HK1190702B

HK1190702B - 1,4 thiazepines/sulfones as bace1 and/or bace2 inhibitors

Info

Publication number: HK1190702B
Application number: HK14103749.2A
Authority: HK
Inventors: 汉斯．希尔珀特; 马克．罗杰斯-埃文斯; 迪迪埃．罗姆巴赫
Original assignee: F.Hoffmann-La Roche Ag
Priority date: 2011-03-04
Filing date: 2012-02-28
Publication date: 2017-09-29

Description

1, 4 thiazepine/sulfone 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 orientation, 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 of The amyloid beta-protein precursor and The mechanistic of Alzheimer's disease), Annu Rev Cell biol.1994; 10: 373. 403). Both pathological states are also commonly observed in patients with down syndrome (trisomy 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. Several 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 develop pathological states that share many similarities with human disease. A β -peptide is produced from APP by the sequential action of 2 proteolytic enzymes called β -and γ -secretases. Beta-secretase first cleaves the transmembrane domain in the extracellular domain of APP

About 28 amino acids outside (TM), thereby generating a C-terminal fragment of APP containing 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 subgroup of which is very likely the presenilins (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 ABOLISHED GENERATION (BACE1, Alzheimer's β -secretase deficient Mice have normal phenotype and eliminated β -amyloid production), Nat Neurosci.2001, 3 months 4 (3): 231-2, robers et al, BACE knockdown out micro enzyme synthesis, activating the protein a-secretion activity in Mice, polypeptides for Alzheimer's disease, although the activity of BACE in mouse is deficient in the brain 10. beta-secretase, 24. beta. -secretase secretion in 10 years, 10. for healthy brain-10. beta. -peptide (Hubei-10). 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 (mccallogue et al, Partial reduction of BACE1 ha pharmaceutical effects on Alzheimer's disease and synthetic pathology in APP Transgenic rice (Partial reduction of BACE1 has a profound effect on Alzheimer's plaques and synaptic pathological states in Transgenic Mice), J Biol chem.2007, 7 months 9 (282 (36): 26326). Therefore, it is expected that inhibitors of BACE1 activity may be useful agents for therapeutic intervention in Alzheimer's Disease (AD).

Type 2 diabetes (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 type 2 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, gastrins 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 the preservation of islet mass in type 2 diabetes", annu. rev. med.2006, 57, 265) -281).

Tmem27 has been identified as a protein that promotes beta-Cell proliferation (P Akpinar, S Kuwajima, J Krultzfeldt, 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-1 target collectin control insulin exocytosis by SNARE complex formation" (HNF-1 target collectin formation control insulin emesis by SNARE complex), "Cell, 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 cellular 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 Tmem27 siRNA knockdown resulted in a low proliferation rate. Thus, it was concluded that BACE2 is 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 BACE2 is 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 2 is 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-1 receptor by, alpha beta-, and gamma-secretase (Interleukin-1 receptor in-membrane proteolysis of the interleukin-1 receptor 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 BACE2 is 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, the formation, or formation and deposition, of β -amyloid peptide in, on or around neural tissue (e.g., the brain) is inhibited by the compounds of the invention, i.e., inhibition of production of a β from APP or an APP fragment.

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 type 2 diabetes.

Technical Field

The present invention relates to 1, 4-thiazepine having BACE1 and/or BACE2 inhibitory propertiesAnd 1, 4-sulfones, their preparation, 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 pharmaceutically acceptable salts 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, or 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 type 2 diabetes and other metabolic diseases.

Detailed Description

The present invention provides compounds of formula I and their pharmaceutically acceptable salts, the manufacture of the above compounds, medicaments comprising them and their manufacture as well as the use of the above 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 type 2 diabetes. Furthermore, by inhibiting 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_1-6-alkyl ", alone or in combination with other groups, represents a hydrocarbon group which may be of formula (I)Single or multiple branched straight or branched chain, wherein the alkyl group typically comprises 1 to 6 carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, isopropyl (iso-propyl), n-butyl, isobutyl (iso-butyl), 2-butyl (sec-butyl), tert-butyl (tert-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 "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. A particular halogen is fluorine. Specific "halo-C_1-6-alkyl "is fluoro-C_1-6-an alkyl group. Examples are difluoromethyl, chloromethyl, fluoromethyl and the like. In particular trifluoromethyl and difluoromethyl.

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 "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. Specific "heteroaryl" groups are pyridyl and 2H-pyrazolyl. Particular are pyridin-2-yl and 2H-pyrazol-3-yl.

The term "C_1-6-alkoxy ", alone or in combination with other groups, represents-O-C_1-6An alkyl radical, which may be linear or branched with single or multiple branches, wherein the alkyl radical generally comprises from 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. Specific "C_1-6-alkoxy "is a group having 1 to 4 carbon atoms. Particularly methoxy and ethoxy (ethoxy).

The term "heterocyclyl", alone or in combination with other groups, refers to a 4-8 membered ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, respectively. Preferably 1 or 2 ring heteroatoms. Specifically 4-6 membered "heterocyclyl", more specifically 5-6 membered "heterocyclyl", each ring containing 1 or 2 ring heteroatoms selected from N, O or S, specifically O. In particular a 5-membered heterocyclic ring comprising one O. Examples of "heterocyclyl" include azepanyl (azepanyl), azetidinyl, diazepanyl (diazepanyl), morpholinyl, oxepanyl (oxazepanyl), oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl (tetrahydropyrryl), tetrahydrothienyl, thiazolidinyl, thiomorpholinyl, and the like. In particular tetrahydrofuranyl.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but not limited to: acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid (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 any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term "inhibitor" refers to a compound that competes with or reduces or prevents the binding of a particular ligand to a particular receptor, or 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 in an exponential manner. IC50 values are not absolute values, but depend on 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 a 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 a greater potency in an exponential manner.

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 results in the formation of the specified and/or desired product.

The term "protecting group" is used in synthetic chemistry in its conventional sense to refer to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can be selectively performed at another unprotected reactive site. The protecting group may be removed at a suitable site. Exemplary protecting groups are amino protecting groups, carboxy-protecting groups or hydroxy protecting groups. The term "amino-protecting group" refers to a group intended to protect an amino group, and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethoxycarbonyl (FMOC), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-Butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of such Groups are found in t.w.greene and p.g.m.wuts, "Protective Groups in Organic Synthesis", 2 nd edition, John Wiley & Sons, inc., New York, NY, 1991, chapter 7; haslam, "Protective Groups in Organic Chemistry", J.G.W.McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W.Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with an amino-protecting group. Specific amino-protecting groups are tert-butoxycarbonyl, bis (dimethoxyphenyl) -benzyl and dimethoxytrityl.

The term "leaving group" refers to a group having the meaning conventionally associated therewith in synthetic organic chemistry, i.e., an atom or group that is substitutable under substitution reaction conditions. Examples of leaving groups include halogen, in particular bromine, alkane-or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, toluenesulfonyloxy and thiophenyloxy, dihalophosphonoxy, optionally substituted with benzyloxy, isopropoxy and acyloxy.

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.

Certain embodiments are of the compounds of formula I,

wherein

R¹Selected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halo-C_1-6-an alkyl group;

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁴selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁵is heteroaryl, unsubstituted or substituted with one or two substituents independently selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) a halogen, in the presence of a halogen,

iii)C_1-6-alkoxy, and

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

R⁶is hydrogen；

R⁷Is hydrogen;

R⁸is hydrogen;

R⁹is hydrogen;

or R⁶And R⁸Together form a 5-6 membered heterocyclic group,

x is selected from the group consisting of:

i) -S, and

ii)-SO₂；

or a pharmaceutically acceptable salt thereof.

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

wherein

R¹Selected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halo-C_1-6-an alkyl group;

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁴selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

i)C_1-6-an alkyl group,

ii) a halogen, in the presence of a halogen,

iii)C_1-6-alkoxy, and

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

x is selected from the group consisting of:

i) -S, and

ii)-SO₂；

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to a compound of formula I' a as described herein,

wherein

R¹Selected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halo-C_1-6-an alkyl group;

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁴selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

i)C_1-6-an alkyl group,

ii) a halogen, in the presence of a halogen,

iii)C_1-6-alkoxy, and

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

x is selected from the group consisting of:

i) -S, and

ii)-SO₂；

or a pharmaceutically acceptable salt thereof.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is a halogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is F.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is²Is C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is²Is Me.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is²Is halo-C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is²is-CHF₂。

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is³Is C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is³Is Me.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁴Is C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁴Is Me.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁴Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁶Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁷Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁸Is hydrogen.

One embodiment of the present invention relates toCompounds of formula I as described herein, wherein R⁹Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁶And R⁸Together form a 5-6 membered heterocyclic group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁶And R⁸Forming a tetrahydrofuranyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is SO₂，R¹Is halogen, R²Is C_1-6-alkyl, R³Is hydrogen and R⁴Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is SO₂，R¹Is F, R²Is Me, R³Is hydrogen and R⁴Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is SO₂，R¹Is halogen, R²Is C_1-6-alkyl, R³Is hydrogen and R⁴Is C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is SO₂，R¹Is F, R²Is Me, R³Is hydrogen and R⁴Is Me.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is SO₂，R⁵Is heteroaryl, which is substituted with one halogen selected from chlorine and fluorine.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is halogen, R²Is C_1-6-alkyl, R³Is hydrogen and R⁴Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is F, R²Is Me, R³Is hydrogen and R⁴Is hydrogen.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is halogen, R²Is C_1-6-alkyl, R³Is hydrogen and R⁴Is C_1-6-an alkyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is¹Is F, R²Is Me, R³Is hydrogen and R⁴Is Me.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is heteroaryl, which is substituted with one halogen selected from chlorine and fluorine.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is selected from

i) A chloro-pyridyl group,

ii) fluoro-pyridyl and

iii) 2H-pyrazolyl.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is a chloro-pyridyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is a fluoro-pyridyl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is a 2H-pyrazol-3-yl group.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is 5-chloro-pyridin-2-yl or 5-fluoro-pyridin-2-yl.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is 5-chloro-pyridin-2-yl.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein R is⁵Is 5-fluoro-pyridin-2-yl.

One certain embodiment of the invention relates to a compound of formula I as described herein, wherein X is S.

One certain embodiment of the present invention relates to a compound of formula I as described herein, wherein X is-SO₂。

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

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

4-chloro-2H-pyrazole-3-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

4-chloro-2H-pyrazole-3-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-cyano-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lamda.6- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-cyano-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lamda.6- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides, and

5-cyano-pyridine-2-carboxylic acid [3- ((3aR, 8S, 8aS) -rel-6-amino-8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda.6-thia-7-aza-azulen-8-yl) -4-fluoro-phenyl ] -amide,

or a pharmaceutically acceptable salt thereof.

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides, and

or a pharmaceutically acceptable salt thereof.

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides, and

5-fluoro-pyridine-2-carboxylic acid [3-, ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention relates to a compound of formula I as described herein, which is 5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1 λ⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide.

One certain embodiment of the present invention relates to a compound of formula I as described herein, which is 5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1 λ⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the present invention relates to a compound of formula I as described herein, which is 5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1 λ⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide.

One certain embodiment of the present invention relates to a process for the preparation of a compound of formula I as defined herein, said process comprising reacting a compound of formula a9 into a compound of formula a10,

optionally, the compound of formula A10 may be further reacted with a peroxide to give a compound of formula A11,

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, or 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 substance for the therapeutic and/or prophylactic treatment of diabetes, or type 2 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 compounds of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type 2 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 disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, or alzheimer's disease.

A certain embodiment of the invention 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, or type 2 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 the use of a compound of formula I as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes, or type 2 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 use in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, or alzheimer's disease.

A certain embodiment of the invention 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, or type 2 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 invention relates to compounds of formula I as described herein for use in the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes, or type 2 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 type 2 diabetes, 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 type 2 diabetes, 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 or I 'may exist in tautomeric forms, for example I' may exist in the following tautomeric forms:

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 may 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 so that the individual enantiomers are separated. 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 compounds of formula I 'are compounds of formula I' a or compounds of formula I 'b, in particular compounds of formula I' b, 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.

The compounds of formula I may be prepared by a number of synthetic routes, for example as illustrated in the schemes below. The preparation of the compounds of formula I of the present invention can be carried out in a continuous or convergent synthetic route. The synthesis of the compounds of the invention is shown in the scheme below. The techniques required to carry out the reaction and the purification of the resulting product are known to those skilled in the art. The substituents and indices used in the following description of the process have the meanings indicated above, unless indicated to the contrary.

More specifically, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. However, the reaction sequence is not limited to the one shown in the scheme described below, and the order of the reaction steps may be freely changed depending on the raw materials and their respective reactivities. The starting materials are either commercially available or can be prepared by methods analogous to those given below, by the methods described in the references cited in the specification or described in the examples, or by methods known in the art.

Some typical methods for preparing compounds of formula I are illustrated in schemes a, B and C:

the sulfinyl imine of general formula a2 can be prepared analogously to t.p.tang & j.a.ellman, j.org.chem.1999, 64, 12, i.e. by condensation of an aryl ketone and a sulfinamide, e.g. an alkyl sulfinamide, most preferably (R) - (+) -tert-butyl sulfinamide, in the presence of a lewis acid, such as e.g. titanium (IV) alkoxide, more preferably titanium (IV) ethoxide, in a solvent, such as an ether, e.g. diethyl ether or more preferably THF.

The conversion of sulfinylimine A2 to sulfinamide ester A3 was performed stereoselectively by a chiral directing substituent as described by Tang & Ellman. The sulfinimide a2 can be reacted at low temperature, preferably at-78 ℃, in a solvent such as an ether, e.g. diethyl ether or more preferably THF, with a titanium enolate derived from e.g. alkyl acetate (preferably ethyl acetate), LDA and chlorotriisopropoxytitanium. Alternatively, sulfenamide ester A3 can be prepared from sulfenamide a2 by the Reformatsky reaction of a bromoacetate derivative and zinc dust, optionally in the presence of copper (I) chloride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF, at a temperature of 0-70 ℃, preferably at 23 ℃.

Sulfinamide ester A3 can be reduced to alcohol a4 by reducing the ethyl ester with an alkali metal hydride, preferably lithium borohydride or lithium aluminum hydride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF.

Thioacetate a5 can be prepared from alcohol a4 by the Mitsunobu method in a solvent such as dichloromethane using thioacetic acid, triphenylphosphine and diazocarboxylate, preferably DCAD or DEAD.

An inorganic base (preferably K) may be used in a solvent such as methanol in the presence of an alkylating agent such as a haloacetonitrile (halide acetonitril) analogue₂CO₃) The thioacetate was cleaved to effect the preparation of the sulfinamide nitrile a6 from the thioacetate a 5.

Hydrolysis of the chiral directing substituent in the sulfinamide nitrile a6 can be effected with a mineral acid, such as sulfuric acid or preferably hydrochloric acid, in a solvent such as an ether, e.g. diethyl ether or more preferably 1, 4-dioxane to provide the aminonitrile a 7.

The aminothiazepine can be prepared by reaction of the aminonitrile A7 with trimethylaluminum in a solvent such as xylene, preferably tolueneA8。

The reduction of tin, such as iron or tin, more preferably tin chloride in an alcohol (more preferably an ethanol solution) by a metal at elevated temperature, more preferably 80 ℃, can be achieved in the aminotriazepineThe nitro group in A8 was reduced to aniline a 9.

Amide coupling of aniline a9 and a carboxylic acid can be achieved with a carbodiimide, for example DCC or EDCI or a triazine such as DMTMM in a solvent such as dichloromethane or methanol, respectively, to give amide a 10.

Sulfone a11 can be prepared from amide a10 by treatment with a peroxide, preferably m-chloroperbenzoic acid, in a solvent such as dichloromethane.

Scheme(s) A

Scheme(s) B

The sulfinyl imine of general formula B2 can be prepared analogously to t.p.tang & j.a.ellman, j.org.chem.1999, 64, 12, i.e. by condensation of an aryl ketone and a sulfinamide, e.g. an alkyl sulfinamide, most preferably (R) - (+) -tert-butyl sulfinamide, in the presence of a lewis acid, such as e.g. titanium (IV) alkoxide, more preferably titanium (IV) ethoxide, in a solvent, such as an ether, e.g. diethyl ether or more preferably THF.

The conversion of sulfenimide B2 to sulfenamide B3 was performed stereoselectively by a chiral directing substituent as described by Tang & Ellman. The sulfinimide B2 can be reacted at low temperature, preferably at-78 ℃, in a solvent such as an ether, e.g. diethyl ether or more preferably THF, with a titanium enolate derived from e.g. alkyl acetate (preferably ethyl acetate), LDA and chlorotriisopropoxytitanium. Alternatively, sulfenamide ester B3 can be prepared from sulfenimide B2 by the Reformatsky reaction of a bromoacetate derivative and zinc dust, optionally in the presence of copper (I) chloride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF, at a temperature of 0-70 ℃, preferably at 23 ℃.

The sulfinamide ester B3 can be reduced to alcohol B4 by reducing the ethyl ester with an alkali metal hydride, preferably lithium borohydride or lithium aluminum hydride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF.

Thioacetate B5 can be prepared from alcohol B4 by the Mitsunobu method in a solvent such as dichloromethane using thioacetic acid, triphenylphosphine and diazocarboxylate, preferably DCAD or DEAD.

Thiol B6 can be prepared from thioacetate B5 by cleaving the acetate using an inorganic base, such as potassium carbonate, in methanol as solvent.

The thiol B6 can be alkylated to the ester B7 in acetonitrile as a solvent using an alkylating agent such as an alpha-halide ester analog and an inorganic base such as potassium carbonate.

Hydrolysis of the chirally oriented substituents in ester B7 can be achieved with a mineral acid such as sulfuric acid or preferably hydrochloric acid in a solvent such as ethanol at a temperature from 0-23 ℃ to give amino ester B8.

The amino ester B8 can be cyclized to the lactam B9 using a base such as bis [ bis (trimethylsilyl) amino ] tin (II) in an ether solvent, preferably THF, at a temperature from 23 ℃ to 50 ℃.

Thioether B9 may be oxidized to sulfone B10 by treatment with an oxidizing agent, preferably meta-chloroperbenzoic acid, in dichloromethane as solvent at room temperature.

Thiolactam B11 can be prepared from sulfone B10 using Lawesson's reagent in an ether solvent such as dioxane or preferably THF at reflux.

1, 1-dioxo- [1, 4-dioxo- [ can be prepared from thiolactam B11 by treatment with mercuric (II) chloride and ammonia in methanol in a solvent such as THF at a temperature of 120 ℃ in a microwave chamber]SulfoazazepineB12。

The nitro group is preferably introduced into the 1, 1-dioxo- [1, 4 ] according to standard methods (at low temperatures, preferably at 0 ℃, including sulfuric acid and nitric acid)]SulfoazazepineB12, thereby obtaining B13.

Reduction of the nitro group in B13 to aniline B14 can be achieved by metal reduction such as iron or tin, more preferably tin chloride in an alcohol (more preferably an ethanol solution) at elevated temperature, more preferably 80 ℃.

Amide coupling of aniline B14 and a carboxylic acid can be achieved with a carbodiimide, for example DCC or EDCI or a triazine, such as DMTMM, in a solvent such as dichloromethane or methanol, respectively, to give the amide B15(═ a 11).

Scheme(s) C

The sulfinyl imine of the general formula C2 can be prepared analogously to t.p.tang & j.a.ellman, j.org.chem.1999, 64, 12 by condensation of an aryl ketone and a sulfinamide, e.g. an alkyl sulfinamide, most preferably (R) - (+) -tert-butyl sulfinamide, in the presence of a lewis acid, such as e.g. titanium (IV) alkoxide, more preferably titanium (IV) ethoxide, in a solvent, such as an ether, e.g. diethyl ether or more preferably THF.

The conversion of sulfenimide C2 to sulfenamide C3 was performed stereoselectively by a chiral directing substituent as described by Tang & Ellman. The sulfinimide C2 can be reacted at low temperature, preferably at-78 ℃, in a solvent such as an ether, e.g. diethyl ether or more preferably THF, with a titanium enolate derived from e.g. alkyl acetate (preferably ethyl acetate), LDA and chlorotriisopropoxytitanium. Alternatively, sulfenamide ester C3 can be prepared from sulfenimide C2 by the Reformatsky reaction of a bromoacetate derivative and zinc dust, optionally in the presence of copper (I) chloride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF, at a temperature of 0-70 ℃, preferably at 23 ℃.

The sulfinamide ester C3 can be reduced to the alcohol C4 by reducing the ethyl ester with an alkali metal hydride, preferably lithium borohydride or lithium aluminum hydride, in a solvent such as an ether, e.g. diethyl ether or more preferably in THF.

Thioacetate C5 can be prepared from alcohol C4 by the Mitsunobu method in a solvent such as dichloromethane using thioacetic acid, triphenylphosphine and diazocarboxylate, preferably DCAD or DEAD.

The inorganic base (preferably K) may be used in a solvent such as methanol in the presence of an alkylating agent such as a halide acetonitrile analog₂CO₃) The thioacetate is cleaved and the preparation of the sulfinamide nitrile C6 is effected from the thioacetate C5.

Hydrolysis of the chiral directing substituent in nitrile C6 can be achieved with a mineral acid, such as sulfuric acid or preferably hydrochloric acid, in a solvent such as dioxane, THF, ethyl acetate or methanol at a temperature from 0-23 ℃ to give aminonitrile C7.

The cyclisation of aminonitrile C7 to amidine C8 can be carried out using a lewis acid such as trimethylaluminum in an inert solvent, preferably toluene, at a temperature of from 23 ℃ to 100 ℃, preferably 60 ℃.

Thioether C8 can be oxidized to sulfone C9 by treatment with an oxidizing agent, preferably m-chloroperbenzoic acid, in dichloromethane as solvent at room temperature. Alternatively, the oxidation can be carried out at ambient temperature in a solvent such as methanol using potassium monopersulfate (Oxone).

The amino group in the compound of formula C9 may be protected with a triarylmethyl chloride, such as triphenylmethyl chloride (Tr-Cl), p-methoxyphenyl biphenylmethyl chloride (MMTr-Cl), bis (p-methoxyphenyl) phenylmethyl chloride (DMTr-Cl) or tris (p-methoxyphenyl) methyl chloride (TMTr-Cl), preferably DMTr-Cl, in a chlorinated solvent, such as dichloromethane or chloroform, under basic conditions, for example in the presence of an amine, such as triethylamine or diisopropylethylamine, at a temperature between 0 ℃ and room temperature, to yield an aryl bromide of formula C10.

The catalyst may be prepared at a temperature of between 80 and 110 ℃ in an inert atmosphere, such as nitrogen or argon, in a suitable solvent such as toluene or 1, 4-dioxane, in the presence of a suitable transition metal catalyst such as bis (diphenylmethanone) palladium (0) ((dba)₂Pd) or tris (diphenylmethanone) dipalladium (0) ((dba)₃Pd₂) And a suitable ligand such as rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropylbiphenyl (X-PHOS) or 2-tert-butylphosphino-2', 4 ', 6' -triisopropylbiphenyl (t-Bu X-PHOS), the aryl bromide of formula C10 is reacted with an ammonia equivalent such as benzophenone imine in the presence of a base such as sodium tert-butoxide, potassium phosphate or cesium carbonate to yield the compound of formula C11.

P can be cleaved by first reacting a compound of formula C11 with a strong organic acid such as trifluoroacetic acid in a chlorinated solvent such as dichloromethane or chloroform under anhydrous conditions at a temperature between 0 ℃ and ambient temperature¹One-furnace method of radicals to effect the combination of said formula C11Deprotection of the two amino groups in the product. Next, water or aqueous hydrochloric acid is added to cleave the benzophenone imine and the reaction at ambient temperature produces the diamine of formula B14.

Scheme(s) D

Anellated compounds of formula D20 can be prepared as described in scheme D. 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 indicated to the contrary.

In the presence of an activating agent such as, for example, an isocyanate (specifically phenyl isocyanate) and a catalytic amount of a base (specifically an alkylamine, more specifically Et) in a solvent such as benzene or toluene (specifically benzene) or an alkyl ether (specifically diethyl ether), or in a chlorinated solvent (specifically dichloromethane)₃N), the nitro compound D1 is reacted with an olefin D2 to give the dihydroisoxazole D3.

Arylation of dihydroisoxazole D3 with aryl bromide D4 to give isoxazolidine D5 was carried out by: aryl halides, specifically aryl bromides, are reacted with alkyl lithium reagents, specifically n-BuLi, to give aryl lithium species, which can be reacted with dihydroisoxazole D3 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 at-78 ℃.

Resolution of racemic isoxazolidine D5 can be performed by chiral High Performance Liquid Chromatography (HPLC) using a Chiralpack AD column in a mixture of n-heptane and ethanol as eluent to give chiral isoxazolidine.

Hydrogenolysis of isoxazolidine D5 to amino alcohol D6 can be optimally performed by transfer hydrogenolysis using a Pd-catalyst, specifically palladium on carbon, and a hydrogen source, such as a salt of formic acid (specifically ammonium formate), in a protic solvent such as an alcohol, specifically ethanol.

Chlorosilanes (specifically tert-butylchlorodimethylsilane (PG) can be used in a chlorinated solvent such as dichloromethane in the presence of a trialkylamine base (specifically triethylamine) and a pyridine catalyst (specifically 4-dimethylaminopyridine) at 0 ℃ to 23 ℃ in the presence of a chlorinated solvent such as dichloromethane¹＝t-BuMe₂Si)), the aminoalcohol D6 is selectively protected over oxygen by O-silylation to give O-silylated aminoalcohol D7.

The aldehyde, specifically p-methoxybenzaldehyde (PG), can be used at 0 ℃ to 60 ℃, preferably 23 ℃, in the presence of a weak organic acid, specifically acetic acid, in a chlorinated solvent, specifically 1, 2-dichloroethane or dichloromethane, using a reducing agent, specifically sodium cyanoborohydride or sodium triacetoxyborohydride²PMB) or 2, 4-dimethoxybenzaldehyde (PG)²DMB)) reductively aminated the O-silylated aminoalcohol D7 to give O-silylated N-benzylaminoalcohol D8.

O-silylated N-benzylaminoalcohol D8 can be desilylated to give N-benzylaminoalcohol D9 by reacting it with a fluoride source, specifically tetrabutylammonium fluoride (TBAF), in a solvent such as THF at 0 deg.C to 50 deg.C, preferably at 23 deg.C.

Starting at low temperatures, such as-78 ℃ and warming to 0 ℃ or ambient temperature, the N-benzylated aminoalcohol D9 can be reacted with thionyl chloride in the presence of an amine base, particularly pyridine, in a chlorinated solvent, particularly dichloromethane, to provide cyclic sulfamimide D10.

The oxidation of cyclic sulfamide D10 to cyclic sulfamide D11 can be carried out at a temperature of 0 ℃ to 50 ℃, preferably at 23 ℃, in a solvent mixture consisting of water, acetonitrile and ethyl acetate or tetrachloromethane in the presence of a ruthenium salt, such as ruthenium (III) chloride, with an alkali metal periodate, such as sodium periodate or potassium periodate.

The cyclic sulfate D11 can be opened regioselectively and stereoselectively using a sulfur nucleophile, such as mercaptoacetonitrile, followed by hydrolysis under acidic conditions to the N-benzylated aminonitrile D12. The ring opening is carried out in the presence of an amine base, such as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 1, 3, 3-Tetramethylguanidine (TMG), in a polar aprotic solvent, such as N, N-dimethylformamide, at a temperature between 23 ℃ and 80 ℃, preferably at 60 ℃. After removal of all volatiles from the ring opening step by evaporation under vacuum, the crude reaction mixture is subjected to acidic hydrolysis in a mixture of a mineral acid, in particular 20% aqueous sulfuric acid, and a solvent such as diethyl ether or dichloromethane at a temperature between 0 ℃ and 50 ℃, preferably at 23 ℃.

Deprotection of N-benzylated aminonitrile D12 to aminonitrile D15 was carried out in three steps: first, the N-benzylated aminonitrile D12 is reacted with an organic acid anhydride, in particular trifluoroacetic anhydride, in the presence of an amine base, in particular triethylamine or diisopropylhexylamine, at a temperature between 0 ℃ and 40 ℃, preferably at 23 ℃, in a chlorinated solvent such as dichloromethane, to give the N-benzylated N-trifluoroacetylated aminonitrile D13. Secondly, the N-benzylated N-trifluoroacetylated aminonitrile D13 is debenzylated to an N-trifluoroacetylated aminonitrile D14 by a pure reaction with a strong organic acid, in particular trifluoroacetic acid, at a temperature between 0 ℃ and 50 ℃, preferably at 23 ℃. Thirdly, the N-trifluoroacetylated aminonitrile D14 is deacetylated to the aminonitrile D15 by treatment with a reducing agent, such as sodium borohydride, in an alcoholic solvent (in particular methanol or ethanol) at a temperature between 0 ℃ and 60 ℃, preferably at 23 ℃.

The aminonitrile D15 can be cyclized to the amidine D16 using a lewis acid such as trimethylaluminum in an inert solvent, preferably toluene, at a temperature of 23 ℃ to 100 ℃, preferably at 60 ℃.

Thioether D16 can be oxidized to sulfone D17 by treatment with an oxidizing agent, preferably m-chloroperbenzoic acid, in dichloromethane as solvent at room temperature. Alternatively, the oxidation can be carried out at ambient temperature in a solvent such as methanol using potassium monopersulfate (Oxone).

The amidine D17 was nitrated at temperatures between 0 ℃ and 23 ℃ in the absence of solvent according to standard procedures involving pure sulfuric acid and fuming nitric acid to give nitro-amidine D18.

The nitro group in intermediate D18 may be reduced by hydrogenolysis in a protic solvent such as an alcohol (specifically ethanol or methanol) using a catalyst such as palladium on carbon to give aniline D19.

Selective amide coupling of aniline D19 with a carboxylic acid in a solvent such as an alcohol (specifically methanol) using 4- (4, 6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholine hydrochloride (DMTMM) hydrate affords amide D20.

The corresponding pharmaceutically acceptable salts formed with the acids may be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as, for example, dioxane or THF and adding the appropriate amount of the corresponding acid. The product can usually be isolated by filtration or chromatography. The compounds of formula I can be converted into pharmaceutically acceptable salts with bases by treating the compounds with the bases. One possible way of forming the salt is, for example, by reacting 1/n equivalent of a basic salt such as, for example, M (OH)_n(where M ═ metal or ammonium cations, and n ═ hydroxide anions) are added to a solution of the compound in a suitable solvent (e.g., ethanol-water mixtures, tetrahydrofuran-water mixtures), and the solvent is removed by evaporation or lyophilization. Specific salts are hydrochloride, formate and trifluoroacetate.

To the extent that their preparation is not described in the examples, the compounds of formula I as well as 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.

Cytological 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 incubation, culture supernatants were collected to determine A β 40 concentration.A 96-well ELISA plates (e.g., Nunc Maxisorb) (Brockhaus et al, NeuroReport 9, 1481-1486; 1998) were coated with monoclonal antibodies that specifically recognized the C-terminus of A β 40. after blocking non-specific binding sites with, e.g., 1% BSA and washing, culture supernatants were added at appropriate dilutions along with horseradish peroxidase-conjugated A β detection antibodies (e.g., antibody 4G8, Senetek, Maryl and Heights, MO) and incubated for 5-7 hours. subsequently wells of the microtiter plates were washed extensively with Tris-buffered (Tris-buffered) saline containing 0.05% Tween 20 and 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 by measuring cellular TMEM27 cleavage

The assay uses the following principle: inhibition of endogenous cells in the Ins1e rat cell line BACE2 cleaved human TMEM27 and was released from the cell surface into the culture medium and subsequently detected 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 cultured in non-adherent cultures 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 at the concentration range required for the assay, and after another two hours doxycycline was added to a final concentration of 500 ng/ml. 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 embodiments₅₀Value 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.

The invention also provides medicaments comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as 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 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; compressed in a suitable press.

Examples 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 B-2

Soft gelatin capsules of the following composition were prepared:

table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		Karion 83	8 (Dry matter)
Titanium dioxide	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 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 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	Adjusting to pH 5.0
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 (part). 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 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 PH 102)	1400
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavor 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 flavor 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.

In general:

MS: mass Spectra (MS) were measured on a Perkin-Elmer SCIEX API 300 by either the positive or negative ion spray method (ISP or ISN) or by electron impact method (EI, 70eV) on a Finnigan MAT SSQ 7000 spectrophotometer.

Abbreviations:

DCAD ═ azobis-p-chlorobenzyl azodicarboxylate; DCC ═ N, N '-dicyclohexyl-carbodiimide, DCE ═ 1, 2-dichloroethane, DCM ═ dichloromethane, DIPEA ═ diisopropylethylamine, DMAc ═ dimethylacetamide, DMAP ═ 4-dimethylaminopyridine, DMF ═ N, N-dimethylformamide, DMSO ═ dimethylsulfoxide, EDCI ═ N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide hydrochloride, HATU ═ 1- [ bis (dimethylamino) methylene ] -1H-1, 2, 3-triazolo [4, 5-b ] pyridinium-3-oxide hexafluorophosphate, DMTMM ═ 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride; HCl ═ hydrogen chloride, HPLC ═ high performance liquid chromatography, LDA ═ lithium diisopropylamide, MS ═ mass spectrum, NMR ═ nuclear magnetic resonance, TEA ═ triethylamine, TBME ═ tetrabutylmethyl ether, and THF ═ tetrahydrofuran.

Synthesis of intermediate sulfenimide A2

General procedure

To a solution of (R) - (+) -tert-butylsulfinamide (66mmol) in THF (350ml) was then added ketone A1(72.6mmol) and titanium (IV) ethoxide (132mmol) and the solution was stirred at reflux temperature for 5 hours. The mixture was cooled to 22 ℃, treated with brine (400ml), the suspension stirred for 10 minutes and filtered over a celite plug (dicalite). The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give pure sulfinylimine a 2.

Intermediates A2A

Starting from 1- (2-fluoro-5-nitro-phenyl) -ethaneone, asProduct of light brown oil (R) -2-methyl-propane-2-sulfinic acid [1- (2-fluoro-5-nitro-phenyl) -eth- (E) -ylidene]-an amide. Ms (isp): 287.1[ M + H ] M/z]⁺。

Synthesis of intermediate sulfenamides Esters A3

General procedure (by Reformatsky reaction)

In a drying apparatus, a suspension of freshly activated zinc powder (1.63g, 24.9mmol) in dry THF (70ml) is heated to reflux under an inert atmosphere. A solution of sulfinimide a2(24.9mmol) and bromo-acetate (24.9mmol) in anhydrous THF (15ml) was added dropwise over a period of 15 minutes and the suspension was heated to reflux for 5 hours. The cooled mixture was brought to saturated NH₄Partitioned between aqueous Cl and ethyl acetate, the organic layer was dried and evaporated. The crude material was purified by flash chromatography using heptane/ethyl acetate to afford the sulfonamido ester a 3.

Intermediates A3A

From (R) -2-methyl-propane-2-sulfinic acid [1- (2-fluoro-5-nitro-phenyl) -eth- (E) -ylidene]Amide starting, the product (S) -3- (2-fluoro-5-nitro-phenyl) - (R) -3- (2-methyl-propane-2-sulfonamido) -butyric acid tert-butyl ester is obtained as a light brown oil. Ms (isp): m/z 403.2[ M + H ]]⁺。

Synthesis of intermediate sulfonamides A4

General procedure

A solution of sulfinamide ester A3(12.7mmol) in dry THF (50ml) was treated with lithium borohydride (25.3mmol) at 0 ℃ and stirring continued for 4 h at 0 ℃. The reaction mixture was quenched by the addition of acetic acid (2ml) and water (50ml), extracted with ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by flash chromatography using a mixture of n-heptane/ethyl acetate to give the pure intermediate sulfinamidol a 4.

Intermediates A4A

Starting from (S) -3- (2-fluoro-5-nitro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyric acid tert-butyl ester, the product (R) -2-methyl-prop-2-sulfinic acid [ (S) -1- (2-fluoro-5-nitro-phenyl) -3-hydroxy-1-methyl-propyl ] acid is obtained as a yellow oil]-an amide. Ms (isp): 333.3[ M + H ] M/z]⁺。

Synthesis of intermediate sulfinamide thioacetate A5

General procedure

A solution of triphenylphosphine (4.73g, 18.1mmol) in 50ml anhydrous DCM was treated with DCAD (6.63g, 18.1mmol) at 0 deg.C under argon, and the resulting reaction mixture was stirred at 0 deg.C for 20 min. To the above reaction mixture was added a solution of thioacetic acid (1.37mg, 18.1mmol) and alcohol A4(3.0g, 9.03mmol) in 10mL of anhydrous DCM. The reaction mixture was stirred at 0 ℃ for 20 minutes, warmed to room temperature and stirred at this temperature for 18 h. The white precipitate formed during the reaction was filtered off. The filtrate was diluted with more dichloromethane and extracted with 1M aqueous sodium carbonate. The organic layer was dried over sodium sulfate and evaporated until dry. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 3.2g of pure product.

Intermediates A5A

From (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (2-fluoro-5-nitro-phenyl) -3-hydroxy-1-methyl-propyl]Amide starting, obtaining the product thioacetic acid as a yellow oilS- [ (S) -3- (2-fluoro-5-nitro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyl]And (3) an ester. Ms (isp): m/z 391.3[ M + H%]⁺。

Synthesis of intermediate sulfinamide nitriles A6

General procedure

A solution of thioacetate A5(1.3g, 3.33mmol) in 19ml of methanol was treated with bromoacetonitrile (2.23g, 16.6mmol) and potassium carbonate (460mg, 3.33mmol) under argon. The resulting reaction mixture was stirred at room temperature for one hour. The reaction medium is poured into a separatory funnel filled with ethyl acetate and extracted with water, the organic layer is dried over sodium sulfate and evaporated until dry. The crude product was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 1.05g of sulfonylonitrile A6.

Intermediates A6A

From thioacetic acid S- [ (S) -3- (2-fluoro-5-nitro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyl]Ester starting, the product (R) -2-methyl-propane-2-sulfinic acid [ (S) -3-cyanomethylsulfanyl-1- (2-fluoro-5-nitro-phenyl) -1-methyl-propyl-is obtained as a yellow oil]-an amide. Ms (isp): 388.1[ M + H ] M/z]⁺。

Intermediates A6B

From thioacetic acid S- [ (S) -3- (2-fluoro-5-nitro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyl]Ester starting, the product (R) -2-methyl-propane-2-sulfinic acid [ (S) -3- (cyano-methyl-methylsulfanyl) -1- (2-fluoro-5-nitro-phenyl) -1-methyl-propyl-is obtained as a yellow oil]Amides, which are epimersAnd (3) mixing. Ms (isp): m/z 402.1[ M + H ]]⁺。

Synthesis of intermediate aminonitriles A7

General procedure

A solution of sulfamide nitrile (1g, 2.49mmol) in 20ml MeOH was treated with a 4M solution of hydrochloric acid in dioxane (1.56ml, 6.23mmol) at O ℃, and the reaction was stirred at 0 ℃ for 30 minutes until complete conversion to the desired product. The reaction mixture was diluted with ethyl acetate and extracted with 2M aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 502mg of aminonitrile a 7.

Intermediates A7A

From (R) -2-methyl-propane-2-sulfinic acid [ (S) -3-cyanomethylsulfanyl-1- (2-fluoro-5-nitro-phenyl) -1-methyl-propyl]Amide starting, obtaining the product [ (S) -3-amino-3- (2-fluoro-5-nitro-phenyl) -butylsulfanyl as a yellow oil]-acetonitrile. Ms (isp): 284.3[ M + H ] M/z]⁺。

Intermediates A7B

From (R) -2-methyl-propane-2-sulfinic acid [ (S) -3- (cyano-methyl-methylsulfanyl) -1- (2-fluoro-5-nitro-phenyl) -1-methyl-propyl]Amide starting, obtaining the product 2- [ (S) -3-amino-3- (2-fluoro-5-nitro-phenyl) -butylsulfanyl as a yellow oil]-propionitrile. Ms (isp): 298.0[ M + H ] M/z]⁺。

Synthesis of intermediates 1 ， 4- Sulfoazazepine A8

General procedure

To a solution of aminonitrile A6(0.715g, 2.51mmol) in 25ml of dry toluene at 0 ℃ was slowly added a 2.0M solution of trimethylaluminum in toluene (1.26ml, 2.51 mmol). The resulting reaction mixture was stirred at 0 ℃ for 30 minutes and finally at 60 ℃ for a period of two hours. The reaction mixture was carefully quenched by addition of water at 0 ℃ and stirred for a period of 15 minutes, and the precipitate formed was filtered through Celite (Celite). The filtrate was diluted with ethyl acetate, extracted with 2M aqueous sodium carbonate solution and the organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 575mg of a yellow oil. Yield: 81 percent of

Intermediates A8A

From [ (S) -3-amino-3- (2-fluoro-5-nitro-phenyl) -butylsulfanyl]Starting with acetonitrile, the product (S) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-2, 5, 6, 7-tetrahydro- [1, 4 ] is obtained as a yellow oil]Sulfoazazepine-3-amine. Ms (isp): 284.3[ M + H ] M/z]⁺。

Intermediates A8B

From 2- [ (S) -3-amino-3- (2-fluoro-5-nitro-phenyl) -butylsulfanyl]-propionitrile to obtain the product (S) -5- (2-fluoro-5) as a yellow oil-nitro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-amine. Ms (isp): 298.3[ M + H ] M/z]⁺。

Synthesis of intermediate Aniline A9

General procedure

To a solution of nitrobenzene A7(140mg, 0.47mmol) in 4.0ml EtOH was added SnCl₂·2H₂O (321mg, 1.42mmol) (precipitate formed immediately, which dissolved upon heating). The reaction was stirred at 80 ℃ for 1.5h and Si-NH by TLC₂(CH₂Cl₂/MeOH/NH₄OH 80: 18: 2), which shows complete conversion. The reaction mixture was poured into aqueous NaOH 1N solution, ethyl acetate was added, and the mixture was stirred for 10 minutes. The precipitate was filtered through celite and the two phases were separated in the filtrate. Through Na₂SO₄The organic phase was dried, filtered and evaporated until dryness. Using CH₂Cl₂And MeOH, and the residue was purified by chromatography on amine-modified silica to give pure aniline.

Intermediates A9A

From (S) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-2, 5, 6, 7-tetrahydro- [1, 4]SulfoazazepineStarting with-3-ylamine, the product (S) -5- (5-amino-2-fluoro-phenyl) -5-methyl-2, 5, 6, 7-tetrahydro- [1, 4 ] was obtained as a colorless oil]Sulfoazazepine-3-amine. Ms (isp): 254.3[ M + H ] M/z]⁺。

Intermediates A9B

From (S) -5- (2-fluoro-5-nitro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4]SulfoazazepineStarting with-3-ylamine, the product (S) -5- (5-amino-2-fluoro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4) is obtained as a colorless oil]Sulfoazazepine-3-amine. Ms (isp): 268.1[ M + H ] M/z]⁺。

Synthesis of intermediate amides A10

General procedure

To a solution of the acid (0.16mmol) in MeOH (1ml) at 22 ℃ was added 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methyl-morpholine hydrochloride (0.19mmol) and stirring continued at 0 ℃ for 30 min. To the mixture was added a solution of aniline a9(0.15mmol) in MeOH (2ml) and stirring was continued for 2 hours at 0 ℃. The mixture was saturated with Na₂CO₃The aqueous solution was diluted, MeOH evaporated and the aqueous solution extracted with ethyl acetate. The organic layer was dried, evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloromethane and 3% triethylamine in methanol.

Synthesis of intermediate amides A11

General procedure

Amide A10(0.05g, 0.133mmol) was treated with m-CPBA (0.065g, 0.266mmol) at 0 deg.C in 1.5mL anhydrous CH₂Cl₂And the resulting reaction mixture was stirred at room temperature for a period of 1 h. The reaction mixture was diluted with dichloromethane and extracted with 2M aqueous sodium carbonate. The organic layer was dried over sodium sulfate and evaporated until dry. The crude product was purified by silica gel chromatography using a mixture of dichloromethane and 3% triethylamine in methanol.

Synthesis of intermediate sulfenimide B2

General procedure

To a solution of (R) - (+) -tert-butylsulfinamide (66mmol) in THF (350ml) was then added ketone B1(72.6mmol) and titanium (IV) ethoxide (132mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 ℃, treated with brine (400ml), the suspension stirred for 10 minutes and filtered through a celite plug (dicalite). The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give pure sulfinimide B2.

Intermediates B2A

Starting from 1- (2-fluoro-phenyl) -ethaneone, the product (R) -2-methyl-propan-2-sulfinic acid [1- (2-fluoro-phenyl) -eth- (E) -ylidine) is obtained as a light brown oil]-an amide. Ms (isp): 242.2[ M + H ] M/z]⁺。

Synthesis of intermediate sulfonamides B3

General procedure (by Reformatsky reaction)

In a drying apparatus, a suspension of freshly activated zinc powder (1.63g, 24.9mmol) in dry THF (70ml) is heated to reflux under an inert atmosphere. A solution of sulfinimide B2(24.9mmol) and bromo-acetate (24.9mmol) in anhydrous THF (15ml) was added dropwise over a period of 15 minutes and the suspension was heated to reflux for 5 hours. The cooled mixture was placed in saturated NH₄Partitioned between aqueous Cl and ethyl acetate, the organic layer was dried and evaporated. The crude material was purified by flash chromatography using heptane/ethyl acetate to afford the sulfonamido ester B3.

Intermediates B3A

From (R) -2-methyl-propane-2-sulfinic acid [1- (2-fluoro-phenyl) -ethyl- (E) -ylidene]Amide starting, the product (S) -3- (2-fluoro-phenyl) - (R) -3- (2-methyl-propane-2-sulfonamido) -butyric acid tert-butyl ester is obtained as a light brown oil. Ms (isp): 358.1[ M + H ] M/z]⁺。

Synthesis of intermediate sulfonamides B4

General procedure

A solution of sulfinamide ester B3(12.7mmol) in dry THF (50ml) was treated with lithium borohydride (25.3mmol) at 0 deg.C and stirring continued for 4 h at 0 deg.C. The reaction mixture was quenched by the addition of acetic acid (2ml) and water (50ml), extracted with ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using a mixture of n-heptane and ethyl acetate to give pure intermediate sulfinamidol B4.

Intermediates B4A

Starting from (S) -3- (2-fluoro-phenyl) - (R) -3- (2-methyl-propan-2-sulfonamido) -butyric acid tert-butyl ester, the product (R) -2-methyl-propan-2-sulfinic acid [ (S) -1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl-butyric acid is obtained as a yellow oil]-an amide. Ms (isp): 288.2[ M + H ] M/z]⁺。

Synthesis of intermediate sulfinamide thioacetate B5

General procedure

A solution of triphenylphosphine (4.73g, 18.1mmol) in 50ml anhydrous DCM was treated with DCAD (6.63g, 18.1mmol) at 0 deg.C under argon, and the resulting reaction mixture was stirred at 0 deg.C for 20 min. To the above reaction mixture was added a solution of thioacetic acid (1.37mg, 18.1mmol) and alcohol B4(3.0g, 9.03mmol) in 10mL of anhydrous DCM. The reaction mixture was stirred at 0 ℃ for 20 minutes, warmed to room temperature and stirred at this temperature for 18 h. The white precipitate formed during the reaction was filtered off. The filtrate was diluted with more DCM and 1M Na₂CO₃Extracting with water solution. The organic layer was dried over sodium sulfate and evaporated until dry. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to yield 3.2g of sulfinamide thioacetate B5.

Intermediates B5A

From (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (2-fluoro-phenyl) -3-hydroxy-1-methyl-propyl]Amide starting, the product S- [ (S) -3- (2-fluoro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyl) is obtained as a yellow oil]And (3) an ester. Ms (isp): 346.2[ M + H ] M/z]⁺。

Synthesis of intermediate sulfenamide thiol B6

General procedure

A solution of sulfonamide thioacetate B5(1.25g, 3.62mmol) in 25ml MeOH was dissolved with K₂CO₃(600mg, 4.34mmol) and the reaction mixture stirred at room temperature for a period of one hour. The reaction mixture was diluted with ethyl acetate and extracted with saturated ammonium chloride solution. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 810mg of sulfamide thiol B6.

Intermediates B6A

From thioacetic acid S- [ (S) -3- (2-fluoro-phenyl) - (R) -3- (2-methyl-prop-2-sulfonamido) -butyl]Ester starting, the product (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (2-fluoro-phenyl) -3-mercapto-1-methyl-propyl ] was obtained as a yellow oil]-an amide. Ms (isp): 304.4[ M + H ] M/z]⁺。

Synthesis of intermediate sulfonamides B7

General procedure

Sulfenamide thiol B6(1.8g, 5.93mmol) in 30ml CH₃A solution in CN was treated with bromo ester (1.45g, 7.41mmol) and potassium carbonate (1.23g, 8.9mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with water, the organic layer was dried over sodium sulfate and evaporated until dry. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 1.68g of sulfinamide ester B7 as a colorless oil.

Intermediates B7A

From (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (2-fluoro-phenyl) -3-mercapto-1-methyl-propyl]Amide starting, obtaining the product (R) -2- [ (S) -3- (2-fluoro-phenyl) -3- (2-methyl-prop-2-sulfonamido) -butylsulfanyl as a yellow oil]-2-methyl-propionic acid ethyl ester. Ms (isp): 418.4[ M + H ] M/z]⁺。

Synthesis of intermediate amino esters B8

General procedure

A solution of sulfonamide ester B7(1.47g, 3.52mmol) in 15ml MeOH was treated with a 4M hydrochloric acid solution in dioxane (4.4ml, 17.6mmol) at 0 ℃. The reaction mixture was stirred at room temperature for a period of one hour. The reaction mixture was diluted with ethyl acetate and extracted with 2M aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated in vacuo until dry. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 1.05g of amino ester B8.

Intermediates B8A

From (R) -2- [ (S) -3- (2-fluoro-phenyl) -3- (2-methyl-prop-2-sulfonamido) -butylsulfanyl]Starting from ethyl-2-methyl-propionate, the product 2- [ (S) -3-amino-3- (2-fluoro-phenyl) -butylsulfanyl was obtained as a yellow oil]-2-methyl-propionic acid ethyl ester. Ms (isp): 314.3[ M + H ] M/z]⁺。

Synthesis of intermediate lactam B9

General procedure

A solution of amino ester B8(1.05g, 3.35mmol) in 20mL anhydrous THF at room temperature under argon was reacted with bis [ bis (trimethylsilyl) amino]Tin (II) (1.49ml, 3.85 mmol). The reaction mixture was stirred at 50 ℃ for three hoursTime, and the reaction medium is poured into a mixture of water and ethyl acetate, which is stirred for a period of 15 minutes. Passing the resulting mixture throughThe precipitate was removed by filtration, the organic layer was collected, dried over sodium sulfate and evaporated in vacuo until dry. The residue was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to give 480mg of lactam B9.

Intermediates B9A

From 2- [ (S) -3-amino-3- (2-fluoro-phenyl) -butylsulfanyl]Starting from ethyl 2-methyl-propionate, the product (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl- [1, 4) is obtained as a yellow oil]Sulfoazazepine-3-ketones. Ms (isp): 268.1[ M + H ] M/z]⁺。

Synthesis of intermediate sulfones B10

General procedure

Lactam B9(480mg, 1.8mmol) was treated with m-CPBA (929mg, 3.77mmol) in 15ml CH at room temperature₂Cl₂And the reaction mixture was stirred at room temperature for a period of 14 hours. The reaction mixture was diluted with dichloromethane and extracted with 2M aqueous sodium carbonate solution, the organic layer was dried over sodium sulfate and evaporated in vacuo until dry. The crude product was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to yield 525mg of sulfone B10.

Intermediates B10A

From (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl- [1, 4]SulfoazazepineStarting with-3-one, the product (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda⁶-[1，4]Sulfoazazepine-3-ketones. Ms (isp): m/z 300.1[ M + H ]]⁺。

Synthesis of intermediate thioamides B11

General procedure

A solution of sulfone B10(525mg, 1.75mmol) in 10ml of anhydrous THF was treated with Lawesson's reagent (922mg, 2.28mmol) at room temperature and the reaction mixture was stirred at 85 ℃ for a period of 2 hours. The reaction medium is diluted with ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate and evaporated in vacuo until dry. The crude product was purified by silica gel chromatography using a mixture of n-heptane and ethyl acetate to yield 415mg of thioamide B11.

Intermediates B11A

From (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.⁶-[1，4]SulfoazazepineStarting from-3-one, the product (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda. is obtained as a yellow oil⁶-[1，4]Sulfoazazepine-3-thione. Ms (isp): m/z 316.1[ M + H ]]⁺。

Synthesis of intermediates 1 ， 1- Dioxo (a) -[1 ， 4] Sulfoazazepine B12

General procedure

A solution of thioamide B11(415mg, 1.32mmol) in 5ml THF was treated with a solution of mercury (II) chloride (357mg, 1.32mmol) and 7N ammonia in MeOH (752. mu.L, 5.26 mmol). The reaction mixture was stirred in a microwave chamber at 120 ℃ for 30 minutes. The reaction medium was filtered over celite to remove mercury salts precipitated as a black powder, and the filtrate was diluted with ethyl acetate and extracted with 2M aqueous sodium carbonate. The organic layer was dried over sodium sulfate and evaporated in vacuo until dry. The crude product was purified by silica gel chromatography using a mixture of dichloromethane and methanol to give 1, 1-dioxo- [1, 4 ]]SulfoazazepineB12。

Intermediates B12A

From (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]SulfoazazepineStarting with-3-thione, the product (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine as a colorless oil. Ms (isp): 299.1[ M + H ] M/z]⁺。

Synthesis of intermediate Nitro B13

General procedure

Reacting 1, 1-dioxo- [1, 4 ]]SulfoazazepineB12(300mg, 1.01mmol) dissolved in 97% H₂SO₄In (sonication was necessary to dissolve completely, which once dissolved completely showed a strong dark red color) and the reaction mixture was cooled until 0 ℃, followed by the slow addition of 100% nitric acid (45 μ L, 1.01 mmol). The resulting reaction mixture was stirred at 0 ℃ for 15 minutes. The reaction medium is slowly poured into a mixture of ethyl acetate and water/ice and the resulting mixture is stirred for 10 minutes. The previous mixture was cooled until 0 ℃ and potassium carbonate was added until the pH reached 10-11. The phases were separated and the organic layer was dried over sodium sulfate and evaporated in vacuo until dry. The crude product was purified by silica gel chromatography using a mixture of dichloromethane and 10% triethylamine in methanol to give 185mg of nitro B13.

Intermediates B13A

From (S) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]SulfoazazepineStarting with-3-ylamine to obtain the product (S) -5- (2-fluoro-5-nitro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine as a colorless oil. Ms (isp): 344.1[ M + H ] M/z]⁺。

Synthesis of intermediate Aniline B14

General procedure

To a solution of nitrobenzene B13(140mg, 0.47mmol) in 4.0ml EtOH was added SnCl₂·2H₂O (321mg, 1.42mmol) (precipitate formed immediately, which dissolved upon heating). The reaction was stirred at 80 ℃ for 1.5h and Si-NH by TLC₂(CH₂Cl₂/MeOH/NH₄OH 80: 18: 2), which shows complete conversion. The reaction mixture was poured into aqueous NaOH 1N solution, ethyl acetate was added, and the mixture was stirred for 10 minutes. By passingThe precipitate was filtered and the two phases of the filtrate were separated. Through Na₂SO₄The organic phase was dried, filtered and evaporated until dryness. By CH₂Cl₂And MeOH, and the residue was purified by chromatography on amine-modified silica to give pure aniline B14.

Intermediates B14A

From (S) -5- (2-fluoro-5-nitro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]SulfoazazepineStarting with (3) -amine, the product (S) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine as a colorless oil. Ms (isp): 314.1[ M + H ] M/z]⁺。

Intermediates B14B

Reacting { (RS) -5- [5- (benzhydrylidene-amino) -2-fluoro-phenyl]-5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lamda.⁶-[1，4]Sulfoazazepine-3-yl } - [ bis- (4-methoxy-phenyl) -phenyl-methyl]A solution of the amine (207mg, 263. mu. mol) in dichloromethane (10ml) was treated with trifluoroacetic acid (1.01ml, 13.1 mmol). The orange solution was stirred at room temperature for 1 hour. To cleave the intermediate benzophenone imine, hydrochloric acid (1M, 2.63ml) and dioxane (10ml) were added. The mixture was stirred at 23 ℃ for 4 hours. For work-up, the reaction mixture was poured into aqueous sodium carbonate (1M) and subsequently extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a 110: 10: 1-mixture of dichloromethane, methanol and ammonium hydroxide as eluent. Obtaining (RS) -5- (5-amino-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (72mg, 85% yield) as a light brown foam. Ms (isp): 322.0[ M + H ] M/z]⁺。

Synthesis of intermediate amides B15

General procedure

To a solution of the acid (0.16mmol) in MeOH (1ml) at 22 deg.C was added 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methyl-morpholine hydrochloride (0.19mmol),and stirring was continued at 0 ℃ for 30 minutes. To the mixture was added a solution of aniline B15(0.15mmol) in MeOH (2ml) and stirring was continued for 2h at 0 ℃. The mixture was treated with saturated Na₂CO₃The aqueous solution was diluted, MeOH evaporated and the aqueous solution extracted with ethyl acetate. The organic layer was dried, evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloromethane and 3% triethylamine in methanol.

Intermediates C2A

Starting from 1- (5-bromo-2-fluorophenyl) -2, 2-difluoroethanone (WO 2011009943; CAS 1262858-97-8) in a similar manner as described for the preparation of A2A, the product (R) -2-methyl-propane-2-sulfinic acid [1- (5-bromo-2-fluoro-phenyl) -2, 2-difluoro-eth- (E) -yliden-ylidene) is obtained as a yellow oil]-an amide. Ms (ei): 298[ M-t-Bu + H ] M/z]⁺And 300[ M-t-Bu +2+ H]⁺。

Intermediates C3A

In a manner analogous to that described for preparation A3A, from (R) -2-methyl-propane-2-sulfinic acid [1- (5-bromo-2-fluoro-phenyl) -2, 2-difluoro-eth- (E) -ylidine]Amide starting, the product (S) -3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-3- ((R) -2-methyl-prop-2-sulfonamido) -butyric acid ethyl ester (containing 30% of the undesired (R) -diastereomer, which was removed by preparative Chiral HPLC on a Reprosil chiralnr column with 5% EtOH in n-heptane as eluent) was obtained as a colorless oil. Ms (isp): 444.0[ M + H ] M/z]⁺And 446.0[ M +2+ H ]]⁺。

Intermediates C4A

Starting from (S) -3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-3- ((R) -2-methyl-propane-2-sulfonamido) -butyric acid ethyl ester in a manner analogous to that described for preparation A4A, the product (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (5-bromo-2-fluoro-phenyl) -1-difluoromethyl-3-hydroxy-propyl-butyric acid was obtained as a colorless oil]-an amide. Ms (isn): 399.9[ M-H ] M/z]^-And 401.9[ M +2-H ]]^-。

Intermediates C5A

In a manner analogous to that described for preparation A5A, starting from (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (5-bromo-2-fluoro-phenyl) -1-difluoromethyl-3-hydroxy-propyl]Amide starting, the product thioacetic acid S- [ (S) -3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-3- ((R) -2-methyl-propan-2-sulfonamido) -butyl is obtained as a pale yellow oil]And (3) an ester. Ms (isp): 460.2[ M + H ] M/z]⁺And 462.1[ M +2+ H ]]⁺。

Intermediates C6A

In a manner analogous to that described for preparation A6A, starting from thioacetic acid S- [ (S) -3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-3- ((R) -2-methyl-prop-2-sulfonamido) -butyl]Ester starting, the product (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (5-bromo-2-fluoro-phenyl) -3-cyanomethylsulfanyl-1-difluoromethyl-propyl ] was obtained as a colorless oil]-an amide. Ms (isp): 454.9[ M + H ] M/z]⁺And 457.1[ M +2+ H]⁺。

Intermediates C7A

In a manner analogous to that described for preparation A7A, starting from (R) -2-methyl-propane-2-sulfinic acid [ (S) -1- (5-bromo-2-fluoro-phenyl) -3-cyanomethylsulfanyl-1-difluoromethyl-propyl]Amide starting, the product [ (S) -3-amino-3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-butylsulfanyl ] obtained as a colorless oil]-acetonitrile. Ms (isp): 352.9[ M + H ] M/z]⁺And 354.9[ M +2+ H]⁺。

Intermediates C8A

From [ (S) -3-amino-3- (5-bromo-2-fluoro-phenyl) -4, 4-difluoro-butylsulfanyl in a similar manner as described for the preparation of A8A]Starting from acetonitrile, the product (S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-2, 5, 6, 7-tetrahydro- [1, 4 ] is obtained as a pale yellow solid]Sulfoazazepine-3-amine. Ms (isp): 353.0[ M + H ] M/z]⁺And 355.0[ M +2+ H]⁺。

Intermediates C9A

(S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-2, 5, 6, 7-tetrahydro- [1, 4 ] was treated in two portions with potassium monopersulfate (Oxone) (1.27g, 2.06mmol) at 23 deg.C]Sulfoazazepine-solution of 3-ylamine (364mg, 1.03mmol) in methanol (20 ml). The white suspension was stirred at 23 ℃ for 5 hours. For post-treatmentThe reaction mixture was quenched with water (10ml) at 0 ℃ under vigorous stirring, followed by treatment of the reaction mixture with a dilute solution of sodium bisulfite, a saturated solution of sodium and with dichloromethane. Vigorous stirring was continued for 10 minutes. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to give a colorless oil. The crude product was purified by chromatography on silica gel using a gradient of dichloromethane and methanol from 100: 0 to 90: 10 as eluent. (S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (322mg, 81% yield). Ms (isp): 384.9[ M + H ] M/z]⁺And 386.9[ M +2+ H ═]⁺。

Intermediates C10A

(S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda. at 0 ℃ was treated with 4, 4' -dimethoxytrityl chloride (336mg, 991. mu. mol)⁶[1，4]Sulfoazazepine-a solution of 3-ylamine (318mg, 826. mu. mol) and triethylamine (167mg, 1.65mmol) in dichloromethane (15 ml). The green reaction mixture was stirred at room temperature for 6 hours. The reaction mixture is subsequently evaporated and the crude product is purified by chromatography on silica gel using a gradient of heptane and ethyl acetate from 100: 0 to 50: 50 as eluent. [ bis- (4-methoxy-phenyl) -phenyl-methyl ] was obtained as a gray foam]- [ (S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-yl]Amine (365mg, 63% yield). Ms (isp): 687.0[ M + H ] M/z]⁺And 689.3[ M +2+ H]⁺。

Intermediates C11A

[ bis- (4-methoxy-phenyl) -phenyl-methyl-phenyl ] was treated successively with sodium tert-butoxide (149mg, 1.55mmol), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (33mg, 77.7. mu. mol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (26.8mg, 26. mu. mol) and benzophenone imine (188mg, 1.04mmol) in a tube under an argon atmosphere]- [ (S) -5- (5-bromo-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-yl]A solution of amine (356mg, 518. mu. mol) in toluene (5 ml). The tube was sealed and the mixture was heated at 105 ℃ for 4 hours with stirring. For the work-up, the brown solution was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate from 100: 0 to 50: 50 as eluent. Obtaining { (S) -5- [5- (benzhydrylidene-amino) -2-fluoro-phenyl as a pale yellow foam]-5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lamda.⁶-[1，4]Sulfoazazepine-3-yl } - [ bis- (4-methoxy-phenyl) -phenyl-methyl]Amine (207mg, 51% yield). Ms (isn): 786.5[ M-H ] M/z]^-。

Intermediates D3

A solution of 2, 5-dihydrofuran (5g, 69.9mmol) in ether (90ml) was treated dropwise with a solution of nitroethane (5.46g, 71.3mmol) in ether (15ml) at room temperature. Subsequently, triethylamine (70.7mg, 699. mu. mol) was added, followed by dropwise addition of phenyl isocyanate (17.3g, 143 mmol). The reaction mixture was stirred at room temperature for 3 days. For the work-up, the white precipitate was filtered and washed with ether. The filtrate was evaporated and the crude product was purified by chromatography using a gradient of heptane and ethyl acetate from 100: 0 to 50: 50 as eluent. After the second chromatography, (3aS, 6aS) -rel-3-methyl-3 a, 4, 6, 6 a-tetrahydrofuro [3, 4-d ] isoxazole was obtained aS a yellow oil (58% yield).

Intermediates D5

A solution of 1-bromo-2-fluorobenzene (31.1g, 178mmol) in a mixture of toluene (750ml) and tetrahydrofuran (75ml) was cooled to-100 ℃. A solution of n-butyllithium (1.6M in hexane; 100ml, 160mmol) was added dropwise over a period of 10 minutes at such a rate that the temperature could be maintained between-95 and-102 ℃. After stirring at-100 ℃ for 10 minutes, (3aS, 6aS) -rel-3-methyl-3 a, 4, 6, 6 a-tetrahydrofuro [3, 4-d ] was added over 3-5 minutes]A mixture of isoxazole (11.3g, 88.9mmol) and boron trifluoride diethyl etherate (25.2g, 178mmol) in a mixture of toluene (75ml) and tetrahydrofuran (14ml) was maintained at a temperature below-94 ℃. The reaction mixture was stirred at-95 to-102 ℃ for an additional 10 minutes. For work-up, a saturated solution of ammonium chloride (60ml), water (100ml) and ethyl acetate (200ml) were added and the reaction mixture was warmed to 0 ℃. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography using a gradient of heptane and ethyl acetate 100: 0 to 0: 100 as eluent.(3S, 3aS, 6aS) -rel-3- (2-fluoro-phenyl) -3-methyl-hexahydro-furo [3, 4-d ] is obtained aS an off-white solid]Isoxazole (17g, 81% yield). Ms (isp): 224.1[ M + H ] M/z]⁺。

Intermediates D6

Reacting (3S, 3aS, 6aS) -rel-3- (2-fluoro-phenyl) -3-methyl-hexahydro-furo [3, 4-d]A solution of isoxazole (16.72g, 72.9mmol) in ethanol (300ml) was treated with ammonium formate (36.8g, 583mmol) and palladium (5% on carbon; 7.76 g). The reaction mixture was stirred at room temperature for 18 hours, followed by filtration, and the filtrate was evaporated under reduced pressure. The crude product was triturated with diisopropyl ether (50ml) and filtered. The filtrate was evaporated under reduced pressure and (3S, 4S) -4- [ (S) -rel-1-amino-1- (2-fluoro-phenyl) -ethyl was obtained as a thick colorless oil]Tetrahydro-furan-3-ol (8.69g, 48% yield). Ms (isp): 226.2[ M + H ] M/z]⁺. After filtration a solid material rel- (3S, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl is obtained]-tetrahydro-furan-3-ol formate (8.21g, 42% yield) was treated with a saturated solution of sodium bicarbonate (100ml) and with dichloromethane (100ml) and stirred for 1 hour. The aqueous layer was separated and extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate and evaporated. Obtaining additional amounts of rel- (3S, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl]Tetrahydro-furan-3-ol (5.6g, 31% yield) as a thick colorless oil. Ms (isp): 226.2[ M + H ] M/z]⁺。

Intermediates D7

Triethylamine (8.05g, 79.6mmol) was added to rel- (3S, 4S) -4- ((S) -1-amino-1- (2-fluorophenyl) ethyl) tetrahydrofuran-3-ol (5.6g, 24.9mmol) in dichloromethane (100 ℃)ml), followed by the addition of 4-dimethylaminopyridine (1.52g, 12.4mmol) and subsequently tert-butyldimethylsilyl chloride (7.49g, 49.7 mmol). The reaction mixture was stirred at room temperature overnight. For work-up, the reaction mixture was extracted with a saturated solution of sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0-50: 50 as eluent. Obtaining rel- (S) -1- [ (3S, 4S) -4- (tert-butyl-dimethyl-silanyloxy) -tetrahydro-furan-3-yl]-1- (2-fluoro-phenyl) -ethylamine (8.13g, 96% yield) as a colorless oil. Ms (isp): 340.1[ M + H ] M/z]⁺。

Intermediates D9

A solution of rel- (S) -1- [ (3S, 4S) -4- (tert-butyl-dimethyl-silanyloxy) -tetrahydro-furan-3-yl ] -1- (2-fluoro-phenyl) -ethylamine (8.13g, 23.9mmol) in 1, 2-dichloroethane (80ml) was treated under an argon atmosphere with 2, 4-dimethoxybenzaldehyde (3.98g, 23.9mmol), sodium triacetoxyborohydride (10.2g, 47.9mmol) and acetic acid (1.37ml, 23.9 mmol). The reaction mixture was stirred overnight. To complete the reaction, 2, 4-dimethoxybenzaldehyde (1.99g, 12.0mmol) and sodium triacetoxyborohydride (5.08g, 23.9mmol) were added and the mixture was stirred overnight. Subsequently, the reaction mixture was cooled to 0 ℃ and tetrabutylammonium fluoride trihydrate (7.56g, 23.9mmol) was added. The mixture was allowed to reach room temperature while stirring for 4 hours. To complete the reaction, tetrabutylammonium fluoride trihydrate (2.27g, 7.18mmol) was added again and stirring was continued for 4 days. For work-up, the reaction mixture was extracted twice with a mixture of saturated solution of sodium bicarbonate and dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. Using heptane and ethyl acetate 100: 0-50: a gradient of 50 was used as eluent and the residue was purified by flash chromatography on silica gel. Rel- (3S, 4S) -4- [ (S) -1- (2, 4-dimethoxy-benzylamino) -1- (2-fluoro-phenyl) -ethyl ] -tetrahydro-furan-3-ol (6.8g, 76% yield) was obtained as a colorless amorphous material.

Intermediates D10

Under an anhydrous argon atmosphere, rel- (3S, 4S) -4- [ (S) -1- (2, 4-dimethoxy-benzylamino) -1- (2-fluoro-phenyl) -ethyl]A solution of-tetrahydro-furan-3-ol (6.8g, 18.1mmol) in pyridine (7.32ml, 90.5mmol) and dichloromethane (120ml) was cooled to-77 ℃. The colorless solution was treated dropwise with thionyl chloride (2.15g, 18.1mmol) over about 10 minutes while the temperature was raised to-73 ℃. After removal of the cooling bath, the reaction mixture was allowed to reach room temperature. For work-up, the reaction mixture was diluted with dichloromethane (150ml) and washed successively with saturated solutions of hydrochloric acid (1N) and sodium hydrogencarbonate. The organic layer was dried over sodium sulfate and evaporated. To give (3aS, 7S, 7aS) -rel-6- (2, 4-dimethoxy-benzyl) -7- (2-fluoro-phenyl) -7-methyl-hexahydro-2, 4-dioxa-5-thia-6-aza-indene 5-oxide (7.24g, 95% yield). MS (ISP): (M/z 422.0M + H)]⁺。

Intermediates D11

A solution of (3aS, 7S, 7aS) -rel-6- (2, 4-dimethoxy-benzyl) -7- (2-fluoro-phenyl) -7-methyl-hexahydro-2, 4-dioxa-5-thia-6-aza-indene 5-oxide (7.24g, 17.2mmol) and sodium periodate (4.04g, 18.9mmol) in a mixture of ethyl acetate (60ml), acetonitrile (60ml) and cold water (99.6ml) was treated with ruthenium (III) chloride (35.6mg, 172. mu. mol). The reaction mixture was stirred for 30 minutes at 23 ℃. For work-up, the reaction mixture was extracted with a saturated solution of sodium bicarbonate, the aqueous layer was extracted again with ethyl acetate, and the combined organic layers were passed over sulfurThe sodium salt was dried and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0-0: 100 as eluent. To give (3aS, 7S, 7aS) -rel-6- (2, 4-dimethoxy-benzyl) -7- (2-fluoro-phenyl) -7-methyl-hexahydro-2, 4-dioxa-5-thia-6-aza-indene 5, 5-dioxide (4.1g, 55% yield) aS a light yellow solid. Ms (isp): 460.2[ M + Na ] M/z]⁺。

Intermediates D12

2-mercaptoacetonitrile (1.03g, 14.1mmol) was added dropwise to a solution of (3aS, 7S, 7aS) -rel-6- (2, 4-dimethoxy-benzyl) -7- (2-fluoro-phenyl) -7-methyl-hexahydro-2, 4-dioxa-5-thia-6-aza-indene 5, 5-dioxide (4.1g, 9.37mmol) and 1, 1, 3, 3-tetramethylguanidine (1.62g, 14.1mmol) in N, N-dimethylformamide (55ml) at room temperature. Subsequently, the reaction mixture was stirred at 60 ℃ for 12 hours. For the work-up, the solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (50 ml). After addition of sulfuric acid (20%; 50ml, 185mmol) and stirring overnight, the mixture was poured into a saturated solution of sodium bicarbonate followed by extraction with dichloromethane (2 ×). The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0-0: 100 as eluent. { rel- (3R, 4S) -4- [ (S) -1- (2, 4-dimethoxy-benzylamino) -1- (2-fluoro-phenyl) -ethyl-l-is obtained as a light brown oil]-tetrahydro-furan-3-ylsulfanyl } -acetonitrile (3.92g, 97% yield). Ms (isp): 431.2[ M + H ] M/z]⁺。

Intermediates D13

{ rel- (3R, 4S) -4- [ (S) -1- (2, 4-dimethoxy-benzylamino) -1- (2-fluoro-phenyl) -ethyl ] -was treated dropwise with trifluoroacetic anhydride (1.28g, 861. mu.l, 6.1mmol) at 0 ℃]-a solution of tetrahydro-furan-3-ylsulfanyl } -acetonitrile (1.75g, 4.06mmol) and triethylamine (1.13ml, 8.13mmol) in dichloromethane (8.75 ml). The reaction mixture was allowed to warm to room temperature and stirred overnight. For work-up, the reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. N- [ rel- (S) -1- ((3S, 4R) -4-cyanomethylsulfanyl-tetrahydro-furan-3-yl) -1- (2-fluoro-phenyl) -ethyl was obtained as a pale yellow foam]-N- (2, 4-dimethoxy-benzyl) -2, 2, 2-trifluoro-acetamide (1.65g, 77% yield). Ms (isp): 544.4[ M + NH ] M/z₄]⁺。

Intermediates D14

N- [ rel- (S) -1- ((3S, 4R) -4-cyanomethylsulfanyl-tetrahydro-furan-3-yl) -1- (2-fluoro-phenyl) -ethyl at room temperature]A solution of (E) -N- (2, 4-dimethoxy-benzyl) -2, 2, 2-trifluoro-acetamide (1.65g, 3.13mmol) in trifluoroacetic acid (14.5ml, 188mmol) was stirred overnight. The reaction mixture was extracted with a saturated solution of sodium bicarbonate and a mixture of ethyl acetate/tetrahydrofuran. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. Crude N- [ rel- (S) -1- ((3S, 4R) -4-cyanomethylsulfanyl-tetrahydro-furan-3-yl) -1- (2-fluoro-phenyl) -ethyl was obtained as a white solid]-2, 2, 2-trifluoro-acetamide, which is used in the subsequent step without further purification. Ms (isp): m/z 375.3[ M + H ]]⁺。

Intermediates D15

Crude N- [ rel- (S) -1- ((3S, 4R) -4-cyanomethylsulfanyl-tetrahydro-furan-3-yl) -1- (2-fluoro-phenyl) -ethyl at 0 DEG C]A solution of-2, 2, 2-trifluoro-acetamide (2g, 3.19mmol) in ethanol was reacted with sodium borohydride (482mg, 12.8 mmol). The reaction was allowed to warm to room temperature and stirred overnight. For work-up, the reaction mixture was extracted with a mixture of saturated solution of sodium bicarbonate and ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate 100: 0-0: 100 as eluent. Obtaining { rel- (3R, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl as a pale yellow oil]-tetrahydro-furan-3-ylsulfanyl } -acetonitrile (510mg, 57% yield). Ms (isp): m/z 281.0[ M + H ]]⁺。

Intermediates D16

At room temperature, { rel- (3R, 4S) -4- [ (S) -1-amino-1- (2-fluoro-phenyl) -ethyl]A solution of-tetrahydro-furan-3-ylsulfanyl } -acetonitrile (460mg, 1.64mmol) in toluene (6ml) was treated dropwise with trimethylaluminum (902. mu.l, 1.8 mmol). Subsequently, the reaction mixture was stirred at 60 ℃ for 2 hours and extracted with a mixture of a saturated solution of sodium hydrogencarbonate and ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using a mixture of ethyl acetate, methanol, ammonium hydroxide 100: 10: 1 as eluent. (3aR, 8S, 8aS) -rel-8- (2-fluoro-phenyl) -8-methyl-1, 3, 3a, 5, 8, 8 a-hexahydro-2-oxa-4-thia-7-aza-azulen-6-ylamine (200mg, 43% yield) was obtained aS a pale yellow oil. Ms (isp): m/z 281.0[ M + H ]]⁺。

Intermediates D17

3-Chloroperbenzoic acid (251mg, 1.02mmol) was added to a solution of (3aR, 8S, 8aS) -rel-8- (2-fluoro-phenyl) -8-methyl-1, 3, 3a, 5, 8, 8 a-hexahydro-2-oxa-4-thia-7-aza-azulen-6-ylamine (130mg, 464. mu. mol) in dichloromethane (20ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours, followed by extraction with a mixture of saturated solution of sodium bicarbonate and ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. (3aR, 8S, 8aS) -rel-8- (2-fluoro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda. aS a light brown solid was obtained⁶-thia-7-aza-azulen-6-ylamine (110mg, 76% yield). Ms (isp): m/z 281.0[ M + H ]]⁺。

Intermediates D18

Reacting (3aR, 8S, 8aS) -rel-8- (2-fluoro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda.⁶A solution of-thia-7-aza-azulen-6-ylamine (110mg, 176. mu. mol) in trifluoroacetic acid (1.33g, 11.7mmol) was cooled to 0-5 ℃. Sulfuric acid (149mg, 81.2. mu.l, 1.52mmol) was added slowly, followed by nitric acid (12.1mg, 8.01. mu.l, 192. mu. mol). The reaction mixture was stirred at 0 ℃ for 1 hour. To complete the reaction, an additional equivalent of nitric acid (12.1mg, 8.01. mu.l, 192. mu. mol) was added and stirring continued at 0 ℃ for 2 hours. For work-up, ice water was added to the reaction mixture and the resulting suspension was set to pH-12 by addition of sodium hydroxide solution (32%). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and evaporated. Crude (3aR, 8S, 8aS) -rel-8- (2-fluoro-5-nitro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda⁶-thia-7-azaAzulen-6-ylamine, which is used in the next step without purification. Ms (isp): 358.3[ M + H ] M/z]⁺。

Intermediates D19

Crude (3aR, 8S, 8aS) -rel-8- (2-fluoro-5-nitro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda. -4. mu.m.⁶-thia-7-aza-azulen-6-ylamine (73mg, 204. mu. mol) was hydrogenated. After 3 hours, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. To complete the reaction, the residue was hydrogenated in a mixture of ethanol (5ml) and tetrahydrofuran (5ml) under the aforementioned conditions over the course of 20 hours. Subsequently, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. Crude (3aR, 8S, 8aS) -rel-8- (5-amino-2-fluoro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda.⁶-thia-7-aza-azulen-6-ylamine (70mg), which was used in the next step without further purification. Ms (isp): 328.3[ M + H ] M/z]⁺。

Example 1

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

Using the method for the synthesis of amide A9, starting from (S) -5- (5-amino-2-fluoro-phenyl) -5-methyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-ylamine (intermediate A8A) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 393.3[ (M + H) M/z⁺]。

Example 2

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 1 from (S) -5- (5-amino-2-fluoro-phenyl) -5-methyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-ylamine (intermediate A8A) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): m/z 377.1[ (M + H)⁺]。

Example 3

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

Using the method of synthesizing sulfone A10, from 5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides preparing said compounds. The title compound was obtained as a white solid. Ms (isp): 425.1[ (M + H) M/z⁺]。

Example 4

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner as described in example 3 from 5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides preparing said compounds. The title compound was obtained as a white solid. Ms (isp): 409.1[ (M + H) where M/z is equal to⁺]。

Example 5

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 1 from (S) -5- (5-amino-2-fluoro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-ylamine (intermediate A8B) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 391.1[ (M + H) with M/z⁺]。

Example 6

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4%]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 1 from (S) -5- (5-amino-2-fluoro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-ylamine (intermediate A8B) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 407.0[ (M + H) where M/z is equal to⁺]。

Example 7

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner as described in example 3 from 5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides preparing said compounds. The title compound was obtained as a white solid. Ms (isp): 423.0[ (M + H) where M/z is equal to⁺]。

Example 8

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner as described in example 3 from 5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4 ]]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides preparing said compounds. The title compound was obtained as a white solid. Ms (isp): 439.1[ (M + H) where M/z is equal to⁺]。

Example 9

4-chloro-2H-pyrazole-3-carboxylic acid [3- ((S) -3-amino-2, 5-dimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 3 from (S) -5- (5-amino-2-fluoro-phenyl) -2, 5-dimethyl-2, 5, 6, 7-tetrahydro- [1, 4]Sulfoazazepine-3-ylamine (intermediate A9B) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 428.0[ (M + H) where M/z is equal to⁺]。

Example 10

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

Using the method for the synthesis of amide B15, starting from (S) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (intermediate B14) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 437.1[ (M + H) where M/z is equal to⁺]。

Example 11

4-chloro-2H-pyrazole-3-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 10 from (S) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (intermediate B14) to prepare the compound. The title compound was obtained as a white solid. Ms (isp): 442.4[ (M + H)⁺]。

Example 12

5-cyano-pyridine-2-carboxylic acid [3- ((S) -3-amino-2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 10 from (S) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (intermediate B14) to prepare the compound. The title compound was obtained as a pale yellow oil. Ms (isp): 444.3[ (M + H) where M/z is equal to⁺]。

Example 13

5-cyano-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-amides of

In a similar manner to that described in example 10 from (S) -5- (5-amino-2-fluoro-phenyl) -5-difluoromethyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-3-ylamine (intermediate B14B) to prepare the compound. The title compound was obtained as an off-white solid. Ms (isp): 452.0[ (M + H) where M/z is equal to⁺]。

Example 14

5-cyano-pyridine-2-carboxylic acid [3- ((3aR, 8S, 8aS) -rel-6-amino-8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda. (Lambda)⁶-thia-7-aza-azulen-8-yl) -4-fluoro-phenyl]-amides of

A solution of 5-cyanopyridine-2-carboxylic acid (15.8mg, 107. mu. mol) in methanol (1ml) was cooled to 0 ℃. After addition of 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methyl-morpholine hydrochloride (29.6mg, 107. mu. mol), the mixture was stirred at 0 ℃ for 30 minutes. Adding crude (3aR, 8S, 8aS) -rel-8- (5-amino-2-fluoro-phenyl) -8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda.⁶-thia-7-aza-azulen-6-ylamine (70mg, 107 μmol) and mixingThe mixture was warmed to room temperature. After stirring for 21 hours, the light brown solution was decanted from the viscous solid formed and evaporated under reduced pressure. The remaining amorphous material was purified by preparative HPLC using a gradient of water and methanol from 95: 5 to 0: 100 (+ 0.05% formic acid) as eluent. 5-cyano-pyridine-2-carboxylic acid [3- ((3aR, 8S, 8aS) -rel-6-amino-8-methyl-4, 4-dioxo-3, 3a, 4, 5, 8, 8 a-hexahydro-1H-2-oxa-4. lamda. -is obtained aS a light brown amorphous substance⁶-thia-7-aza-azulen-8-yl) -4-fluoro-phenyl]-amide (17 mg). Ms (isp): 458.4[ (M + H) where M/z is equal to⁺]。

Claims

1. A compound of the formula I' a,

wherein

R¹Is F;

R²is Me;

R³selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁴selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁵selected from:

i) a chloro-pyridyl group,

ii) fluoro-pyridyl, and

iii) 2H-pyrazolyl;

x is selected from the group consisting of:

i) -S, and

ii)-SO₂；

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R³Is C_1-6-an alkyl group.

3. The compound of any one of claims 1-2, wherein R³Is Me.

4. The compound of any one of claims 1-2, wherein R⁴Is C_1-6-an alkyl group.

5. The compound of any one of claims 1-2, wherein R⁴Is Me.

6. The compound of any one of claims 1-2, wherein R⁴Is hydrogen.

7. The compound of any one of claims 1-2, wherein R⁵Is 5-chloro-pyridin-2-yl or 5-fluoro-pyridin-2-yl.

8. The compound of any one of claims 1-2, wherein X is-S.

9. The compound of any one of claims 1-2, wherein X is-SO₂。

10. A compound selected from the group consisting of:

5-chloro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulphur nitrogenHetero compound-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

or a pharmaceutically acceptable salt thereof.

11. A compound selected from the group consisting of:

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-2, 5, 6, 7-tetrahydro-2-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide of the formula (I),

or a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of:

5-fluoro-pyridine-2-carboxylic acid [3- ((S) -3-amino-5-methyl-1, 1-dioxo-2, 5, 6, 7-tetrahydro-1H-1. lambda⁶-[1，4]Sulfoazazepine-5-yl) -4-fluoro-phenyl]-an amide.

13. A process for the preparation of a compound as defined in any one of claims 1 to 9, which process comprises reacting a compound of formula a9 to a compound of formula a 10:

optionally, the compound of formula A10 may be further reacted with a peroxide to a compound of formula A11,

wherein R is¹、R²、R³、R⁴、R⁵As defined in any one of claims 1 to 9.

14. A pharmaceutical composition comprising a compound according to any one of claims 1-12 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

15. Use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease or diabetes.

16. Use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of type 2 diabetes.