HK1190701B - N-[3-(5-amino-3,3a,7,7a-tetrahydro-1h-2,4-dioxa-6-aza-inden-7-yl)-phenyl]-amides as bace1 and/or bace2 inhibitors - Google Patents

Description

N- [3- (5-amino-3, 3A,7, 7A-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -phenyl ] -amide 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 elderly population. The clinical symptoms are impairment of memory, cognition, time and local direction, judgment and reasoning, and severe emotional distress. There is currently no reliable therapy that can prevent the disease or its progression or stably reverse its clinical symptoms. AD has become a major health problem for all societies with a high life expectancy and also a major economic burden for their health care systems.

AD is characterized by The presence of 2 major pathological states in The Central Nervous System (CNS), namely amyloid plaques and neurofibrillary tangles (Hardy et al, The amyloid pathology of Alzheimer's disease: progression and problems in The passage to therapeutics), Science (Science) 2002, 7.19.2002; 297(5580) 353-6, Selkoe, Cell biology, amyloid beta-protein precursor and The mechanism of Alzheimer's disease), Annu Rev Cell biol.1994; 10: 373 403). Both pathological states are also commonly observed in patients with down syndrome (trisomy21 21), which also develops AD-like symptoms early in life. Neurofibrillary tangles are intracellular aggregates of microtubule-associated protein tau (mapt). Amyloid plaques exist in the extracellular space; their main component is a β -peptide. The latter is a group of proteolytic fragments derived from β -Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Some forms of APP have been identified, the most abundant of which are proteins of 695, 751 and 770 amino acids in length. They are all produced from a single gene by differential splicing. A β -peptides are derived from the same domain of APP but differ at their N-and C-termini, the main species being 40 and 42 amino acids in length. There are several lines of evidence that strongly suggest that aggregated a β -peptide is a major molecule in the pathogenesis of AD: 1) amyloid plaque forms of a β peptide are an invariant part of AD pathogenesis; 2) a β -peptide is toxic to neurons; 3) in Familial Alzheimer's Disease (FAD), mutations in the disease genes APP, PSN1, PSN2 result in increased levels of a β -peptide and early cerebral amyloidosis; 4) transgenic mice expressing the FAD gene show pathological states with many similarities to human disease. A β -peptide is produced from APP by the sequential action of 2 proteolytic enzymes called β -and γ -secretases. The β -secretase enzyme first cleaves approximately 28 amino acids outside the transmembrane domain (TM) in the extracellular domain of APP 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 some nearby position in the TM to produce a β peptide and cytoplasmic fragments. Gamma-secretase is a complex of at least 4 different proteins, the catalytic subunit of which is most likely a presenilin (PSEN1, PSEN 2). Beta-secretase (BACE1, Asp 2; BACE stands for beta-site APP-lyase) is an aspartyl protease which is anchored in the membrane via a transmembrane domain (Vassar et al, beta-secretase cleavage of Alzheimer's amyloid protein by the transmembrane amyloid precursor protein BACE (beta-secretase cleaves Alzheimer's amyloid precursor protein by transmembrane aspartic protease BACE), Science (Science) 10.22.1999, (286 (5440): 735). It is expressed in many tissues of human organs, but its levels are particularly high in the CNS. Gene excision of the BACE1 gene in Mice clearly shows that its activity is essential for processing APP leading to A β -peptide production, in the absence of BACE1, no A β -peptide is produced (Luo et al, Mice discovery in BACE1, the Alzheimer's beta-secretase, HAVE NORMAL PHOTOTYPE AND BOARDIALISHED BETA-amyloid production (BACE1, Alzheimer's β -secretase deficient Mice have normal phenotype and eliminated β -amyloid production), Nat neurosci.2001 for 3 months; 4 (3): 231-2, Robers et al, BACE knockout of mouse chemoassay with mutated the protein produced the protein a-secretory activity in Mice: polypeptides for Alzheimer's disease, although the activity of BACE in Hutz-13 Mice is deficient for healthy brain-peptide production, 10.7 for 10 months for 10 years). When β -secretase activity is reduced by gene excision of one BACE1 allele, Mice that have been genetically engineered to express the human APP gene and develop extensive amyloid plaques and Alzheimer-like pathological states during the course of aging are not (McConlogue et al, Partial reduction of BACE1ha pharmaceutical effects on Alzheimer's disease and synthetic pathology in APP Transgenic Mice (Partial reduction of BACE1has a profound effect on Alzheimer's plaque and synaptic pathological states in APP Transgenic Mice J Biol chem.2007.7.9.7.282 (36): 26326). Therefore, it is expected that inhibitors of BACE1 activity may be useful agents for therapeutic intervention in Alzheimer's Disease (AD).

Type2diabetes (T2D) results from poor glycemic control and hyperglycemia due to insulin resistance and insufficient insulin secretion by pancreatic β -cells (M Prentki & CJ Nolan, "Islet beta-cell failure in type2 diabetes." j.clin.investig.2006, 116(7), 1802-. Patients with T2D have an increased risk of microvascular and macrovascular disease and the range of associated complications includes diabetic nephropathy, retinopathy and cardiovascular disease. In 2000, an estimated 1 million 7 million people with the disease, this number is expected to double by 2030 (S Wild, G Roglic, A Green, R.Sicree & H King, "Global prediction of Diabetes", Diabetes Care 2004, 27(5), 1047 one 1053), making the disease a major health Care issue. The increase in the prevalence of T2D is associated with a sedentary lifestyle and high energy food intake that is increasing in the world population (P Zimmet, KGMM Alberti & J Shaw, "Global and social indications of the diabetes epidemic," Nature 2001, 414, 782- "787).

Beta-cell failure and subsequent large decline in insulin secretion and hyperglycemia marked the onset of T2D. Most current treatments do not prevent the loss of the beta cell population that characterizes significant T2D. However, recent developments with GLP-1 analogues, gastrin and other agents have been shown to achieve maintenance and proliferation of β -cells, leading to improved glucose tolerance and slowing down progression to overt T2D (LL Baggio & DJ Drucker, "Therapeutic approaches to maintaining islet mass in type2diabetes mellitus", annu. rev. med.2006, 57, 265) -281).

Tmem27 has been identified as a protein that promotes beta-Cell proliferation (P Akpinar, S Kuwajima, JKrultz feldt, M Stoffel, "Tmem 27: A cleared and plated membrane protein proteins across cultures promotion (Tmem 27: cleaved and released plasma membrane proteins that stimulate pancreatic 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 collectin control insulin exocytosis by SNARE complex formation" (HNF-1 target collectin kinase protein complex formation), "Cell emesis, Cell 2005, 2, Met 384. 373). Tmem27 is a 42kDa membrane glycoprotein that is constitutively released from the surface of β -cells due to degradation of full-length cells Tmem 27. Overexpression of Tmem27 in transgenic mice increased the β -cell population and improved glucose tolerance in the diet-induced obesity DIO model of diabetes. Furthermore, siRNA knockdown by Tmem27 in rodent β -cell proliferation assays (e.g., using INS1e cells) reduced the proliferation rate, showing a role for Tmem27 in controlling β -cell populations.

In the same proliferation assay, BACE2 inhibitors also increased proliferation. However, BACE2 inhibition in combination with Tmem27siRNA knockdown resulted in a low proliferation rate. Thus, it was concluded that BACE2is the protease responsible for Tmem27 degradation. Moreover, BACE2 cleaves peptides based on the sequence of Tmem27 in vitro. The closely related protease BACE1 does not cleave this peptide and selective inhibition of BACE1 alone does not increase beta-cell proliferation.

The close homologue BACE2is a membrane-bound aspartyl protease and it is co-localized with Tmem27 in human pancreatic β -cells (G Finzi, F Franzi, C Placidi, F Acquati et al, "BACE 2is stored in secreted granules of mouse and rat pancreatic β -cells", BACE2 stored in secretory granules of mouse and rat pancreatic β -cells ", Ultrastruct Pathol.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 amyloid precursor protein at the β -secretase site (ASP1(BACE2) cleaves amyloid precursor 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 transmembrane protein analysis of the interleukin-1receptor by, alpha beta-, and gamma-secretase (Interleukin-1 receptor in-membrane proteolysis of the interleukin-1receptor mediated by α, β, and γ -secretases) "J.Biol.Chem.2007, 2007, 82, 11982) and 119282. The ability to degrade ACE2 shows the possible role of BACE2 in controlling hypertension.

Therefore, inhibition of BACE2is proposed as a therapeutic approach to T2D that can maintain and restock the β -cell population 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, particularly in the treatment and/or prevention of diseases which are associated with the inhibition of BACE 2.

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

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 type2 diabetes.

Technical Field

The present invention relates to N- [3- (5-amino-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -phenyl ] -amides having BACE1 and/or BACE2 inhibitory properties, their manufacture, pharmaceutical compositions comprising them and their use as therapeutically active substances.

Summary of The Invention

The present invention relates to compounds of formula (I),

wherein the substituents and variables are as described below and in the claims; or a pharmaceutically acceptable salt thereof.

The compounds of the present invention have Asp2(β -secretase, BACE1 or Memapsin-2) inhibitory activity and may therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and other deposits, in particular 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 comprising 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 type2 diabetes. Furthermore, by inhibiting the production of a β from APP or an APP fragment, the compounds of the invention inhibit the formation, or the formation and deposition, of β -amyloid plaques in, on or around neural tissue (e.g., the brain).

The following definitions of general terms used in the present description apply regardless of whether the terms are present alone or in combination with other groups.

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

The term "C_1-6Alkyl ", alone or in combination with other groups, represents a hydrocarbon group, which may be linear or branched, with single or multiple branches, wherein alkyl groups generally comprise from 1 to 6 carbon atoms, such as, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (i-butyl), 2-butyl (s-butyl), t-butyl (t-butyl), isopentyl, 2-ethyl-propyl, 1, 2-dimethyl-propyl, and the like. Specific "C_1-6-alkyl "is a group having 1 to 5 carbon atoms. Particular are methyl, ethyl and tert-butyl. Most particularly methyl.

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

The term "halo-C_1-6-alkyl ", alone or in combination with other groups, refers to C as defined herein_1-6-alkyl substituted with one or more halogens, preferably 1-5 halogens, more preferably 1-3 halogens, most preferably 1 or 3 halogens. Utensil for cleaning buttockThe halogen of the body is fluorine. Examples are difluoromethyl, chloromethyl, fluoromethyl and the like, in particular-CH₂CH₂F、CH₂CHF₂or-CF₃. In particular trifluoromethyl.

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

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

The term "halogen", alone or in combination with other groups, refers to chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). Specific "halogen" are Cl and F. In particular F.

The term "aryl", alone or in combination with other groups, refers to an aromatic carbocyclic group containing 6 to 14, preferably 6 to 10, carbon atoms and having at least one aromatic ring or a plurality of fused rings, and in which at least one ring is aromatic. Examples of "aryl" include benzyl, biphenyl, indanyl, naphthyl, phenyl (Ph), and the like. A specific "aryl" group is phenyl.

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, comprising 6 to 14, in particular 6 to 10 ring atoms and comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, in particular from N and O, in which at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include benzofuranyl, benzimidazolyl, 1H-benzimidazolyl, benzoxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, 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 and pyrazinyl. Particular are pyridin-2-yl and pyrazin-2-yl.

The term "C_1-6-alkoxy ", alone or in combination with other groups, represents-O-C_1-6An alkyl group, which may be linear or branched with single or multiple branches, wherein the alkyl group typically comprises 1 to 6 carbon atoms, such as methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, isobutoxy (i-butoxy), 2-butoxy (sec-butoxy), tert-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy), and the like. In particular "C_1-6-alkoxy "is a group having 1 to 4 carbon atoms. Particularly methoxy, ethoxy and ethoxy.

The term "halo-C_1-6-alkoxy ", alone or in combination with other groups, refers to C as defined herein_1-6Alkoxy, which is substituted by one or more halogens, in particular by fluorine. Particular "halo-C_1-6-alkoxy "is fluoro-C_1-6-alkoxy groups. In particular 2, 2, 2-trifluoro-ethoxy-.

The term "C_2-6-alkynyl-C_1-6-alkoxy ", alone or in combination with other groups, refers to C as defined herein_1-6-alkoxy, which is substituted by one or more C as defined herein_2-6-alkynyl substitution. Specific "C_2-6-alkynyl-C_1-6-alkoxy "is 5-but-2-ynyloxy-pyrazin-2-yl.

The term "C_2-6-alkynyl ", alone or in combination with other groups, means a monovalent straight or branched chain saturated hydrocarbon radical of 2 to 6 carbon atoms, in particular of 2 to 4 carbon atoms, and comprising one, two or three triple bonds. "C_2-6Examples of the "alkynyl group" include ethynyl, propynyl, prop-2-ynyl, isopropynyl and n-butynyl groups. Particularly ethynyl and propynyl.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts of inorganic and organic acids formed 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 (sulfuric acid), tartaric acid, trifluoroacetic acid, and the like. Preferred are formic acid, trifluoroacetic acid and hydrochloric acid.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Preferably, it encompasses products comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as products formed directly or indirectly from the combination, complexation or aggregation of any two or more of the ingredients, or any product formed directly or indirectly from dissociation of one or more of the ingredients, or any product formed directly or indirectly from other types of reactions or interactions of one or more of the ingredients.

The term "inhibitor" refers to a compound that: which competes with or reduces or prevents binding between a particular ligand and a particular receptor, or which reduces or prevents inhibition of the function of a particular protein.

The term "half maximal inhibitory concentration" (IC)₅₀) Refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted into pIC₅₀Value (-log IC)₅₀) Wherein a higher value indicates a greater titer exponentially. IC (integrated circuit)₅₀The values are not absolute values but depend on the experimental conditions, such as the concentrations used. IC (integrated circuit)₅₀Values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmacol (1973) 22: 3099). The term "inhibition constant" (Ki)) Refers to the absolute binding affinity of a particular inhibitor to the receptor. It is measured using a competitive binding assay and is equal to the concentration where a particular inhibitor would occupy 50% of the receptors if no competitive ligand (e.g., radioligand) were present. Ki value pairs can be converted numerically to pKi values (-log Ki), with higher values indicating titers that are greater logarithmically.

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

When referring to variables, the terms "as defined herein" and "as described herein" are used in conjunction with the broad definition of the variable, as well as the preferred, more preferred and most preferred definitions (if any).

The terms "treating", "contacting" and "reacting" when referring to a chemical reaction mean the addition or mixing of two or more reagents under suitable conditions to produce a specified and/or desired product. It will be appreciated that the reaction which produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially charged, i.e., there may be one or more intermediates produced in the mixture which ultimately result in the formation of the specified and/or desired product.

The term "aromatic" means the conventional definition of aromaticity as described in the literature, in particular as described in the IUPAC-Complex of Chemical Terminology (Compendium of Chemical nomenclature), 2 nd edition, A.D.McNaught & A.Wilkinson (Eds.) Blackwell Scientific Publications, Oxford (1997).

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

Whenever a chiral carbon is present in a chemical structure, the structure is intended to encompass all stereoisomers associated with that chiral carbon.

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 invention are compounds of formula I,

wherein

R¹Selected from the group consisting of:

i) an aryl group, a heteroaryl group,

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

iii) heteroaryl, and

iv) heteroaryl substituted with 1-4 substituents independently selected from cyano, cyano-C_1-6-alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-alkoxy-C_1-6Alkyl radical, C_2-6-alkynyl-C_1-6-alkoxy, C_2-6-alkynyl and 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) halogen;

R³selected from the group consisting of:

i)C_1-6-alkyl, and

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

R⁴selected from the group consisting of:

iii) hydrogen, and

iv)C_1-6-an alkyl group, and

R⁵selected from the group consisting of:

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

ii) halo-C_1-6-alkyl, and

iii)C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention are compounds of formula I,

wherein

R¹Selected from the group consisting of:

i) an aryl group, a heteroaryl group,

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

iii) heteroaryl, and

iv) heteroaryl substituted with 1-4 substituents independently selected from cyano, cyano-C_1-6-alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-alkoxy-C_1-6Alkyl radical, C_2-6-alkynyl-C_1-6-alkoxy, C_2-6-alkynyl and 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) halogen;

R³is C_1-6-an alkyl group,

R⁴selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group, and

R⁵selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to compounds of formula Ia,

wherein R is¹、R²、R³、R⁴And R⁵As defined herein; or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to compounds of formula Ia,

wherein R is¹、R²、R³、R⁴And R⁵As defined herein; or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is²Is a halogen.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is²Is F.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³Is C_1-6-an alkyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³Is methyl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³Is halo-C_1-6-an alkyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³is-CH₂CH₂F or-CH₂CHF₂。

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³is-CH₂CH₂F。

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³is-CH₂CHF₂。

A certain embodiment of the invention relates to a compound as defined herein, wherein R is³Is methyl, -CH₂CH₂F or-CH₂CHF₂。

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁴Is C_1-6-an alkyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁴Is hydrogen.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁵Is hydrogen.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁵Is C_1-6-an alkyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁵Is halo-C_1-6-an alkyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is⁵is-CF₃。

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is heteroaryl or heteroaryl substituted with 1-2 substituents independently selected from cyano, halogen, halo-C_1-6-alkoxy and C_2-6-alkynyl-C_1-6-alkoxy groups.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is a heteroaryl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is a pyridyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is heteroaryl substituted with 1-2 substituents independently selected from cyano, halogen, halo-C_1-6-alkoxy and C_2-6-alkynyl-C_1-6-alkoxy groups.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is pyridyl substituted with 1-2 substituents independently selected from cyano, halogen and halo-C_1-6-alkoxy groups.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-chloro-pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 3, 5-dichloro-pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-cyano-pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-fluoro-pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is halogenated-C_1-6-alkoxy or C_2-6-alkynyl-C_1-6-an alkoxy-substituted pyrazinyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5- (2, 2, 2-trifluoro-ethoxy) -pyrazin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-but-2-ynyloxy-pyrazin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is a pyridyl group; pyridinyl substituted with 1-2 substituents independently selected from cyano, halogen and halo-C_1-6-an alkoxy group; or is halogenated-C_1-6-alkoxy or C_2-6-alkynyl-C_1-6-an alkoxy-substituted pyrazinyl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-chloro-pyridin-2-yl, 3, 5-dichloro-pyridin-2-yl, 5- (2, 2, 2-trifluoro-ethoxy) -pyrazin-2-yl, 5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-yl, 5-but-2-ynyloxy-pyrazin-2-yl, 5-cyano-pyridin-2-yl, 5-fluoro-pyridin-2-yl or pyridin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is 5-cyano-pyridin-2-yl or 5-but-2-ynyloxy-pyrazin-2-yl.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is an aryl group.

A certain embodiment of the invention relates to a compound as defined herein, wherein R is¹Is aryl substituted with 1-4 substituents independently selected from cyano, cyano-C_1-6-alkyl, halogen, halo-C_1-6-alkoxy, halo-C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-alkoxy-C_1-6Alkyl radical, C_2-6-alkynyl-C_1-6-alkoxy, C_2-6-alkynyl and C_1-6-an alkyl group.

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

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-Cyclopropylmethoxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

n- (3- (rel- (4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-cyanopyridinamide,

n- (3- (rel- (4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5- (but-2-ynyloxy) pyrazine-2-carboxamide,

n- (3- ((4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-chloropyridinamide,

n- (3- ((4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-cyanopyridinamide,

5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

n- (3- ((4S, 4aS, 7aS) -2-amino-4-methyl-4 a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -3-chloro-5-cyanopyridinamide,

pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide, and

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

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

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide, and

pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention relates to a method of synthesizing a compound of formula I as described herein, the method comprising reacting a compound of formula XI with a compound of formula XII to yield a compound of formula I:

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

One embodiment of the present invention relates to compounds of formula I as described herein, prepared by the above-described process.

A certain embodiment of the invention relates to compounds of formula I as described herein for use as therapeutically active substances.

A certain embodiment of the invention relates to compounds of formula I as described herein for use as inhibitors of BACE1 and/or BACE2 activity.

A certain embodiment of the invention relates to compounds of formula I as described herein for use as inhibitors of BACE1 activity.

A certain embodiment of the invention relates to compounds of formula I as described herein for use as inhibitors of BACE2 activity.

A certain embodiment of the invention relates to compounds of formula I as described herein for use as inhibitors of BACE1 and BACE2 activity.

A certain embodiment of the present invention relates to compounds of formula I as described herein 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, in particular alzheimer's disease.

A certain embodiment of the present invention relates to compounds of formula I as described herein for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of alzheimer's disease.

A certain embodiment of the present invention relates to compounds of formula I as described herein for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of diabetes, in particular type2 diabetes.

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

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

A certain embodiment of the invention relates to 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 relates to 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 relates to 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 relates to 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 present invention relates to 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 conditions characterized by: characterized by elevated beta-amyloid levels and/or beta-amyloid oligomers and/or beta-amyloid plaques and further deposits, in particular Alzheimer's disease.

A certain embodiment of the invention relates to 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 relates to 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, in particular type2 diabetes.

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

A certain embodiment of the invention relates to compounds of formula I as described herein for use in inhibiting BACE1 activity.

A certain embodiment of the invention relates to compounds of formula I as described herein for use in inhibiting BACE2 activity.

A certain embodiment of the invention relates to compounds of formula I as described herein for use in inhibiting BACE1 and BACE2 activity.

A certain embodiment of the present invention relates to compounds of formula I as described herein for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by: characterized by elevated beta-amyloid levels and/or beta-amyloid oligomers and/or beta-amyloid plaques and further deposits, in particular Alzheimer's disease.

A certain embodiment of the invention relates to compounds 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 relates to compounds of formula I as described herein for use in the therapeutic and/or prophylactic treatment of diabetes, in particular type2 diabetes.

A certain embodiment of the invention relates to compounds of formula I as described herein for the therapeutic and/or prophylactic treatment of diabetes.

A certain embodiment of the present invention relates to 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 present invention relates to 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.

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

One skilled in the art will appreciate that the compounds of formula I may exist in tautomeric forms, for example, in the tautomeric forms described below.

The present invention encompasses all tautomeric forms.

The compounds of formula I may contain one or more asymmetric centers 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 the invention is intended to include all possible optical isomers and diastereomers as mixtures and as pure or partially purified compounds. The present invention is intended to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved in a manner known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of the crystalline product or, if desired, of a crystalline intermediate derivatized with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. Separation can be carried out by methods well known in the art, such as by coupling 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. Preferred examples of isomers of the compounds of formula I are compounds of formula Ib or compounds of formula Ic, in particular compounds of formula Ib, wherein the residues have the meaning as indicated in any of the embodiments:

in embodiments where an optically pure enantiomer is provided, by optically pure enantiomer is meant a compound comprising > 90% by weight of the desired isomer, preferably > 95% by weight of the desired isomer, or more preferably > 99% by weight of the desired isomer, based on the total weight of the isomer or isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. The separation of the enantiomers may be performed 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. Any previously defined residues and variables will continue to have the previously defined meanings unless otherwise indicated.

In the presence of an activating reagent such as, for example, an isocyanate, in particular, a phenyl isocyanate, and a catalytic amount of a base, in particular an alkylamine, more particularly NEt, in a solvent such as benzene or toluene, in particular benzene, or an alkyl ether, in particular diethyl ether₃In this case, the nitro compound (II) is reacted with an olefin (olefine) (III) to give a dihydroisoxazole IV.

Arylation of dihydroisoxazole (IV) with aryl bromide (V) to isoxazolidine (VI) is carried out by: aryl halides, specifically aryl bromides, are reacted with alkyl lithium reagents, specifically n-BuLi, to provide aryl lithium species, which can be reacted with dihydroisoxazole (IV) in the presence of a lewis base, preferably boron trifluoride etherate, in a solvent mixture consisting of an ether (specifically THF) and toluene at-100 ℃ to-20 ℃ (specifically, -78 ℃).

Resolution of racemic isoxazolidine (VI) can be performed by chiral High Performance Liquid Chromatography (HPLC) in a mixture of n-heptane and ethanol using a Chiralpack AD column to provide chiral isoxazolidine (VII).

Hydrogenolysis of chiral isoxazolidine (VII) to amino alcohol (VIII) can best be achieved by transfer hydrogenolysis in a protic solvent such as an alcohol, specifically ethanol, using a Pd-catalyst, specifically palladium on carbon (Pd on carbon) and a hydrogen source such as a salt of formic acid, specifically ammonium formate.

Can be prepared by dissolving in a solvent such as alcohol (specificallyEthanol) and reacting the amino alcohol (VIII) with cyanogen bromide at elevated temperature to produce the oxazine (IX). Alternatively, the reaction may be carried out in the presence of a solvent such as, for example, CH₃CN, using cyanogen bromide and a buffer such as, for example, sodium acetate, in a two-step sequence followed by cyclization of the intermediate in the presence of a mineral acid, specifically hydrochloric acid, in a solvent such as an ether (specifically, 1, 4 dioxane).

The nitration of oxazines (IX) to give nitrooxazines (X) is carried out according to standard procedures involving pure sulfuric acid and fuming nitric acid but without the use of solvents.

Reduction of the nitro group in intermediate (X) to provide aniline (XI) may be achieved by hydrogenolysis in a protic solvent such as an alcohol (in particular ethanol or methanol) using a catalyst such as Pd/C.

Selective amide coupling of aniline (XI) and carboxylic acid (XII) can be achieved with 4- (4, 6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride (DMTMM) hydrate in a solvent such as an alcohol (specifically, methanol) to provide amide (I).

Scheme 1: synthesis of R²＝F、R³Methyl, R⁴H and R⁵A compound of formula I ═ H, (I').

Scheme 2: synthesis of R²＝F、R³A compound of formula I, wherein (I) is methyl.

Scheme 3: synthesis of R²A compound of formula I' ″ where F is。

The compounds of formula I' "can be prepared as described in scheme 3. Chlorosilanes (specifically, t-butylchlorodimethylsilane (PG) can be prepared in a chlorinated solvent such as dichloromethane at 0 ℃ to 23 ℃ in the presence of a trialkylamine base (specifically, triethylamine) and a pyridine catalyst (specifically, 4-dimethylaminopyridine)¹＝t-BuMe₂Si)) on oxygen to selectively protect the above amino alcohol VIIIb by O-silylation to give an O-silylated amino alcohol XIIIb.

Use of a sulfinyl chloride (specifically, t-butylsulfinyl chloride (PG), in the presence of an amine base (such as triethylamine or diisopropylethylamine) in a chlorinated solvent (specifically, dichloromethane), at 0 ℃ to 60 ℃, preferably 23 ℃²t-BuSO)) to the O-silylated amino alcohol XIIIb to the O-silylated N-sulfinylated amino alcohol XIVb.

It can be desilylated to the N-sulfinylated aminoalcohol XVb by reacting the O-silylated N-sulfinylated aminoalcohol XIVb with a fluoride source, specifically tetrabutylammonium fluoride (TBAF), in a solvent such as THF at 0 ℃ to 50 ℃, preferably at 23 ℃.

The N-sulfinylated amino alcohol XVb can be oxidized to the N-sulfinylated amino ketone XVIb by a combination of reagents such as oxalyl chloride, dimethyl sulfoxide and an amine base such as triethylamine or diisopropylamine in a chlorinated solvent, in particular dichloromethane, at from-78 ℃ to ambient temperature.

The N-sulfinylated amino ketone XVIb can be converted to the N-sulfinylated amino- α -trifluoromethylalcohol xviiib by reacting it with a trifluoromethylating agent, such as (trifluoromethyl) trimethylsilane (Ruppert's reagent), in the presence of a fluoride source, in particular tetrabutylammonium fluoride (TBAF), in a solvent such as THF at 0 ℃ to 50 ℃, preferably at 0 to 23 ℃.

The N-sulfinylated amino- α -trifluoromethylalcohol XVIIIb can be deprotected to amino- α -trifluoromethylalcohol XVIIIb by reaction with a strong aqueous mineral acid (specifically, hydrochloric acid) in a solvent such as THF, ethyl acetate, methanol or ethanol at a temperature between 0 and 23 ℃.

The strong silylating agent (specifically, t-butyldimethylsilyl trifluoromethanesulfonate (PG) can be used at a temperature of 0 ℃ to 23 ℃ in an ether solvent such as THF in the presence of a strong base (specifically, sodium hydroxide)¹＝t-BuMe₂Si)), amino- α -trifluoromethylalcohol XVIIIb is selectively protected by O-silylation on oxygen to O-silylated amino- α -trifluoromethylalcohol XIXb.

The O-silylated amino- α -trifluoromethylalcohol XIXb may be converted to the O-silylated α -trifluoromethylalcohol isothiocyanate XXb by treatment with thiophosgene or an equivalent reagent such as 1, 1' -thiocarbonyldiimidazole in the presence of a weak base such as sodium bicarbonate in a chlorinated solvent, specifically dichloromethane, at a temperature between 0 and 23 ℃, preferably 23 ℃.

The O-silylated α -trifluoromethylalcohol isothiocyanate XXb can be converted to N-benzylated oxazines XXIb: 1 by a three-step one-pot process with an amine, specifically p-methoxybenzylamine (PG) (specifically acetonitrile), in a solvent (specifically acetonitrile) at 0 ℃ to 100 ℃, preferably 80 ℃³PMB) or 2, 4-dimethoxybenzylamine (PG)³DMB)) to the corresponding O-silanized thiourea. 2.) the O-silanized thiourea can be reacted with a fluoride source (in particular tetrabutylammonium fluoride trihydrate (TBAF 3H) in a solvent such as acetonitrile at a temperature of 0 ℃ to 80 ℃, preferably at 23 ℃₂O)) to desilylate it to α -trifluoromethylolthiourea.3.) α -trifluoromethylolthiourea can be cyclized to N-benzylated oxazine XXIb by treatment with a carbodiimide, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, at 23-100 ℃, preferably at 80 ℃, in a solvent such as acetonitrile.

The N-benzylated oxazine XXIb is debenzylated to oxazine XXIIb by neat reaction with a strong organic acid, in particular trifluoroacetic acid, at a temperature between 0 ℃ and 50 ℃, preferably at 23 ℃.

The oxazine XXIIb may be converted to a compound of formula I' "via the nitro oxazine XXIIIb and the aniline XXIVb as already described above for oxazines IX and Ixa.

To the extent that 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 set forth herein. The starting materials are commercially available, known in the art or can be prepared by methods known in the art or analogous thereto.

It is to be understood that the compounds of general formula I of the present invention may be derivatized at functional groups to provide derivatives that are capable of conversion back to the parent compound in vivo.

Pharmacological testing

The compounds of formula I and their pharmaceutically acceptable salts have 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 studied according to the tests given below.

Cellular a β -lowering assay:

human HEK293 cells stably transfected with a vector expressing cDNA of the human APP wt gene (APP695) were used to assess the potency of compounds in cellular assays. Cells were seeded in 96-well microtiter plates in cell culture medium (Iscove, plus 10% (v/v) fetal calf serum, glutamine, penicillin/streptomycin) to about 80% confluence and the compound was added at 10x concentration to 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 medium culture, culture supernatants are collected to determine A β 40 concentration.coating 96-well ELISA plates (e.g., Nunc Maxisorb) (Brockhaus et al, NeuroReport9, 1481-1486; 1998) with monoclonal antibodies that specifically recognize the C-terminus of A β 40. after blocking non-specific binding sites with, e.g., 1% BSA and washing, culture supernatants are combined with horseradish peroxidase-conjugated A β detection antibodies (e.g., antibody 4G8, Senetek, Maryl and Heights, MO) at an appropriate dilution) Added together and incubated for 5-7 hours. The wells of the microtiter plates were then washed extensively with Tris-buffered (Tris-buffered) saline containing 0.05% Tween20 and with tetramethylbenzidine/H in citrate buffer₂O₂The measurements were developed. In 1 volume of 1N H₂SO₄After termination of the reaction, the reaction was measured at a wavelength of 450nm in an ELISA reader the A β concentration in the culture supernatant was calculated from a standard curve obtained with a known amount of pure A β peptide.

BACE inhibition was determined by measuring TMEM27 lysis of cells

The assay uses the following principle: inhibit human TMEM27 lysis in the Ins1e rat cell line caused by BACE2 of endogenous cells, and release from the cell surface into culture medium, followed by detection in an ELISA assay. Inhibition of BACE2 prevents cleavage and release in a dose-dependent manner.

The stable cell line "INS-TMEM 27" represents an INS1 e-derived cell line that inducibly expresses (using the TetOn system) full-length hTMEM27 in a doxycycline-dependent manner throughout the experiment, cells were cultured in RPMI1640+ Glutamax (Invitrogen) penicillin/streptomycin, 10% fetal bovine serum, 100mM pyruvate, 5mM β -mercaptoethanol, 100 microgram/ml G418, and 100 microgram/ml hygromycin and grown in non-adherent culture at 37 ℃ in standard CO₂A cell culture box.

INS-TMEM27 cells were seeded in 96-well plates. After 2 days in culture, BACE2 inhibitor was added in the concentration range required for the assay and doxycycline was added to a final concentration of 500ng/ml after another 2 hours. The cells were cultured for another 46 hours and the supernatant was collected to detect released TMEM 27.

TMEM27 was detected in the medium using an ELISA assay (using a pair of mouse anti-human-TMEM 27 antibodies raised against the extracellular domain of TMEM 27). The number of ELISA reads for each inhibitor concentration was used to calculate the EC for BACE2 inhibition using standard curve-fitting software of the Excel spaadesheet program, such as XLFit₅₀。

Table 1: IC of selected example₅₀Value of

Pharmaceutical composition

The compounds of formula I and their 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 can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereof may be processed with pharmaceutically inert inorganic or organic carriers to produce pharmaceutical formulations. 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, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, no carriers are generally 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, semi-liquid or liquid polyols, and the like.

Furthermore, the pharmaceutical preparations may contain pharmaceutically auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Medicaments comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as are processes for their preparation, which comprise 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 the case of oral administration, the dosage for an adult may vary from about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses, and further, when the daily dose is specified, the upper limit may also be exceeded.

The following examples illustrate the invention and are not to be construed as limiting but merely as representative thereof. The pharmaceutical formulation conveniently comprises from about 1 to 500mg, preferably 1 to 100mg, of a compound of formula I. Examples of compositions according to the invention are:

examples of the invention A

Tablets of the following composition were prepared in a general manner:

table 2: possible tablet compositions

Preparation method

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

2. The particles were dried at 50 ℃.

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

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

Examples of the invention B-1

Capsules of the following composition were prepared:

table 3: possible capsule ingredient composition

Preparation method

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

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

3. Filling into suitable capsules.

The compound of formula I, lactose and corn starch are first mixed in a mixer, followed by mixing in a pulverizer. The mixture was returned to the mixer, talc was added thereto and thoroughly mixed. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Examples of the invention 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 amount of	165

Table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		Karion83	8 (dry weight)
DioxygenTitanium nitride	0.4
		Iron oxide yellow	1.1
Total amount of	116.5

Table 5: possible soft gelatin capsule compositions

Preparation method

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

Examples of the invention C

Suppositories of the following composition were prepared:

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

Table 6: possible suppository composition

Preparation method

The suppository blocks were melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ℃. Thereupon, a fine powder of the compound of formula I is added thereto and stirred until it is thoroughly dispersed. Pouring the mixture into suppository molds of suitable size, and cooling; the suppositories are then removed from the moulds and packed in wax paper or metal foil, respectively.

Examples of the invention 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	Adjusted to pH5.0
Water for injection solution	Adding to 1.0ml

Table 7: possible injection solution compositions

Preparation method

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

Examples of the invention E

A sachet (sachet) of the following composition was prepared:

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

Table 8: possible sachet composition

Preparation method

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 the sachets.

Experimental part

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

General procedure A : synthesis of intermediate dihydroisoxazole IV

To a stirred solution of nitro compound II (72.8mmol) and alkene III (71.3mmol) in benzene (105ml) was added triethylamine (NEt)₃) (10 drops) then a solution of phenyl isocyanate (146mmol) in benzene (15ml) was added and stirring continued for 1h at 22 ℃ and 1h at reflux temperature. Alternatively, diethyl ether may be used as the solvent, and the reaction mixture stirred at 22 ℃ for 3 days. The suspension was filtered and chromatographed on silica using a mixture of cyclohexane and ethyl acetate (AcOEt) to provide pure dihydroisoxazole IV.

Intermediate IV-1: starting from nitroethane and 2, 5-dihydro-furan, the product (3aS, 6aS) -rel-3-methyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole was obtained aS a pale yellow solid.

Intermediate IV-2: (3aS, 6aS) -rel-1- (3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] was treated dropwise with a solution of (diethylamino) sulfur trifluoride (15.4mmol) in dichloromethane (5ml) at-70 deg.C]Isoxazol-3-yl) -methanol (14.0mmol) in dichloromethane (40 ml). The colorless turbid solution was stirred at-70 ℃ for 30 minutes and then allowed to warm to room temperature while its color turned brown. After stirring for one hour, the dark brown solution was cooled in an ice bath and quenched with saturated sodium bicarbonate solution (50 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate 100: 0 to 80: 20 as eluent. (3aS, 6aS) -rel-3-fluoromethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] is obtained aS a pale yellow solid]Isoxazole (814mg, 40% yield). MS: 146.2[ M + H ] M/z]⁺。

(3aS, 6aS) -rel-1- (3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazol-3-yl) -methanol was obtained aS follows:

starting from commercially available (Z) -ethyl 2-chloro-2- (hydroxyimino) acetate nitroethane and 2, 5-dihydro-furan, following general procedure a, the product (3aS, 6aS) -rel-3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole-3-carboxylic acid ethyl ester was obtained aS a yellow liquid.

Reacting (3aS, 6aS) -rel-3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d]A solution of isoxazole-3-carboxylic acid ethyl ester (18.9mmol) (intermediate IV-2) in ethanol (60ml) was cooled to 5 ℃. Sodium borohydride (37.8mmol) was added portionwise over 15 minutes. During the evaporation of the gas, the temperature is maintained between 5-10 ℃. Subsequently, the reaction mixture was stirred for 1 hour between 25-28 ℃. For work-up, the reaction mixture was cooled in an ice bath and 3M hydrochloric acid (12ml) was added dropwise. The mixture was allowed to warm to room temperature and was then treated with sodium carbonate solution (2M; 10 ml). The suspension was concentrated under reduced pressure, the resulting solid was stirred in dichloromethane, followed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate 100: 0 to 0: 100 as eluent. (3aS, 6aS) -rel-1- (3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] is obtained aS a pale yellow oil]Isoxazol-3-yl) -methanol (2.06g, 76% yield). MS: 144.0[ M + H ] M/z]⁺。

Intermediate IV-3: a solution of (3aS, 6aS) -rel-3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole-3-carbaldehyde (35.4mmol) in dichloromethane (20ml) was treated dropwise with (diethylamino) sulfur trifluoride (42.5mmol) at-2 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours. For the work-up, the reaction mixture was carefully quenched dropwise with a saturated solution of sodium bicarbonate (25ml) and subsequently adjusted to basic pH by the addition of sodium carbonate solution (10%). The mixture was extracted three times with dichloromethane, the organic layers were combined, dried over sodium sulfate and evaporated. For purification, the crude product was distilled under reduced pressure. (3aS, 6aS) -rel-3-difluoromethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole was obtained aS a pale yellow oil (2.9g, 50% yield).

(3aS, 6aS) -rel-3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole-3-carbaldehyde was obtained aS follows:

starting from commercially available 1, 1-dimethoxy-2-nitroethane (CAS69425-53-2) and 2, 5-dihydro-furan, following general procedure a, the product (3aS, 6aS) -rel-3-dimethoxymethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] isoxazole was obtained aS a light brown oil.

Mixing (3aS, 6aS) -rel-3-dimethoxymethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d]A solution of isoxazole (35.3mmol) in trifluoroacetic acid (30ml) was treated with water (1.3 ml). The mixture was stirred at room temperature for 30 minutes. For work-up, the reaction mixture was diluted with water (100ml) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a 5: 1-mixture of dichloromethane and heptane as eluent. (3aS, 6aS) -rel-3a, 4, 6, 6 a-tetrahydro-furo [3, 4-d ] is obtained aS a yellow oil]Isoxazole-3-carbaldehyde (4.79g, 96% yield). MS: 144.0[ M + H ] M/z]⁺。

General procedure B : synthesis of intermediate isoxazolidines VI And VII

to a stirred solution of aryl bromide V (8.26mmol) in THF (5ml) and toluene (15ml) at-78 deg.C over 10 min was added n-BuLi (1.6M in hexane, 4.9ml) and stirring continued at-78 deg.C for 1 h.

To a solution of dihydroisoxazole IV (3.9mmol) in toluene (35ml) was added boron trifluoride etherate (BF) at-78 deg.C₃.Et₂O) (7.9mmol), followed by the addition of the phenyllithium reagent prepared above over a period of 10 minutes using an insulated cannula, maintaining the temperature below-70 ℃. The mixture was stirred at-78 ℃ for 1 hour and saturated ammonium chloride (NH)₄Cl) aqueous solution andextraction was performed with AcOEt. The organic layer was washed with brine, dried, evaporated and the residue was chromatographed on silica using a mixture of cyclohexane and AcOEt to afford pure isoxazolidine VI.

Intermediate VI-1: from (3aS, 6aS) -rel-3-methyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d]Starting with isoxazole, the product (3S, 3aS, 6aS) -rel-3- (2-fluorophenyl) -3-methylhexahydropurano [3, 4-d) is obtained aS an off-white solid]Isoxazoles. MS: 224.2[ M + H ] M/z]⁺。

Intermediate VI-2: from (3aS, 6aS) -rel-3-fluoromethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d]Starting with isoxazole and 1-bromo-2-fluorobenzene, the product (3S, 3aS, 6aS) -rel-3-fluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d ] was obtained aS a pale yellow oil]Isoxazoles. MS: 242.1[ M + H ] M/z]⁺。

Intermediate VI-3: from (3aS, 6aS) -rel-3-difluoromethyl-3 a, 4, 6, 6 a-tetrahydro-furo [3, 4-d]Starting with isoxazole and 1-bromo-2-fluorobenzene, the product (3S, 3aS, 6aS) -rel-3-difluoromethyl-3- (2-fluorophenyl) -hexahydro-furo [3, 4-d) was obtained aS an orange oil]Isoxazoles. MS: m/z 260.2[ M + H ]]⁺。

Intermediate VII-1: the racemate of (3S, 3aS, 6aS) -3- (2-fluorophenyl) -3-methylhexahydropyrano [3, 4-d ] isoxazole was resolved on a chiral High Performance Liquid Chromatography (HPLC) column (Chiralpack AD) using n-heptane/ethanol (85: 15) to give the desired (3S, 3aS, 6aS) -3- (2-fluorophenyl) -3-methylhexahydropyrano [3, 4-d ] isoxazole (aS the faster eluting enantiomer) and (3R, 3aR, 6aR) -3- (2-fluoro-phenyl) -3-methyl-hexahydro-furo [3, 4-d ] isoxazole (aS the slower eluting enantiomer).

Intermediate VII-2: the racemate of (3S, 3aS, 6aS) -3-fluoromethyl-3- (2-fluorophenyl) -hexahydro-furo [3, 4-d ] isoxazole was resolved on a chiral High Performance Liquid Chromatography (HPLC) column (Chiralpack AD) using n-heptane/ethanol (85: 15), to give the desired (3S, 3aS, 6aS) -3-fluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d ] isoxazole (aS the faster eluting enantiomer) and (3R, 3aR, 6 aR-3-fluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d ] isoxazole (aS the slower eluting enantiomer).

Intermediate VII-3: resolution of the racemate of (3S, 3aS, 6aS) -3-difluoromethyl-3- (2-fluorophenyl) -hexahydro-furo [3, 4-d ] isoxazole on a chiral High Performance Liquid Chromatography (HPLC) column (Chiralpack AD) using n-heptane/isopropanol, thus, the desired (3S, 3aS, 6aS) -3-difluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d ] isoxazole (aS the second eluting enantiomer) and (3R, 3aR, 6 aR-3-difluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d ] isoxazole (aS the first eluting enantiomer) were obtained.

General procedure C : synthesis of intermediate amino alcohols VIII

To isoxazolidine VII (6.4mmol) in EtOH (40ml)Pd/C (10%, 288mg) and ammonium formate (3.2g) were added to the solution and the mixture was stirred continuously at 22 ℃ for 3 h. The suspension was filtered, the filtrate evaporated and the residue taken up in AcOEt with saturated sodium bicarbonate (NaHCO)₃) The aqueous solution was partitioned. The organic layer was dried, evaporated and a mixture of cyclohexane and AcOEt was used in Si-NH₂The residue was chromatographed on a column to afford pure amino alcohol VIII.

Intermediate VIII-1: from (3S, 3aS, 6aS) -3- (2-fluorophenyl) -3-methylhexahydrofurano [3, 4-d]Starting from isoxazole, the product (3S, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl) was obtained as a colorless oil]-tetrahydro-furan-3-ol. MS: 226.2[ M + H ] M/z]⁺。

Intermediate VIII-2: from (3S, 3aS, 6aS) -3-fluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d]Starting from isoxazole, the product (3S, 4S) -4- [ (S) -1-amino-2-fluoro-1- (2-fluoro-phenyl) -ethyl was obtained as a white solid]-tetrahydro-furan-3-ol. MS: 244.2[ M + H ] M/z]⁺。

Intermediate VIII-3: from (3S, 3aS, 6aS) -3-difluoromethyl-3- (2-fluoro-phenyl) -hexahydro-furo [3, 4-d]Starting from isoxazole, the product (3S, 4S) -4- [ (S) -1-amino-2, 2-difluoro-1- (2-fluoro-phenyl) -ethyl was obtained as a colorless solid]-tetrahydro-furan-3-ol. MS: 262.2[ M + H ] M/z]⁺。

General procedure D : synthesis of intermediate oxazines IX

To a solution of amino alcohol VIII (5.9mmol) in THF (130ml) was added a solution of sodium acetate (6.8mmol) and cyano bromide (Br-CN) (5M in acetonitrile (CH)₃CN), 6.8mmol) and the mixture was stirred at reflux temperature for 16 h. The mixture was diluted with hydrochloric acid (HCl) in 1, 4-dioxane (4M, 7.1ml) and stirring was continued at 22 ℃ for 1 h. The mixture was dissolved in AcOEt and saturated sodium carbonate (Na)₂CO₃) The aqueous solution was partitioned between, the organic layer dried, evaporated and the residue chromatographed on silica using a mixture of AcOEt and methanol (MeOH) (9: 1) to afford pure oxazine IX.

Intermediate IX-1: from (3S, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl]Starting from tetrahydro-furan-3-ol, the product (3aS, 7S, 7aS) -7- (2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine) was obtained aS a pale yellow amorphous solid. MS: 251.1[ M + H ] M/z]⁺。

Intermediate IX-2: from (3S, 4S) -4- [ (S) -1-amino-2-fluoro-1- (2-fluoro-phenyl) -ethyl]Starting from tetrahydro-furan-3-ol, the product (3aS, 7S, 7aS) -7-fluoromethyl-7- (2-fluoro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine was obtained aS a white foam. MS: 269.1[ M + H ] M/z]⁺。

Intermediate IX-3: from (3S, 4S) -4- [ (S) -1-amino-2, 2-difluoro-1- (2-fluoro-phenyl) -ethyl]Starting from tetrahydro-furan-3-ol, the product (3aS, 7S, 7aS) -7-difluoromethyl-7- (2-fluoro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine was obtained aS a colorless solid. MS: 287.2[ M + H ] M/z]⁺。

General procedure E : synthesis of intermediate Nitro - Oxazines X

Oxazine IX (3.0mmol) was added portionwise to concentrated sulphuric acid (13ml) at 22 ℃ and the resulting solution was cooled to 0 ℃ over 20 minutes and treated with red fuming nitric acid (HNO)₃) (0.19ml) and stirring was continued at 0 for 1 h. The reaction mixture was slowly added to crushed ice (60g), the pH was adjusted to 10 using sodium hydroxide (NaOH), the aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was chromatographed on silica using a mixture of AcOEt/MeOH (9: 1) to afford pure nitrooxazine X.

Intermediate X-1: starting from (3aS, 7S, 7aS) -7- (2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, the product (3aS, 7S, 7aS) -7- (2-fluoro-5-nitro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine) was obtained aS a pale yellow amorphous solid. MS: 296.2[ M + H ] M/z]⁺。

Intermediate X-2: starting from (3aS, 7S, 7aS) -7-fluoromethyl-7- (2-fluoro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, the product (3aS, 7S, 7aS) -7-fluoromethyl-7- (2-fluoro-5-nitro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine) was obtained aS a white solid. MS: 313.9[ M + H ] M/z]⁺。

Intermediate X-3: starting from (3aS, 7S, 7aS) -7-difluoromethyl-7- (2-fluoro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, the product (3aS, 7S, 7aS) -7-difluoromethyl-7- (2-fluoro-5-nitro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine) was obtained aS a light yellow solid. MS: 332.2[ M + H ] M/z]⁺。

General procedure F : synthesis of intermediate Aniline XI

Nitro-oxazin X (2.6mmol) in EtOH (40ml) and NEt₃The suspension in (0.2ml) was treated with Pd/C (10%, 80mg) and the mixture was hydrogenated at atmospheric pressure and 22 ℃ for 2 h. The mixture was filtered, the filtrate evaporated and washed with a mixture of AcOEt/MeOH (9: 1) in Si-NH₂The residue was chromatographed on a column to afford pure aniline XI.

Intermediate XI-1: starting from (3aS, 7S, 7aS) -7- (2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine was obtained aS a white amorphous solid. MS: 266.1[ M + H ] M/z]⁺。

Intermediate XI-2: starting from (3aS, 7S, 7aS) -7-fluoromethyl-7- (2-fluoro-5-nitro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, (3aS, 7S, 7aS) -7-fluoromethyl-7- (5-amino-2-fluoro-5-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine was obtained aS a white foam. MS: 284.1[ M + H ] M/z]⁺。

Intermediate XI-3: starting from (3aS, 7S, 7aS) -7-difluoromethyl-7- (2-fluoro-5-nitro-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine, (3aS, 7S, 7aS) -7-difluoromethyl-7- (5-amino-2-fluoro-5-phenyl) -3,3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine was obtained aS a colorless foam. MS: m/z 302.3[ M + H]⁺。

General procedure G : synthesis of intermediates O- Protected aminoalcohols XIIIb

A solution of amino alcohol VIIIb (13.9mmol) in dichloromethane (91ml) was treated at 0 ℃ with triethylamine (4.48g, 44.3mmol) and 4- (dimethylamino) -pyridine (846mg, 6.93mmol) followed by tert-butyldimethylchlorosilane (4.18g, 27.7 mmol). The reaction mixture was warmed to room temperature and stirred overnight. Dilution with dichloromethane, extraction of the reaction mixture with a saturated solution of sodium bicarbonate NaHCO3, separation of the organic layer, drying over sodium sulfate and evaporation gave the crude product, which was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate 100: 0-0: 100 as eluent.

Intermediate XIIIb-1: starting from rel- (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) tetrahydrofuran-3-ol) rel- (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine was obtained as a colorless oil.

Intermediate XIIIb-2: starting from (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) tetrahydrofuran-3-ol) was obtained (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine as a colorless oil. MS: 340.3[ M + H ] M/z]⁺。

General procedure H : synthesis of intermediate deprotected amino alcohols XIVb

A solution of the protected amino alcohol XIIIb (19.1mmol) and triethylamine (2.9g, 28.6mmol) in dichloromethane (34ml) was treated dropwise with tert-butyl thionyl chloride (2.95g, 21.0mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 3 hours. To complete the reaction, tert-butyl thionyl chloride (0.5ml, 4mmol) was added again and the reaction mixture was stirred at 0 ℃ for 20 min. For work-up, the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of sodium bicarbonate NaHCO 3. The organic layer was separated and dried over sodium sulfate. Evaporation gave the crude product which was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate from 100: 0 to 0: 100 as eluent.

Intermediate XIVb-1: starting from rel- (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine, (R) -N-rel- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2-sulfinamide and (S) -N-rel- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2- Sulfenamides, both of which are colorless oils.

Intermediate XIVb-2: starting from (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine, (R) -N- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2-sulfinamide and (S) -N- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2-sulfinamide were obtained, both are colorless oils.

General procedure I : synthesis of intermediates N- Protected aminoalcohols XVb

A solution of the deprotected amino alcohol XIVb (5.43mmol) in tetrahydrofuran (7ml) was treated with tetrabutylammonium fluoride (1M in tetrahydrofuran) (7.0ml, 7.00mmol) at 23 ℃ and stirred for 45 min. For work-up, the reaction mixture was poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated and washed with brine. The combined aqueous layers were extracted again with ethyl acetate and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate 100: 0 to 0: 100 as eluent.

Intermediate XVb-1: starting from (S or R) -N-rel- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2-sulfinamide, (S or R) -N-rel- ((SR) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide is obtained as a white solid.

Intermediate XVb-2: starting from (S or R) -N- ((S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethyl) -2-methylpropan-2-sulfinamide, (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide is obtained as an off-white solid. MS: 330.1[ M + H ] M/z]⁺。

General procedure J : synthesis of intermediate ketones XVIb

Oxalyl chloride (896mg, 7.06mmol) was dissolved in dry dichloromethane (16.5ml) under a dry argon atmosphere. Anhydrous dimethyl sulfoxide (1.00ml, 14.1mmol) was added dropwise via syringe at-78 ℃. The resulting mixture was stirred for 15 minutes, followed by addition of a fine suspension of the N-protected amino alcohol XVb (4.71mmol) in dry dichloromethane (19ml) via syringe. The mixture was stirred at-78 ℃ for 30 minutes. Triethylamine (3.28ml, 23.5mmol) was then added and the resulting mixture was stirred at-78 ℃ for 10 minutes, followed by stirring between-78 ℃ and 10 ℃. For work-up, the reaction was quenched with ammonium chloride solution (20ml), diluted with dichloromethane, extracted with citric acid (pH 2-3), washed with sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate 100: 0 to 20: 80 as eluent.

Intermediate XVIb-1: starting from (S or R) -N-rel- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, (S or R) -N-rel- ((S) -1- (2-fluorophenyl) -1- ((S) -4-oxotetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide is obtained as a pale yellow oil. MS: 328.2[ M + H ] M/z]⁺。

Intermediate XVIb-2: starting from (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, the (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((S) -4-oxotetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide is obtained as a pale yellow oil. MS: 328.2[ M + H ] M/z]⁺。

General procedure K : synthesis of intermediate trifluoromethyl derivatives XVIIb

A solution of intermediate ketone XVIb (2.72mmol) in tetrahydrofuran (15ml) was treated dropwise with (trifluoromethyl) trimethylsilane (580mg, 603. mu.l, 4.08mmol) at 0 ℃. Subsequently, tetrabutylammonium fluoride (1M in tetrahydrofuran) (136. mu.l, 136. mu. mol) was added at 0 ℃. The brown solution was allowed to warm to room temperature and stirred for 3 hours. To complete the reaction tetrabutylammonium fluoride (1M in tetrahydrofuran) (4.08ml, 4.08mmol) was added and stirring continued for 1 hour. For work-up, the reaction mixture was quenched with water, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. After evaporation under reduced pressure, the residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate of 100: 0 to 0: 100 as eluent.

Intermediate XVIIb-1: starting from (S or R) -N-rel- ((S) -1- (2-fluorophenyl) -1- ((S) -4-oxotetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, (S or R) -N-rel- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxy-4- (trifluoromethyl) tetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide was obtained as a pale brown solid. MS: 398.1[ M + H ] M/z]⁺。

Intermediate XVIIb-2: starting from (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((S) -4-oxotetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxy-4- (trifluoromethyl) tetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide was obtained as a light brown foam. MS: 398.1[ M + H ] M/z]⁺。

General procedure L : synthesis of intermediate amino alcohols XVIIIb

A solution of intermediate trifluoromethyl derivative XVIIb (1.4mmol) in tetrahydrofuran (15ml) was treated with hydrochloric acid (37% in water) (573. mu.l, 6.98mmol) at 23 ℃. The yellow solution was stirred for 2 hours at 23 ℃ and then poured into sodium carbonate solution (1M). The mixture was extracted 2 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. Through Na₂SO₄The combined organic layers were dried, filtered and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0 to 50: 50 as eluent.

Intermediate XVIIb-1: starting from (S or R) -N-rel- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxy-4- (trifluoromethyl) tetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, rel- (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) -3- (trifluoromethyl) tetrahydrofuran-3-ol was obtained as a pale yellow oil. MS: 294.1[ M + H ] M/z]⁺。

Intermediate XVIIb-2: starting from (S or R) -N- ((S) -1- (2-fluorophenyl) -1- ((3S, 4S) -4-hydroxy-4- (trifluoromethyl) tetrahydrofuran-3-yl) ethyl) -2-methylpropan-2-sulfinamide, (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) -3- (trifluoromethyl) tetrahydrofuran-3-ol was obtained as a brown oil. MS: 294.2[ M + H ] M/z]⁺。

General procedure M : synthesis of intermediates O- Protected aminoalcohols XIXb

Sodium hydride (55% dispersion in oil) (116mg, 2.67mmol) was added to a solution of amino alcohol XVIII Ib (1.48mmol, Eq: 1.00) in N, N-dimethylformamide (6ml) at 0 ℃. After stirring at 23 ℃ for 30 min, the reaction mixture was treated with tert-butyldimethylsilyl triflate (728mg, 632. mu.l, 2.67mmol) at 0 ℃. After stirring for 16 hours, the reaction mixture was extracted with a mixture of dichloromethane and a saturated solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0 to 50: 50 as eluent.

Intermediate XIXb-1: starting from rel- (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) -3- (trifluoromethyl) tetrahydrofuran-3-ol, rel- (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) -4- (trifluoromethyl) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine was obtained as a colorless oil.

Intermediate XIXb-2: starting from (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) -3- (trifluoromethyl) tetrahydrofuran-3-ol, (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) -4- (trifluoromethyl) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine was obtained as a pale yellow oil. MS: 408.3[ M + H ] M/z]⁺。

General procedure N : synthesis of intermediate isothiocyanate XXb

A mixture of the O-protected amino alcohol XIXb (908. mu. mol) and sodium hydrogencarbonate (381mg, 4.54mmol) in dichloromethane (6ml) was treated with thiophosgene (129mg, 86.1. mu.l, 1.09mmol) at 0 ℃. The reaction mixture was stirred at 23 ℃ for 4 hours. For work-up, the reaction mixture is extracted with a mixture of dichloromethane and water. The organic layer was separated, dried over sodium sulfate and evaporated. The crude product was used in the next step without further purification.

Intermediate XXb-1: starting from rel- (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) -4- (trifluoromethyl) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine tert-butyl-rel- ((3S, 4S) -4- ((S) -1- (2-fluorophenyl) -1-isothiocyanatoethyl) -3- (trifluoromethyl) tetrahydrofuran-3-yloxy) dimethylsilane was obtained as a colorless oil.

Intermediate XXb-2: starting from (S) -1- ((3S, 4S) -4- (tert-butyldimethylsilyloxy) -4- (trifluoromethyl) tetrahydrofuran-3-yl) -1- (2-fluorophenyl) ethylamine, tert-butyl- ((3S, 4S) -4- ((S) -1- (2-fluorophenyl) -1-isothiocyanatoethyl)) -3- (trifluoromethyl) tetrahydrofuran-3-yloxy) dimethylsilane was obtained as a brown oil.

General procedure O : synthesis of intermediates N- Benzylated oxazines XXIb

A solution of isothiocyanate XXb (1.09mmol) in acetonitrile (11ml) was treated with 2, 4-dimethoxybenzylamine (273mg, 246. mu.l, 1.63mmol) at room temperature. The colorless solution was stirred at 70 ℃ for 16 hours. Tetrabutylammonium fluoride trihydrate (378mg, 1.2mmol) was added at 23 ℃ and stirring continued for 2 hours. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (418mg, 2.18mmol) was then added and stirring continued at 80 ℃ for 16 h. For work-up, the reaction mixture was extracted with a mixture of ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0-65: 35 as eluent.

Intermediate XXIb-1: starting from tert-butyl-rel- ((3S, 4S) -4- ((S) -1- (2-fluorophenyl) -1-isothiocyanatoethyl) -3- (trifluoromethyl) tetrahydrofuran-3-yloxy) dimethylsilane, rel- (4S, 4aS, 7aS) -N- (2, 4-dimethoxybenzyl) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] was obtained aS a white solid][1，3]Oxazin-2-amines. MS: 469.23[ M + H ] M/z]⁺。

Intermediate XXIb-2: starting from tert-butyl ((3S, 4S) -4- ((S) -1- (2-fluorophenyl) -1-isothiocyanatoethyl) -3- (trifluoromethyl) tetrahydrofuran-3-yloxy) dimethylsilane, (4S, 4aS, 7aS) -N- (2, 4-dimethoxybenzyl) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-2-amine was obtained aS a colorless oil.

General procedure P : synthesis of intermediate oxazines XXIIb

A solution of N-benzyloxazine XXIb (758. mu. mol) in trifluoroacetic acid (4.32g, 2.92ml, 37.9mmol) was stirred for 5 h. Trifluoromethanesulfonic acid (341mg, 202. mu.l, 2.27mmol) was added and stirring was continued for an additional 2 hours. The dark red solution was poured into sodium carbonate solution (1M) and extracted 2 times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a 19: 1-mixture of heptane and methanol as eluent.

Intermediate XXIIb-1: from rel- (4S, 4aS, 7aS) -N- (2, 4-dimethoxybenzyl) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ]][1，3]Starting with oxazin-2-amine, rel- (4S, 4aS, 7aS) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] was obtained aS a white solid][1，3]Oxazin-2-amines. MS: 319.0[ M + H ] M/z]⁺。

Intermediate XXIIb-2: from (4S, 4aS, 7aS) -N- (2, 4-dimethoxybenzyl) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e [ ]][1，3]Starting with oxazin-2-amine, (4S, 4aS, 7aS) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] to give a white gum][1，3]Oxazin-2-amines. MS: 319.0[ M + H ] M/z]⁺。

Synthesis of intermediate nitrooxazines XXIIIb

Intermediate XXIIIb-1: following general procedure E, rel- (4S, 4aS, 7aS) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-E][1，3]Nitration of oxazin-2-amines yields rel- (4S, 4aS, 7aS) -4- (2-fluoro-5-nitrophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] aS a light brown solid][1，3]Oxazin-2-amines. MS:m/z＝364.0[M+H]⁺。

intermediate XXIIIb-2: following general procedure E, (4S, 4aS, 7aS) -4- (2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-E][1，3]Nitration of oxazin-2-amines to produce (4S, 4aS, 7aS) -4- (2-fluoro-5-nitrophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] aS a light brown foam][1，3]Oxazin-2-amines. MS: 364.0[ M + H ] M/z]⁺。

Synthesis of intermediate Aniline XXIVb

Intermediate XXIVb-1: following general procedure F, rel- (4S, 4aS, 7aS) -4- (2-fluoro-5-nitrophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ]][1，3]Reduction of oxazin-2-amine gave rel- (4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] aS an off-white solid][1，3]Oxazin-2-amines. MS: m/z is 334.2[ M + H ]]⁺。

Intermediate XXIVb-2: following general procedure F, (4S, 4aS, 7aS) -4- (2-fluoro-5-nitrophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e [ ]][1，3]Reduction of oxazin-2-amine to give (4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] aS a light brown foam][1，3]Oxazin-2-amines. MS: m/z is 334.2[ M + H ]]⁺。

For synthesizing the final examples I Method (2) Q

To a solution of the acid XII (0.16mmol) in MeOH (1ml) at 22 deg.C was added 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methyl-morpholinium chloride (0.19mmol) and stirring continued at 0 deg.C for 30 min. To the mixture was added a solution of aniline XI (0.15mmol) in MeOH (2ml) and stirring was continued for 4h at 0 ℃. The mixture was evaporated and washed with saturated Na₂CO₃The residue was partitioned between aqueous and ethyl acetate. The organic layer was dried, evaporated and applied to a preparative HPLC RP18 column using water/NEt₃(99.9∶0.1)→CH₃CN gradient purification residue. Alternatively, AcOEt can be used by adding Si-NH₂The above chromatography purified the crude material, followed by trituration with diethyl ether to provide the final example of formula I.

Example 1

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-chloro-pyridine-2-carboxylic acid following procedure G gave the title compound aS a white solid. MS: 405.3% m/z&407.2[M+H]⁺。

Example 2

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 3, 5-dichloro-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 439.1 m/z&441.1[M+H]⁺。

Example 3

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

(3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-fluoro-pyridine-Coupling of 2-carboxylic acid following method G yielded the title compound as a white solid. MS: 389.2[ M + H ] M/z]⁺。

Example 4

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 396.2[ M + H ] M/z]⁺。

Example 5

Pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and pyridine-2-carboxylic acid following procedure G yielded the title compound aS a colorless solid. MS: 371.2[ M + H ] M/z]⁺。

Example 6

5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid (prepared aS described in WO2010/128058 by Banner d. et al) according to method G gave the title of a colorless solidA compound is provided. MS: 469.2[ M + H ] M/z]⁺。

Example 7

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-but-2-alkynyloxy-pyridine-2-carboxylic acid (prepared aS described in Tamura y. et al, WO 2010/113848) following method G yielded the title compound aS a colorless solid. MS: 440.4[ M + H ] M/z]⁺。

Example 8

5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid (prepared aS described in Suzuki y et al, WO 2009/091016) according to method G yielded the title compound aS a colorless solid. MS: 470.2[ M + H ] M/z]⁺。

Example 9

5-Cyclopropylmethoxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

(3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-cyclopropylmethoxy-pyridine-2-methyl-amineCoupling of the acid (prepared as described in Scott, J et al, WO 2011/044181) following method G yielded the title compound as a colorless solid. MS: 441.3[ M + H ] M/z]⁺。

Example 10

5-but-2-ynyloxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

5-But-2-alkynyloxy-pyridine-2-carboxylic acid methyl ester

A mixture of methyl 5-hydroxy-pyridine-2-carboxylate (271mg) and 1-bromo-2-butyne (283mg) in DMF (5ml) was treated with potassium carbonate (367mg) and heated to 100 ℃ for 16 h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue was purified by chromatography using heptane/ethyl acetate (gradient from 0-80% ethyl acetate) to give the title product as a pale yellow solid (266 mg). MS: 206.1[ M + H ] M/z]⁺。

5-but-2-ynyloxy-pyridine-2-carboxylic acid

To a solution of methyl 5-but-2-ynyloxy-pyridine-2-carboxylate (234mg) in THF (20ml) and water (15ml) was added an aqueous LiOH solution (1M, 2.3ml) and the mixture was stirred at 22 ℃ for 1 h. The mixture was treated with aqueous HCl (1M, 2.3ml), evaporated slowly, the resulting suspension filtered, the residue washed with water and dried to give the title product as a white solid (165 mg). MS: 192.1[ M + H ] M/z]⁺。

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-but-2-ynyloxy-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 439.2[ M + H ] M/z]⁺。

Example 11

5- (2, 2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5- (2, 2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid (prepared aS described in Banner, d. et al, WO 2011/069934) following method G yielded the title compound aS a white solid. MS: m/z 501.1[ M + H%]⁺。

Example 12

N- (3- ((4S, 4aS, 7aS) -2-amino-4-methyl-4 a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -3-chloro-5-cyanopyridinamide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a light yellow solid. MS: 430.2[ M + H ] M/z]⁺。

Example 13

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 414.1[ M + H ] M/z]⁺。

Example 14

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-chloro-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 423.0[ M + H ] M/z]⁺。

Example 15

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-fluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-fluoro-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a white solid. MS: 407.3[ M + H ] M/z]⁺。

Example 16

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-chloro-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a colorless solid. MS: 441.2[ M + H ] M/z]⁺。

Example 17

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound aS a colorless solid. MS: m/z 432.3[ M + H ]]⁺。

Example 18

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide

Coupling of (3aS, 7S, 7aS) -7- (5-amino-2-fluoro-phenyl) -7-difluoromethyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-5-ylamine and 5-but-2-ynyloxy-pyridine-2-carboxylic acid (prepared aS described in Tamura y. et al, WO 2010/113848) following procedure G yielded the title compound aS a colorless solid. MS: m/z 476.2[ M + H ]]⁺。

Example 19

N- (3- (rel- (4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-cyanopyridinamide

rel- (4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e][1，3]Coupling of oxazin-2-amine (intermediate XXIVb-1) and 5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound as an off-white foam. MS: m/z 464.1[ M + H ]]⁺。

Example 20

N- (3- (rel- (4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5- (but-2-ynyloxy) pyrazine-2-carboxamide

rel- (4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e][1，3]Coupling of oxazin-2-amine (intermediate XXIVb-1) and 5- (but-2-ynyloxy) pyrazine-2-carboxylic acid following procedure G yielded the title compound as a white foam. MS: m/z 508.2[ M + H ]]⁺。

Example 21

N- (3- ((4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-chloropyridinamide

(4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e][1，3]Coupling of oxazin-2-amine (intermediate XXIVb-2) and 5-chloro-pyridine-2-carboxylic acid following method G yielded the title compound as a white solid. MS: 473.1[ M + H ] M/z]⁺。

Example 22

N- (3- ((4SR, 4aSR, 7aSR) -2-amino-4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -5-cyanopyridinamide

(4S, 4aS, 7aS) -4- (5-amino-2-fluorophenyl) -4-methyl-7 a- (trifluoromethyl) -4a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e][1，3]Coupling of oxazin-2-amine (intermediate XXIVb-2) and 5-cyano-pyridine-2-carboxylic acid following procedure G yielded the title compound as a white solid. MS: m/z 464.1[ M + H ]]⁺。

Claims (9)

1. A compound of formula Ib:

wherein

R¹Is a pyridyl group, substituted by 1-2 substituents independently selected from cyano, halogen and halo-C_1-6Pyridyl substituted by substituents of alkoxy, or by halo-C_1-6-alkoxy or C_2-6-alkynyl-C_1-6-an alkoxy-substituted pyrazinyl group;

R²is F;

R³is C_1-6-an alkyl group;

R⁴is hydrogen; and

R⁵is hydrogen;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R¹Is 5-chloro-pyridin-2-yl, 3, 5-dichloro-pyridin-2-yl, 5- (2, 2, 2-trifluoro-ethoxy) -pyrazin-2-yl, 5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-yl, 5-but-2-ynyloxy-pyrazin-2-yl, 5-cyano-pyridin-2-yl, 5-fluoro-pyridin-2-yl or pyridin-2-yl.

3. The compound of any one of claims 1-2, wherein R¹Is 5-cyano-pyridin-2-yl or 5-but-2-ynyloxy-pyrazin-2-yl.

4. The compound according to any one of claims 1-2, selected from the group consisting of:

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-Cyclopropylmethoxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 3, 3-tetrafluoro-propoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

n- (3- ((4S, 4aS, 7aS) -2-amino-4-methyl-4 a, 5, 7,7 a-tetrahydro-4H-furo [3, 4-e ] [1, 3] oxazin-4-yl) -4-fluorophenyl) -3-chloro-5-cyanopyridinamide,

pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide, and

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-2, selected from the group consisting of:

5-chloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

3, 5-dichloro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-cyano-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

5-fluoro-pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide, and

pyridine-2-carboxylic acid [3- ((3aS, 7S, 7aS) -5-amino-7-methyl-3, 3a,7,7 a-tetrahydro-1H-2, 4-dioxa-6-aza-inden-7-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of formula Ib according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound of formula Ib according to any one of claims 1-5 and a pharmaceutically acceptable auxiliary substance.

8. Use of a compound of formula Ib according to any one of claims 1-5 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease.

9. Use of a compound of formula Ib according to any of claims 1-5 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of diabetes.