HK1191943A

HK1191943A - 1,3 oxazines as bace1 and/or bace2 inhibitors

Info

Publication number: HK1191943A
Application number: HK14105121.5A
Authority: HK
Inventors: 汉斯．希尔珀特; 沃尔夫冈．沃斯特
Original assignee: 霍夫曼-拉罗奇有限公司; 锡耶纳生物技术股份公司
Priority date: 2011-04-11
Filing date: 2012-04-10
Publication date: 2014-08-08

Description

1,3 oxazines as BACE1 and/or BACE2 inhibitors

Background

Alzheimer's Disease (AD) is a neurodegenerative disease of the central nervous system and is a major cause of progressive dementia in the middle-aged and older population. The clinical symptoms are impairment of memory, cognition, temporal and local orientation, judgment and reasoning, and severe emotional disturbances. There is currently no effective treatment that can prevent the disease or its progression or stably reverse its clinical symptoms. AD is a major health problem in all societies with a high life expectancy and also becomes a significant economic burden for these societal health systems.

AD is characterized by 2 major pathological features in the Central Nervous System (CNS): the appearance of amyloid plaques and The presence of neuronal fibrillar tangles (Hardy et al, The amyloid hypothesises of Alzheimer's disease: progress and publications on The road to therapy. science 2002Jul 19; 297 (5580: 353-6, Selkoe, Cell biology of The amyloid beta-protein precusor and The mechmnism of Alzheimer's disease, AnnuRevCell Bio 1.1994; 10: 373) in patients with Down syndrome (trisomy 21) are also commonly found with these two pathological features, which also show AD-like symptoms at an early stage. neuronal fibrillar tangles are intracellular aggregation plaques of microtubule binding protein (MAPT) present in extracellular space; their main component is The A beta-amyloid peptide, which is a group of amyloid proteins recognized by The APP protein (APP protein) via The series of steps, the largest of these are proteins of 695, 751 and 770 amino acids in length. They are all produced from one gene via differential splicing. The A β -peptides are derived from the same domain as APP but differ at their N-and C-termini, with the main species being 40 and 42 amino acid long species. There are several chains of evidence that strongly suggest that aggregated a β -peptide is an essential molecule in the pathogenesis of AD: 1) amyloid plaques formed by a β -peptide are an invariant part of AD pathology; 2) a β -peptide is toxic to neurons; 3) in Familial Alzheimer's Disease (FAD), mutations in the causative genes APP, PSN1, PSN2 result in increased levels of a β -peptide and early cerebral amyloidosis; 4) transgenic mice expressing this FAD gene exhibit pathology with many similarities to human disease. A β -peptide is produced by APP through the sequential action of 2 proteolytic enzymes named β -and γ -secretases. The β -secretase enzyme first cleaves the extracellular domain of APP of approximately 28 amino acids outside the transmembrane domain (TM) to generate a C-terminal fragment of APP containing the TM-and cytoplasmic domains (CTF β). CTF β is a substrate for γ -secretase, which cleaves at several adjacent positions within the TM to produce a β peptide and cytoplasmic fragments. Gamma-secretase is a complex of at least 4 different proteins whose catalytic subunits closely resemble presenilin proteins (PSEN1, PSEN 2). Beta-secretase (BACE1, Asp 2; BACE stands for. Beta. -position APP-cleaving enzyme) is an aspartyl protease anchored in the membrane via the transmembrane domain (Vassar et al, Beta-secretase cleavage of Alzheimer's amyloid accurproprotein by the transmembrane enzymatic protease BACE, Science 1999Oct 22; 286 (55440): 735). It is expressed in many tissues of the human body, but its levels are particularly high in the CNS. The gene defect of the BACE1 gene in Mice clearly shows that its activity is important in APP processing leading to the production of A β -peptide, without the BACE1 (Luo et al, Mice discovery in BACE1, the Alzheimer's beta-secretase, had normal genomic and extracted beta-amplified generation, Nat neurosci.2001Mar; 4 (3): 231-2, robers et al, k nock non nucleic acid amide synthesis in amplification in purity: experiments for Alzheimer's disease therapeutics, Hum BACE Genet (human molecular genetics) JJ 1; 2001-13112). Mice that have been genetically engineered to express the human APP gene and develop extensive amyloid plaques and Alzheimer's disease pathology during aging no longer exhibit this when β -secretase activity is reduced by genetic disruption of one of the BACE1 alleles (McConlogue et al, Partial reduction of BACE1ha reactive effects on Alzheimer's disease and systemic pathology in APP Transgenic Rice Jbiol Chem. (J. biol. Chem.) 2007Sep 7; 282 (36): 26326). It is therefore speculated that inhibitors of BACE1 activity may be agents useful in the therapeutic intervention of Alzheimer's Disease (AD).

Type2diabetes (T2D) is caused by insulin resistance and insufficient insulin secretion from pancreatic β -cells resulting in poor glycemic control and hyperglycemia (M Prentki and CJ Nolan, "Islet beta-cell failure in type2diabetes. Patients with T2D have an increased risk of acquiring: microvascular and macrovascular diseases and a variety of associated complications including diabetic nephropathy, retinopathy and cardiovascular disease. In 2000, it was estimated that one hundred million people had the disease, and it was expected that this number will double by 2030 (S Wild, G Roglic, a Green, r.secret and H King, "Global prediction of Diabetes", Diabetes Care2004, 27(5), 1047-1053), making the disease a major health problem. The rising incidence of T2D is associated with an increasing sedentary lifestyle and high energy food intake in the world population (PZimmet, KGMM Alberti and J Shaw, "Global and social indications of the diabetes epidemic" Nature 2001, 414, 782- "787).

Beta cell failure and the resulting marked decrease in insulin secretion and hyperglycemia marked the onset of T2D. Most of the current treatments do not prevent the loss of the beta cell population characteristic of T2D. However, recent studies with the GLP-1 analog gastrin and other drugs have shown that it is possible to achieve preservation and proliferation of beta cells, leading to improved glucose tolerance and slowing progression to overt T2D (LL Baggio and DJ Drucker, "Therapeutic applications to predictive islets in type2 diabetes", annu. rev. med. d.2006, 57, 265 aspirates).

Tmem27 has been identified as a protein that promotes beta Cell proliferation (P Akpinar, S Kuwajima, JKrultzfeldt, M Stoffel, "Tmem 27: A cleaned and plated membrane proteins across cultures beta Cell proliferation," Cell Metab.2005, 2, 385 397) and insulin secretion (K Fukui, Q Yang, Y Cao, N Takahashi et al, "the HNF-1target collectricntrol insulin exocytosis by ARE complex formation," Cell Met.2005, 2, 373 ab 384). Tmem27 is a 42kDa membrane glycoprotein constitutively shed from the surface of beta cells, degraded from full-length cells Tmem 27. Over-expression of Tmem27 in transgenic mice increased the β -cell population and improved glucose tolerance in a Diet Induced Obesity (DIO) model of diabetes. Furthermore, sirnas that knock out Tmem27 in rodent beta cell proliferation assays (e.g., using INS1e cells) reduced the rate of proliferation, suggesting a role for Tmem27 in controlling the beta cell population.

In the same proliferation assay, BACE2 inhibitors also increased proliferation. However, BACE2 inhibition combined with Tmem27siRNA knockdown resulted in lower proliferation rates. Therefore, BACE2 was concluded to be a protease associated with degradation of Tmem 27. Furthermore, BACE2 cleaves peptides based on the Tmem27 sequence in vitro. The closely related protease BACE1 does not cleave this peptide and selective inhibition of BACE1 alone does not enhance beta cell proliferation.

The proximal homologue BACE2is a membrane-bound aspartyl protease and is co-localized with Tmem27 in beta cells of the human pancreas (G Finzi, F Franzi, C Placidi, F Acquati et al, "BACE 2is stored in recombinant granules of mouse and rat pancreatic beta cells". Ultrastrucct Patho1.2008, 32(6), 246-. It is also known to degrade APP (I Hussain, D Powell, D Howlett, G Chapman et al, "ASP 1(BACE2) cleaves the amyloidovorsor protein at the β -secretase site" Mol Cell neurosci.2000, 16, 609-619), IL-1R2(P Kuhn, E Marjaux, A Imhof, B De Strooper et al, "regulated interaction network protein of the interaction-1 receptor II by alpha-, beta-, and-secretase" J.Biochem.1. chem. (J.Biol.Chem.) 2007, 282(16), 11982-11995) and ACE 2. The ability to degrade ACE2 suggests a possible role for BACE2 in hypertension control.

Therefore, inhibition of BACE2 has been proposed as a treatment for T2D, taking advantage of the potential to preserve and restore β -cell populations and stimulate insulin secretion in pre-diabetic and diabetic patients. It is therefore an object of the present invention to provide selective BACE2 inhibitors. Such compounds are useful as therapeutically active substances, especially for the treatment and/or prevention of diseases which are associated with the inhibition of BACE 2.

Furthermore, the formation or formation and deposition of β -amyloid peptides in, on or around neural tissue (e.g., the brain) is inhibited by the compounds of the invention, i.e., inhibition of a β -production from APP or APP fragments.

In addition BACE1 and/or BACE2 inhibitors may be useful in the treatment of the following diseases: IBM (Inclusion myositis) (Vattemi G. et al, Lancet.2001Dec8; 358 (9297): 1962-4), Down syndrome (Barbiero L. et al, Exp neuro1.2003 aug; 182 (2): 335-45), Wilson's disease (Sugimoto I. et al, J Biol chem.2007Nov30; 282 (48): 34896-,http：／／www.ebi.ac.uk／microarray-as／aer／resultqueryFor=PhysicalArrayDesitn &aAccession=AMEXP-258), rheumatoid arthritis (ungentherm u. et al, GSE2053), amyotrophic lateral sclerosis (Koistinen h. et al, Muscle nerve.2006 oct; 34(4): 444-50, Li Q.X. et al, Aging cell.2006Apr; 5(2): 153-65), Huntington's disease (Kim Y J. et al, Neurobiol Dis.2006May; 22(2): 346-56. Epub2006Jan19 and hodgsa et al, Hum Mol genet.2006mar15; 15(6): 965-77. Epub2006Feb8), multiple myeloma (mieloma) (Kihara Y et al, Proc Natl Acad Sci U sa.2009dec22; 106(51): 21807-12), malignant melanoma (Talantov D. et al, Clin Cancer Res.2005Oct 15; 11(20): 7234-42), sjogren's syndrome (Basset C. et al, Scand J Immuno 1.2000Mar; 51(3): 307-11), lupus erythematosus (Grewal P k. et al, Mol Cell bio1.2006, Jul; 26(13): 4970-81), macrophage myofascitis (macrophagic myofasciitis), juvenile idiopathic arthritis, granulomatous arthritis, breast Cancer (Hedlund M. et al, Cancer Res.2008Jan 15; 68(2): 388-94 and Kondoh KBreast Cancer Res treat.2003Mar; 78(1): 37-44), gastrointestinal disease (HoffmeisteriA. et al, JOP.2009Sep4; 10(5): 501-6), autoimmune/inflammatory diseases (Woodard-gricea.v et al, J Biol chem.2008sep26; 283(39): 26364-73.Epub2008Jul23), rheumatoid arthritis (to egel s. et al, Osteoarthritis cartilage.2010feb; 18(2): 240-8.Epub2009Sep22), inflammatory response (lichtenshaler s.f. et al, J Biol chem.2003dec5; 278(49): 48713-9. Epub2003Sep24), arterial thrombosis (Merten m. et al, Z kardio 1.2004nov; 93(11): 855-63), cardiovascular diseases such as myocardial infarction and stroke (Maugeri n. et al, Srp Arh celoklek.2010jan; 138Suppl 1: 50-2) and Graves disease (Kilja u ski J. et al, Thyroid.2005Jul; 15(7): 645-52).

The present invention provides novel compounds of formula I, their manufacture, medicaments based on compounds according to the invention and their manufacture as well as the use of compounds of formula I in the control or prevention of diseases such as alzheimer's disease and type2diabetes. Furthermore, there is the use of a compound 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's sarcoma, costmann Disease (Kostmann Disease), lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, Whipple's Disease (Whipple's Disease) and wilson's Disease. The novel compounds of formula I have improved pharmacological properties.

Technical Field

The present invention provides 4- (3-amino-phenyl) -5, 6-dihydro-4H- [1,3] oxazin-2-ylamines having BACE1 and/or BACE2 inhibitory properties, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

Disclosure of Invention

The present invention provides a compound of formula I,

wherein the substituents and variables are as described below and in the claims, or pharmaceutically acceptable salts thereof.

The compounds of the present invention have Asp2 (3-secretase, BACE1 or endo-APP (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, especially alzheimer's disease and/or the compounds of the present invention have BACE2 inhibitory activity and may therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders such as type2diabetes and other metabolic diseases.

Detailed Description

The present invention provides compounds of formula I and their pharmaceutically acceptable salts, the preparation of such compounds, medicaments containing them and their manufacture, as well as the use of such compounds in the therapeutic and/or prophylactic treatment of diseases and disorders associated with the inhibition of BACE1 and/or BACE2 activity, such as alzheimer's disease and type2diabetes. In addition, the compounds of the invention inhibit the formation or formation and deposition of β -amyloid plaques in, on or around neural tissue (e.g., the brain) by inhibiting the production of a β from APP or an APP fragment.

The following definitions of general terms used in the present specification apply irrespective of whether the terms in question appear alone or in combination with other groups.

Unless otherwise indicated, the following terms used in the present application, including the specification and claims, have the definitions set forth below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "C_1-6-alkyl ", alone or in combination with other groups, denotes such hydrocarbon radicals: which may be linear or branched, with single or multiple branches, wherein the alkyl group typically contains 1 to 6 carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl, 1, 2-dimethyl-propyl, and the like. The term "C_1-3-alkyl ", alone or in combination with other groups, denotes such hydrocarbon radicals: it may be linear or branched, wherein the alkyl group contains 1 to 3 carbon atoms. In particular "C_1-6-alkyl "is" C_1-3-an alkyl group ". In particular methyl and ethyl. Most particularly methyl.

The term "cyano-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl substituted by one or more cyano groups, in particular 1 to 5 cyano groups, more in particular 1 cyano group. Examples are cyano-methyl and the like.

The term "halo-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl substituted with one or more halogens, in particular 1 to 5 halogens, more in particular 1 to 3 halogens, most in particular 1 halogen or 3 halogens. The term "halo-C_1-3-alkyl ", alone or in combination with other groups, means C as defined herein_1-3Alkyl substituted by one or more halogens, in particular from 1 to 5 halogens, more particularly from 1 to 3 halogens,most particularly 1 halogen or 3 halogen substitution. A particular halogen is fluorine. Particular "halo-C_1-6-alkyl "is fluoro-C_1-6-alkyl and in particular "halo-C_1-3-alkyl "is fluoro-C_1-3-an alkyl group. Examples are difluoromethyl, chloromethyl, fluoromethyl and the like. In particular trifluoromethyl, -CH₂-CHF₂and-CH₂-CH₂F。

The term "C_1-6-alkoxy-C_1-6-alkyl ", alone or in combination with other groups, means C_1-6-alkyl, which is substituted by one or more C as defined herein_1-6-alkoxy substituted. Examples are MeO-CH₂-, 1MeO-Et, 2MeO-Et, 1MeO-2 EtO-propyl, and the like.

The term "C_3-6-cycloalkyl-C_1-6-alkyl ", alone or in combination with other groups, means C_1-6-alkyl, which is substituted by one or more C as defined herein_3-6-cycloalkyl substitution. Examples are cyclopropyl-methyl and the like.

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

The term "hydroxy", alone or in combination with other groups, refers to HO-.

The term "halogen", alone or in combination with other groups, denotes chloro (C1), iodo (I), fluoro (F) and bromo (Br). Particular "halogens" are Cl and F. In particular F.

The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group having a single 4 to 8 membered ring or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms independently selected from N, O and S, especially N and O, in which at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include: benzofuranyl, benzimidazolyl, iH-benzimidazolyl, benzoxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazolyl), 1H-pyrazolyl, pyrazolo [1,5-a ] pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6, 7-dihydro-5H- [1] azoindenyl, and the like. Particular "heteroaryl" groups are pyridyl, pyrazinyl, furyl, thiazolyl, 2H-pyrazolyl and 1H-pyrazolyl. In particular pyridin-2-yl, pyrazin-2-yl, furan-3-yl, thiazol-5-yl, 2H-pyrazol-3-yl and 1H-pyrazol-3-yl.

The term "heterocyclyl", alone or in combination with other groups, denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings having two common ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclyl groups are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocyclyl groups are 8-aza-bicyclo [3.2.1] octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl, 9-aza-bicyclo [3.3.1] nonyl, 3-oxa-9-aza-bicyclo [3.3.1] nonyl or 3-thia-9-aza-bicyclo [3.3.1] nonyl. Examples of partially unsaturated heterocyclyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl, or dihydropyranyl.

The term "C_1-6-alkoxy ", alone or in combination with other groups, denotes-O-C which may be linear or branched, with a single or multiple branching_1-6Alkyl groups, wherein the alkyl group typically contains from 1 to 6 carbon atoms, e.g. methoxy (OMe, MeO), ethoxy (OEt),Propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy), and the like. In particular "C_1-6-alkoxy "is a group with 1 to 4 carbon atoms. Particularly methoxy and ethoxy (ethoxy).

The term "halo-C_1-6-alkoxy ", alone or in combination with other groups, means C as defined herein_1-6-alkoxy substituted by one or more halogens, in particular fluorine. Particular "halo-C_1-6-alkoxy "is fluoro-C_1-6-alkoxy groups. In particular difluoromethoxy and trifluoromethoxy.

The term "C_3-6-cycloalkyl-C_1-6-alkoxy ", alone or in combination with other groups, means C as defined herein_1-6-alkoxy, which is substituted by one or more "C" as defined herein_3-6Cycloalkyl "is especially cyclopropyl substituted. In particular "C_3-6-cycloalkyl-C_1-6-alkoxy "is cyclopropyl-C_1-6-alkoxy groups. In particular cyclopropyl-methoxy and cyclopropyl-ethoxy.

The term "C_3-6-cycloalkyl-C_2-6-alkynyl ", alone or in combination with other groups, means" C "as defined herein_3-6-cycloalkyl "via" C "as defined herein_2-6-alkynyl "linkage. In particular cyclopropyl-ethynyl.

The term "C_3-6-cycloalkyl ", alone or in combination with other groups, means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 6 ring carbon atoms, in particular of 3 to 5 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having two carbon atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two carbon atoms. In particular C_3-6-cycloalkyl is monocyclic. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. An example of bicyclic cycloalkyl is bicyclo [2.2.1]Heptyl, bicyclo [2.2.2]Octyl or goldA rigid alkyl group. In particular "C_3-6-cycloalkyl "is cyclohexyl.

The term "C_2-6-alkynyl ", alone or in combination with other groups, denotes a monovalent linear or branched unsaturated hydrocarbon radical of 2 to 6 carbon atoms, in particular 2 to 4 carbon atoms, and comprises one, two or three triple bonds. C_2-6Examples of-alkynyl include ethynyl, propynyl, prop-2-ynyl and n-butynyl. Particularly ethynyl and propynyl.

The term "C_2-6-alkynyl-C_1-6-alkoxy ", alone or in combination with other groups, means" C "as defined herein_2-6-alkynyl "via" C "as defined herein_1-6-alkoxy "linkage. In particular 5-but-2-ynyloxy.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but not limited to: acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like. In particular formic acid, trifluoroacetic acid and hydrochloric acid. In particular hydrochloric acid, trifluoroacetic acid and fumaric 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" includes a product comprising the specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. In particular, it comprises: a product comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from decomposition 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" means a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or that reduces or prevents the inhibition of the function of a particular protein.

The term "half maximal inhibitory concentration" (IC)₅₀) Representing the concentration of the particular compound required to obtain 50% inhibition of the biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted into pIC₅₀Value (-1og IC)₅₀) Wherein a higher value indicates a greater exponential increase in potency. IC (integrated circuit)₅₀The values are not absolute values but depend on the experimental conditions, e.g. the concentrations employed. IC (integrated circuit)₅₀Values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmaco1 (1973) 22: 3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor for a receptor. It is measured using a competitive binding assay and, if no competing ligand (e.g., a radioligand) is present, is equal to the concentration at which 50% of the receptor is occupied by that particular inhibitor. Ki values can be logarithmically converted to pKi values (log Ki), where higher values indicate a greater exponential increase in potency.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment for that disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and other factors.

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

The terms "treating", "contacting" and "reacting", when referring to a chemical reaction, mean adding or mixing two or more reagents under suitable conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or desired product may not necessarily be the result of a combination of the two reagents from the initial addition, i.e., more than one intermediate produced may be present in the mixture that ultimately results in the formation of the indicated and/or desired product.

The term "protecting group" means a group that, in the meaning conventionally associated therewith in synthetic chemistry, selectively blocks one reactive site in a polyfunctional compound such that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group may be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" denotes a group intended to protect an amino group and includes benzyl, benzyloxycarbonyl (benzyloxyformyl, CBZ), 9-Fluorenylmethoxycarbonyl (FMOC), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-Butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of such Groups are found in T.W Greene and P G.M.Wuts, "Protective Groups in Organic Synthesis", 2 nd edition, John Wiley & Sons, Inc., New York, NY, 1991, Chapter 7; haslam, "Protective Groups in Organic chemistry", edited by J.G.W McOmie, Plenum Press, New York, NY, 1973, Chapter 5, and T.W Greene, "Protective Groups in Organic Synthesis", John Wileyand Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with an amino-protecting group, particularly the amino-protecting groups are t-butyloxycarbonyl, bis (dimethoxyphenyl) -phenylmethyl, and dimethoxytrityl.

The term "leaving group" denotes a group having the meaning conventionally associated with it in synthetic organic chemistry, i.e. an atom or group which may be substituted under the substitution reaction conditions. Examples of leaving groups include halogen, in particular bromine, alkyl-or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, toluenesulfonyloxy, and thienyloxy, dihalophosphonoxy, optionally substituted benzyloxy, isopropoxy, and acyloxy groups.

The term "aromaticity" denotes the conventional meaning of aromaticity as defined in the literature, in particular in IUPAC-Complex of chemical technology, 2 nd edition, A.D.McNaught & A.Wilkinson (eds.), Blackwell Scientific Publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" means any ingredient which is not therapeutically active and which is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

As long as a chiral carbon is present in a chemical structure, all stereoisomers associated with that chiral carbon are intended to be encompassed within that structure.

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

All individual embodiments may be combined.

One embodiment of the present invention is a compound of formula I,

wherein

R¹Selected from the group consisting of:

i) the presence of hydrogen in the presence of hydrogen,

ii) halogen, and

iii)C_1-6-an alkyl group;

R²selected from the group consisting of:

i) the presence of hydrogen in the presence of hydrogen,

ii)C_1-6-alkyl, and

iii) halo-C_1-3-alkyl radical，

R³Selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R⁴selected from the group consisting of:

i) the halogen(s) are selected from the group consisting of,

ii)C_1-6-alkyl, and

iii) halo-C_1-6-an alkoxy group,

R⁵is-C (= O) -R⁶，

R⁶Selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

ii) heteroaryl substituted with 1-4 substituents independently selected from cyano, cyano-C_1-6Alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl radical, C_3-6-cycloalkyl radical, C_3-6-cycloalkyl-C_1-6-alkoxy radical, C_3-6-cycloalkyl-C_1-6-alkyl radical, C_3-6-cycloalkyl-C_2-6-alkynyl, C_2-6-alkynyl-C_1-6-alkoxy and C_1-6-an alkyl group,

iii)C_3-6-a cycloalkyl group,

iv) C substituted by 1 to 4 substituents_3-6-cycloalkyl, said substituents being independently selected from cyano, cyano-C_1-6Alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6Alkyl, hydroxy, C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl and C_1-6-an alkyl group,

v) a heterocyclic group, and

vi) heterocyclyl substituted with 1-4 substituents independently selected from cyano, cyano-C_1-6Alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl and C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a compound of formula Ia as described herein,

wherein R is¹，R²，R³，R⁴，R⁵As defined herein.

A certain embodiment of the invention provides a compound as described herein, wherein

R¹Is a halogen, and the halogen is a halogen,

R²is C_1-6-an alkyl group,

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R⁴selected from the group consisting of:

i) halogen, and

ii) halo-C_1-6-an alkoxy group,

R⁵is-C (= O) -R⁶，

R⁶Selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

ii) heteroaryl substituted with 1-4 substituents independently selected from cyano, halogen, halo-C_1-6-alkoxy, halo-C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-alkyl radical, C_3-6-cycloalkyl radical, C_3-6-cycloalkyl-C_1-6-alkoxy radical, C_2-6-alkynyl-C_1-6-alkoxy and C_3-6-cycloalkyl-C_2-6-an alkynyl group,

iii)C_3-6-a cycloalkyl group, and

iv) C substituted by 1 to 4 substituents_3-6-cycloalkyl, said substituents being independently selected from cyano and halogen,

or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention are provided compounds as described herein, wherein R is¹Is a halogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is¹Is F.

In one embodiment of the invention are provided compounds as described herein, wherein R is¹Is hydrogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is¹Is C_1-6-an alkyl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is²Is C_1-6-an alkyl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is²Is Me.

In one embodiment of the invention are provided compounds as described herein, wherein R is²Is hydrogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is²Is halo-C_1-3-an alkyl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is²is-CH₂-CHF₂。

In one embodiment of the invention are provided compounds as described herein, wherein R is²is-CH₂-CH₂F。

In one embodiment of the invention are provided compounds as described herein, wherein R is³Is hydrogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is³Is C_1-6-an alkyl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁴Is a halogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁴Is F.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁴Is halo-C_1-6-alkoxy groups.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁴is-OCH₂CF₃。

In one embodiment of the invention are provided compounds as described herein, wherein R is⁴Is C_1-6-an alkyl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁵is-C (= O) -R⁶。

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a heteroaryl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is pyridin-2-yl.

According to the inventionIn one embodiment, there is provided a compound as described herein, wherein R⁶Is a 1H-pyrazol-3-yl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a 2H-pyrazol-3-yl group.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is furan-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is thiazol-5-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is pyridin-2-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, pyrazin-2-yl, furan-3-yl or thiazol-5-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is heteroaryl substituted with 1-2 substituents independently selected from cyano and halogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 3-chloro-5-cyano-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is heteroaryl substituted with 1-2 substituents independently selected from halo-C_1-6-alkyl and halogen.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 3-fluoro-5-trifluoromethyl-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 3-chloro-5-trifluoromethyl-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 4-chloro-1- (2, 2-difluoro-ethyl) -1H-pyrazol-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is heteroaryl substituted with 1-2 halogens.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-fluoro-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 3, 5-difluoro-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-difluoromethyl-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-chloro-3-fluoro-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 3, 5-dichloro-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-chloro-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 2-chloro-thiazol-5-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 4-chloro-1H-pyrazol-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is heteroaryl substituted by cyano.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-cyano-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is halogenated-C_1-6-alkoxy substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-fluoromethoxy-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-fluoromethoxy-pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-difluoromethoxy-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5- (2,2, 2-trifluoro-ethoxy) -pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5- (2, 2-difluoro-ethoxy) -pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_1-6-alkyl-substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 2, 5-dimethyl-furan-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 1, 5-dimethyl-1H-pyrazol-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_3-6-cycloalkyl-C_1-6-alkyl-substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-cyclopropyl-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_3-6-cycloalkyl-C_2-6-alkynyl-substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-cyclopropylethynyl-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_2-6-alkynyl-C_1-6-alkoxy substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-but-2-ynyloxy-pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_3-6-cycloalkyl-C_1-6-alkoxy substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-cyclopropylmethoxy-pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-cyclopropylmethoxy-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is halogenated-C_1-6-alkyl-substituted heteroaryl.

One embodiment of the present inventionProviding a compound as described herein, wherein R⁶Is 5-difluoromethyl-pyrazin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is halogenated-C_1-6-alkyl and C_1-6-alkyl-substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is a quilt C_1-6-alkoxy substituted heteroaryl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is 5-methoxy-pyridin-2-yl.

In one embodiment of the invention are provided compounds as described herein, wherein R is⁶Is heteroaryl substituted with 1-2 substituents independently selected from cyano, halogen and C_3-6-cycloalkyl-C_2-6-alkynyl.

In one embodiment of the invention are provided compounds as described herein, wherein R is²Is pyridyl substituted with 1-2 substituents independently selected from cyano, chloro and cyclopropylethynyl-.

A certain embodiment of the invention provides a compound as described herein, selected from the group consisting of:

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-fluoromethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-difluoromethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3-chloro-5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-chloro-3-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-fluoromethoxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-difluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-methoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyclopropylethynyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-difluoromethyl-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyclopropyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

2-chloro-thiazole-5-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

4-chloro-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

thiazole-5-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

1-cyano-cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3-chloro-5-cyano-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-chloro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide,

5-fluoro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide,

5-cyano-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4S,5R) -2-amino-5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4S, 5S) -2-amino-5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -or (4R,5S) -2-amino-4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide,

5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

1, 5-dimethyl-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2-difluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2-difluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

4-chloro-1- (2, 2-difluoro-ethyl) -1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

2, 2-difluoro-cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

2, 5-dimethyl-furan-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3, 5-difluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide, and

3, 5-dichloro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide,

or a pharmaceutically acceptable salt thereof.

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

thiazole-5-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide, and

or a pharmaceutically acceptable salt thereof.

5-cyano-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide, and

or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention provides a compound as described herein which is 5-chloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide.

A certain embodiment of the invention provides a compound as described herein which is 3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide.

A certain embodiment of the invention provides a compound as described herein which is 5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide.

A certain embodiment of the invention provides a compound as described herein, which is 5-cyano-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide.

A certain embodiment of the invention provides a compound as described herein which is 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide.

A certain embodiment of the invention provides a compound as described herein, the method comprising reacting a compound of formula C4 to a compound of formula I,

wherein R is¹，R²，R³，R⁴，R⁵And R⁶As defined herein.

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

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 use as an inhibitor of BACE1 and/or BACE2 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use as an inhibitor of BACE1 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use as an inhibitor of BACE2 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use as an inhibitor of BACE1 and BACE2 activity.

A certain embodiment of the present invention provides compounds of formula I as described herein for use as therapeutically active substances 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 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 use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes, or type2diabetes.

A certain embodiment of the invention provides a compound of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes.

A certain embodiment of the invention provides a compound of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes or type2diabetes.

A certain embodiment of the present invention provides a compound of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type2diabetes.

A certain embodiment of the present invention provides a compound of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of the following diseases: 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 responses, kaposi's sarcoma, costerman's disease, lupus erythematosus, macrophage myofascitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 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, together with 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 inhibiting BACE1 and/or BACE2 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 inhibiting 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 inhibiting BACE2 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 inhibiting BACE1 and BACE2 activity.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the preparation 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 preparation 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 preparation of a medicament for the therapeutic and/or prophylactic treatment of diabetes or type2diabetes.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of diabetes.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the preparation of a medicament, the medicament is used 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 disease, glioblastoma multiforme, graves ' disease, huntington's disease, Inclusion Body Myositis (IBM), inflammatory response, kaposi's sarcoma, costermann disease, lupus erythematosus, macrophage myofascitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, whipple's disease or wilson's disease.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type2diabetes.

A certain embodiment of the invention provides the use of a compound of formula I as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of type2diabetes.

A certain embodiment of the invention provides a compound of formula I as described herein for use in inhibiting BACE1 and/or BACE2 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use in inhibiting BACE1 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use in inhibiting BACE2 activity.

A certain embodiment of the invention provides a compound of formula I as described herein for use in inhibiting BACE1 and BACE2 activity.

A certain embodiment of the invention provides compounds of formula I as described herein for 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 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 use in the therapeutic and/or prophylactic treatment of diabetes or type2diabetes.

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

A certain embodiment of the invention provides a compound of formula I as described herein for use in the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type2diabetes.

A certain embodiment of the invention provides a compound of formula I as described herein for 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 responses, kaposi's sarcoma, costermann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, whipple's disease or wilson's disease.

A certain embodiment of the present invention provides a method for the inhibition of BACE1 and/or BACE2 activity, in particular 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, alzheimer's disease, diabetes or type2diabetes, comprising 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 therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type2diabetes, 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 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 therapeutic and/or prophylactic treatment of diabetes, 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 therapeutic and/or prophylactic treatment of type2diabetes, which method comprises administering a compound of formula I as described herein to a human being or animal.

One embodiment of the present invention provides a method 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, a method of treating dermatomyositis, down's syndrome, gastrointestinal disease, glioblastoma multiforme, graves ' disease, huntington's disease, Inclusion Body Myositis (IBM), inflammatory response, kaposi's sarcoma, costermann disease, lupus erythematosus, macrophage myofascitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, whipple's disease or wilson's disease, comprising administering a compound of formula I as described herein to a human being or animal.

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

One skilled in the art will recognize that the compounds of formula I may exist in tautomeric forms, for example the following tautomeric forms:

all tautomeric forms are included in the invention.

The compounds of formula I may contain more than one asymmetric center and may therefore exist as: racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the different substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all possible optical isomers and diastereomers as mixtures, and as pure or partially purified compounds, are encompassed within this invention. The present invention is intended to encompass all such isomeric forms of these compounds. The individual syntheses of these diastereomers or their chromatographic separations may be achieved by appropriate modification of the methods disclosed herein, as is known in the art. Their absolute stereochemistry may be determined by the x-ray crystallography of the crystal products or crystal intermediates derived therefrom, if desired, using reagents containing asymmetric centers of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to separate their individual enantiomers. Separation can be carried out by methods well known in the art, such as the combination of a racemic mixture of compounds with 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. Particular examples of isomers of the compounds of the formula I are compounds of the formula Ia or compounds of the formula Ib, Ia-I, Ia-II, Ib-I or Ib-II, in particular compounds of the formula Ia, in which the residues have the meanings as described in any of the embodiments.

In embodiments where optically pure enantiomers are provided, by optically pure enantiomer is meant a compound containing > 90% by weight of the desired isomer, specifically > 95% by weight of the desired isomer, or more specifically > 99% by weight of the desired isomer, based on the total weight of one or more isomers of the compound. Chirally pure or chirally enriched compounds may be prepared by chiral selective synthesis or by separation of enantiomers. The separation of the enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

The compounds of formula I may be prepared according to the following scheme. The starting materials are commercially available or can be prepared according to known methods. Unless otherwise indicated, any previously defined residues and variables will continue to have the previously defined meanings.

The sulfinylimines of the formula A2 can be prepared as follows: analogously to T.P Tang & j.a.ellman, j.org.chem.1999, 64, 12, by condensation of aryl ketones a1 with sulfinamides, such as alkyl sulfinamides, most particularly (R) - (+) -tert-butyl sulfinamide, in the presence of lewis acids such as, for example, titanium (IV) alkoxides, more particularly titanium (IV) ethoxide, in solvents such as ethers, for example diethyl ether or more particularly tetrahydrofuran.

The conversion of sulfinylimine a2 to sulfinamide ester A3 proceeds stereoselectively via a chiral directing group as described by Tang & Ellman. The sulfinimide A2 can be reacted with a zinc enolate in a Levomacityl reaction, the activated zinc powder being reacted at ambient to elevated temperature, particularly at 23 to 60 ℃, in a solvent such as an ether, for example diethyl ether or more particularly tetrahydrofuran. The zinc enolate is produced from alkyl acetates or alkyl propionates substituted by halogen, such as in particular bromo-fluoro-ethyl acetate or 2-bromo-2-fluoro-ethyl propionate. The sulfinyl imine a2 can also be reacted with an alkyl acetate substituted by halo-alkoxy, such as, for example, ethyl 2- (2,2, 2-trifluoroethoxy) acetate, in the presence of a strong base, such as n-butyllithium, at from 0 to-78 ℃ in an inert solvent, such as an ether, for example diethyl ether or more particularly tetrahydrofuran.

The alcohol of formula a4 can be prepared by: the reduction of an ethyl ester of formula a3 with a basic hydride, in particular lithium borohydride or lithium aluminium hydride, in a solvent such as an ether, for example diethyl ether or more particularly tetrahydrofuran.

Hydrolysis of the chiral directing group in the sulfinamidol of formula a4, which gives an aminoalcohol of formula a5, can be achieved with a mineral acid, for example sulphuric acid or, in particular, hydrochloric acid, in a solvent such as an ether, for example diethyl ether, tetrahydrofuran or, more particularly, 1, 4-dioxane.

Aminooxazines of formula a 6may be prepared by reaction of an aminoalcohol of formula a5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.

Scheme A: synthesis of intermediates of formula I.

The nitro derivative of formula a7 may be represented by the formula wherein R⁷Nitration of oxazine a6, which is hydrogen, was carried out according to standard procedures using pure sulfuric acid and fuming nitric acid without solvent.

The reduction of the nitro group in the compound of formula A7 to give the aniline of formula A8 can be achieved by hydrogenation using a catalyst, such as palladium on charcoal, in a protic solvent, such as an alcohol, in particular ethanol or methanol.

Alternatively, aniline of formula A8 is given wherein R⁷The reduction of the derivatives of formula a6, which are nitro groups, can be achieved by hydrogenation using a catalyst, such as palladium on charcoal, in a protic solvent, such as an alcohol, in particular ethanol or methanol.

Anilines of the formula A8 giving amides of the formula I with the formula R⁶Selective reaction of the carboxylic acid-COOH may be achieved by chlorination of 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholine(DMTMM) hydrate is accomplished in a solvent such as methanol.

Scheme B: alternative synthesis of aniline intermediate A8.

Another typical procedure for the preparation of the compound of formula A8 is shown in scheme B.

Preparation of aryl bromides of formula B1 wherein R⁷Protection of the amino group in compounds of formula a6, which are bromine, can be carried out as follows: with triarylmethyl chlorides, such as triphenylmethyl chloride (Tr-C1), p-methoxyphenyl diphenylmethyl chloride (MMTr-C1), bis (p-methoxyphenyl) phenylmethyl chloride (DMTr-C1) or tris (p-methoxyphenyl) methyl chloride (TMTr-C1), in particular DMTr-C1, under basic conditions, for example in the presence of amines, such as triethylamine or diisopropylethylamine, in chlorinated solvents, such as dichloromethane or chloroform, at temperatures between 0 ℃ and ambient temperature.

The aryl bromide of formula B1 can be reacted with an ammonia equivalent, such as benzophenone imine, in the presence of a suitable transition metal catalyst, such as bis (dibenzylideneacetone) palladium (0) ((dba)₂Pd) or tris (dibenzylideneacetone) dipalladium (0) ((dba)₃Pd₂) And a suitable ligand, such as rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphino-2', 4 ', 6' -triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base, such as sodium tert-butoxide, potassium phosphate or cesium carbonate, in a suitable solvent, such as toluene or 1, 4-dioxane, under an inert atmosphere, such as nitrogen or argon, at a temperature of 80 to 110 ℃ to prepare the compound of formula B2.

Deprotection of the two amino groups in the compound of formula B2 can be accomplished as follows: by a one-pot procedure, it is first reacted with a strong organic acid, such as trifluoroacetic acid, in a chlorinated solvent, such as dichloromethane or chloroform, under anhydrous conditions at a temperature between 0 ℃ and ambient temperature to cleave P¹-a group to obtain an intermediate of formula B3. Water is then added to cleave the benzophenone imine and the reaction at ambient temperature produces the diamine of formula A8.

An alternative procedure for the preparation of the compound of formula I is shown in scheme C.

To prepare the general formulaWherein R of C1 compound⁷The protection of the amino group in the compound of formula a7, which is a nitro group, can be carried out as follows: by reaction with di-tert-butyl dicarbonate under basic conditions, for example in the presence of an amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, at a temperature between 0 ℃ and ambient temperature and in the presence of 4-dimethylamino-pyridine as catalyst.

The selective cleavage of one of the tert-butoxycarbonyl groups in the compound of formula C1 may be carried out with an acid, such as trifluoroacetic acid, to prepare a compound of formula C2 together with a small amount of a compound of formula a7.

The reduction of the nitro group in the protected aminooxazines of formula C2 to the protected anilines of formula C3 can be accomplished by hydrogenation in protic solvents, such as alcohols, in particular ethanol or methanol, using a catalyst such as palladium on charcoal.

Scheme C: alternative synthesis of compounds of formula I.

Anilines of the formula C3 giving amides of the formula C4 and of the formula R⁶The amide coupling of the-COOH carboxylic acid can be accomplished as follows: in a solvent such as methanol, with 4- (4, 6-dimethoxy [1.3.5 ] chloride]Triazin-2-yl) -4-methylmorpholineHydrates (DMTMM) or other condensing agents, e.g. O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HATU) in the presence of an amine, such as triethylamine or diisopropylethylamineIn an agent such as acetonitrile or N, N-dimethylformamide at a temperature between 0 ℃ and ambient temperature.

The cleavage of the protected t-butoxycarbonyl group in the compound of formula C4 for the preparation of the compound of formula I may be carried out by acid, such as trifluoroacetic acid, in an inert solvent, such as dichloromethane, at a temperature between 0 ℃ and ambient temperature.

Scheme D: alternative syntheses of intermediates a 6' and B3.

Alternatively, the compound of formula a 6' may be obtained as follows: the selective protection of the primary alcohol in the compound of formula a5 can be carried out with chloro-silyl derivatives, such as tert-butyl-chlorodimethyl-silane or tert-butyl-chlorodiphenyl-silane (silylane), under basic conditions, for example in the presence of an amine, such as triethylamine or diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or chloroform, at a temperature between 0 ℃ and ambient temperature and in the presence of 4-dimethylamino-pyridine as catalyst.

The choice of isothiocyanate used to form the thiourea of formula D2 depends on the reactivity of the amino functional group. Preferably, the acylated thiourea of formula D2 is prepared using benzoyl isocyanate in an inert solvent, such as acetone, at a temperature of 0 to 100 ℃.

Cyclization to N-acyloxazines of formula D3 with concomitant loss of the silyl protecting group may be accomplished as follows: by reacting the acylated thiourea of formula D2 with an alkyl oxide in an inert solvent, e.g. in a chlorinated solvent, such as dichloromethane or chloroform, at a temperature between 0 ℃ and ambient temperatureSalts, e.g. trimethyl oxideTetrafluoroborate or triethoxyAnd (4) treating tetrafluoroborate.

Cleavage of the acyl residue in the compound of formula D3 under basic conditions, for example with an alkali metal carbonate, in a polar solvent such as an alcohol, for example methanol or ethanol, affords the compound of formula a 6'.

Alternatively, imines of formula B3 (see scheme B) may be obtained as follows: by reacting an aryl bromide of the formula D3 with an ammonia equivalent, such as benzophenone imine, in the presence of a suitable transition metal catalyst, such as bis (dibenzylideneacetone) palladium (0) ((dba)₂Pd) or tris (dibenzylideneacetone) dipalladium (0) ((dba)₃Pd₂) And a suitable ligand, such as rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphino-2', 4 ', 6' -triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base, such as sodium tert-butoxide, potassium phosphate or cesium carbonate, in a suitable solvent, such as toluene or 1, 4-dioxane, under an inert atmosphere, such as nitrogen or argon, at a temperature of between 80 and 110 ℃.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as dioxane or Tetrahydrofuran (THF) and adding the appropriate amount of the corresponding acid. The product can generally be isolated by filtration or by chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base may be carried out by treating such a compound with such a base. One possible way of forming such salts is, for example, by adding to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) 1/n equivalent of a basic salt such as M (OH)_nWherein M = metal or ammonium cation and n = number of hydroxide anions, and removing the solvent by evaporation or freeze-drying. Particular salts are the hydrochloride, formate and trifluoroacetate salts.

In case their preparation is not described in the examples, the compounds of formula I as well as all intermediate products may be prepared according to analogous methods or according to the methods given herein. The starting materials are commercially available, known in the art or can be prepared by or analogously to methods known in the art.

It will be appreciated that the compounds of formula I of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Pharmacological testing

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 the inhibition of BACE1 and/or BACE2 activity. The compounds were investigated according to the tests given below.

Cellular a β reduction assay:

human HEK293 cells stably transfected with a vector expressing cDNA of the human APP wt gene (APP695) were used to assess potency of compounds in cellular assays. Cells were plated in 96-well microtiter plates to about 80% confluency in cell culture medium (Iscove, plus 10% (v/v) fetal calf serum, glutamine, penicillin/streptomycin) and compounds were added at 10x concentration in 1/10 volumes of medium without FCS containing 8% DMSO (final concentration of DMSO was maintained at 0.8% v/v). In a humidified incubator at 37 ℃ and 5% CO₂After 18-20 hours of incubation, the culture medium supernatant was harvested for determination of the concentration of A.beta.40. 96-well ELISA plates (e.g., NuncMaxisorb) were coated with monoclonal antibodies (Brockhaus et al, NeuroReport9, 1481-1486; 1998) that specifically recognized the C-terminal end of A.beta.40. After blocking non-specific binding sites with, e.g., 1% BSA and washing, the culture supernatant is added at an appropriate dilution with horseradish peroxidase-conjugated a β detection antibody (e.g., antibody 4G8, Senetek, Maryland Heights, MO) and incubated for 5 to 7 hours. The wells of the microtiter plate were then plated with tris (hydroxymethyl) ammonia containing 0.05% Tween20The methyl-buffered saline was thoroughly washed and the test was applied to tetramethylbenzidine/H in citric acid buffer solution₂O₂Color development (develoop). In using a volume of 1N H₂SO₄After stopping the reaction, the reaction was measured at 450nm wavelength on an ELISA reader. The concentration of a β in the culture supernatant was calculated from a standard curve obtained with known amounts of pure a β peptide.

BACE inhibition assay by measuring cellular TMEM27 lysis:

this assay uses the principle of inhibition of human TMEM27 being cleaved by endogenous cellular BACE2 and shed from the cell surface into the culture medium in an lnsle rat cell line (then detected in an ELISA assay). Inhibition of BACE2 prevents cleavage and shedding in a dose-related manner.

The stable cell line "INS-TMEM 27" represents an INSle-derived cell line with inducible expression (using the TetOn system) of full-length hTMEM27 in a doxycycline-associated manner. Throughout the experiment, cells were cultured in RPMI1640+ Glutamax (Invitrogen) penicillin/streptomycin, 10% fetal bovine serum, 100mM pyruvate, 5mM beta-mercaptoethanol, 100 microgram/ml G418, and 100 microgram/ml hygromycin and incubated in standard CO₂Growth was performed in a cell culture incubator at 37 ℃ in non-adherent culture (inadherent culture).

INS-TMEM27 cells were plated in 96-well plates. After 2 days in culture, BACE2 inhibitor was added at the concentration range required for the assay, and doxycycline was added to a final concentration of 500 ng/ml after two further hours of incubation. The cells were further incubated for 46 hours and the supernatant was harvested for detection of outflowing TMEM 27.

An ELISA assay (using a pair of mouse anti-human TMEM27 antibodies, directed against the extracellular domain of TMEM 27) was used for detection of TMEM27 in culture. EC for BACE2 inhibition was calculated for each inhibitor concentration using ELISA readings using standard curve fitting software such as XLFit for Excel spreadsheet program₅₀。

Table 1: IC of selected embodiments₅₀Value of

Pharmaceutical composition

The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration may also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of ampoules.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, and semi-solid and liquid polyols and the like. However, depending on the nature of the active ingredient, no carriers are often required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations can 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 may also contain other therapeutically valuable substances.

The invention also provides medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, which, as with the process for their preparation, 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 must, of course, be adjusted to the individual requirements in each particular case. In general, in the case of oral administration, the dosage for adults can vary from about 0.01 mg/day to about 1000 mg/day of a compound of formula I or of a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered in a single dose or in divided doses and, in addition, when indicated, the upper limit may also be exceeded.

The following examples illustrate the invention, but are not intended to be limiting and are intended to be exemplary only. The pharmaceutical preparations advantageously contain about 1 to 500mg, in particular 1 to 100mg, of a compound of the formula I. Examples of compositions according to the invention are:

example A

Tablets of the following composition were made in the usual manner:

table 2: possible tablet compositions

Manufacturing process

1. Ingredients 1, 2,3 and 4 were mixed and granulated with pure water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

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

Example B-1

Capsules of the following composition were prepared:

table 3: possible capsule ingredient composition

Manufacturing process

1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Ingredients 4 and 5 were added and mixed for 3 minutes.

3. Filling into suitable capsules.

The compound of formula I, lactose and corn starch are first mixed in a mixer and then mixed in a mill. Returning the mixture to the mixer; talc was added thereto and mixed well. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Example B-2

Soft gelatin capsules of the following composition were prepared:

composition (I)	mg/capsule
		A compound of formula I	5
Yellow wax	8
		Hydrogenated soybean oil	8

Partially hydrogenated vegetable oils	34
		Soybean oil	110
Total of	165

Table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		karion83	8 (Dry matter)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 5: possible soft gelatin capsule compositions

Manufacturing process

The compound of formula I is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules were processed according to the general procedure.

Example C

Suppositories of the following composition were prepared:

composition (I)	mg/suppository
		A compound of formula I	15
Suppository block	1285
		Total of	1300

Table 6: possible suppository composition

Manufacturing process

The suppository blocks were melted in a glass or steel vessel, mixed well and cooled to 45 ℃. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it is completely dispersed. Pouring the mixture into suppository molds with proper size, standing and cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.

Example D

Injection solutions of the following composition were prepared:

composition (I)	mg/injection solution
		A compound of formula I	3
Polyethylene glycol 400	150
		Acetic acid	Appropriate amount to pH5.0
Water for injection solution	To 1.0ml

Table 7: possible injection solution compositions

Manufacturing process

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 by acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Example E

Sachets of the following composition were made:

composition (I)	mg/sachet
		A compound of formula I	50
Lactose, fine powder	1015
		Microcrystalline cellulose (AVICEL PH102)	1400
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavouring additives	1
Total of	2500

Table 8: possible sachet composition

Manufacturing process

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Experimental part

The following examples are provided to illustrate the present invention. They should not be construed as limiting the scope of the invention but merely as being representative thereof.

Intermediate sulfinylimine A2.1 (R) ⁷ Synthesis of = H)

A solution of 1- (2-fluorophenyl) ethanone (20g, 145mmo1) in tetrahydrofuran (250m1) was treated under an inert atmosphere at room temperature with (R) - (+) -tert-butylsulfinamide (21.1g, 174mmo1) followed by the addition of titanium (IV) ethoxide (66.1g, 290mmo 1). The solution was stirred at 50 ℃ for 15 hours. For work-up, the dark brown solution was cooled to room temperature and then poured into a saturated solution of ammonium chloride. After addition of ethyl acetate, the mixture was stirred vigorously for 15 minutes. After separation of the layers, the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by purification on silica gel using 4: 1-mixtureTo yield (R) -E-N (1- (2-fluorophenyl) ethylene) -2-methylpropane-sulfinamide (25.9g, 74% of theory) as a brown oil. Ms (isp): m/z =242.3[ M + H [ ]]⁺。

Intermediate A2.2

Reaction of 2-fluoro-1- (2-fluoro-phenyl) -ethanone with (R) -tert-butylsulfinamide in an analogous manner to that described for the preparation of sulfinimide a2.1 gives (R) -2-methyl-propane-2-sulfinic acid [ 2-fluoro-1- (2-fluoro-phenyl) -ethylidene- (Z) -yl ] -sulfinic acid]Amide (52% of theory) as an orange oil. Ms (isp): m/z =260.2[ M + H%]⁺。

2-fluoro-1- (2-fluoro-phenyl) -ethanone was obtained as follows:

1- (2-fluorophenyl) -2-hydroxyacetophenone [ CAS 218771-68-7; a solution of WO9857925 (example 16) (2.77g, 18.0mmo1) in dichloromethane (42m1) was treated at 0 ℃ with triethylamine (6.36g, 62.8mmo1), triethylamine trihydrofluoride (3.05g, 18.0mmo1) and nonafluoro-n-butylsulfonyl fluoride (8.48g, 26.9mmo1) in that order. The tube was sealed and the reaction mixture was stirred at room temperature overnight. For work-up, the dark red solution was poured onto a saturated solution of sodium bicarbonate and ice, then extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate and evaporated. The crude material was purified by flash chromatography on silica gel (Telos FlashSilica) using dichloromethane as eluent to give 2-fluoro-1- (2-fluoro-phenyl) -ethanone (1.23g, 61% of theory) as a yellow semisolid.

Intermediate A2.3

Reaction of 1- (5-bromo-2-fluoro-phenyl) -2, 2-difluoro-ethanone (CAS 1262858-97-8; WO2011009943) with (R) -tert-butylsulfinamide in an analogous manner to that described for the preparation of sulfinimide A2.1 gives (R) -2-methyl-propane-2-sulfinic acid [1- (5-bromo-2-fluoro-phenyl) -2, 2-difluoro-ethylidene- (E) -yl]Amide (77% of theory) as a yellow oil. Ms (isp): m/z =356.1[ M + H%]⁺And 358.0[ M +2+ H]⁺。

Synthesis of intermediate sulfonamido ester A3

General procedure (Jingluomargiz reaction)

In a dry apparatus, a suspension of freshly activated zinc powder (1.63g, 24.9mmo1) in dry tetrahydrofuran (70m1) was heated to reflux under an inert atmosphere. A solution of sulfinimide a2(24.9mmo1) and bromo-acetate (24.9mmo1) in dry tetrahydrofuran (15m1) was added dropwise over 15 minutes and the suspension was heated to reflux for 5 hours. For work-up, the cooled mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a mixture of heptane and ethyl acetate as eluent to give sulfonamido ester a3.

Intermediates A3.1 and A3.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [1- (2-fluorophenyl) - (E) -ethylene]Amide (intermediate a2.1) and ethyl 2-bromo-2-fluoroacetate, obtaining the minor isomer (2S,3R) -2-fluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl) which elutes faster-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.1) as a dark brown oil. Ms (isp): m/z =348.2[ M + H ]]⁺。

The second fraction contained the slower eluting major isomer (2R,3R) -2-fluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.2) as a brown oil. Ms (isp): m/z =348.2[ M + H ]]⁺。

Synthesis of intermediate sulfonamido esters A3.3 and A3.4

In a dry apparatus, a solution of diisopropylamine (3.35g, 101mmo1) in tetrahydrofuran (25M1) was treated with n-butyllithium (1.6M in hexane, 20.7M1) under an inert atmosphere. The solution was stirred at-7 ℃ for 40 minutes. Thereafter, the solution was cooled to-75 ℃ and a solution of ethyl 2-fluoropropionate (3.98g, 33.2mmo1) in tetrahydrofuran (5m1) was added dropwise. After 40 minutes, a solution of titanium chloropicrin triisopropanol (8.64g, 33.2mmo1) in tetrahydrofuran (15m1) was slowly added dropwise. After 40 minutes at-72 deg.C, (R) -2-methyl-propane-2-sulfinic acid [1- (2-fluorophenyl) - (E) -ethylene ] is added dropwise to the orange solution]A solution of amide (intermediate a2.1) (4.0g, 16.6mmo1) in tetrahydrofuran (5m 1). Stirring was continued for 4 hours at-72 ℃ and the reaction mixture was then held at-20 ℃ for 17 hours. For work-up, the reaction mixture was quenched with aqueous ammonium chloride (13%, 100m 1). The precipitate formed was diluted with water and the resulting mixture was extracted three times with ethyl acetate. The organic layers were washed with brine, then combined, dried and evaporated under reduced pressure. The crude product was purified by purification on silica gel using heptane and ethyl acetate 5: 2-chromatographic purification of the mixture as eluent to give (2S,3R) -2-fluoro-3- (2-fluoro-phenyl) -2-methyl-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (a3.3) and 1: 2Mixture (4.43g, 74%) as light yellow oil. Ms (isp): m/z =362.2[ M + H [ ]]⁺。

Synthesis of intermediate sulfonamido esters A3.5 and A3.6

In a dry apparatus, a solution of diisopropylamine (1.19g, 11.8mmo1) in tetrahydrofuran (15M1) was slowly treated with n-butyllithium (1.6M in hexane, 7.34M1) at-20 ℃ under an inert atmosphere. The solution was stirred at 0 ℃ for 30 minutes. Freshly prepared lithium diisopropylamide solution was added dropwise to a solution of ethyl 2- (2,2, 2-trifluoroethoxy) acetate (2.19g, 11.8mmo1) in tetrahydrofuran (45m1) at-78 ℃ over 20 minutes under an inert atmosphere. The colorless clear solution was stirred at-78 ℃ for 30 minutes. Thereafter, a solution of (R) -E-N (1- (2-fluorophenyl) ethylene) -2-methylpropane-sulfinamide (1.13g, 4.7mmo1) in tetrahydrofuran (4m1) was added. The mixture was allowed to warm to-20 ℃ and stirring was continued for 30 minutes. For work-up, the reaction mixture was hydrolyzed with half-saturated ammonium chloride solution and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by purification on silica gel using heptane/ethyl acetate = 5/1 to 2: chromatographic purification with gradient of 1 as eluent to give 1: 6-mixture as a yellow oil (1.35g, 67% of theory). MS: m/z =428.2[ M + H%]⁺。

Ethyl 2- (2,2, 2-trifluoroethoxy) acetate is obtained very analogously to the procedure described in EP0532178 for the corresponding methyl ester.

Intermediate sulfonamide esters A3.7 and A3.8 (via)Levomastix reaction) synthesis

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 2-fluoro-1- (2-fluoro-phenyl) -ethylidene- (Z) -yl]Amide (intermediate a2.2) and ethyl 2-bromo-2-fluoroacetate, on Silica gel (Telos Flash Silica) using heptane/ethyl acetate = 4: 1 to 1: 2 as eluent, the faster eluting isomer, ethyl (2R,3S) -2, 4-difluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyrate, was obtained as a yellow oil. Ms (isp): m/z =366.2[ M + H [ ]]⁺。

The second eluting minor isomer was obtained after chromatography on preparative chiral HPLC (Chiralpak AD; eluent: 40% isopropanol/heptane), (2S,3S) -2, 4-difluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.8) as a yellow oil. Ms (isp): m/z =366.2[ M + H [ ]]⁺。

Synthesis of intermediate sulfonamide esters A3.9 and A3.10 (via the Lipomatsyl reaction)

Starting from (R) -2-methyl-propane-2-sulfinic acid [1- (5-bromo-2-fluoro-phenyl) -2, 2-difluoro-ethylidene- (E) -yl]Amide (intermediate a2.3) and ethyl 2-bromo-2-fluoroacetate, on Silica gel (Telos Flash Silica) using heptane/ethyl acetate = 100: 0 to 60: after chromatography with a gradient of 30 as eluent, a mixture of 2 diastereomers of ethyl (2R,3R) -3- (5-bromo-2-fluoro-phenyl) -2,4, 4-trifluoro-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyrate and ethyl (2S,3R) -3- (5-bromo-2-fluoro-phenyl) -2,4, 4-trifluoro-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyrate was obtainedThe material (1 major component) was a pale yellow viscous oil. Ms (isp): m/z =462.2[ M + H ]]⁺And 464.2[ M +2+ H ]]⁺。

Synthesis of intermediate sulfonamidol A4

General procedure

A solution of sulfonamido ester A3(12.7mmo1) in dry tetrahydrofuran (50m1) was treated with lithium borohydride (25.3mmo1) at 0 ℃ and stirring was continued at 0 ℃ for 4 h. The reaction mixture was quenched by addition of acetic acid (2m1) and water (50m1), extracted with ethyl acetate and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using a mixture of n-heptane and ethyl acetate as eluent to give the pure intermediate sulfinamidol a4.

Intermediate A4.1

Starting from (2S,3R) -2-fluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.1), 2-methyl-propane-2-sulfinic acid [ (1R,2S) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl) -is obtained]Amides as colorless viscous oils. Ms (isp): m/z =306.1[ M + H%]⁺。

Intermediate A4.2

Starting from (2R,3R) -2-fluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.2), 2-methyl-propane-2-sulfinic acid [ (1R,2R) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl ] acid is obtained]Amide, as pale red crystals. Ms (isp):m／z=306.1[M+H]⁺。

alternatively, the two epimers a4.1 and a4.2 may be obtained by reducing a mixture thereof as described above, followed by separation on chiral hplc (chiralpak ad), wherein a4.1 is the second eluting epimer and a4.2 is the first eluting epimer.

Intermediate A4.3

Starting from 1 of (2S,3R) -2-fluoro-3- (2-fluoro-phenyl) -2-methyl-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.3) and (2R,3R) -2-fluoro-3- (2-fluoro-phenyl) -2-methyl-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a 3.4): 2-mixture to obtain 2-methyl-propane-2-sulfinic acid [ (1R,2R) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1, 2-dimethyl-propyl ] -amide (a4.3) as a white solid. Ms (isp): m/z =320.1[ M + H ] +. The minor isomer was not isolated.

Intermediate A44

Starting from 1 of (2S,3R) -3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -2- (2,2, 2-trifluoro-ethoxy) -butyric acid ethyl ester (intermediate a3.5) and (2R,3R) -3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -2- (2,2, 2-trifluoro-ethoxy) -butyric acid ethyl ester (a 3.6): 6-mixture to give (R) -N- ((2R) -2- (2-fluorophenyl) -4-hydroxy-3- (2,2, 2-trifluoroethoxy) but-2-yl) -2-methylpropane-2-sulfinamide (A4.4) as a light yellow oil. Ms (isp): m/z =386.1[ M + H%]⁺. The minor isomer was not isolated.

Intermediate A45

Starting from (2R,3S) -2, 4-difluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.7), the (2R) -methyl-propane-2-sulfinic acid [ (1S,2R) -2-fluoro-1-fluoromethyl-1- (2-fluoro-phenyl) -3-hydroxy-propyl ester is obtained]Amides, as viscous colorless oils. Ms (isp): m/z =324.3[ M + H%]⁺。

Intermediate A4.6

Starting from (2S,3S) -2, 4-difluoro-3- (2-fluoro-phenyl) -3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediate a3.8), the (2R) -methyl-propane-2-sulfinic acid [ (1S,2S) -2-fluoro-1-fluoromethyl-1- (2-fluoro-phenyl) -3-hydroxy-propyl ester is obtained]Amides as colorless oils. Ms (isp): m/z =324.3[ M + H%]⁺。

Intermediates A4.7 and A4.8

Starting from a mixture of (2S,3R) -and (2R,3R) -3- (5-bromo-2-fluoro-phenyl) -2,4, 4-trifluoro-3- ((R) -2-methyl-propane-2-sulfinylamino) -butyric acid ethyl ester (intermediates a3.9 and a3.10), the (R) -2-methyl-propane-2-sulfinic acid [ (1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-phenyl) -1-difluoromethyl-2-fluoro-3-hydroxy-propyl-butyric acid is obtained]A mixture of amides as a white foam. Ms (isp): m/z =420.2[ M + H%]⁺And 422.0[M+2+H]⁺。

Synthesis of intermediate amino alcohol A5

General procedure

A solution of sulfenamidol a4(3.4mmo1) in methanol (12m1) was treated with a solution of hydrochloric acid in dioxane (17.1mmo1) at 0 ℃. The reaction mixture was allowed to warm and held at room temperature for 16 hours. For work-up, the reaction mixture is evaporated under reduced pressure. The solid residue was partitioned between water (10m1) and ethyl acetate (25m 1). The aqueous layer was separated and extracted again with ethyl acetate (25m 1). The combined organic layers were washed with water (5m1), the aqueous layers were combined and treated with aqueous sodium carbonate solution to adjust the pH to 9-10. After this time, the aqueous layer was extracted with ethyl ester (3 × 35m 1). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate amino alcohol A5.1

Starting from 2-methyl-propane-2-sulfinic acid [ (1R,2S) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl]Amide (intermediate a4.1) to give (2S,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -butan-1-ol (98% yield) as a colorless oil. Ms (isp): m/z =202.3[ M + H%]⁺。

Intermediate amino alcohol A5.2

Starting from 2-methyl-propane-2-sulfinic acid [ (1R,2R) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl]Amide (intermediate A4.2) to give (2R,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -butan-1-ol (95% yield) as a light brown oil. Ms (isp): m/z =202.2[ M + H%]⁺。

Intermediate amino alcohol A5.3

Starting from 2-methyl-propane-2-sulfinic acid [ (1R,2R) -2-fluoro-1- (2-fluoro-phenyl) -3-hydroxy-1, 2-dimethyl-propyl]Amide (intermediate a4.3) to give (2R,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -2-methyl-butan-1-ol (a5.3) as a colorless oil. Ms (isp): m/z =216.3[ M + H%]⁺。

Intermediate amino alcohol A5.4

Starting from (R) -N- ((2R) -2- (2-fluorophenyl) -4-hydroxy-3- (2,2, 2-trifluoroethoxy) but-2-yl) -2-methylpropane-2-sulfinamide (intermediate a4.4), the (2R,3R) -3-amino-3- (2-fluoro-phenyl) -2- (2,2, 2-trifluoro-ethoxy) -butan-1-ol (a5.4) was obtained as a colorless oil. Ms (isp): m/z =282.3[ M + H%]⁺。

Intermediate amino alcohol A5.5

Starting from 2-methyl-propane-2-sulfinic acid [ (1S,2R) -2-fluoro-1-fluoromethyl-1- (2-fluoro-phenyl) -3-hydroxy-propyl]Amide (intermediate a4.5) to give (2R,3S) -3-amino-2, 4-difluoro-3- (2-fluoro-phenyl) -butan-1-ol as a pale yellow viscous oil. Ms (isp): m/z =220.2[ M + H%]⁺。

Intermediate amino alcohol A5.6

Starting from 2-methyl-propane-2-sulfinic acid [ (1S,2S) -2-fluoro-1-fluoromethyl-1- (2-fluoro-phenyl) -3-hydroxy-propyl]Amide (intermediate a4.6) to give (2S,3S) -3-amino-2, 4-difluoro-3- (2-fluoro-phenyl) -butan-1-ol as a light yellow oil. Ms (isp): m/z =220.3[ M + H%]⁺。

Intermediates A5.7 and A5.8

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-phenyl) -1-difluoromethyl-2-fluoro-3-hydroxy-propyl]-a mixture of amides (intermediates a4.7 and a4.8) to obtain (2R,3R) -and (2S,3R) -3-amino-3- (5-bromo-2-fluoro-phenyl) -2,4, 4-trifluoro-butan-1-ol as a viscous pale yellow oil. Ms (isp): m/z =315.9[ M + H%]⁺And 317.9[ M +2+ H]⁺。

Synthesis of intermediate aminooxazine A6

General procedure

The dried tube was charged with a mixture of amino alcohol a5(18.8mmo1), cyanogen bromide (33.9mmo1) and ethanol (61m 1). The tube was sealed and heated at 90 ℃ for 16 hours. For work-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (150m1) and saturated aqueous sodium carbonate solution (50m 1). The aqueous layer was separated and re-extracted with ethyl acetate (2 × 50m 1). The organic layers were washed with brine (50m1), then combined, dried over sodium sulfate and evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate amino oxazine A6.1

Starting from (2S,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -butan-1-ol (intermediate a5.1), the (4R,5S) -5-fluoro-4- (2-fluoro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (85% yield) as a colorless viscous oil. Ms (isp): m/z =227.2[ M + H ]]⁺。

Intermediate amino oxazine A6.2

Starting from (2R,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -butan-1-ol (intermediate a5.2), obtained in quantitative yield (4R,5R) -5-fluoro-4- (2-fluoro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a light yellow solid. Ms (isp): m/z =227.2[ M + H ]]⁺。

Intermediate amino oxazine A6.3

Starting from (2R,3R) -3-amino-2-fluoro-3- (2-fluoro-phenyl) -2-methyl-butan-1-ol (intermediate a5.3), the (4R,5R) -5-fluoro-4- (2-fluoro-phenyl) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 3-is obtained]Oxazin-2-ylamine (a6.3) as a white solid. Ms (isp): m/z =241.2[ M + H%]⁺。

Intermediate amino oxazine A6.4

Starting from (2R,3R) -3-amino-3- (2-fluoro-phenyl) -2- (2,2, 2-trifluoro-ethoxy) -butan-1-ol (intermediate a5.4), the (4R,5R) -4- (2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (a6.4) as a colorless oil. Ms (isp): m/z =307.2[ M + H [ ]]⁺。

Intermediate amino oxazine A6.5

Starting from (2R,3S) -3-amino-2, 4-difluoro-3- (2-fluoro-phenyl) -butan-1-ol (intermediate a5.5), the (4S,5R) -5-fluoro-4-fluoromethyl-4- (2-fluoro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a white solid. Ms (isp): m/z =245.2[ M + H [ ]]⁺。

Intermediate amino oxazine A6.6

Starting from (2S,3S) -3-amino-2, 4-difluoro-3- (2-fluoro-phenyl) -butan-1-ol (intermediate a5.6), the (4S,5S) -5-fluoro-4-fluoromethyl-4- (2-fluoro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a white solid. Ms (isp): m/z =245.2[ M + H [ ]]⁺。

Alternative Synthesis of intermediate aminooxazines A6' Via N-Acylaminooxazine D3

General procedure

A solution of N-acylaminooxazine D3(761 μmo1) in methanol (12m1) was treated with potassium carbonate (383mg, 2.74mmol, 3.6 eq). The reaction mixture was stirred at 50 ℃ overnight, after which it was evaporated under reduced pressure. The crude material was directly purified by chromatography on Silica gel (Telos Flash Silica) using a gradient of heptane and ethyl acetate as eluent.

Intermediate aminooxazines A6 '. 1 and A6'. 2

Starting from N- [ (4R,5R) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl]Benzamide (intermediates D3.1 and D3.2) to give (4R,5R) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a white crystalline solid. Ms (isp): m/z =341.1[ M + H [ ]]⁺，343.3[M+2+H]⁺。

Synthesis of intermediate nitrooxazine A7

General procedure

A dispersion of aminooxazine a6(2.8mmo1) in sulfuric acid (22.1g, 216mmo1) was cooled to 0 ℃ and stirring was continued until a complete solution was obtained. Fuming nitric acid (300mg, 214. mu.l, 4.29mmo1) was added dropwise in 4 portions at 0 ℃. After the addition was complete, the ice bath was removed and stirring was continued at room temperature for 30 minutes. For the work-up, the solution was added dropwise to a mixture of crushed ice (50g) and water (50 g). The pH was adjusted to 7-8 with aqueous sodium hydroxide. The aqueous layer was extracted twice with ethyl acetate, after which the combined organic layers were washed with brine, then dried over sodium sulfate and evaporated under reduced pressure. The product was used in step without further purification.

Intermediate nitrooxazine A7.1

Starting from (4R,5S) -5-fluoro-4- (2-fluoro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.1) to give (4R,5S) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (86% yield) as a pale yellow foam. Ms (isp): m/z =272.1[ M + H%]⁺。

Intermediate nitrooxazine A7.2

Starting from (4R,5R) -5-fluoro-4- (2-fluoro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.2) to give (4R,5R) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (75% yield) as white foam. Ms (isp): m/z =272.3[ M + H%]⁺。

Intermediate nitrooxazine A7.3

Starting from (4R,5R) -5-fluoro-4- (2-fluoro-phenyl) -4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.3) to give (4R,5R) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (a7.3) as a light yellow oil. Ms (isp): m/z =286.1[ M + H [ ]]⁺。

Intermediate nitrooxazine A7.4

Starting from (4R,5R) -4- (2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.4) to give (4R,5R) -4- (2-fluoro-5-nitro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (a7.4) as a light yellow foam. Ms (isp): m/z =352.2[ M + H [ ]]⁺。

Intermediate nitrooxazine A7.5

Starting from (4S,5R) -5-fluoro-4-fluoromethyl-4- (2-fluoro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.5) to give (4S,5R) -5-fluoro-4-fluoromethyl-4- (2-fluoro-5-nitro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a light yellow solid. Ms (isp): m/z =290.1[ M + H%]⁺。

Intermediate nitrooxazine A7.6

Starting from (4S,5S) -5-fluoro-4-fluoromethyl-4- (2-fluoro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a6.6) to give (4S,5S) -5-fluoro-4-fluoromethyl-4- (2-fluoro-5-nitro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a light yellow solid. Ms (isp): m/z =290.1[ M + H%]⁺。

Synthesis of intermediate aniline A8

General procedure

A solution of nitrooxazine a7(3mmo1) in ethanol (31m1) was hydrogenated at atmospheric pressure using palladium (10% on charcoal) (159mg, 150 μmo1) as catalyst. The reaction was complete after 90 minutes. The reaction mixture was filtered through a layer of celite (dicalite) and washed with ethanol (3 × 20m 1). The combined ethanol solutions were evaporated under reduced pressure. The product was used in step without further purification.

Intermediate aniline A8.1

Starting from (4R,5S) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.1) to give (4R,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (98% yield) as a white foam. Ms (isp): m/z =242.2[ M + H [ ]]⁺。

Intermediate aniline A8.2

Starting from (4R,5R) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.2) to give (4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (97% yield) as a white foam. Ms (isp): m/z =242.3[ M + H [ ]]⁺。

Intermediate aniline A8.3

Starting from (4R,5R) -5-fluoro-4- (2-fluoro-5-nitro-phenyl) -4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.3) to give (4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (a8.3) as a white solid. Ms (isp): m/z =265.2[ M + H [ ]]⁺。

Intermediate aniline A8.4

Starting from (4R,5R) -4- (2-fluoro-5-nitro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.4) to give (4R,5R) -4- (5-amino-2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (a8.4) as a light yellow solid. Ms (isp): m/z =322.2[ M + H%]⁺。

Intermediate aniline A8.5

Starting from (4S,5R) -5-fluoro-4-fluoromethyl-4- (2-fluoro-5-nitro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.5) to give (4S,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as an off-white solid. Ms (isp): m/z =260.2[ M + H%]⁺。

Intermediate aniline A8.6

Starting from (4S,5S) -5-fluoro-4-fluoromethyl-4- (2-fluoro-5-nitro-phenyl) -5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a7.5) to give (4S,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine as a white foam. Ms (isp): m/z =260.2[ M + H%]⁺。

Alternative Synthesis of intermediate Aniline A8

General procedure

A solution of DMTr-imine B2 (219. mu. mo1) in dichloromethane (3m1) was treated with trifluoroacetic acid (171. mu.1, 2.19mmol, 10 eq.) at 22 ℃. After 30 minutes (follow the progress of the reaction by TLC) the solution was evaporated. Thereafter, hydrochloric acid (1M; 2.19M1, 10 eq.) was added to the crude intermediate imine B3. After 30 minutes at room temperature (follow the progress of the reaction by TLC) the reaction mixture was poured into cold sodium carbonate solution (1M; 14M 1). The aqueous phase was extracted 3 times with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was passed through a column of silica-NH 2(Telos Flash NH)₂) Above, purification by chromatography using a gradient of heptane and ethyl acetate as eluent.

Intermediate anilines A8.7 and A8.8

Starting from { (4R,5R) -and (4R,5S) -4- [5- (diphenylmethylene-amino) -2-fluoro-phenyl]-4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl } - [ bis- (4-methoxy-phenyl) -phenyl-methyl]-amines (intermediates B2.1 and B2.2) to give (4R,5R) -and (4R,5S) -4- (5-amino-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine, a pale yellow crystalline material. Ms (isp): m/z =278.4[ M + H ]]⁺。

Synthesis of intermediate DMTr-oxazine B1

General procedure

A solution of aminooxazine A6 '(574. mu. mol 1) in dichloromethane (8m1) was treated at 0 ℃ with N-ethyldiisopropylamine (195. mu.l, 1.15mmol, 2eq) and 4, 4' -dimethoxytriphenylmethyl chloride (292mg, 861. mu. mol, 1.5eq) in that order. After 16 hours at 22 ℃ the reaction mixture was washed with water, the organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by chromatography on Silica gel (TelosFlash Silica) using a gradient of heptane and ethyl acetate as eluent.

Intermediates B1.1 and B1.2

Starting from (4R,5R) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediates a6 '. 1 and a 6'. 2) to give [ bis- (4-methoxy-phenyl) -phenyl-methyl]- [ (4R,5S) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl]Amine as a white solid. R_f：0.52(SiO₂(ii) a Heptane: ethyl acetate = 2: 1; and (3) detection: UV, 254 nm).

Synthesis of intermediate imine B2

General procedure

A solution of DMTr-oxazine B1 (454. mu. mo1) in toluene (6m1) was treated with sodium tert-butoxide (131mg, 1.36mmol, 3eq), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (28.9mg, 68.1. mu. mol, 0.15eq), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (24.2mg, 22.7. mu. mol, 0.05eq), and benzophenone imine (170mg, 157. mu. l, 908. mu. mol, 2eq) in that order at 22 ℃ under argon atmosphere. The tube was sealed and heated to 105 ℃ for 60 hours. The mixture was cooled to 22 ℃, evaporated under reduced pressure and passed over an amine phase (Telos Flash NH)₂) Using heptane and ethyl acetateAs eluent.

Intermediates B2.1 and B2.2

Starting from [ bis- (4-methoxy-phenyl) -phenyl-methyl]- [ (4R,5S) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl]-amines (intermediates B1.1 and B1.2) to give { (4R,5R) -and (4R,5S) -4- [5- (diphenylmethylene-amino) -2-fluoro-phenyl]-4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl } - [ bis- (4-methoxy-phenyl) -phenyl-methyl]Amine, as light yellow foam. Ms (isp): m/z =744.5[ M + H [ ]]⁺，442.4[M-DMTr+H]⁺。

Intermediate O _- Synthesis of protected amino alcohol D1

A solution of (2R,3R) -and (2S,3R) -3-amino-3- (5-bromo-2-fluoro-phenyl) -2,4, 4-trifluoro-butan-1-ol (4.49g, 14.2mmo1) (intermediates a5.7 and a5.8) in dichloromethane (120m1) was treated with triethylamine (4.35ml, 31.3mmo1), 4-dimethylaminopyridine (868mg, 7.11mmo1), and tert-butyl-chloro-dimethyl-silane (4.51g, 28.4mmo1) and stirred at room temperature overnight. For work-up, the reaction mixture was extracted with a saturated solution of sodium bicarbonate (40m1), water (40m1) and brine (40m 1). The aqueous bicarbonate solution was extracted with dichloromethane, and the organic layers were combined, dried over sodium sulfate and evaporated. The crude product was purified by purification on Silica gel (Telos Flash Silica) using heptane/ethyl acetate = 100: 0 to 90: chromatographic purification with a gradient of 10 as eluent. To obtain (1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-benzeneYl) -3- (tert-butyl-dimethyl-silanyloxy) -1-difluoromethyl-2-fluoro-propylamine (2.05g, 85% of theory) as a viscous colorless oil. Ms (isp): m/z =430.3[ M + H [ ]]⁺And 432.2[ M +2+ H]⁺。

Synthesis of intermediate O-protected isothiocyanate adduct D2

(1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-phenyl) -3- (tert-butyl-dimethyl-silanyloxy) -1-difluoromethyl-2-fluoro-propylamine (intermediates D1.1 and D1.2) (2.4551g, 5.7mmo1) and benzoyl isothiocyanate (1.12g, 6.85mmo1) were dissolved in acetone (25m1) in a microwave tube. The tube was sealed and heated at 70 ℃ overnight. For work-up, the reaction mixture was evaporated under reduced pressure and the residue was purified by filtration on Silica gel (Telos Flash Silica) using heptane/ethyl acetate = 100: 0 to 80: chromatography with a gradient of 20 as eluent directly purified. To obtain 1-benzoyl-3- [ (1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-phenyl) -3- (tert-butyl-dimethyl-silanyloxy) -1-difluoromethyl-2-fluoro-propyl]Thiourea (2.05g, 61% of theory) as pale yellow foam. Ms (isp): m/z =623.0[ M + H [ ]]⁺And 625.1[ M +2+ H]⁺。

Synthesis of intermediate oxazine D3

Reacting 1-benzoyl-3- [ (1R,2R) -and (1R,2S) -1- (5-bromo-2-fluoro-phenyl) -3- (tert-butyl-dimethyl-silanyloxy) -1-difluoromethyl-2-fluoro-propyl]-a solution of thiourea (intermediates D2.1 and D2.2) (2.021g, 3.41mmo1) in dichloromethane (100m1) was cooled to 0 ℃ and trimethyl oxide was addedTetrafluoroborate (557mg, 3.58mmo1) was added in one portion. The reaction mixture was stirred at 0 ℃ for 40 minutes and then at room temperature for 3 hours. To complete the reaction, another equivalent of trimethyl oxide is addedTetrafluoroborate (557mg, 3.58mmo1) and stirring was continued overnight. For work-up, the reaction mixture was evaporated and the residue was purified by filtration on Silica gel (Telos Flash Silica) using heptane/ethyl acetate = 100: 0 to 0: chromatography with a gradient of 100 as eluent directly purified. N- [ (4R,5R) -and (4R,5S) -4- (5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Oxazin-2-yl]Benzamide (962mg, 63.5% of theory) as white foam. Ms (isp): m/z =445.4[ M + H%]⁺And 447.3[ M +2+ H]⁺。

Synthesis of amides of formula I

General procedure I:

a solution of carboxylic acid (0.23mmo1) in methanol (5m1) was cooled to 0 ℃. Adding 4- (4, 6-dimethoxy [1.3.5 ] chloride]Triazin-2-yl) -4-methylmorpholineHydrate (DMTMM) (80mg, 0.27mmo1) and the solution was stirred at 0 ℃ for 30 minutes. Thereafter, a solution of intermediate diamine A8(0.21mmo1) in methanol (5m1) was added dropwise via syringe at 0 ℃. The reaction mixture was stirred at 23 ℃ for 18-60 hours. For work-up, the reaction mixture was poured into sodium carbonate solution (1M) followed by extraction with dichloromethane. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure leaving a light brown oil which was purified by chromatography on silica gel using a mixture of dichloromethane and methanol (0-10%) to give the pure amide of formula I.

The following examples have basic groups. Depending on the reaction and purification conditions, they are isolated in the form of the free base, or as a salt, or as both the free base and the salt.

Example 1

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-chloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a crystalline white solid. Ms (isp): m/z =381.2[ M + H [ ]]⁺。

Example 2

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 3, 5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) according to procedure I gave the title compound as a crystalline white solid. Ms (isp): m/z =415.1[ M + H%]⁺And 417.1[ M +2+ H]⁺。

Example 3

3, 5-difluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 3, 5-difluoro-pyridine-2-carboxylic acid (CAS745784-04-7) following procedure I gave the title compound as a white solid. Ms (isp): m/z =383.3[ M + H [ ]]⁺。

Example 4

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R)-4-(5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-cyano-pyridine-2-carboxylic acid (CAS 53234-55-2) according to procedure I gave the title compound as a crystalline white solid. Ms (isp): m/z =372.2[ M + H ]]⁺。

Example 5

5-Fluoromethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS 1174321-03-9) according to procedure I gave the title compound as a white foam. Ms (isp): m/z =395.1[ M + H [ ]]⁺。

Example 6

5-difluoromethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS 1174323-34-2) following procedure I gave the title compound as a white foam. Ms (isp): m/z =413.3[ M + H]⁺。

Example 7

3-chloro-5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =406.2[ M + H%]⁺。

Example 8

5-chloro-3-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1, 31 oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid (CAS207994-08-9) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =399.1[ M + H [ ]]⁺。

Example 9

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS80194-68-9) according to procedure I gave the title compound as a white foam. Ms (isp): m/z =449.1[ M + H [ ]]⁺。

Example 10

5-fluoromethoxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-fluoromethoxy-pyrazine-2-carboxylic acid (CAS 1174321-00-6) according to procedure I gave the title compound as a white foam. Ms (isp): m/z =396.2[ M + H%]⁺。

Example 11

5-difluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-difluoromethyl-pyridine-2-carboxylic acid following procedure I gave the title compound as a white foam. MS (ISP)：m／z=397.3[M+H]⁺。

Starting from 5-methyl-pyridine-2-carboxylic acid, very similar to the preparation of the corresponding 5-difluoromethyl-pyrazine-2-carboxylic acid as described in US2009209757, 5-difluoromethyl-pyridine-2-carboxylic acid was obtained (CAS 859538-41-3).

Example 12

3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS89402-28-8) according to procedure I gave the title compound as a white foam. Ms (isp): m/z =433.3[ M + H ]]⁺。

Example 13

5-methoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-methoxy-pyridine-2-carboxylic acid (CAS29082-92-6) following procedure I gave the title compound as a white solid. Ms (isp): m/z =377.3[ M + H [ ]]⁺。

Example 14

5-Cyclopropylethynyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro

-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS 1174322-62-3; WO2009091016) following procedure I gave the title compound as a white foam. Ms (isp): m/z =411.3[ M + H [ ]]⁺。

Example 15

5-difluoromethyl-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-difluoromethyl-pyrazine-2-carboxylic acid (CAS 1174321-06-2, US2009209757) following procedure I gave the title compound as a light yellow solid. Ms (isp): m/z =398.2[ M + H ]]⁺。

Example 16

5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =418.3[ M + H%]⁺。

5-cyclopropylmethoxy-pyrazine-2-carboxylic acid was obtained according to the following general procedure:

a solution of 5-chloro-pyrazine-2-carboxylic acid (1.50g, 9.46mmo1) in dry dimethyl sulfoxide (5m1) was treated with cyclopropyl-methanol (1.02g, 14.1mmo1) and powdered potassium hydroxide (2.12g, 37.4mmo1) at 25 ℃. The mixture was heated in a microwave oven at 80 ℃ for 90 minutes. For work-up, the reaction mixture was quenched with aqueous citric acid (10%) and then extracted with ethyl acetate (5 × 30m1) followed by 4: 1-extraction of the mixture. The combined organic layers were washed with brine (200m1), dried and evaporated under reduced pressure. After lyophilization, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (yield 34%) was obtained as a white solid. Ms (isp): m/z =195.0[ M + H ]]⁺。

Example 17

5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =445.3[ M + H [ ]]⁺。

5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid was obtained as follows:

a)5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid methyl ester

A solution of methyl 5-hydroxy-pyridine-2-carboxylate (200mg, 1.31mmo1) in N, N-dimethylformamide (2m1) was treated with sodium hydride (55% dispersion in oil, 64mg) at room temperature under a nitrogen atmosphere. After gas formation had ceased, the suspension was cooled to 0 ℃ and trifluoro-methanesulfonic acid 2,2, 2-trifluoro-ethyl ester (364mg, 1.57mmo1) was added. After stirring at room temperature for 2 hours, about 50% of the starting material remained. An additional 364mg of trifluoro-methanesulfonic acid 2,2, 2-trifluoro-ethyl ester was added and the reaction was complete after 30 minutes. For work-up, the reaction mixture was treated with a saturated solution of sodium carbonate and then extracted with ethyl acetate (3 ×). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by purification on silica gel using heptane and ethyl acetate 3: 1-chromatographic purification of the mixture as eluent. Methyl 5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylate was obtained as a white solid (216mg, 70% of theory). Ms (isp): m/z =236.3[ M + H%]⁺。

b)5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid

A solution of 5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid methyl ester (216mg, 0.92mmo1) in methanol (1m1) was treated with a solution of lithium hydroxide monohydrate (78mg, 1.84mmo1) in methanol (0.1m1) under a nitrogen atmosphere. After stirring for 2 hours the reaction mixture was evaporated under reduced pressure. The residue was treated with hydrochloric acid (1N), the solid material was filtered, then washed with water and finally dried under high vacuum. 5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid was obtained as a white solid (125mg, 61% of theory).

Example 18

2, 5-dimethyl-furan-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 2, 5-dimethyl-furan-3-carboxylic acid (CAS636-44-2) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =364.3[ M + H [ ]]⁺。

Example 19

5- (2, 2-difluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5- (2, 2-difluoro-ethoxy) -pyrazine-2-carboxylic acid (CAS 1174323-38-6; WO2009091016) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =428.2[ M + H%]⁺。

Example 20

5-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-fluoro-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =365.2[ M + H%]⁺。

Example 21

5- (2, 2-difluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5- (2, 2-difluoro-ethoxy) -pyridine-2-carboxylic acid (CAS 1097730-45-4; WO2009091016) according to procedure I gave the title compound as a white foam. Ms (isp): m/z =427.2[ M + H [ ]]⁺。

Example 22

5-cyclopropyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-cyclopropyl-pyridine-2-carboxylic acid (CAS 1174322-66-7; WO2009091016) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =387.3[ M + H ]]⁺。

Example 23

5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5-cyclopropylmethoxy-pyridine-2-carboxylic acid following procedure I gave the title compound as a white foam. Ms (isp): m/z =417.3[ M + H%]⁺。

5-Cyclopropylmethoxy-pyridine-2-carboxylic acid was prepared in a similar manner as described for the preparation of 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 16) in a microwave oven at 100 ℃ for 90 minutes. 5-Cyclopropylmethoxy-pyridine-2-carboxylic acid (25% yield) was obtained as an off-white solid. Ms (isp): m/z =194.0[ M + H ]]⁺。

Example 24

5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid following procedure I gave the title compound as a white foam. Ms (isp): m/z =477.1[ M + H [ ]]⁺。

5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid was prepared as follows:

a)5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid methyl ester

A solution of methyl 5-hydroxy-pyridine-2-carboxylate (2.0g, 13.1mmo1) in acetone (40m1) was treated with potassium carbonate (5.415g, 39.2mmo1) and trifluoro-methanesulfonic acid 2,2,3, 3-tetrafluoropropyl ester. After stirring at room temperature for 4 hours, the suspension was diluted with diethyl ether. After filtration, the solution was evaporated and the yellow solid was purified by filtration on silica gel using heptane/ethyl acetate = 100: 0 to 30: chromatographic purification with a gradient of 70 as eluent. Methyl 5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylate was obtained as a pale yellow solid (3.49g, 76% of theory). Ms (isp): m/z =468.1[ M + H [ ]]⁺。

b)5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid

In a similar manner to that described in example 17b), 5- (2,2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid methyl ester was hydrolyzed with lithium hydroxide to give the title compound as a pale yellow solid (yield 94% of theory). Ms (isp): m/z =253[ M [ ]]⁺。

Example 25

5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (intermediate a8.2) and 5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acidCondensation according to procedure I gave the title compound as a white foam. Ms (isp): m/z =495.2[ M + H [ ]]⁺。

5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid was obtained as follows:

a) in a similar manner to that described in example 24a), 5-hydroxy-pyridine-2-carboxylic acid methyl ester was alkylated with potassium carbonate and trifluoro-methanesulfonic acid 2,2,3, 3, 3-pentafluoropropyl ester to give 5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid methyl ester as a light yellow oil. Ms (isp): m/z =285[ M%]⁺。

b) In a similar manner as described in example 17b), 5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid methyl ester was hydrolyzed with lithium hydroxide to give 5- (2,2, 3,3, 3-pentafluoro-propoxy) -pyridine-2-carboxylic acid as a white solid. Ms (isp): m/z =271[ M + H ]]⁺。

Example 26

2-chloro-thiazole-5-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 2-chloro-thiazole-5-carboxylic acid (CAS 101012-12-8) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =387.2[ M + H [ ]]⁺。

Example 27

2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (CAS 128694-63-3) following procedure I gave the title compound as a white solid. Ms (isp): m/z =418.3[ M + H%]⁺。

Example 28

4-chloro-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 4-chloro-1H-pyrazole-3-carboxylic acid (CAS 84547-87-5) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =370.1[ M + H [ ]]⁺。

Example 29

Thiazole-5-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and thiazole-5-carboxylic acid (CAS14527-41-4) following procedure I gave the title compound as a white solid. Ms (isp): m/z =353.2[ M + H ]]⁺。

Example 30

1, 5-dimethyl-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 1, 5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS5744-59-2) following procedure I gave the title compound as a white solid. Ms (isp): m/z =364.3[ M + H [ ]]⁺。

Example 31

1-cyano-cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and 1-cyano-cyclopropanecarboxylic acid (CAS6914-79-0) according to procedure IThe title compound was a white foam. Ms (isp): m/z =335.3[ M + H [ ]]⁺。

Example 32

Cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.2) and cyclopropanecarboxylic acid following procedure I gave the title compound as a white foam. Ms (isp): m/z =310.2[ M + H%]⁺。

Example 33

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]

Oxazin-4-yl) -4-fluoro-phenyl ] -amides

(4R,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.1) and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =372.2[ M + H ]]⁺。

Example 34

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.1) and 5-chloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =381.1[ M + H [ ]]⁺。

Example 35

3-chloro-5-cyano-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.1) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as an off-white foam. Ms (isp): m/z =406.2[ M + H%]⁺。

Example 36

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3- ((4R,5S) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (intermediate a8.1) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =449.2[ M + H [ ]]⁺。

Example 37

3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid (CAS 1250130-41-6) following procedure I gave the title compound as a white solid. Ms (isp): m/z =459.2[ M + H [ ]]⁺。

3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid was prepared as follows:

a) to a solution of methyl 3-hydroxy-pyridine-2-carboxylate (200mg, 1.3mmo1) in N, N-dimethylformamide (2.0m1) was added sodium hydride (55% in oil, 64mg) at 22 ℃ and stirring was continued until gas evolution ceased. The suspension was cooled to 0 ℃ and treated with trifluoroethyl trifluoromethanesulfonate (728mg) and stirring was continued at 22 ℃ for 2 h. The mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3: 1) as eluent to give 3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acidMethyl ester as a pale green oil. Ms (isp): m/z =236[ M + H ]]⁺。

b) A solution of methyl 3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylate (216mg, 0.9mmo1) in methanol (1m1) was treated with a solution of lithium hydroxide (78mg, 3.3mmo1) in water (0.1m1) and stirring was continued for 2 hours at 22 ℃. The solution was evaporated and the residue was triturated with 1N aqueous hydrochloric acid. The suspension was filtered and the residue was washed with water and dried to give 3- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid as a colorless solid. Ms (isn): m/z =220[ M-H ] -.

Example 38

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a colorless solid. Ms (isp): m/z =386.2[ M + H [ ]]⁺。

Example 39

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 3, 5-dichloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a colorless solid. Ms (isp): m/z =429.2[ M + H%]⁺And 431.1[ M +2+ H]⁺。

Example 40

4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (A8.3) and 4-chloro-1Condensation of-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =434.2[ M + H%]⁺。

4-chloro-1-difluoromethyl-1H-py τ azole-3-carboxylic acid was obtained as follows:

a) 1-difluoromethyl-1H-oxazole-3-carboxylic acid methyl ester

A solution of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid (CAS 925179-02-8) (500mg, 3.1mmo1) in methanol (18m1) was cooled to 0 ℃ and treated with sulfuric acid (98%, 0.2ml, 3.1mmo 1). The mixture was heated to reflux for 2 hours. For work-up, the solution was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (25m1) and water (30m 1). The organic layer was separated and washed with water until the aqueous phase showed a neutral pH. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure. Methyl 1-difluoromethyl-1H-pyrazole-3-carboxylate was obtained as a colorless liquid (535mg, 99% of theory) pure enough to be used in the next step without further purification. Ms (isp): m/z =177.1[ M + H%]⁺。

b) 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester

A mixture of methyl 1-difluoromethyl-1H-pyrazole-3-carboxylate (535mg, 3mmo1) and N-chloro-succinimide (1.22g, 9.1mmo1) in N, N-dimethylformamide (5m1) was heated at 50 ℃ overnight. The reaction mixture was cooled, poured into water (20m1), and then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulfate and finally evaporated under reduced pressure. The yellow crude material was purified by washing on silica gel with 3: 1-chromatographic purification of the mixture as eluent. Methyl 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylate was obtained as a white solid (540mg, 84% of theory). Ms (isp): m/z =209.9[ M]⁺。

c) 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid

A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540mg, 2.6mmo1) in tetrahydrofuran (18m1) was dissolved with lithium hydroxide (135mg, 5.6mmo1) in 1: the solution in 1-mixture (12m1) was treated at room temperature. After 1 hour, the reaction was complete and the solvent was evaporated under reduced pressure. The residue was dissolved in water (10M1) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate and drying of the organic layer over sodium sulphate and evaporation under reduced pressure gave a white solid (555mg) which was triturated with pentane (10m 1). The solid material was filtered, washed with pentane and dried. After drying under reduced pressure, 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477mg, 95% of theory). Ms (isp): m/z =195.0[ M-H ] -.

EXAMPLE 41

5-chloro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 5-chloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a colorless solid. Ms (isp): m/z =395.1[ M + H [ ]]⁺。

Example 42

5-fluoro-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 5-fluoro-pyridine-2-carboxylic acid following procedure I gave the title compound as a colorless solid. Ms (isp): m/z =379.3[ M + H [ ]]⁺。

Example 43

4-chloro-1- (2, 2-difluoro-ethyl) -1H-pyrazole-3-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Oxazin-2-ylamine (A8.3) and 4-chloro-1- (2, 2-difluoro-ethyl) -1H-pyrazole-3-Condensation of formic acid (CAS 1006486-42-5) following procedure I gave the title compound as a white solid. Ms (isp): m/z =448.2[ M + H [ ]]⁺。

Example 44

2, 2-difluoro-cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 2, 2-difluoro-cyclopropanecarboxylic acid (CAS 107873-03-0) according to procedure I gave the title compound as a white solid. Ms (isp): m/z =360.3[ M + H [ ]]⁺。

Example 45

5-chloro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.4) and 5-chloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =461.2[ M + H%]⁺。

Example 46

5-fluoro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.4) and 5-fluoro-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =445.3[ M + H [ ]]⁺。

Example 47

5-cyano-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.4) and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =452.1[ M + H [ ]]⁺。

Example 48

3, 5-dichloro-pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.4) and 3, 5-dichloro-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =495.1[ M + H [ ]]⁺And 497.2[ M +2+ H]⁺。

Example 49

5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid {3- [ (4R,5R) -2-amino-4-methyl-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-4-yl ] -4-fluoro-phenyl } -amide

Condensation of (4R,5R) -4- (5-ammonio-2-fluoro-phenyl) -4-methyltoma-5- (2,2, 2-trifluoro-ethoxy) -5, 6-dihydro-4H- [1,3] oxazin-2-ylamine (a8.4) and 5- (2,2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z = 525.2.

Example 50

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.3) and 5-but-2-ynyloxy-pyridine-2-carboxylic acid (prepared as described in Tamura Y et al, WO 2010/113848) according to procedure I gave the title compoundAs a white solid. Ms (isp): m/z =430.3[ M + H [ ]]⁺。

Example 51

5-cyano-pyridine-2-carboxylic acid [3- ((4S,5R) -2-amino-5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4S,5R) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.5) and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a light yellow solid. Ms (isp): m/z =390.2[ M + H ]]⁺。

Example 52

5-cyano-pyridine-2-carboxylic acid [3- ((4S, 5S) -2-amino-5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4S,5S) -4- (5-amino-2-fluoro-phenyl) -5-fluoro-4-fluoromethyl-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine (a8.6) and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =390.4[ M + H [ ]]⁺。

Example 53

5-cyano-pyridine-2-carboxylic acid [3- ((4R,5R) -or (4R,5S) -2-amino-4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide

(4R,5R) -and (4R,5S) -4- (5-amino-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5, 6-dihydro-4H- [1,3]Condensation of oxazin-2-ylamine and 5-cyano-pyridine-2-carboxylic acid following procedure I gave the title compound as a white solid. Ms (isp): m/z =408.4[ M + H ]]⁺. The minor isomer was not isolated.

Claims

1. A compound of the formula I,

wherein

R¹Selected from the group consisting of:

i) the presence of hydrogen in the presence of hydrogen,

ii) halogen, and

iii)C_1-6-an alkyl group;

R²selected from the group consisting of:

i) the presence of hydrogen in the presence of hydrogen,

ii)C_1-6-alkyl, and

iii) halo-C_1-3-an alkyl group,

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

r4 is selected from the group consisting of:

i) the halogen(s) are selected from the group consisting of,

ii)C_1-6-alkyl, and

iii) halo-C_1-6-an alkoxy group,

R⁵is-C (= O) -R⁶，

R⁶Selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

iii)C_3-6-a cycloalkyl group,

v) a heterocyclic group, and

or a pharmaceutically acceptable salt thereof.

2. A compound of formula Ia according to claim 1,

wherein R is¹，R²，R³，R⁴，R⁵As defined in claim 1.

3. A compound according to any one of claims 1-2, wherein

R¹Is a halogen, and the halogen is a halogen,

R²is C_1-6-an alkyl group,

R³selected from the group consisting of:

i) hydrogen, and

ii)C₁ ^- ₆-an alkyl group,

R⁴selected from the group consisting of:

i) halogen, and

ii) halo-C_1-6-an alkoxy group,

R⁵is-C (= O) -R⁶，

R⁶Selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

iii)C_3-6-a cycloalkyl group, and

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein R¹Is a halogen.

5. A compound according to any one of claims 1 to 4, wherein R¹Is F.

6. A compound according to any one of claims 1 to 5, wherein R²Is C_1-6-an alkyl group.

7. A compound according to any one of claims 1 to 6, wherein R²Is M_e。

8. A compound according to any one of claims 1 to 7, wherein R³Is hydrogen.

9. A compound according to any one of claims 1 to 8, wherein R⁴Is a halogen.

10. The compound according to any one of claims 1-9, wherein R⁴Is F.

11. A compound according to any one of claims 1 to 8, wherein R⁴Is halo-C_1-6-An alkoxy group.

12. A compound according to any one of claims 1 to 8 or 11, wherein R⁴is-OCH₂CF₃。

13. A compound according to any one of claims 1 to 12, wherein R⁶Is heteroaryl substituted with 1-2 substituents independently selected from cyano, halogen and C_3-6-cycloalkyl-C_2-6-alkynyl.

14. A compound according to any one of claims 1 to 13, wherein R²Is pyridyl substituted with 1-2 substituents independently selected from cyano, chloro and cyclopropylethynyl-.

15. A compound according to any one of claims 1 to 14 selected from the group consisting of:

5-methoxy-pyridine-2-carboxylic acid [3- ((4R,5R) -2-aminomethane-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 15 selected from the group consisting of:

cyclopropanecarboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide, and

or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 16 selected from the group consisting of:

5-cyclopropylethynyl-pyridine-2-carboxylic acid [3- ((4R,5R) -2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H- [1,3] oxazin-4-yl) -4-fluoro-phenyl ] -amide, and

or a pharmaceutically acceptable salt thereof.

18. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 17, which process comprises: reacting a compound of formula C4 to a compound of formula I,

wherein R is¹，R²，R³，R⁴，R⁵And R⁶As defined in any one of claims 1 to 14.

19. A compound of formula I according to any one of claims 1 to 17, whenever prepared by a process as defined in claim 18.

20. Compounds of formula I according to any one of claims 1-17 for use as therapeutically active substances.

21. A compound of formula I according to claims 1-17 for 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. Compounds of formula I according to claims 1-17 for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of diabetes or type2diabetes.

23. Compounds of formula I according to claims 1-17 for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of the following diseases: 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 responses, kaposi's sarcoma, costerman's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, whipple's disease or wilson's disease.

24. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 17, together with a pharmaceutically acceptable carrier and/or pharmaceutically acceptable auxiliary substances.

25. The use of a compound of formula I according to any one of claims 1 to 17 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease.

26. The use of a compound of formula I according to any one of claims 1 to 17 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of diabetes.

27. The use of a compound of formula I according to any one of claims 1 to 17 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of the following diseases: 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 responses, kaposi's sarcoma, costerman's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, whipple's disease or wilson's disease.

28. A method for the therapeutic and/or prophylactic treatment of alzheimer's disease, which method comprises administering a compound of formula I according to any of claims 1-17 to a human being or animal.

29. A method for the therapeutic and/or prophylactic treatment of diabetes or type2diabetes, which method comprises administering a compound of formula I according to any one of claims 1 to 17 to a human being or animal.

30. A method 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, a dermatomyositis, Down's syndrome, a gastrointestinal disease, glioblastoma multiforme, Graves' disease, Huntington's disease, Inclusion Body Myositis (IBM), an inflammatory response, Kaposi's sarcoma, Coasteman's disease, lupus erythematosus, macrophage myofascitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia type 1, spinocerebellar ataxia type 7, Whipple's disease or Wilson's disease, the method comprising administering a compound of formula I according to any one of claims 1 to 17 to a human being or animal.

31. The invention as hereinbefore described.