(2-(2-ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifiuoiOmethyl)-5,6-dihydro-4H-l,3-oxazin-2-amirie 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2-(difiuoromethoxy)ethoxy)p

methyl-6-ί t ifluoromethyl )-5.6-dihydro-4l \- 1 .3 -oxazin-2 amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- ( trifluorornethyl )-5,6-dihydro-4H- 1 ,3-oxazin-2 -arrii ne 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl- 6-itri fluoi omethyl )-5,6-dihydro-4H - 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5 ,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(ethylamino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-chloro-3-fluoropyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-

(trifluoromethyl)-5,6-dihydiO-4H-l,3-oxaziii-2-amine 2,2,2-trifluoroacetate, (4S,6S)-4-(5-(3-(5-chloro-3-methylpyridin-2-yl)isoxazol^^

( t r i Π u o ro m e t h y I ) - 5 , 6 - d i h yd ro - 4 H - 1 ,3 - o x az i n - 2 - a m i n e 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-f!uorophenyl)-4-(fluorom

itri fluoromethyl )- ,6-dihydro-4H- 1 ,3 oxazin-2-amine,

(4S,6S)-4-(5-(3-(6-(difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-m

(t!"iflii()romethyl )-5,6 -d!hydro-4H- 1 ,3-oxazin- 2-amine,

(4S,6S)-4-[2-fluoro-5-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]isoxazol-5-yl]phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- l,3-oxazin-2-amine,

(4S,6S)-4~[2-fluoiO-5-[3-[5-(2~methoxyethoxy)pyrazin-2-yl]-l,2-oxazol-5-yl]p eiiyl]-4-metliyl- 6-(trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-arnine,

(4S,6S)-4-[2-fluoro-5-[3-[5-(methylamino)pyrazin-2-yl]- l ,2-oxazol-5-yl]phenyl]-4-rnethyl-6- (trifluoromethyl)-5,6-dihydro- l,3-oxazin-2-amine,

(4S,6S)-4-[5-[l-(5-chloiOpyrimidiii-2-yl)pyrazol-4-yl]-2-fluoi p enyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-bromopyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-but-2-ynoxy-2-pyridyl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-chloro-2-pyridyl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-ethoxypyrazin-2-yl)-l,2-oxazol-5-yl]-2-fliioiOphenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxa/.in-2-amine.

(4S,6S)-4-[5-[3-[l-(difluoromethyl)pyrazol-3-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

2-((2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l ,3-ox

fluorophenyl)isoxazol-3-yl)pyrimidin-5-yl)oxy)ethanol 2,2,2 -trifluoroacetate,

2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l_^

fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate, and

6-[4-[3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro- l,3-oxazin-4-yl]-4-fl^ phenyl] pyrazol- 1 - yl] pyridine- 3 -c arbonitrile . A certain embodiment of the invention provides a compound of formula I as described herein, which is selected from the group consisting of

(4S,6S l-4-(2-fluoro-5-( I -( 5-methoxypyrazin-2-yl }- 1 H-pyrazol-4-yl iphenyl )-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2 -amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( tri fluoromethyl )-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoi -5"(3"(5-(methyliMo)pyrimidin-2-yl isoxazol-5-yl)phenyl -4-methyl"6" (trifluoromethyl)-5,6-dihydro-4H- 1.3 oxazin-2-amiiie 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( t r i f Ί u o ro m e t h y I ! - 5 , 6 ~ d i h yd ro^■ 4 H ~ 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (tri fluoromethyl )-5,6-dihydro-4l i- 1 ,3-oxazin-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6- ( t ri f Ί u o ro m ethyl ) -5,6-dih yd ro - 411 - 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( tri fluoromethyl )-5,6-dihvdro- 4H- 1 ,3 oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-( l-(2,2-difluoroethyl)- l H-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl- 6-(trifluoromethyl i-5,6-dihydro-4H- 1 .3-oxazin-2-ami ne.

(4S,6S)-4-(5-(3-( l-(dif]uoromethyl)- l H-pyrazol-4-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- ( tri fluoromethyl )-5,6 dihydro -4H- 1 ,3-oxazin-2-amine 2,2.2-tri fl uoroacetate,

(4S,6S)-4-(5-(3-(4-chloro- l H-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- ( tri fluoromethyl j-5.6-dihydro-411- 1.3-oxazin-2-amine.

(4S,6S)-4-(5-(3-(5-((2,2-dif]uoroethyl)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl^■()-( tri fluoromethyl )-5,6-dihydro-41 1^■■ 1 ,3-oxazin-2 amine,

(4S,6S)-4-(5-(3-(5-(2-(2-ethoxyethoxy)ethoxy)pyrazin-2-yr)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-( tri fluoromethyl )-5,6-dihydtO-4H- 1 ,3-oxazin-2-amine 2,2,2- trifkioroacetate, and

(4S,6S)-4-(5-(3-(5-(2-(difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluoropheny methy -6-(tri fluoromethyl S-5,6-dihydiO-4H- 1 ,3 -oxazin-2 amine 2,2,2-tri Π uoroacetate. A certain embodiment of the invention provides a compound of formula I as described herein, which is selected from the group consisting of

(4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-[2-fluoro-5-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]isoxazol-5-yl]phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-bromopyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine,

6-[4-[3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-4-yl]-4-fluoro- phenyl] pyrazol- 1 - yl] pyridine- 3 -c arbonitrile,

6-[5-[3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-4-yl]-4-fluoro- phenyl]isoxazol-3-yl]pyridine-3-carbonitrile,

(4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(6-(difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, and

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, or pharmaceutically acceptable salts thereof.

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

(4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( trifluorometh yl !-5,6 dih vdro-4t i- 1 ,3-oxa/m-2 arnine 2,2,2 trifhioroacetate. (4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyritnidin^

(trifluorometh yl !-5,6 dih vdro-4i 1- 1 ,3- oxazin-2-amine 2,2,2-tri fluoroacetate.

(4S,6S)~4-(2-fliioi -5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2 , 2 , 2 - 1 r i f Ί u o ro ac e t a t e ,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyri

6 - ( t r i Π II o ro m e t h y I ) - 5 ,6 - d i h yd ro -4 H - 1 ,3-oxazi n-2-am i ne 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin^

(trifluorometh yl)-5 ,6-dihydro-4H- 1 ,3-oxazin -2 amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine, and 2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l ,3-oxazin-4-yl)-4- fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate,

A certain embodiment of the invention provides a compound of formula I as described herein, which is selected from the group consisting of (4S,6S)-4-(2-fluoro-5-(3-(5- methoxypyrimidin-2-y ii soxazol-5-yl !phenyi )-4- methyl- 6-( tn fluoromethyl )-5.6-dih ydro -4H- 1 ,3- oxazin-2-amine 2,2,2-tiifluoiOacetate and 2-(5-(3-((4S,6S)-2-amino-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l ,3-oxazin-4-yl)-4-fluorophenyl)isoxazol-3-yl)pyrimidine-5- carbonitrile 2,2,2-trifluoroacetate.

A certain embodiment of the invention provides a compound of formula I as described herein, whenever prepared by a process as defined 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 compound of formula I as described herein for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson'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 BACE1 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 amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson'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 compound of formula I as described herein for the use in the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson'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.

A certain embodiment of the invention provides a method for the use in the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson'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. Stereoisomers of compounds of formula I are compounds of formula la or compounds of formula lb, in particular compounds of formula la, wherein the residues have the meaning as described in any of the embodiments.

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 may be prepared in accordance with the following schemes. The starting material is commercially available or may be prepared in accordance with known methods. Any previously defined residues and variables will continue to have the previously defined meaning unless otherwise indicated.

Compounds of formula I may be prepared as follows: The synthesis of compounds of formula (I) in which Hetl is an isoxazole is illustrated in Scheme 1.

Scheme 1

LG: leaving group, e.g. I, Br

PG: protecting group, e.g. BOC, DMTr

R: alkyl, e.g. Me

(I) Het is isoxazol (IX) (VII)

The synthesis of starting materials (II) can be carried out as described in H. Hilpert et. al. and in WO2013110622³⁴. Compounds (II) can be converted into compounds (III) containing a leaving group such as iodide or bromide by e.g. iodination using an iodinating agent such as N- iodosuccinimide in the presence of an acid such as trifluoromethanesulfonic acid or tetrafluoroboric acid in a solvent such as dichloromethane at a temperature between 0 °C and reflux temperature of the solvent or by bromination using a brominating agent such as N- bromosuccinimide in the presence of an acid or acid mixtures such as trifluoroacetic acid and sulfuric acid.

Protection of the amino group in compounds of formula (III) to produce compounds of formula (IV) can be performed by treatment with e.g. di-iert-butyl dicarbonate in a solvent such as dichloromethane at temperatures between between 0 °C and reflux temperature of the solvent or by treatment with triarylmethyl chlorides, such as triphenylmethyl chloride (Tr-Cl), di(p- methoxyphenyl)phenylmethyl chloride (DMTr-Cl) under basic conditions, e.g. in the presence of an amine, such as triethylamine or diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or chloroform, at temperatures between 0 °C and ambient temperature. Sonogashira coupling of terminal alkynes (V) with compounds of formula (IV) in which LG is preferably iodide to yield compounds of formula (VI) can be achieved with a palladium catalyst, e.g. bis(triphenyphosphine)palladium(II) chloride, a copper(I) co-catalyst, e.g. copper(I) iodide, and an amine base, e.g. triethylamine under conditions known to those skilled in the art. Removal of the R₃S1 group of compound (VI) to give terminal acetylenes (VII) can be achieved by methods well known in the art, e.g. by treatment with fluoride containing reagents such as tetrabutylammonium fluoride in a solvent such as dichloromethane or THF at a temperature between 0 °C and ambient temperature or by treatment with potassium carbonate in a solvent such as ethanol or methanol at ambient temperature.

Conversion of acetylenes (VII) into isoxazoles (IX) can be achieved by a 1,3-dipolar cycloaddition with a reagent system consisting of a heteroaryl-carboximidoyl chloride (VIII) and a base such as sodium bicarbonate or triethylamine in a solvent such as THF or isopropanol at temperatures between between 0 °C and reflux temperature of the solvent. Removal of the amine-protecting group PG to give compounds of formula (I) can be achieved by methods well known in the art, e.g. by treatment with strong carbonic acids, e.g. trifluoroacetic acid, in a halogenated solvent, e.g. dichloromethane, at temperatures between 0 °C and 23 °C.

Scheme 2

(X) (XI) (VI I I) Heteroaryl-carboximidoyl chlorides (VIII) are known or can be prepared in analogy to methods known in the art or using methods illustrated in Scheme 2. Heteroaryl nitriles (X) can be converted into heteroaryl amidoximes (XI) by treatment with hydroxylamine or a hydroxylamine salt such as hydroxylamine hydrochloride in the presence of a base such as sodium hydroxide or triethylamine in a solvent or solvent mixtures such as water and ethanol at temperatures between between 0 °C and reflux temperature of the solvent. Conversion of compounds (XI) into heteroaryl-carboximidoyl chlorides (VIII) can be performed by a Sandmeyer-type reaction by treatment with a nitrite such as sodium nitrite in the presence of aqueous hydrochloric acid preferably at a temperature < 10 °C.

An alternative synthesis of compounds of formula (I) is depicted in Scheme 3: compounds (IV) containing a leaving group such as I or Br can be coupled with metal derivatives such as boronic acids or boronic acid esters (XII) using well-known cross-coupling reaction conditions. In particular, the coupling of compounds (IV) with a boronic acid or a boronic ester (XII) to the compound of formula (XIII) can be effected with a ferrocen derived catalyst, in particular 1,1'- bis(diphenylphosphino)-ferrocene-palladium(II)dichloride complex with dichloromethane and a metal carbonate, in particular cesium carbonate in a solvent mixture of an ether and water, in particular THF and water at elevated temperture, in particular between 80-90 °C.

Removal of the amine-protecting group PG to give compounds of formula (I) can be achieved by methods well known in the art, e.g. by treatment with strong carbonic acids, e.g. trifluoroacetic acid, in a halogenated solvent, e.g. dichloromethane, at temperatures between 0 °C and 23 °C.

Scheme 3

LG: leaving group, e.g. I, Br

PG: protecting group, e.g. BOC, DMTr

M: Metal derivative, e.g B(OH)₂, B(pin), B(MIDA)

(IV) (XIII) (I)

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. Specific is 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% C0₂ 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 IC₅₀ values were calculated using the Excel XLfit software.

Table 1 : IC₅₀ values of selected exam les

CYP inhibition assay

Inhibition of cytochromes P450 (CYPs) 2C9, 2D6 and 3A4 was assessed using human liver microsomes and CYP-selective substrate metabolism reactions. 50 μΐ incubations were made up containing (finally) 0.2 mg/ml pooled human liver microsomes, 5 μΜ substrate (diclofenac for CYP2C9 [4'hydroxylase], dextromethorphan for CYP2D6 [O-demethylase] or midazolam for CYP3A4 [1 'hydroxylase]), 0.25 DMSO containing test inhibitor and NADPH regenerating system. Test inhibitor concentrations of 50, 16.7, 5.6, 1.9, 0.6 and 0.2 μΜ were assessed in singlicate. Incubations were prewarmed to 37 °C for 10 minutes before initiation by addition of NADPH regenerating system. Incubations were quenched after 5 minutes (20 minutes for dextromethorphan) by addition of 50 μΐ cold acetonitrile containing 20 ng/ml 4-OH- diclofenac- 13C6, 20 ng/mL dextrorphan-D3 and 20 ng/mL l-OH-midazolam-D4. Quenched incubates were stored at -20 °C for at least 1 hour before centrifugation (20,000x g, 20 minutes). Supernatants were removed and diluted 1 : 1 with water prior to analysis using a RapidFire sample injector system and API4000 mass spectrometer. Peak areas for substrate, metabolite and stable-labelled metabolite standard were determined using MS/MS. The peak area ratios between the metabolite generated by the enzymatic reaction and the internal standard were used in subsequent calculations. The percentage of (DMSO) control activity was calculated for each incubate and IC₅₀ values estimated by non-linear regression. Sulfaphenazole, quinidine or ketoconazole were tested in each CYP2C9, CYP2D6 or CYP3A4 inhibition experiment, respectively, to ensure assay sensitivity and reproducibility. (Validated assays for human cytochrome P450 activities, R.L.Walsky et al. )

Cathepsin D and cathepsin E fluorescent substrate kinetic assays

General assay principle

The MR121 fluorescence assays described below are based on the fact that MR121 forms a non-fluorescent ground state complex with tryptophan. In solution this formation occurs at millimolar concentrations of tryptophan. The mechanism can be used to design a generic biochemical assay for proteases. A substrate peptide is labeled at the N-terminus with tryptophan and at the C-terminus with the f uorophore MR121 (for cathepsin D the 10 amino acid peptide WTS VLM AAPC-MR 121 was used; for cathepsin E, MR 121 -CKLVFFAEDW was used). In absence of protease activity, the substrates remain intact and the MR121 fluorescence is reduced by the high local Trp-concentration. If the substrates are cleaved by the enzymes the MR121 fluorescence is recovered.

Assay procedure

The fluorescent substrate cathepsin D and cathepsin E kinetic assays were performed at room temperature in 384- well micro titer plates (black with clear flat bottom, non-binding surface plates from Corning) in a final volume of 51 μΐ. The test compounds were serially diluted in DMSO (15 concentrations, 1/3 dilution steps) and Ιμΐ of diluted compounds were mixed for 10 min with 40 μΐ of cathepsin D (from human liver, Calbiochem) diluted in assay buffer (100 mM sodium acetate, 0.05% BSA, pH 5.5; final concentration: 200 nM) or with 40 μΐ of recombinant human cathepsin E (R&D Systems) diluted in assay buffer (100 mM sodium acetate, 0.05% BSA, pH 4.5; final concentration: 0.01 nM). After addition of 10 μΐ of the cathepsin D substrate WTS VLM AAPC-MR 121 diluted in cathepsin D assay buffer (final concentration: 300 nM) or 10 μΐ of the cathepsin E substrate MR121 -CKLVFFAEDW diluted in cathepsin E assay buffer (final concentration: 300 nM), the plates were strongly shaken for 2 minutes. The enzymatic reaction was followed in a plate: vision reader (Perkin Elmer) (excitation wavelength: 630 nm; emission: 695 nm) for at least 30 minutes in a kinetic measurement detecting an increase of MR121 fluorescence during the reaction time. The slope in the linear range of the kinetic was calculated and the IC₅₀ of the test compounds were determined using a four parameter equation for curve fitting. In vitro transport experiments

Bidirectional transcellular transport using LLC-PK1 and L-MDR1 LLC-PK1 cells exogenously expressing the human MDR1)

The method used for transport experiments was reported Schwab et al.⁴⁰. The experiments were performed on a TECAN automated liquid handling system. Briefly, medium was removed from all compartments and the medium of receiver side was replaced with culture medium. The trans-cellular transport measurements were initiated by adding the substrate together with extracellular marker lucifer yellow to the donor side. Inhibitors were added to both sides (1 μΜ elacridar). Transport experiments were performed both in the basolateral-to-apical and apical-to- basolateral directions with 3 wells each. The plates were incubated at 37°C and 5% C0₂ in a Liconic incubator. Samples were taken from the donor and the opposite (acceptor) side after 2 hours incubation. Concentrations of substrate in both compartments were determined by scintillation counting (digoxin) or by LC-MS/MS. The extracellular marker (lucifer yellow) was quantified using a spectrafluor plus reader at 430/535 nm (Ex/Em). In each experiment 3 different inserts were used for each condition and a mean was calculated.

Data analysis

Bidirectional transcellular transport using LLC-PK1 and L-MDR1 cells For the transcellular transport, the following equation was used for data evaluation:

1 * dQ

P™ =

A * C_n dt

Where P_app, A, Co, and dQIdt represent the apparent permeability, the filter surface area, the initial concentration, and the amount transported per time period, respectively. P_app values were calculated on the basis of a single time point (2 h).

P BA

Transport efflux ratios (ER) were calculated as follows: ER =

P_appAB

Where P_appBA is the permeability value in the basolateral-to-apical direction, and P_appAB the permeability value in the apical-to-basolateral direction. P_app were not corrected for flux of the extracellular marker lucifer yellow, which was used to assess the quality of the cell monolayers.

Results

NF = in vitro no significant adduct formation relative to control, A < 80% of control @ 30 mg/kg mouse, B < 90% of control @ 30 mg/kg mouse, C = IC₅₀ > 50 μΜ, D = IC₅₀ > 40 μΜ, E = IC₅₀ > 20 μΜ, F = IC₅₀ > 10 μΜ

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 press.

Example B-l Capsules of the following composition are manufactured: ingredient mg/capsule

5 25 100 500

Compound of formula I 5 25 100 500 Hydrous Lactose 159 123 148 -

Corn Starch 25 35 40 70

Talk 10 15 10 25

Magnesium Stearate 1 2 2 5

Total 200 200 300 600

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:

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:

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.

Intermediate II tert-Butyl (4S,6S)-4-(2-fluoro-5-iodophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-ylcarbamate

Step 1: A solution of (4S,6S)-4-(2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine (CAS#1432511-74-4, 175 mg) in dichloromethane (8.8 ml) was cooled under argon in an ice bath. Trifluoromethanesulfonic acid (1.9 g) was added and the solution was allowed to warm to room temperature. N-Iodosuccinimide (171 mg) was added at once and the mixture was stirred for 3 h. The dark purple mixture was added dropwise to a sat. aqueous NaHC0₃ solution (50 ml). The aqueous layer was separated and extracted once more with dichloromethane. The organic layers were washed with 0.1M aqueous sodiumthio sulphate solution, dried over MgS0₄, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give (4S,6S)-4-(2- fluoro-5-iodophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine (216 mg) as an off-white solid. MS: m/z = 403.1 [M+H]⁺.

Step 2: To a stirred solution of (4S,6S)-4-(2-fluoro-5-iodophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine (2.03 g) in dichloromethane (60 ml) was added di-iert-butyl dicarbonate (1.16 g).The reaction mixture was stirred for 5 days at room temperature. The mixture was concentrated to dryness and the product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in n-heptane) to give tert-butyl (4S,6S)-4-(2- fluoro-5-iodophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (2.40 g) as a colorless amorphous solid. MS: m/z = 503.1 [M+H]⁺.

Intermediate 12 tert-Butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-ylcarbamate

Step 1: tert- utyl (4S,6S)-4-(2-fluoro-5-iodophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate II, 2 g), trimethylsilylacetylene (782 mg), bis(triphenylphosphine)palladium (II) chloride (196 mg), copper (I) iodide (30.3 mg) and triethylamine (1.21 g) were mixed under argon at room temperature with THF (39.4 ml) and stirred for 2.5 h at 65°C in a sealed tube. The reaction mixture was diluted with EtOAc, filtered through a glassfiber filter, concentrated and purified by flash chromatography (silica gel, 0% to 60% EtOAc in n-heptane) to give tert-butyl (4S,6S)-4-(2-fluoro-5- ((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2- ylcarbamate (1.5 g) as a light yellow solid. MS: m/z = 473.2 [M+H]⁺.

Step 2: To a solution of tert-butyl (4S,6S)-4-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (1.49 g) in

dichloromethane (13.4 ml) was added a solution of tetrabutylammonium fluoride (1 M in THF, 3.47 ml) at 0 °C. The mixture was stirred for 45 min at 0 °C. The reaction mixture was diluted with dichloromethane and washed twice with water. The aqueous phase was backextracted with dichloromethane. The combined organic layers were dried over sodium sulphate, evaporated and dried at high vacuo to give iert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (1.36 g, 93% pure) as an off-white solid. MS: m/z = 401.2 [M+H]⁺.

Example 1

6 5 3 (4S,6S)-2-amino-4-methyl-6 trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4- yl)-4-fluorophenyl)isoxazol-3-yl)nicotinonitrile

Step 1: To a cooled suspension of 5-cyano-N'-hydroxypicolinimidamide (CAS# 453565-48-5, 1.873 g) in 3.7 M aqueous hydrochloric acid (32.5 ml) was slowly added a solution of sodium nitrite (988 mg) in Water (5 ml) at 0 °C. The mixture was stirred at 0 °C for 1 h. Aqueous sat. NaHC0₃ (10 ml) was slowly added at 0 °C (mixture still acidic) and the solid was collected by filtration. The solid was washed with cold water and dried to give 5-cyano-N- hydroxy-pyridine-2-carboximidoyl chloride (1.937 g) as an off-white solid.

Step 2: tert-Butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12, 42.8 mg) was dissolved in

THF (2.00 ml). After addition of 5-cyano-N-hydroxy-pyridine-2-carboximidoyl chloride (29.1 mg) and sodium bicarbonate (18.0 mg) the reaction mixture was stirred at room temperature in a sealed tube for 22 h. The reaction mixture was diluted with EtOAc, filtered, evaporated and purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give impure ie/t-butyl N-[(4S,6S)-4-[5-[3-(5-cyano-2-pyridyl)isoxazol-5-yl]-2-fluoro-phenyl]-4- methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-yl]carbamate (36 mg, purity ~ 70%) which was used in the next step without further purification.

Step 3: tert-Butyl N-[(4S,6S)-4-[5-[3-(5-cyano-2-pyridyl)isoxazol-5-yl]-2-fluoro- phenyl]-4-methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-yl]carbamate (36 mg, purity ~ 70%) was dissolved in dichloromethane (1 ml). After addition of trifluoroacetic acid (740 mg) the reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated, the residue was dissolved in EtOAc and washed with sat. aqueous sodium carbonate solution and water. The organic layer was concentrated and the product was purified by chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 6-(5-(3-((4S,6S)-2-amino-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4-yl)-4-fluorophenyl)isoxazol-3-yl)nicotinonitrile (20.4 mg) as a colorless solid. MS: m/z = 446.1 [M+H]⁺. Example 2

(4S,6S)-4-(5-(3-(5-chloropyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 1, step 1, 5-chloro-N'-hydroxypicolinimidamide (CAS# 327056-55-3) was converted to 5-chloro-N-hydroxypicolinimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. The compound was not obtained pure and was used for the next step without further purification.

Step 2: tert-Butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12, 45 mg) was dissolved in THF (2.1 ml). After addition of 5-chloro-N-hydroxypicolinimidoyl chloride (32.2 mg) and sodium bicarbonate (18.9 mg) the reaction mixture was stirred at room temperature in a sealed tube for 18 h. 5-Chloro-N-hydroxypicolinimidoyl chloride (10.7 mg) was added and stirring was continued for 24 h at room temperature. The reaction mixture was diluted with EtOAc, filtered over a 5 g silica-NH₂-column, evaporated and purified by flash chromatography (silica gel, 0% to 50% EtOAc in n-heptane) to give ie/t-butyl (4S,6S)-4-(5-(3-(5-chloropyridin-2-yl)isoxazol-5- yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (60.7 mg) as a colorless solid. MS: m/z = 555.2 [M+H]⁺.

Step 3: In analogy to Example 1, step 3, iert-butyl (4S,6S)-4-(5-(3-(5-chloropyridin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- ylcarbamate was converted to (4S,6S)-4-(5-(3-(5-chloropyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 455.09 [M+H]⁺.

Example 3

(4S,6S)-4-(5-(3-(5-bromopyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: To a stirred suspension of 5-bromopyrimidine-2-carbonitrile (CAS# 38275-57-9, 2.84 g) in ethanol (23.0 ml), hydroxylamine hydrochloride (1.13 g) and sodium hydroxide solution, 1M in H₂0 (15.6 ml) were added. The reaction mixture was stirred at room temperature for 19 h. The product was collected by filtration, washed with cold H₂0 and dried in high vacuo to give 5-bromo-N'-hydroxypyrimidine-2-carboximidamide (2.80 g) as a yellow solid. MS: m/z = 217.0 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, 5-bromo-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-bromo-N-hydroxypyrimidine-2-carboximidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Light brown solid. Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(5-bromopyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with 5- bromo-N-hydroxypyrimidine-2-carboximidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 600.3 [M-H]^~.

Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(5-bromopyrimidin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- ylcarbamate was converted to (4S,6S)-4-(5-(3-(5-bromopyrimidin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2- trifluoroacetate by treatment with trifluoro acetic acid in dichloromethane. After the reaction was completed, the solvent was evaporated. The residual gum was evaporated with dichloromethane- hexane and once with hexane. The colorless solid was suspended in hexane, filtered, washed with hexane and dried at high vacuo. Colorless solid. MS: m/z = 502.1 [M+H]⁺. Example 4

(4S,6S)-4 5 3 5 but-2-ynyloxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 3, step 1, 5-hydroxypicolinonitrile (CAS# 86869-14-9) was converted to N',5-dihydroxypicolinimidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Light brown solid. MS: m/z = 154.0 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, N',5-dihydroxypicolinimidamide was converted to N,5-dihydroxypyridine-2-carboximidoyl chloride by treatment with sodium nitrite in water /HC1 at 0°C. Light brown solid. Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-hydroxypyridin-2-yl)isoxazol-5-yl)phenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with N,5- dihydroxypyridine-2-carboximidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 535.3 [M-H]^~.

Step 4: To a solution of tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-hydroxypyridin-2- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (40 mg) in acetone (2 ml) were added cesium carbonate (36.4 mg), and l-bromo-2-butyne (10.4 mg). The reaction mixture was stirred at room temperature over night. More l-bromo-2-butyne (4.96 mg) was added and stirring was continued for 2.5 h. The reaction mixture was diluted with EtOAc, filtered, evaporated and purified by chromatography (silica gel, 0% to 70% EtOAc in n- heptane) to give tert-butyl (4S,6S)-4-(5-(3-(5-(but-2-ynyloxy)pyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate (29 mg) as an off-white solid. MS: m/z = 589.2 [M+H]⁺. Step 5: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(5-(but-2- ynyloxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(5-(3-(5-(but-2-ynyloxy)pyridin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. After the reaction was completed, the solvent was evaporated. The residual gum was evaporated with dichloromethane-hexane and once with hexane.The solid was suspended in hexane, filtered, washed with hexane and dried at high vacuo. Off-white solid. MS: m/z = 489.2 [M+H]⁺.

Example 5

(4S,6S)-4-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)isoxazol-5-yl)phenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 5-(2,2,2-trifluoroethoxy)picolinonitrile (CAS# 1551364-82-9) was converted to N'-hydroxy-5-(2,2,2-trifluoroethoxy)picolinimidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. Step 2: In analogy to Example 1, step 1, N'-hydroxy-5-(2,2,2- trifluoroethoxy)picolinimidamide was converted to N-hydroxy-5-(2,2,2- trifluoroethoxy)picolinimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Light brown waxy solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)isoxazol- 5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate by treatment with N-hydroxy-5-(2,2,2-trifluoroethoxy)picolinimidoyl chloride in the presence of sodium bicarbonate. Off-white solid.

Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 519.2 [M+H]⁺.

Example 6

(4S,6S)-4 5^3 5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 5-(2,2-difluoroethoxy)pyrazine-2-carbonitrile (CAS# 1544861-08-6) was converted to 5-(2,2-difluoroethoxy)-N'-hydroxypyrazine-2- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 219.1 [M+H]⁺. Step 2: In analogy to Example 1, step 1, 5-(2,2-difluoroethoxy)-N'-hydroxypyrazine-2- carboximidamide was converted to 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Yellow solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate by treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 602.3 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 502.2 [M+H]⁺.

Example 7

6-(4-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4- yl)-4-fluorophenyl)-lH-pyrazol-l-yl)nicotinonitrile

Step 1: In a sealed tube, 6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile (CAS# 1178198-39- 4, 1 g) , bis(pinacolato)diboron (2.55 g) and potassium acetate (1.58 g) were combined at room temperature under argon with dioxane (11 ml), then [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (294 mg) was added to give a yellow suspension. The reaction mixture was heated to 95 °C and stirred for 3.5 h.The reaction mixture was cooled down to room temperature and then diluted with 25 ml EtOAc, filtered through a pad of celite and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 60% EtOAc in n-heptane) followed by dissolution in dichloromethane and precipitation with n-hexane to give 6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)nicotinonitrile (645 mg) as a colorless solid.

Step 2: tert-Butyl (4S,6S)-4-(2-fluoro-5-iodophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate II, 70 mg), 6-(4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)nicotinonitrile (51.6 mg), cesium carbonate (159 mg) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.1 mg) were suspended in THF (lmL) and Water (0.5 mL), degassed by bubbling argon through the mixture and stirred for 35 min at 80°C in a sealed tube. The reaction mixture was diluted with EtOAc, the layers were separated and the organic layer was evaporated. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give tert-butyl (4S,6S)-4-(5-(l- (5-cyanopyridin-2-yl)-lH-pyrazol-4-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate (69 mg) as an off-white solid. MS: m/z = 545.3 [M+H]⁺.

Step 3: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(l-(5-cyanopyridin-2-yl)- lH-pyrazol-4-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- ylcarbamate was converted to 6-(4-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-4-yl)-4-fluorophenyl)-lH-pyrazol-l-yl)nicotinonitrile by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 445.2 [M+H]⁺.

Example 8 (4S,6S)-4-(5-(3-(l-(difluoromethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, l-(difluoromethyl)-lH-pyrazole-3-carbonitrile (CAS# 1379276-84-2) was converted to l-(difluoromethyl)-N'-hydroxy-lH-pyrazole-3- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 177.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, l-(difluoromethyl)-N'-hydroxy-lH-pyrazole-3- carboximidamide was converted to l-(difluoromethyl)-N-hydroxy-lH-pyrazole-3-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(l-(difluoromethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate by treatment with l-(difluoromethyl)-N-hydroxy-lH-pyrazole-3-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 560.2 [M+H]⁺. Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(l-(difluoromethyl)- lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(5-(3-(l-(difluoromethyl)-lH-pyrazol-3- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 460.2 [M+H]⁺.

Example 9

(4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 5-chloropyrimidine-2-carbonitrile (CAS# 38275-56-8) was converted to 5-chloro-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 173.0 [M+H]⁺. Step 2: In analogy to Example 1, step 1, 5-chloro-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid. MS: m/z = 192.0 [M+H]⁺.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with 5- chloro-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 556.2 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(5-chloropyrimidin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- ylcarbamate was converted to (4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m z = 456.2 [M+H]⁺.

Example 10 (4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-

5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, pyrimidine-4-carbonitrile (CAS# 42839-04-3) was converted to N'-hydroxypyrimidine-4-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 139.0 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, N'-hydroxypyrimidine-4-carboximidamide was converted to N-hydroxypyrimidine-4-carbimidoyl chloride by treatment with sodium nitrite in water /HC1 at 0°C. Colorless solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4-yl)isoxazol-5-yl)phenyl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with N- hydroxypyrimidine-4-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 522.2 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(pyrimidin-4-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 422.2 [M+H]⁺.

Example 11

(4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 3-methylisothiazole-5-carbonitrile (CAS# 57352-00-8) was converted to N'-hydroxy-3-methylisothiazole-5-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off- white solid. MS: m/z = 158.0 [M+H]⁺. Step 2: In analogy to Example 1, step 1, N'-hydroxy-3-methylisothiazole-5- carboximidamide was converted to N-hydroxy-3-methylisothiazole-5-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5-yl)isoxazol-5-yl)phenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with N- hydroxy-3-methylisothiazole-5-carbimidoyl chloride in the presence of sodium bicarbonate. Off- white solid. MS: m/z = 541.2 [M+H]⁺. Step 4: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(3- methylisothiazol-5-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3- oxazin-2-ylcarbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 441.2 [M+H]⁺.

Example 12

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: 2-(Methylthio)pyrimidin-5-ol (CAS# 75670-14-3, 3.5 g) was dissolved in DMF (68.6 ml) After addition of potassium carbonate (3.74 g) and ethyl chlorodifluoroacetate (4.29 g) the reaction mixture was stirred for 48h at 65 °C. The reaction mixture was diluted with water and extracted twice with AcOEt. The organic layers were washed with brine, dried over sodium sulphate, evaporated and purified by chromatography (silica gel, 0% to 40% EtOAc in n-heptane) to give 5-(difluoromethoxy)-2-(methylthio)pyrimidine (2.25 g) as a light yellow liquid. MS: m/z = 193.1 [M+H]⁺.

Step 2: 5-(Difluoromethoxy)-2-(methylthio)pyrimidine (2.2 g) was dissolved in dichloromethane (45 ml). After addition of meta-chloroperoxybenzoic acid (7.7 g) the reaction mixture was stirred for 90 min at room temperature. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium carbonate solution and water. The aqueous layer was extracted once more with dichloromethane. The organic layers were combined, dried over sodium sulphate and evaporated.The crude product was purified by filtration with dichloromethane through a 20g silica-NH₂ column to give 5-(difluoromethoxy)-2- (methylsulfonyl)pyrimidine (2.4 g) as a colorless solid.

Step 3: 5-(Difluoromethoxy)-2-(methylsulfonyl)pyrimidine (2.4 g) was dissolved in dichloromethane (26.4 ml). After addition of tetrabutylammonium cyanide (3.59 g) the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was directly purified by chromatography (silica gel, 100% dichloromethane) to give 5-(difluoromethoxy)pyrimidine-2- carbonitrile (1.29 g) as a colorless liquid. MS: m/z = 172.0 [M+H]⁺.

Step 4: In analogy to Example 3, step 1, 5-(difluoromethoxy)pyrimidine-2-carbonitrile was converted to 5-(difluoromethoxy)-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 204.9 [M+H]⁺.

Step 5: In analogy to Example 1, step 1, 5-(difluoromethoxy)-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-(difluoromethoxy)-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Colorless solid. Step 6: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate by treatment with 5-(difluoromethoxy)-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 586.6 [M-H]^~.

Step 7: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(5- (difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(5-(3-(5- (difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 488.4 [M+H]⁺.

Example 13

(4S,6S)-4 5 3 6 difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: 2-Bromo-6-(difluoromethyl)pyridine (CAS# 872365-91-8, 1 g) was dissolved under argon in N,N-dimethylacetamide (10 ml), then copper (I) cyanide (340 mg) and sodium cyanide (193 mg) were added. The reaction mixture was stirred in a sealed tube for 24 h at 120°C and for 6 days at 125°C. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHC0₃. AcOEt was added and the solids were removed by filtration. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 6- (difluoromethyl)picolinonitrile (720 mg) as a colorless semisolid.

Step 2: In analogy to Example 3, step 1, 6-(difluoromethyl)picolinonitrile was converted to 6-(difluoromethyl)-N'-hydroxypicolinimidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 188.1 [M+H]⁺.

Step 3: In analogy to Example 1, step 1, 6-(difluoromethyl)-N'-hydroxypicolinimidamide was converted to 6-(difluoromethyl)-N-hydroxypicolinimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Colorless solid.

Step 4: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(5-(3-(6-(difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-ylcarbamate by treatment with 6-(difluoromethyl)-N-hydroxypicolinimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 571.3 [M+H]⁺.

Step 5: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(5-(3-(6- (difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-ylcarbamate was converted to (4S,6S)-4-(5-(3-(6- (difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 471.2 [M+H]⁺.

Example 14

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 1, step 1, N'-hydroxy-5-methoxypyrazine-2- carboximidamide (CAS# 1344885-60-4) was converted to N-hydroxy-5-methoxypyrazine-2- carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Off-white solid. MS: m/z = 188.3 [M+H]⁺. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-

4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate by treatment with N- hydroxy-5-methoxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 452.4 [M+H-BOC]⁺.

Step 3: In analogy to Example 1, step 3, tert-butyl (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin- 2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- ylcarbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m z = 452.4 [M+H]⁺.

Example 15

(4S,6S)-4-[5-[l-(5-Chloropyrimidin-2-yl)pyrazol-4-yl]-2-fluorophenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine

In analogy to Example 7, step 2, tert-butyl (4S,6S)-4-(2-fluoro-5-iodophenyl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate II) was treated with

5- chloro-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)pyrimidine (CAS# 1402174-54-2) in the presence of cesium carbonate and [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give (4S,6S)-4-[5-[l-(5- chloropyrimidin-2-yl)pyrazol-4-yl]-2-fluorophenyl]-4-methyl-6-(trifluoromethyl)-5,6-dih l,3-oxazin-2-amine as light brown solid (the BOC protecting group was cleaved during the reaction). MS: m/z = 455.2 [M+H]⁺.

Example 16 (4S,6S)-4-[5-[3-(5-Ethoxypyrazin-2-yl)-l,2-oxazol-5-yl]-2-fluorophenyl]-4-methyl-6-

(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine

Step 1: In analogy to Example 1, step 1, 5-ethoxy-N'-hydroxypyrazine-2- carboximidamide (CAS# 1344793-71-0) was converted to 5-ethoxy-N-hydroxypyrazine-2- carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Off-white solid. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-ethoxypyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with 5- ethoxy-N-hydroxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off- white solid. MS: m/z = 566.3 [M+H]⁺.

Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-ethoxypyrazin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate was converted to (4S,6S)-4-[5-[3-(5-ethoxypyrazin-2-yl)-l,2-oxazol-5-yl]-2- fluorophenyl]-4-methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 466.3 [M+H]⁺.

Example 17

(4S,6S)-4-[2-Fluoro-5-[3-[5-(2-methoxyethoxy)pyrazin-2-yl]-l,2-oxazol-5-yl]phenyl]-4- methyl-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine

Step 1: In analogy to Example 1, step 1, N'-hydroxy-5-(2-methoxyethoxy)pyrazine-2- carboximidamide (CAS# 1344861-89-7) was converted to N-hydroxy-5-(2- methoxyethoxy)pyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Off-white solid.

Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(2-methoxyethoxy)pyrazin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-(2-methoxyethoxy)pyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 596.3 [M+H]⁺. Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(2- methoxyethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-[2-fluoro-5-[3-[5-(2- methoxyethoxy)pyrazin-2-yl]-l,2-oxazol-5-yl]phenyl]-4-methyl-6-(trifluoromethyl)-5,6- dihydro-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 496.3 [M+H]⁺.

Example 18

(4S,6S)-4-(5-(3-(5-(2-(2-Ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2- trifluoroacetate

Step 1: To a a solution of 5-bromopyrazine-2-carbonitrile (0.863 g) in N,N- dimethylacetamide (2 ml) were added 2-(2-ethoxyethoxy)ethanol (0.692 g) and potassium carbonate (0.713 g). The mixture was stirred for 26 h at room temperature. Water was added and the mixture was extracted with EtOAc. The organic layers were dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% EtOAc in n-heptane) to give 5-[2-(2-ethoxyethoxy)ethoxy]pyrazine-2-carbonitrile (0.655 g) as light yellow oil.

Step 2: In analogy to Example 3, step 1, 5-[2-(2-ethoxyethoxy)ethoxy]pyrazine-2- carbonitrile was converted to 5-(2-(2-ethoxyethoxy)ethoxy)-N'-hydroxypyrazine-2- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 271.2 [M+H]⁺.

Step 3: In analogy to Example 1, step 1, 5-(2-(2-ethoxyethoxy)ethoxy)-N'- hydroxypyrazine-2-carboximidamide was converted to 5-(2-(2-ethoxyethoxy)ethoxy)-N- hydroxypyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Colorless solid.

Step 4: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-(2-(2-ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5- yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-(2-(2-ethoxyethoxy)ethoxy)-N-hydroxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 652.6 [M-H]^~.

Step 5: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-(2-(2- ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-(2-(2- ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 554.3 [M+H]⁺.

Example 19

(4S,6S)-4 2-Fluoro-5 3 5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 3, step 1, 5-fluoropyrimidine-2-carbonitrile (CAS# 38275- 55-7) was converted to 5-fluoro-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 157.0 [M+H]⁺. Step 2: In analogy to Example 1, step 1, 5-fluoro-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-fluoro-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HC1 at 0°C. Off-white solid. MS: m/z = 176.0 [M+H]⁺.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with 5- fluoro-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 440.2 [M+H-BOC]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5- fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3- oxazin-2-yl)carbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 440.3 [M+H]⁺.

Example 20

(4S,6S)-4-(2-Fluoro-5-(3-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 1, step 1, N'-hydroxy-5-((2- methoxyethyl)(methyl)amino)pyrazine-2-carboximidamide (CAS# 1344799-46-7) was converted to N-hydroxy-5-((2-methoxyethyl)(methyl)amino)pyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Brown gum, not totally pure, was used in the next step without further purification. MS: m z = 245.2 [M+H]⁺. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate by treatment with N-hydroxy-5-((2-methoxyethyl)(methyl)amino)pyrazine-2- carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 607.5 [M-H]^~.

Step 3: In analogy to Example 1, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-((2- methoxyethyl)(methyl)amino)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-((2- methoxyethyl)(methyl)amino)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Light yellow solid. MS: m/z = 509.3 [M+H]⁺.

Example 21 (4S,6S)-4-(5-(3-(l-(Difluoromethyl)-lH-pyrazol-4-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 3, step 1, l-(difluoromethyl)-lH-pyrazole-4-carbonitrile (CAS# 1229623-41-9) was converted to l-(difluoromethyl)-N'-hydroxy-lH-pyrazole-4- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless Oil. MS: m/z = 177.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, l-(difluoromethyl)-N'-hydroxy-lH-pyrazole-4- carboximidamide was converted to l-(difluoromethyl)-N-hydroxy-lH-pyrazole-4-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Light yellow solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(l-(difluoromethyl)-lH-pyrazol-4-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with l-(difluoromethyl)-N-hydroxy-lH-pyrazole-4-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 558.4 [M-H]^". Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(l-(difluoromethyl)- lH-pyrazol-4-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(l-(difluoromethyl)-lH-pyrazol-4- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 460.2 [M+H]⁺. Example 22

(4S,6S)-4 5 3 5-Chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-(fluoromethyl)-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to the synthesis of Intermediate II, step 2, (4S,6S)-4-(2-fluoro-5- iodophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine (CAS# 1620829-05-1) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-iodophenyl)-4-(fluoromethyl)- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with di-tert-butyl dicarbonate in dichloromethane. Off-white solid. MS: m/z = 521.2 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate 12, step 1, tert-butyl ((4S,6S)-4-(2- fluoro-5-iodophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)- 4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with trimethylsilylacetylene in the presence of bis(triphenylphosphine)palladium (II) chloride, copper (I) iodide and triethylamine. Yellow waxy solid. MS: m/z = 491.3 [M+H]⁺. Step 3: In analogy to the synthesis of Intermediate 12, step 2, tert-butyl ((4S,6S)-4-(2- fluoro-5-((trimethylsilyl)ethynyl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-yl)carbamate was converted to tert-butyl ((4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with tetrabutylammonium fluoride. Off-white solid. MS: m/z = 419.3 [M+H]⁺. Step 4: In analogy to Example 2, step 2, tert-butyl ((4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with

5- chloro-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 572.3 [M-H]^~.

Step 5: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-chloropyrimidin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3- oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)- 2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine by treatment with trifluoro acetic acid in dichloromethane. Off-white solid. MS: m/z = 474.2 [M+H]⁺.

Example 23

(4S,6S)-4-(2-Fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine Step 1: In analogy to Example 2, step 2, tert-butyl ((4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 570.3 [M+H]⁺.

Step 2: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5- methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-yl)carbamate was converted to(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2- yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 470.3 [M+H]⁺.

Example 24

(4S,6S)-4-(2-Fluoro-5-(l-(5-methoxypyrazin-2-yl)-lH-pyrazol-4-yl)phenyl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: 2-(4-Bromo-lH-pyrazol-l-yl)-5-chloropyrazine (CAS# 1353854-32-6, 4.9 g). was combined with MeOH (25.3 ml) under argon to give a off-white suspension, then cooled down in an ice-bath. A 5.4 M solution of sodium methoxide in MeOH (7 ml) was added. The reaction mixture was stirred for 15 min. The ice bath was removed and stirring was continued for 1 h. The mixture was heated to 70°C and stirred for 5 h. After cooling to room temperature overnight, water was added and the mixture was concentrated in vacuo to a volume of about 50 mL and extracted with diethyl ether. The org. layers were dried over MgS0₄, filtered and concentrated to dryness to give 2-(4-bromo-lH-pyrazol-l-yl)-5-methoxypyrazine (2.8 g) as off- white solid. MS: m/z = 255.0 [M+H]⁺. Step 2: In analogy to Example 7, step 1, 2-(4-bromo-lH-pyrazol-l-yl)-5- methoxypyrazine was treated with bis(pinacolato)diboron in the presence of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium acetate to give 2- methoxy-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)pyrazine as colorless solid. MS: m/z = 303.2 [M+H]⁺. Step 3: In analogy to Example 7, step 2, tert-butyl (4S,6S)-4-(2-fluoro-5-iodophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate II) was treated with 2-methoxy-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)pyrazine in the presence of cesium carbonate and [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give (4S,6S)-4-(2-fluoro-5-(l-(5- methoxypyrazin-2-yl)-lH-pyrazol-4-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-amine as colorless solid (the BOC protecting group was cleaved during the reaction). MS: m/z = 451.3 [M+H]⁺.

Example 25

(4S,6S)-4 5 3 5 2,2-Difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: To a solution of 2-(methylthio)pyrimidin-5-ol (CAS# 4874-33-3, 2 g) in acetone (50 ml) were added potassium carbonate (2.92 g) and 2,2-difluoroethyl trifluoromethanesulfonate (3.46 g) and the mixture was stirred for 3h at room temperature.Diethyl ether (200 ml) was added and the mixture was filtered.The filtrate was concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 50% EtOAc in n-heptane) to give 5-(2,2-difluoroethoxy)-2-(methylthio)pyrimidine (2.65 g) as light yellow solid. MS: m/z = 207.0 [M+H]⁺.

Step 2: 5-(2,2-Difluoroethoxy)-2-(methylthio)pyrimidine (2.46 g) was dissolved in dichloromethane (45 ml). After addition of 3-chloroperbenzoic acid (4.03 g, 16.3 mmol, Eq: 3) (8.02 g) the mixture was stirred for 90 min at room temperature. The mixture was diluted with dichloromethane, washed with aqueous saturated sodium carbonate solution and with water. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by filtration with dichloromethane through a 50g silica-NH2 column to give 5-(2,2- difluoroethoxy)-2-(methylsulfonyl)pyrimidine (2.73 g) as colorless solid. MS: m/z = 239.1 [M+H]⁺.

Step 3: 5-(2,2-Difluoroethoxy)-2-(methylsulfonyl)pyrimidine (2.31 g) was dissolved in Dichloromethane (26.4 ml). After addition of tetrabutylammonium cyanide (3.25 g) the mixture was stirred for 18 h at room temperature. The mixture was evaporated to a smaller volume and directly purified by chromatography (silica gel, dichloromethane) to give 5-(2,2- difluoroethoxy)pyrimidine-2-carbonitrile (2.19 g) as light yellow liquid.

Step 4: In analogy to Example 3, step 1, 5-(2,2-difluoroethoxy)pyrimidine-2-carbonitrile was converted to 5-(2,2-difluoroethoxy)-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Colorless solid. MS: m/z = 219.1 [M+H]⁺. Step 5: In analogy to Example 1, step 1, 5-(2,2-difluoroethoxy)-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-(2,2-difluoroethoxy)-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Colorless solid.

Step 6: In analogy to Example 2, step 2, iert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 600.5 [M-H]^~. Step 7: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 502.3 [M+H]⁺.

Example 26

(4S,6S)-4-(5-(3-(5-(2-(Difl oromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2- trifluoroacetate Step 1: To a solution of 2-bromo-5-(methylthio)pyrazine (CAS#1049026-49-4, 5 g) in

N,N-dimethylacetamide (10 ml) were added ethane- 1,2-diol (7.57 g) and potassium carbonate (5.05 g). The mixture was stirred at room temperature for 18 h. The mixture was heated to 60 °C for 8 h and stirred at room temperature for 3 days. The mixture was heated to 90 °C for 1.5 h. The temperature was raised to 100 °C and the mixture was stirred for 2 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic layers were dried (MgS04), filtered and concentrated in vacuo.The crude material was purified by flash chromatography (Si02, 0% to 50% EtOAc in n-heptane) to give 2-((5-(methylthio)pyrazin-2- yl)oxy)ethanol (2.88 g) as colorless solid. MS: m/z = 187.1 [M+H]⁺.

Step 2: To a solution of 2-((5-(methylthio)pyrazin-2-yl)oxy)ethanol (2.88 g) in dry acetonitrile (60 ml) under argon was added copper (I) iodide (1.77 g). The mixture was heated to 45 °C. 2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.51 g) was added dropwise over 30 min. The mixture was stirred for 1.5 h at 45 °C. The mixture was allowed to cool down in the oilbath while stirring overnight. The mixture was again heated to 45 °C, copper (I) iodide (1.77 g) was added and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.75 g) was added dropwise. The mixture was stirred for 30 min at 45 °C. The mixture was filtered and the filtrate was concentrated. EtOAc was added and washed with sat. aq. NaHC0₃ solution, with diluted aq. NH₃ and with water. The organic layers were dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Si0₂, 0% to 50% EtOAc in n-heptane) to give 2- (2-(difluoromethoxy)ethoxy)-5-(methylthio)pyrazine (0.83 g) as light yellow oil. MS: m z = 237.1 [M+H]⁺. Step 3: In analogy to the synthesis of Example 26, step 2, 2- (2- (difluoromethoxy)ethoxy)-5-(methylthio)pyrazine was oxidized to 2-(2-

(difluoromethoxy)ethoxy)-5-(methylsulfonyl)pyrazine. Colorless oil. MS: m/z = 269.1 [M+H]⁺.

Step 4: In analogy to the synthesis of Example 26, step 3, 2- (2- (difluoromethoxy)ethoxy)-5-(methylsulfonyl)pyrazine was converted to 5-(2- (difluoromethoxy)ethoxy)pyrazine-2-carbonitrile by treatment with tetrabutylammonium cyanide. Light yellow oil. MS: m/z = 216.1 [M+H]⁺.

Step 5: In analogy to Example 3, step 1, 5-(2-(difluoromethoxy)ethoxy)pyrazine-2- carbonitrile was converted to 5-(2-(difluoromethoxy)ethoxy)-N'-hydroxypyrazine-2- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 249.2 [M+H]⁺.

Step 6: In analogy to Example 1, step 1, 5-(2-(difluoromethoxy)ethoxy)-N'- hydroxypyrazine-2-carboximidamide was converted to 5-(2-(difluoromethoxy)ethoxy)-N- hydroxypyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 7: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-(2-(difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-

5- yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with 5-(2-(difluoromethoxy)ethoxy)-N-hydroxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m z = 630.4 [M-H]^~.

Step 8: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-(2- (difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3- (5-(2-(difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-

(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 532.2 [M+H]⁺.

Example 27

(4S,6S)-4-(2-Fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1, N'-hydroxy-5-(3-methoxypropoxy)pyrazine-2- carboximidamide (CAS # 1344886-98-1) was converted to N-hydroxy-5-(3- methoxypropoxy)pyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HC1 at 0°C. Off-white solid. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-(3-methoxypropoxy)pyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 608.5 [M-H]^~.

Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(3- methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-(3- methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 510.3 [M+H]⁺.

Example 28

(4S,6S)-4-(5-(3-(l-(2,2-Difluoroethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluoroph.

methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, l-(2,2-difluoroethyl)-lH-pyrazole-3-carbonitrile (CAS# 1245773-06-1) was converted to l-(2,2-difluoroethyl)-N'-hydroxy-lH-pyrazole-3- carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 191.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, l-(2,2-difluoroethyl)-N'-hydroxy-lH-pyrazole-3- carboximidamide was converted to N-(chloro(l-(2,2-difluoroethyl)-lH-pyrazol-3- yl)methyl)hydroxylamine by treatment with sodium nitrite in water /HQ at 0°C. Light yellow solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(l-(2,2-difluoroethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with N-(chloro(l-(2,2-difluoroethyl)-lH-pyrazol-3-yl)methyl)hydroxylamine in the presence of sodium bicarbonate. Off-white oil. MS: m/z = 574.3 [M+H]⁺. Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(l-(2,2- difluoroethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(l-(2,2-difluoroethyl)- lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 474.3 [M+H]⁺. Example 29

2-(5 3 (4S,6S)-2-Amino-4-methyl-6 trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4-yl)-4- fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate

Step 1: In analogy to Example 3, step 1, pyrimidine-2,5-dicarbonitrile (CAS# 38275-58-0) was converted to 5-cyano-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Light brown solid. MS: m/z = 164.057 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, 5-cyano-N'-hydroxypyrimidine-2- carboximidamide was converted to 5-cyano-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-cyanopyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with 5- cyano-N-hydroxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Colorless solid. MS: m/z = 545.4 [M-H]^~.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-cyanopyrimidin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate was converted to 2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H- 1 ,3-oxazin-4-yl)-4-fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile 2,2,2- trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 447.2 [M+H]⁺.

Example 30

(4S,6S)-4-(5-(3-(5-(Ethylamino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 5-(ethylamino)pyrazine-2-carbonitrile (CAS# 1409987-87-6) was converted to 5-(ethylamino)-N'-hydroxypyrazine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off- white solid. MS: m/z = 182.1 [M+H]⁺. Step 2: In analogy to Example 1, step 1, 5-(ethylamino)-N'-hydroxypyrazine-2- carboximidamide was converted to 5-(ethyl(nitroso)amino)-N-hydroxypyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-(ethyl(nitroso)amino)pyrazin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-(ethyl(nitroso)amino)-N-hydroxypyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Light yellow oil. MS: m/z = 594.3 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5- (ethyl(nitroso)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5- (ethylamino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off- white solid. MS: m/z = 465.1678 [M+H]⁺.

Example 31

(4S,6S)-4-[2-Fluoro-5-[3-[5^methylamino)pyrazin-2-yl]-l,2-oxazol-5-yl]phenyl]-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine Step 1: In analogy to Example 3, step 1, 5-(methylamino)pyrazine-2-carbonitrile (CAS#

1342365-74-5) was converted to N'-hydroxy-5-(methylamino)pyrazine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Light brown solid. MS: m/z = 168.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 1, N'-hydroxy-5-(methylamino)pyrazine-2- carboximidamide was converted to N-hydroxy-5-(methyl(nitroso)amino)pyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(methyl(nitroso)amino)pyrazin-2- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate by treatment with N-hydroxy-5-(methyl(nitroso)amino)pyrazine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 580.0 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5- (methyl(nitroso)amino)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-[2-fluoro-5-[3-[5- (methylamino)pyrazin-2-yl]-l,2-oxazol-5-yl]phenyl]-4-methyl-6-(trifluoromethyl)-5,6-dihydro- l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 451.3 [M+H]⁺. Example 32

(4S,6S)-4-(5-(3-(4-Chloro-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 4-chloro-lH-pyrazole-3-carbonitrile (CAS# 36650-75-6) was converted to 4-chloro-N'-hydroxy-lH-pyrazole-3-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off- white solid.

Step 2: In analogy to Example 1, step 1, 4-chloro-N'-hydroxy-lH-pyrazole-3- carboximidamide was converted to 4-chloro-N-hydroxy-lH-pyrazole-3-carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(4-chloro-lH-pyrazol-3-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 4-chloro-N-hydroxy-lH-pyrazole-3-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 542.4 [M-H]^~.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(4-chloro-lH- pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3- oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(4-chloro-lH-pyrazol-3-yl)isoxazol-5- yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine by treatment with trifluoro acetic acid in dichloromethane. Off-white solid. MS: m/z = 444.2 [M+H]⁺.

Example 33

(4S,6S)-4-(5-(3-(5-((2,2-Difluoroethyl)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

Step 1: In analogy to Example 3, step 1, 5-((2,2-difluoroethyl)amino)pyrazine-2- carbonitrile (CAS# 1550418-74-0) was converted to 5-((2,2-difluoroethyl)amino)-N'- hydroxypyrazine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Light yellow solid. MS: m/z = 218.1 [M+H]⁺. Step 2: In analogy to Example 1, step 1, 5-((2,2-difluoroethyl)amino)-N'- hydroxypyrazine-2-carboximidamide was converted to 5-((2,2-difluoroethyl)(nitroso)amino)-N- hydroxypyrazine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Light yellow solid. Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-((2,2-difluoroethyl)(nitroso)amino)pyrazin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- yl)carbamate by treatment with 5-((2,2-difluoroethyl)(nitroso)amino)-N-hydroxypyrazine-2- carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 630.3 [M+H]⁺.

Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-((2,2- difluoroethyl)(nitroso)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3- (5-((2,2-difluoroethyl)amino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 501.2 [M+H]⁺.

Example 34 2 (2 5 3 (4S,6S)-2-Amino-4-methyl-6 trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4-^ 4-fluorophenyl)isoxazol-3-yl)pyrimidin-5-yl)oxy)ethanol 2,2,2-trifluoroacetate

Step 1: A suspension of 2-(methylthio)pyrimidin-5-ol (CAS 4874-33-3, 2g), 1,3- dioxolan-2-one (1.42 g) and K₂C0₃ (1.94 g) in DMF (45.5 ml) was heated to 100°C for 15.5 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was dried, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 2-((2- (methylthio)pyrimidin-5-yl)oxy)ethanol (2.03 g) as orange solid. MS: m/z = 187.1 [M+H]⁺.

Step 2: 2-((2-(Methylthio)pyrimidin-5-yl)oxy)ethanol (1.38g) and imidazole (1.01 g) were combined with DMF (21.9 ml). 4-Dimethylaminopyridine (136 mg) was added, tert- Butyldimethylsilyl chloride (1.45 g) was added and the mixture was stirred for 74h. The reaction mixture was poured into 150 mL H₂0 and extracted with diethyl ether. The organic phase was dried, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 0% to 40% EtOAc in n-heptane) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2- (methylthio)pyrimidine (2.14 g) as yellow solid. MS: m/z = 301.2 [M+H]⁺. Step 3: In analogy to the synthesis of Example 26, step 2, 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-2-(methylthio)pyrimidine was oxidized to 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-2-(methylsulfonyl)pyrimidine. Off-white solid. MS: m/z = 333.2 [M+H]+.

Step 4: In analogy to the synthesis of Example 26, step 3, 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-2-(methylsulfonyl)pyrimidine was converted to 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)pyrimidine-2-carbonitrile by treatment with tetrabutylammonium cyanide. Off-white solid. MS: m/z = 280.2 [M+H]+.

Step 5: In analogy to Example 3, step 1, 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)pyrimidine-2-carbonitrile was converted to 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-N'-hydroxypyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off-white solid. MS: m/z = 313.2 [M+H]⁺.

Step 6: In analogy to Example 1, step 1, 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-N'- hydroxypyrimidine-2-carboximidamide was converted to N-hydroxy-5-(2- hydroxyethoxy)pyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Colorless solid.

Step 7: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(2-hydroxyethoxy)pyrimidin-2-yl)isoxazol- 5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-(2-hydroxyethoxy)pyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 580.4 [M-H]^~.

Step 8: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(2- hydroxyethoxy)pyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-yl)carbamate was converted to 2-((2-(5-(3-((4S,6S)-2-amino-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4-yl)-4-fluorophenyl)isoxazol-3-yl)pyrimidin-5- yl)oxy)ethanol 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 482.2 [M+H]⁺.

Example 35 (4S,6S)-4 5 3 5 2,2-Difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1, 5-(2,2-difluoroethoxy)-N'- hydroxypicolinimidamide (CAS # 1564176-84-6) was converted to 5-(2,2-difluoroethoxy)-N- hydroxypicolinimidoyl chloride by treatment with sodium nitrite in water /HCl at 0°C. Off-white solid.

Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-(2,2-difluoroethoxy)-N-hydroxypicolinimidoyl chloride in the presence of sodium bicarbonate. Colorless oil. MS: m/z = 601.2 [M+H]⁺.

Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-(2,2- difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Light yellow solid. MS: m/z = 501.2 [M+H]⁺.

Example 36 (4S,6S)-4 5 3 5-Chloro-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1, 5-chloro-N'-hydroxy-3-methylpicolinimidamide (CAS # 721450-77-7) was converted to 5-chloro-N-hydroxy-3-methylpicolinimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-

4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-chloro-3-methylpyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-chloro-N-hydroxy-3-methylpicolinimidoyl chloride in the presence of sodium bicarbonate. Colorless oil. MS: m/z = 569.2 [M+H]⁺.

Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-chloro-3- methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro- 4H-l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-chloro-3-methylpyridin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 469.2 [M+H]⁺.

Example 37

(4S,6S)-4-(2-Fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate Step 1: In analogy to Example 1, step 1, N'-hydroxy-5-methoxypyrimidine-2- carboximidamide (CAS # 143031-89-4) was converted to N-hydroxy-5-methoxypyrimidine-2- carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid. MS: m/z = 188.1 [M+H]⁺. Step 2: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 550.3 [M-H]^~.

Step 3: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5- methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3- oxazin-2-yl)carbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2- yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Colorless solid. MS: m/z = 452.2 [M+H]⁺.

Example 38

(4S,6S)-4 5 3 5-Chloro-3-fluoropyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(5-(3-(5-chloro-3-fluoropyridin-2-yl)isoxazol-5-yl)-2- fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with 5-chloro-3-fluoro-N-hydroxypicolinimidoyl chloride (CAS# 1600511-92-9) in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 573.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(5-(3-(5-chloro-3- fluoropyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(5-(3-(5-chloro-3-fluoropyridin-2- yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2- amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 473.1 [M+H]⁺.

Example 39

(4S,6S)-4-(2-Fluoro-5-(3-(5-(methylthio)pyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate

Step 1: In analogy to Example 3, step 1, 5-(methylthio)pyrimidine-2-carbonitrile (CAS# 1459749-03-1) was converted to N'-hydroxy-5-(methylthio)pyrimidine-2-carboximidamide by treatment with hydroxylamine hydrochloride in the presence of aqueous sodium hydroxide. Off- white solid. MS: m/z = 185.1 [M+H]⁺. Step 2: In analogy to Example 1, step 1, N'-hydroxy-5-(methylthio)pyrimidine-2- carboximidamide was converted to N-hydroxy-5-(methylthio)pyrimidine-2-carbimidoyl chloride by treatment with sodium nitrite in water /HQ at 0°C. Off-white solid.

Step 3: In analogy to Example 2, step 2, tert-butyl (4S,6S)-4-(5-ethynyl-2-fluorophenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate (Intermediate 12) was converted to tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-(methylthio)pyrimidin-2-yl)isoxazol-5- yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-yl)carbamate by treatment with N-hydroxy-5-(methylthio)pyrimidine-2-carbimidoyl chloride in the presence of sodium bicarbonate. Off-white solid. MS: m/z = 566.3 [M-H]^~. Step 4: In analogy to Example 1, step 3, tert-butyl ((4S,6S)-4-(2-fluoro-5-(3-(5-

(methylthio)pyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l,3-oxazin-2-yl)carbamate was converted to (4S,6S)-4-(2-fluoro-5-(3-(5-(methylthio)pyrimidin- 2-yl)isoxazol-5-yl)phenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid in dichloromethane. Off-white solid. MS: m/z = 468.1 [M+H]⁺.

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Claims

1. A compound of formula I,

wherein Het¹ is a 5-membered heteroaromatic ring containing 2 heteroatoms,

R¹ is each individually selected from the group consisting of Ci-6-alkoxy, cyano, halogen, halogen-Ci-6-alkoxy; halogen-C_1-6-alkyl, HO-Ci_₆-alkyl-0-, N(R²,R³), -0-Ci_₆-alkoxy, -0- (CH₂)i-4-0-Ci-₆-alkoxy, -0-C₂_₆-alkynyl, -0-halogen-Ci_₆-alkyl, -S-C_1-6-alkyl and Ci_₆-alkyl;

R is selected from the group consisting of H and Ci-6-alkyl;

R is selected from the group consisting of H, halogen-Ci-6-alkyl, Ci-6-alkoxy and Ci-6-alkyl; or pharmaceutically acceptable salts thereof.

2. A compound of formula I according to claim 1, wherein Het¹ is a 5-membered heteroaromatic ring containing 2 heteroatoms,

2

halogen-Ci-6-alkoxy; halogen-Ci-6-alkyl, N(R ,R ), -0-Ci_6-alkoxy, -0-C₂_6-alkynyl, -O-halogen- Ci-6-alkyl and Ci-6-alkyl; R is selected from the group consisting of H and Ci-6-alkyl;

R is selected from the group consisting of H, halogen-Ci-6-alkyl and Ci-6-alkyl; or pharmaceutically acceptable salts thereof.

3. A compound of formula I according to any one of claims 1-2 that is of formula la

wherein Het 1 and Het 2 are as defined in any one of claims 1-3.

4. A compound of formula I according to anyone of claims 1-4, wherein Het¹ is selected from the group consisting of 1,2-oxazolyl, lH-pyrazolyl, isoxazolyl and pyrazolyl.

5. A compound of formula I according to anyone of claims 1-4, wherein Het¹ is selected from the group consisting of isoxazolyl and pyrazolyl.

6. A compound of formula I according to anyone of claims 1-5, wherein Het¹ is selected from the group consisting of isoxazol-3-yl, isoxazol-5-yl and pyrazol-l-yl.

7. A compound of formula I according to anyone of claims 1-6, wherein Het¹ is isoxazolyl.

8. A compound of formula I according to anyone of claims 1-7, wherein Het is selected from the group consisting of lH-pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each individually substituted by one or two R¹ as defined in any one of claims 1-2.

9. A compound of formula I according to anyone of claims 1-8, wherein Het is selected from the group consisting of isothiazolyl, pyridyl, pyrazinyl, pyrazolyl and pyrimidinyl, each individually substituted by one R¹ as defined in any one of claims 1-2.

10. A compound of formula I according to anyone of claims 1-9, wherein Het is pyrimidinyl, substituted by one R¹ as defined in any one of claims 1-2.

11. A compound of formula I according to anyone of claims 1-10, wherein R¹ is selected from the group consisting of 2-(2-ethoxyethoxy)ethoxy, 2-(difluoromethoxy)ethoxy, 2- methoxyethoxy, 3-methoxypropoxy, Br, -CH₂CHF₂, -CHF₂, CI, CN, F, CH₃, - N(H,CH₂CHF₂), -N(H,CH₂CH₂), -N(H,CH₂), -N(CH₃,methoxyethyl), -0-CH₂-C≡C-CH₃, - 0-CH₂-CF₃, -0-CH₂-CH₂OH, -OCH₂CHF₂, -OCHF₂, -OCH₂CH₃, -OCH₃, -SCH₃.

12. A compound of formula I according to anyone of claims 1-11, wherein R¹ is selected from the group consisting of Br, CH_3, CF₃, CI, CN, -0-CH₂-C≡C-CH₃, -0-CH₃, -0-CH₂-CF₃, - 0-CHF₂, -0-CH₂-CHF₂ and -CHF₂.

13. A compound of formula I according to anyone of claims 1-12, wherein Het 2 -R 1 is selected from the group consisting of l-(difluoromethyl)pyrazol-3-yl, 3-(5-but-2-ynoxy-2-pyridyl), 3-methylisothiazol-5-yl, 5-(2,2,2-trifluoroethoxy)-2-pyridyl, 5-(2,2- difluoroethoxy)pyrazin-2-yl, 5-(difluoromethoxy)pyrimidin-2-yl, 5-(trifluoromethyl)-2- pyridyl, 5-bromopyrimidin-2-yl, 5-chloro-2-pyridyl, 5-cyano-2-pyridyl, 5-methoxypyrazin-

2-yl and 6-(difluoromethyl)pyridin-2-yl.

14. A compound of formula I according to anyone of claims 1-13, wherein Het 2 -R 1 is selected from the group consisting of 5-methoxypyrimidin-2-yl and 5-cyanopyrimidin-2-yl.

15. A compound according to anyone of claims 1-15, which is selected from the group consisting of

(4S,6S )-4-(2-fluoi -5-( I -(5-methoxypyrazin-2-yl }- 1 H-pyrazol-4-yl iphenyl l-4-methy!-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl )-5,6-dihvdro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-(methylthio)pyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1.3 oxa/.in-2-amiiie 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( t r i f Ί u o ro m e t h y I ! - , 6^■■ d i h yd ro^■ 4 H ~ 1 ,3-oxazin-2-amine 2,2,2-triiluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (tri fluorom thyl )-5,6-dihydro-4l i- 1 ,3-oxazin-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6- ( t ri f Ί u o ro m ethyl ) 0,6-dih yd ro - 4 H - 1 ,3-oxazin-2 -amine,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( trifluoromethyl )-5,6-dihvdfo-4U- 1 ,3 oxaz.in-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-( l-(2,2-difluoroethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl- 6-(trifluoromethyl i-5,6-dihydro-4H- 1.3-oxazin-2-amine.

( t r i Π u o ro m e t h y 1 ! - , 6 - d i h y d r o - 4 H - 1 ,3-oxazi n-2 -ami ne 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(4-chloro- l H-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-((2,2-difluoroet yl)ainino)pyrazin-2-yl)isoxazol-5-yl)-2-tluoiOphenyl)-4- methyl-6-( tnfluoromethyl )-5,6-dihydro-411- ! ,3- oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-(2-(2-ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- methyl -6 -( tnfluoron 'thyl )-5.6-dihydro-411- 1 .3 oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2-(difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-flu

methyl -6-f tri fluoromethy ! )-5,6-dihydro-4H^■ 1 ,3-oxa/.in^■ 2-ami lie 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- ( t !"i fl 11 o ro I n ethyl )^■ 5 , 6- d ihyd ro- 4 1^■ 1 , 3 - o x az i n - 2 - a m i n e 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-m 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluoropheny

(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(ethylamino)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-rnethyl-6- ( t ri f ! u o ro me t h y 1 ) -5, 6^■ d i h yd ro -411 - 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-chloro-3-fluoropyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5 ,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-chloro-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- ( tri luoromethyl !-5,6-dihydro-4! I- 1 ,3-oxazm- 2 -amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-(fluoromethyl)-6- ( t ri Π u o ro m e t h y 1 ! -5 , 6^■ d i h yd ro - 4 H - 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(6-(difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trif^'iiioromethyl ) -5,6 dihvdro -41 i- 1 ,3-oxazin-2-amine.

(4S,6S)-4-[2-fluoro-5-[3-[5-(2-methoxyethoxy)py.razin-2-yl]- l,2-oxazol-5-yl]phenyl]-4-methyl- 6-(trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[2-fluoro-5-[3-[5-(methylamino)pyrazin-2-yl]- l,2-oxazol-5-yl]phenyl]-4-methyl-6- ( tri f Ί u o ro m ethyl )-5,6 - d i h yd ro - 1 ,3-oxazin-2-amine, (4S,6S)-4-[5-[l-(5-chloropyriiTiidin-2-yl)pyrazol-4-yl]-2-flBorop enyl]-4-m.etliyl-6- (trifluorometh yl ) -5 , 6-dihydro- 1 ,3-oxa/in-2--amine,

(4S,6S)-4-[5-[3-(5-bromopyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5, 6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-but-2-ynoxy-2-pyridyl)isoxazol-5-yl]-2-f uoro-phenyl]-4-methyl-6- (trif uoromethyl)-5, 6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-chloro-2-pyridyl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trif uoromethyl)-5, 6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-(5-ethoxypyrazin-2-yl)-l ,2-oxazol-5-yl]-2-fluorophenyl]-4-methyl-6- (trifluoromethyl )-5, -dihydro- 1 ,3-oxa/.in -2-amine,

(4S,6S)-4-[5-[3-[l-(difluoromethyl)pyrazol-3-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trif uoromethyl)-5, 6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifhioromethyl)-5, 6-dihydro- 1 ,3-oxazin-2-amine,

2-((2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(t^^^

fluorophenyl)isoxazol-3-yl)pyrirriidin-5-yl)oxy)ethanol 2,2,2-trifluoroacetate,

2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l ,3-oxazin-4-yl)-4-

2,2,2-trifluoroacetate, and

6-[4-[3-[(4S, 6S)-2-amino-4-methyl-6-(trifluoromethyl)-5, 6-dihydro- l,3-oxazin-4-yl]-4-f uoro- phenyl] pyrazol- 1 - yl] pyridine- 3 -c arbonitrile .

16. A compound according to anyone of claims 1-15, which is selected from the group consisting of

(4S,6S)-4-(2-fluoro-5-( l-(5-methoxypyrazin-2-yl)- lH-pyrazol-4-yl)phenyl)-4-methyl-6- ί trifluoromethyl ) - 5.6 -d i h yd to - 4 ί I - 1 .3 oxazin-2-amine.

(4S,6S)-4-(2-f]uoro-5-(3-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)isoxazol-5- yl !phenyl j-4-methyl-6- (trifluoromethyl )-5,6-dihydro-4U- 1 .3 xa/.in-2-arnine.

(4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-(methylthio)pyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1.3-oxa in-2-amine 2,2.2- tniluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3 oxazin -2-amine 2,2,2-trifluoroacetate, (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)plienyl)-4-m.etliyl-6- (trifluorometh yl !-5,6- dih ydro-411- 1 ,3- oxazin-2-arnine,

(4S,6S)-4-(2-fluoro-5-(3-(5-niethoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-6- (tntluoromethy )-5.6-dih dro-4H- 1.3-oxazin-2-amine.

(4S,6S)-4-(2-fluoro-5-(3-(5-inethoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- ( tri Π u o ro m e t h y 1 ) - , 6 - d i h y d ro - 4 H - 1 ,3~oxazin-2 amine 2,2,2 tri fl uoroacetate,

(4S,6S)-4-(5-(3-(l-(2,2-difluoroethyl)-lH-pyrazol-3-yl)isoxazol-5-yl)-2-f!uorophenyl)-4- 6-(trifluorom.etliyl)-5,6-dihydiO-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(l-(difluoromethyl)- lH-pyrazol-4-yl)isoxazol-5-yl)-2-fluorophenyl)-4-me^^ (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2 amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(4-chloro- l H-pyrazol-3-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (tnfluoromethyl )-5,6-dihydro-4! 1- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-((2,2-difluoroethy¾

rnethy]-6-( tnfl LHjromethy l h5,6 dihydro-4f I- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-(2-(2-ethoxyethoxy)ethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4- meth \ 1- 6^■ ί tri fl uoromet h y ! ) -5.6- dih yd ro^■ 1 i- 1 ,3-oxazin-2-amine 2,2,2 tri Π uoroacetate, and

(4S,6S)-4-(5-(3-(5-(2-(difluoromethoxy)ethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fl^

methyl-6 (trifli)oromethyl j-5,6 dihydro-411- 1 ,3-oxa/.in-2-amine 2 , 2 , 2 - 1 ri f 1 u o i"oaee t a te .

17. A compound according to anyone of claims 1-16, which is selected from the group consisting of

(4S,6S)-4-[5-[3-(5-chloro-2-pyridyl)isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine, (4S,6S)-4-[5-[3-[l-(difluoromethyl)pyrazol-3-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-fluoro-5-(3-(3-methylisothiazol-5-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trif uoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trif uoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(5-(3-(6-(difluoromethyl)pyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-methyl-6- (trif uoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, and

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trif uoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, or pharmaceutically acceptable salts thereof.

18. A compound according to anyone of claims 1-17, which is selected from the group consisting of (4S,6S)-4-(2-fluoro-5-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-4-iT!ethyl-6- ( t r i f Ί 11 o i t) m e t h y I ) - , 6 - d i h yd i o^■■ 4 H - 1.3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-fluoropyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethy] )-5,6-dihydro-4l I- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-f!uorophenyl)-4-methyl- 6-( trinuoromethyl )-5,6-dihydro- H- ! ,3 oxa/in-2 am i iie 2,2,2-trifluoroacetate,

(4S,6S)-4-(5-(3-(5-(difluoromethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-4-met^

2,2,2-trifluoroacetate,

(4S,6S)-4-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine, and -(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluorometh^

uoropheny! )isoxa/.ol-3~yl ipynmidine-? -carbon itrile 2 , 2 , 2 - 1 ri f Ί u o ro acetate.

19. A compound according to anyone of claims 1-18, which is selected from the group consisting of (4S,6S)-4-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1.3 oxazin-2-amine 2,2,2-trifluoroacetate and 2-(5-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- l ,3-oxazin-4-yl)-4- fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate.

20. A compound of formula I according to anyone of claims 1-19 for use as therapeutically active substance.

21. A compound of formula I according to anyone of claims 1-19 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.

22. A compound of formula I according to anyone of claims 1-19 for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson's Disease.

23. A pharmaceutical composition comprising a compound of formula I according to anyone of claims 1-19 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

24. Use of a compound of formula I according to anyone of claims 1-19 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson's Disease.

25. A method for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease or amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson's Disease, which method comprises administering a compound of formula I according to anyone of claims 1-19 to a human being or animal.

26. The invention as hereinbefore described.

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