HK1201261B

HK1201261B - 5-amino[1,4]thiazines as bace 1 inhibitors

Info

Publication number: HK1201261B
Application number: HK15101737.9A
Authority: HK
Inventors: 汉斯．希尔珀特; 托马斯．沃尔特林
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2012-05-24
Filing date: 2013-05-21
Publication date: 2018-07-13

Description

5-amino [1, 4] thiazines as BACE1 inhibitors

Background

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

AD is characterized by 2 major pathological features in the Central Nervous System (CNS): the appearance of amyloid plaques and neurofibrillary tangles (Hardy et al, The amyloid hypothesiosis of Alzheimer's disease: progression and schemes on The road to therapeutics, Science 2002Jul 19; 297(5580) 353-6, Selkoe, Cell biology of The amyloid β -protein precursor and The mechanism of Alzheimer's disease, Annu Rev Cell biol. 1994; 10: 373. 403). Both pathological features are also commonly found in patients with down syndrome (trisomy 21), which also exhibit AD-like symptoms at an early stage. Neurofibrillary tangles are intracellular aggregates of microtubule-associated protein tau (MAPT). Amyloid plaques occur in the extracellular space; their main component is the a β -peptide. The latter is a group of proteolytic fragments derived from the β -Amyloid Precursor Protein (APP) via a series of proteolytic cleavage steps. Several forms of APP have been identified, the largest of which are proteins of 695, 751 and 770 amino acids in length. They are all produced from one gene via differential splicing. The A β -peptides are derived from the same domain as APP but differ at their N-and C-termini, with the main species being 40 and 42 amino acid long species. There are several chains of evidence that strongly suggest that aggregated a β -peptide is an essential molecule in the pathogenesis of AD: 1) amyloid plaques formed by a β -peptide are an invariant part of AD pathology; 2) a β -peptide is toxic to neurons; 3) in Familial Alzheimer's Disease (FAD), mutations in the causative genes APP, PSN1, PSN2 result in increased levels of a β -peptide and early cerebral amyloidosis; 4) transgenic mice expressing this FAD gene exhibit pathology with many similarities to human disease. A β -peptide is produced by APP through the sequential action of 2 proteolytic enzymes named β -and γ -secretases. The β -secretase enzyme first cleaves the extracellular domain of APP of approximately 28 amino acids outside the transmembrane domain (TM) to generate a C-terminal fragment of APP containing the TM-and cytoplasmic domains (CTF β). CTF β is a substrate for γ -secretase, which cleaves at several adjacent positions within the TM to produce a β peptide and cytoplasmic fragments. Gamma-secretase is a complex of at least 4 different proteins whose catalytic subunits closely resemble presenilin proteins (PSEN1, PSEN 2). Beta-secretase (BACE1, Asp 2; BACE stands for Beta-site APP-cleaving enzyme) is an aspartyl protease anchored in the membrane via a transmembrane domain (Vassar et al, Beta-secretase cleavage of Alzheimer's amyloid polypeptide by the transmembrane enzymatic protein, Science 1999Oct 22; 286 (5440): 735). It is expressed in many tissues of the human body, but its levels are particularly high in the CNS. The gene defect of the BACE1 gene in Mice clearly shows that its activity is important in APP processing leading to the production of A β -peptide, without the BACE1 (Luo et al, Mice discovery in BACE1, the Alzheimer's beta-secretase, ha normal genotype and extracted beta-amyloid division, Nat neurosci.2001 Mar; 4 (3): 231-2, robers et al, BACE knockdown micro enzyme affinity deletion in the majority of beta-amyloid peptides for Alzheimer's disease therapeutics, m Hull genetic et al (human molecular genetics) 2001; 10-24) 1317). Mice that have been genetically engineered to express the human APP gene and develop extensive amyloid plaques and Alzheimer's disease pathology during aging no longer exhibit this when β -secretase activity is reduced by genetic disruption of one of the BACE1 alleles (McConlogue et al, Partial reduction of BACElhas draft effects on Alzheimer's disease and synthetic pathology in Apperrans genetic Mice.J Biol Chem. (J. Biol. Chem.) 2007 Sep 7; 282 (36): 26326). It is therefore speculated that inhibitors of BACE1 activity may be agents useful in the therapeutic intervention of Alzheimer's Disease (AD).

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

WO2012139425 describes iminothiazine compounds and monoxides and dioxides as BACE1 inhibitors. WO2011020806 describes 3-amino-5-phenyl-5, 6-dihydro-2H- [1, 4]Azines act as BACE1 inhibitors. WO2011069934 describes 2-amino-5, 5-difluoro-5, 6-dihydro-4H- [1, 3]Oxazin-4-yl) -phenyl]Amides as BACE1 inhibitors. WO2011029803 describes the use of aminodihydrothiazine derivatives for the treatment or prevention of metabolic diseases, such as preferably diabetes, especially type 2 diabetes. The compounds are BACE2 inhibitors.

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 illnesses such as alzheimer's disease. The novel compounds of formula I have improved pharmacological properties.

Technical Field

The present invention provides 5-amino- [1, 4] thiazines having BACE1 inhibitory properties, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

Disclosure of Invention

The present invention provides a compound of formula I,

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

The compounds of the present invention have Asp2(β -secretase, BACE1 or endo-APP (Memapsin-2) inhibitory activity and may therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, especially alzheimer's disease.

Detailed Description

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

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

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

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

The term "halogen-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl substituted with one or more halogens, in particular 1-5 halogens, more in particular 1-3 halogens. A particular halogen is fluorine. Particular "halogen-C_1-6-alkyl "is fluoro-C_1-6Alkyl and especially "halogen-C_1-3-alkyl "is fluoro-C_1-3-an alkyl group. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and the like. In particularThe group is difluoromethyl.

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

The term "C_1-6-alkoxy-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl, which is substituted by one or more C as defined herein_1-6Alkoxy, especially 1C_1-6-alkoxy substitution. In particular "C_1-6-alkoxy-C_1-6-alkyl "is methoxy-C_1-6-an alkyl group. Examples are methoxymethyl, methoxyethyl, and the like.

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

The term "halogen", alone or in combination with other groups, denotes chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). Particular "halogens" are Cl and F. A particular group is F.

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

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

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

The term "C_2-6-alkynyl-C_1-6-alkoxy ", alone or in combination with other groups, means C as defined herein_1-6-alkoxy, which is substituted by one or more C as defined herein_2-6Alkynyl, especially 1C_2-6-alkynyl substitution.

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

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

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. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid.

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

The term "pharmaceutical composition" includes a product comprising the specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. In particular, it comprises: a product comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

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

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

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

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

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

The term "protecting group" means a group that, in the meaning conventionally associated therewith in synthetic chemistry, selectively blocks one reactive site in a polyfunctional compound such that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group may be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" (also referred to herein as P)¹) Denotes a group intended to protect an amino group, and includes benzylBenzyloxycarbonyl (benzyloxyformyl, 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", 4 th edition, John Wiley&Sons, inc., New York, NY, 2007, chapter 7; haslam, "Protective Groups in Organic Chemistry", edited by J.G.W.McOmie, Plenum Press, New York, NY, 1973, Chapter 5, and T.W.Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with an amino-protecting group, particularly the amino-protecting groups are t-butyloxycarbonyl and dimethoxytrityl.

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

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

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

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

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

All individual embodiments may be combined.

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

wherein

R¹Selected from the group consisting of:

i) an aryl group, a heteroaryl group,

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

iii) heteroaryl, and

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

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halogen;

R³selected from the group consisting of:

i)C_1-6-alkyl, and

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

R⁴selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

R⁵selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

or R⁴And R⁵Together form C_3-7-a cycloalkyl ring, optionally substituted with one or more halogens,

x is a number of 0 or 2,

or a pharmaceutically acceptable salt thereof.

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

wherein

R¹Selected from the group consisting of:

i) an aryl group, a heteroaryl group,

iii) heteroaryl, and

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halogen;

R³selected from the group consisting of:

i)C_1-6-alkyl, and

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

R⁴selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

R⁵selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

x is a number of 0 or 2,

or a pharmaceutically acceptable salt thereof.

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

wherein

R¹Selected from the group consisting of:

i) pyridyl substituted with one substituent selected from cyano, halogen and halogen-C_1-6-alkoxy, and

ii) pyrazinyl substituted with one substituent selected from C_1-6Alkoxy and halogen-C_1-6-an alkyl group;

R²is a halogen, and the halogen is a halogen,

R³is C_1-6-an alkyl group,

R⁴selected from the group consisting of:

i)C_1-6-alkyl, and

ii) hydrogen, in the presence of hydrogen,

R⁵selected from the group consisting of:

i)C_1-6-alkyl, and

ii) hydrogen, in the presence of hydrogen,

or R⁴And R⁵Together form C_3-7-a cycloalkyl ring,

x is a number of x being 2,

or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is²Is a halogen.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is²Is F.

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

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is³Is methyl.

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

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴Is methyl.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴Is hydrogen.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁵Is halogen-C_1-6-an alkyl group.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁵Is C_1-6-an alkyl group.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁵Is methyl.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁵Is hydrogen.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Is hydrogen.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Is C_1-6-an alkyl group.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Is methyl.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together form C_3-7-a cycloalkyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together form C substituted by more than one halogen_3-7-a cycloalkyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together form C substituted by one halogen_3-7-a cycloalkyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together forming a cyclobutyl or cyclopentyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together forming a cyclobutyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is⁴And R⁵Together forming a cyclopentyl ring.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is¹Is heteroaryl substituted with one substituent independently selected from cyano, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy and C_1-6-alkoxy groups.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is¹Is pyridyl or pyrazinyl, each substituted with one substituent independently selected from cyano, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy and C_1-6-alkoxy groups.

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is¹Is cyano-pyridyl, chloro-pyridyl, difluoromethoxy-pyridyl, methoxy-pyrazinyl or difluoromethyl-pyrazinyl (pyrazinl).

In one embodiment of the invention, there are provided compounds of formula I as described herein, wherein R is¹Is 5-cyano-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-difluoromethoxy-pyridin-2-yl, 5-methoxy-pyrazin-2-yl or 5-difluoromethyl-pyrazin-2-yl.

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

A certain embodiment of the invention provides a compound of formula I as described herein, wherein x is 0.

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

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

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

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

5-cyano group-pyridine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lambda⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-methoxy-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda. -)⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-difluoromethyl-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda. (R))⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide of the formula (I),

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

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

5-cyano-pyridine-2-carboxylic acid [3- ((R) -9-amino-7-methyl-5, 5-dioxo-5. lamda.)⁶-thia-8-aza-spiro [3.5]Non-8-en-7-yl) -4-fluoro-phenyl]-an amide of the formula (I),

5-chloro-pyridine-2-carboxylic acid [3- ((R) -9-amino-7-methyl-5, 5-dioxo-5. lamda.)⁶-thia-8-aza-spiro [3.5]Non-8-en-7-yl) -4-fluoro-phenyl]-amides, and

5-cyano-pyridine-2-carboxylic acid [3- ((R) -10-amino-8-methyl-6, 6-dioxo-6. lamda.)⁶-thia-9-aza-spiro [4.5]]Dec-9-en-8-yl) -4-fluoro-phenyl]-an amide of the formula (I),

or a pharmaceutically acceptable salt thereof.

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

One embodiment of the present invention provides a compound of formula I as described herein,it is 5-difluoromethoxy-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lambda⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-chloro-pyridine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-cyano-pyridine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-methoxy-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-difluoromethyl-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-cyano-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide.

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

In a certain embodiment of the invention there is provided a compound of formula I as described herein, which is 5-cyano-pyridine-2-carboxylic acid [3 ]- ((R) -9-amino-7-methyl-5, 5-dioxo-5. lamda.)⁶-thia-8-aza-spiro [3.5]Non-8-en-7-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-chloro-pyridine-2-carboxylic acid [3- ((R) -9-amino-7-methyl-5, 5-dioxo-5. lamda.)⁶-thia-8-aza-spiro [3.5]Non-8-en-7-yl) -4-fluoro-phenyl]-an amide.

A certain embodiment of the invention provides a compound of formula I as described herein, which is 5-cyano-pyridine-2-carboxylic acid [3- ((R) -10-amino-8-methyl-6, 6-dioxo-6. lamda. -)⁶-thia-9-aza-spiro [4.5]]Dec-9-en-8-yl) -4-fluoro-phenyl]-an amide.

A process for the preparation of a compound of formula I as described herein, said process comprising: reacting a compound of formula XI with a compound of formula XII to form a compound of formula I.

Wherein x and R¹、R²、R³、R⁴And R⁵As defined herein.

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

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

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

A certain embodiment of the present invention provides compounds of formula I as described herein for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, or alzheimer's disease.

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

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

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

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

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

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

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

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

A certain embodiment of the present invention provides a method for the inhibition of BACE1 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 or alzheimer's disease, which method comprises administering a compound of formula I as described herein to a human being or animal.

A certain embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, 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 of the compounds of formula I, i.e. diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers, and solvates thereof.

One skilled in the art will recognize that the compounds of formula I may exist in tautomeric forms of the formula

All tautomeric forms are included in the invention.

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

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

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

The compounds of formula I can be prepared by a variety of synthetic routes, for example as described in schemes 1-5. The preparation of the compounds of formula I according to the invention can be carried out in a continuous or convergent synthetic route. The synthesis of the compounds of the present invention is shown in schemes 1-4 below. The skills for carrying out the reaction and purifying the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and symbols used in the following description have the meanings given herein before.

In more detail, 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. The reaction sequence is not limited to the sequence shown in the scheme described below, but the order of the reaction steps may be freely changed depending on the raw materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those given below, by methods described in the references cited in the specification, or by methods known in the art.

The compounds of formula I depicted in schemes 1-5 can be isolated by methods known to those skilled in the art, such as, but not limited to, ion exchange chromatography, solid phase extraction, liquid-liquid extraction, silica chromatography, crystallization, and preparative HPLC.

In more detail, the compounds of formula I according to the invention can be prepared by the methods and procedures given below. Some typical procedures for the preparation of compounds of formula I are described in schemes 1-5.

Scheme 1: synthesis of intermediate aminothiazine A15

Non-commercial ketones of the general formula A3 can be prepared byOr by other routes known to those skilled in the art. The Weinreb amides of formula a2 can be obtained by standard condensation reactions of acids of formula a1 with N, O-dimethylhydroxylamine or by intermediate formation of acid chlorides of formula a1 using reagents such as oxalyl chloride or thionyl chloride using standard conditions such as triethylamine/dichloromethane. The amide of formula A2 may be reacted with an organometallic such as methylmagnesium bromide (for R) in an inert aprotic solvent such as tetrahydrofuran or diethyl ether³Me) to yield the desired ketone of formula a 3.

According to scheme 1, ketones of general formula A3 (wherein Y has the meaning of a leaving group, such as halogen, e.g. bromide ion) can be reacted with a cyanide compound, such as potassium cyanide, together with ammonium carbonate in a polar solvent, such as an alcohol, e.g. ethanol, water or tetrahydrofuran, and mixtures thereof, to form an acetolactam of formula a 4. The acetolactam can then be treated with water and a base such as sodium hydroxide or a strong acid such as sulfuric acid at a temperature ranging from ambient temperature to reflux to yield the amino acid of formula a 5. The amino alcohol of formula a7 is obtained by esterification of an acid of formula a5 with a lower alcohol such as methanol or ethanol, followed by reduction of the resulting amino ester of formula a6 with lithium aluminum hydride or other suitable reagent, both steps being carried out under conditions known to those skilled in the art.

The aminoalcohol of formula a7 may be selectively aminated to the N-benzylated aminoalcohol of formula A8 by: with an aldehyde, in particular p-methoxybenzaldehyde (R ═ H) or 2, 4-dimethoxybenzaldehyde (R ═ OMe), using a reducing agent, in particular sodium cyanoborohydride or sodium triacetoxyborohydride, in a chlorinated solvent, in particular 1, 2-dichloroethane or dichloromethane, in the presence of a weak organic acid, in particular acetic acid, at from 0 ℃ to 60 ℃, in particular 23 ℃.

The lambda-benzylated aminoalcohol of formula A8 may be reacted with thionyl chloride in the presence of an amine base, particularly pyridine, in a chlorinated solvent, particularly dichloromethane, starting at a low temperature, such as-78 deg.C, and warming to 0 deg.C or ambient temperature to form a cyclic sulfamate (sulfamide) of formula A9.

The cyclic aminosulfinate of the formula a9 can be oxidized to the cyclic sulfamate of the formula a10 (sulfamidate) by a periodate base such as sodium or potassium periodate in the presence of a ruthenium salt such as ruthenium (III) chloride in a solvent mixture consisting of water, acetonitrile and ethyl acetate or tetrachloromethane at a temperature between 0 ℃ and 50 ℃, in particular at 23 ℃.

The cyclic sulfamate of formula a10 can be regioselectively opened with a sulfur nucleophile such as mercaptoacetonitrile and subsequently hydrolyzed under acidic conditions to the N-benzylated aminonitrile of formula a 11. The ring opening is carried out in the presence of an aminic 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 ℃, in particular at 60 ℃. After removal of all volatiles from the ring opening step by evaporation in vacuo, the crude reaction mixture is subjected to acidic hydrolysis in a mixture of a mineral acid, especially 20% aqueous sulfuric acid, and a solvent such as diethyl ether or dichloromethane at a temperature between 0 ℃ and 50 ℃, especially at 23 ℃.

Deprotecting the N-benzylated aminonitrile of formula A11 in a three-step process to an aminonitrile of formula A14: first, the N-benzylated aminonitrile of formula a11 is reacted with an organic acid anhydride, in particular trifluoroacetic anhydride, in the presence of an amine base, in particular triethylamine or diisopropylethylamine, in a chlorinated solvent such as dichloromethane at a temperature between 0 ℃ and 40 ℃, in particular at 23 ℃, to give the N-benzylated N-trifluoroacetylated aminonitrile of formula a 12. Second, the N-benzylated N-trifluoroacetylated aminonitrile of the formula A12 is debenzylated by reaction with a strong organic acid, in particular trifluoromethanesulfonic acid, in trifluoroacetic acid at a temperature of between 0 ℃ and 50 ℃ and in particular at 23 ℃ to give an N-trifluoroacetylated aminonitrile of the formula A13. Thirdly, the N-trifluoroacetylated aminonitrile of formula a13 is deacylated 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 ℃, in particular at 23 ℃, to the aminonitrile of formula a 14.

The aminonitrile of formula a14 can be cyclized to the aminothiazine of formula a15 in an inert solvent, especially toluene, using a lewis acid such as trimethylaluminum at a temperature of from 23 ℃ to 100 ℃, especially 60 ℃.

Scheme 2: synthesis of Compounds of formula I

The cyclic sulfamate of formula a10 can be regioselectively opened with a sulfur nucleophile such as mercaptoacetate and subsequently hydrolyzed under acidic conditions to the N-benzylated amino ester of formula a 16. The ring opening is carried out in the presence of an aminic 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 ℃, in particular at 60 ℃. After removal of all volatiles from the ring opening step by evaporation in vacuo, the crude reaction mixture is subjected to acidic hydrolysis in a mixture of a mineral acid, especially 20% aqueous sulfuric acid, and a solvent such as diethyl ether or dichloromethane at a temperature between 0 ℃ and 50 ℃, especially at 23 ℃.

The N-benzylated amino ester of formula a16 can be saponified to the N-benzylated amino acid of formula a17 by treatment with an alkali hydroxide such as lithium, sodium or potassium hydroxide in an aqueous alcoholic solvent such as, for example, methanol or ethanol at a temperature between 23 and 100 ℃.

The N-benzylated amino acid of formula A17 can be cyclized to the N-benzylated lactam of formula A18 by treatment with the cyclic trimer of N-propylphosphonic acid (2, 4, 6-trioxo-2, 4, 6-tri-N-propyl-1, 3, 5, 2, 4, 6-trioxatriphosphane; CAS-no68957-94-8) in the presence of a base, especially an alkylamine such as Diisopropylethylamine (DIPEA) or Triethylamine (TEA), or a tertiary amine such as N-methylmorpholine or 4- (dimethylamino) -pyridine. The reaction is carried out in a suitable solvent such as, for example, MN-Dimethylformamide (DMF), dimethylacetamide (DMAc), Dichloromethane (DCM) or ethyl acetate (AcOEt) at a temperature between 0 ℃ and ambient temperature.

The thioether a18 can be oxidized to the sulfone a19 by treatment with an oxidizing agent, in particular meta-chloroperbenzoic acid, in dichloromethane as solvent at room temperature. Alternatively, the oxidation can be carried out in a solvent such as methanol at room temperature using potassium peroxymonosulfate (Oxone).

The N-benzylated lactam of formula A19 can be debenzylated to the β -sulfonyllactam of formula A20 by net reaction in trifluoroacetic acid with a strong organic acid, in particular trifluoromethanesulfonic acid, at a temperature between 0 ℃ and 50 ℃, in particular at 23 ℃.

In an ethereal solvent such as THF, 1, 2-dimethoxyethane or 1, 4-bisAlkanes, especially 1, 4-bisIn an alkane, β -sulfonyllactam of formula A20 is reacted with 2, 4-disulfide 2, 4-bis- (4-methoxy-phenyl) - [1, 3, 2, 4] at a temperature between 23 and 100 ℃, in particular between 50 and 80 ℃]Dithiadiphosphetanes (Laowerson reagent) or phosphorus pentasulfide to the thiolactone A21.

The β -sulfonylamidines of formula a22 can be prepared from thiolactones of formula a21 by reaction with a solution of ammonia in a protic solvent such as methanol, ethanol or water, in the presence or absence of a mild oxidizing agent such as tert-butyl hydroperoxide, at temperatures between 0 and 60 ℃, particularly at 23 ℃ in the presence or in the absence of an oxidizing agent, or at 50 to 60 ℃.

If the β -sulfonamidine of formula a22 contains Y ═ Br, the reduction to Y ═ H can be accomplished by hydrogenation using a catalyst such as Pd/C in a protic solvent such as an alcohol, particularly ethanol or methanol, particularly in the presence of ammonium hydroxide, particularly at ambient temperature.

The nitration of β -sulfonylamidines of formula a22 having Y ═ H follows standard procedures involving pure sulfuric acid and fuming nitric acid, without the use of solvents, at temperatures from 0 ℃ to 23 ℃, giving nitro- β -sulfonylamidines a 23.

Reduction of the nitro group in nitro- β -sulfonamidine a23 can be accomplished by hydrogenation using a catalyst in a protic solvent such as an alcohol, particularly ethanol or methanol, at ambient temperature to give aniline a 24.

Can be prepared by chlorination of 4- (4, 6-dimethoxy [1.3.5 ] chloride in a solvent such as an alcohol, particularly methanol, at ambient temperature]Triazin-2-yl) -4-methylmorpholine(DMTMM) hydrate, completing the selective amide coupling of aniline A24 with carboxylic acid to give amide Ib.

Scheme 3: alternative Synthesis of Compounds of formula I

Protection of the amino group in the compound of formula a15 can be carried out with a triarylmethyl chloride, such as triphenylmethyl chloride (Tr-Cl), p-methoxyphenyl diphenylmethyl chloride (MMTr-Cl), bis (p-methoxyphenyl) phenylmethyl chloride (DMTr-Cl) or tris (p-methoxyphenyl) methyl chloride (TMTr-Cl), especially DMTr-Cl, under basic conditions, for example in the presence of an amine, such as triethylamine or diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or chloroform, at temperatures from 0 ℃ to ambient temperature, to prepare the aryl bromide of formula a 25.

In the presence of a suitable transition metal catalyst such as bis (dibenzylideneacetone) palladium (0) ((dba)₂Pd) or tris (dibenzylideneacetone) dipalladium (0) ((dba)₃Pd₂) And a suitable ligand such as rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphino-2', 4 ', 6' -triisopropylbiphenyl (t-Bu X-PHOS) in the presence of a base such as sodium tert-butoxide, potassium phosphate or cesium carbonate, in the presence of a base such asSuitable solvents, e.g. toluene or 1, 4-bisThe aryl bromide of formula a25 is reacted with an ammonia equivalent such as benzophenone imine in an alkane under an inert atmosphere such as nitrogen or argon at a temperature of 80 to 110 ℃ to prepare the compound of formula a 26.

Deprotection of the two amino groups in a compound of formula a26 can be accomplished by a one-pot method by the following procedure: first it is reacted with a strong organic acid, such as trifluoroacetic acid, in a chlorinated solvent, such as dichloromethane or chloroform, under anhydrous conditions at a temperature of 0 ℃ to ambient temperature to cleave P¹A group. Subsequently, water or aqueous hydrochloric acid is added to cleave the benzophenone imine and the reaction at ambient temperature produces the diamine of formula a 27.

4- (4, 6-dimethoxy [1.3.5 ] chloride may be used in a solvent such as an alcohol, particularly methanol]Triazin-2-yl) -4-methylmorpholine(DMTMM) hydrate, completing selective amide coupling of aniline A27 with carboxylic acid to give amide I'.

The thioether I 'can be oxidized to the sulfone I' by treatment with an oxidizing agent, in particular m-chloroperbenzoic acid, in dichloromethane as solvent at room temperature.

Scheme 4: an alternative synthesis of an intermediate aminoalcohol of formula a 7.

Alternatively, an intermediate aminoalcohol of formula a7 may be obtained as follows: according to scheme 4, methyltriphenyl-substituted compounds prepared by a strong base such as butyllithium in a solvent such as tetrahydrofuran or toluene at temperatures between-78 ℃ and 0 ℃Inner partSalt formation followed by addition of the ketone of formula A3 produced the desired olefin of formula a 28. The olefin may then be reacted with a mixture of silver cyanate and iodine in a solvent such as diethyl ether or a mixture of ethyl acetate and acetonitrile. The resulting iodoisocyanate of formula A29 may then be heated with an alcohol such as t-butanol and a base such as triethylamine or Nissi (Huenig) base to produce an iodoisocyanate of formula A30An oxazolidinone. The resulting compound of formula A30 is reacted with an aqueous base such as lithium hydroxideThe oxazolidinone is hydrolyzed to produce the aminoalcohol of formula a 7.

Scheme 5: enantioselective synthesis of intermediate aminoalcohols of formula a 7.

The intermediate amino alcohol of formula a7 can be prepared in an enantioselective manner as follows: the aromatic ketones of formula A3 can be converted, analogously to t.p.tang & j.a.ellman, j.org.chem.1999, 64, 12, to sulfinamides such as alkyl sulfinamides, in which case most especially (R) - (+) -tert-butyl sulfinamide is condensed to the sulfinimide of formula a 31: in the presence of a lewis acid such as, for example, titanium (IV) alkoxide (more particularly titanium (IV) ethoxide) in a solvent such as an ether, for example diethyl ether or more particularly tetrahydrofuran, at a temperature of from 23 ℃ to 70 ℃.

The conversion of the sulfinimide of the formula A31 to the nitrile of the formula A32 is stereospecifically carried out by a chiral directing group as described by Tang & Ellman or as described by A.Avenoza, J.H.Butto, F.Corzana, J.M.Peregrina, D.Sucunza, M.M.Zurbano in Synthesis2005, (4), 575-. The sulfenimide of formula A31 can be treated to produce a nitrile of formula A32 as described, for example, by A.Avenoza, J.H.Busto, F.Corzana, J.M.Peregrina, D.Sucunza, M.M.Zurbano in Synthesis2005, (4), 575-.

It is possible to use a mineral acid, for example sulfuric acid or, in particular, hydrochloric acid, in a solvent such as an ether, for example diethyl ether, tetrahydrofuran or, more particularly, 1, 4-diIn an alkane, hydrolysis of the chiral directing group in the nitrile of formula a32 is accomplished, giving first a chiral aminonitrile, followed by another acidic reaction with a mineral acid, such as anhydrous hydrochloric acid or especially sulfuric acid, in a solvent such as an aliphatic alcohol, e.g. ethanol or more especially methanol, at a temperature of 23 ℃ to 80 ℃ to give a chiral amino ester of formula a 6.

The chiral amino ester of formula a6 can also be reduced to the chiral amino alcohol of formula a7 by reaction with a reducing agent such as, for example, lithium borohydride or, more specifically, lithium aluminum hydride, in an ether solvent such as, for example, diethyl ether or, more specifically, in THF, at a temperature between 0 ℃ and 50 ℃, especially at 23 ℃.

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

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

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

Pharmacological testing

The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds of the present invention have been found to be associated with the inhibition of BACE1 activity. The compounds were investigated according to the tests given below.

Cellular a β reduction assay:

HEK293 APP cells can be used A β 40 AlphaLISA determination HEK293 APP cells planted in 96 hole microtiter plate, in cell culture medium (Iscove's, plus 10% (v/v) fetal bovine serum, penicillin/streptomycin), to about 80% confluency, and at 3x concentration in 1/3 volume of culture medium (DMSO final concentration is maintained at 1% v/v) compound in a humid incubator at 37 degrees C and 5% CO₂After 18-20 hours of incubation, the media supernatant was harvested for determination of A β 40 concentration using the Perkin-Elmer Human Amyloid β 1-40 (high specificity) Kit (Cat # AL 275C).

In a Perkin-Elmer White Optiplate-384(Cat #6007290), 2ul of culture medium supernatant was combined with 2. mu.l of 10X AlphaLISA Anti-hA. beta. acceptor beads + biotinylated antibody Anti-A. beta.1-40 Mix (50. mu.g/mL/5 nM). After 1 hour incubation at room temperature, 16. mu.l of 1.25X preparation Streptavidin (SA) donor beads (25. mu.g/mL) were added and incubated for 30 minutes in the dark. The luminescence at 615nm was then recorded using an EnVision-Alpha Reader. The a β 40 level in the culture supernatant was calculated as the percentage of the maximal signal (cells treated with 1% DMSO without inhibitor). IC50 values were calculated using ExcelXLfit software.

Table 1: IC of selected embodiments₅₀Value of

Pharmaceutical composition

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

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

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

The invention also provides medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, which, as with the process for their preparation, comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and must, of course, be adjusted to the individual requirements in each particular case. In general, in the case of oral administration, the dosage for adults can vary from about 0.01 mg/day to about 1000 mg/day of a compound of formula I or of a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered in a single dose or in divided doses and, in addition, when indicated, the upper limit may also be exceeded.

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

example A

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

table 2: possible tablet compositions

Manufacturing process

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

2. The granules were dried at 50 ℃.

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

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

Example B-1

Capsules of the following composition were prepared:

table 3: possible capsule ingredient composition

Manufacturing process

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

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

3. Filling into suitable capsules.

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

Example B-2

Soft gelatin capsules of the following composition were prepared:

composition (I)	mg/capsule
		A compound of formula I	5
Yellow wax	8
		Hydrogenated soybean oil	8
Partially hydrogenated vegetable oils	34
		Soybean oil	110
Total of	165

Table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		Karion 83	8 (Dry matter)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 5: possible soft gelatin capsule compositions

Manufacturing process

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

Example C

Suppositories of the following composition were prepared:

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

Table 6: possible suppository composition

Manufacturing process

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

Example D

Injection solutions of the following composition were prepared:

composition (I)	mg/injection solution
		A compound of formula I	3
Polyethylene glycol 400	150
		Acetic acid	Proper amount to pH 5.0
Water for injection solution	To 1.0ml

Table 7: possible injection solution compositions

Manufacturing process

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

Example E

Sachets of the following composition were made:

composition (I)	mg/sachet
		A compound of formula I	50
Lactose, fine powder	1015
		Microcrystalline cellulose (AVICEL PH 102)	1400
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavouring additives	1
Total of	2500

Table 8: possible sachet composition

Manufacturing process

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

Experimental part

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

And (4) summarizing:

NMR: TMS (tetramethylsilane) or residues of the deuterated solvents were used on a Bruker AC-300 spectrometer at 25 deg.C¹H as an internal standard, record¹H NMR spectrum.

MS: mass Spectra (MS) were measured on a Perkin-Elmer SCIEX API 300 with either positive or negative ion spray (ISP or ISN) method, or by electrospray on a single quadrupole mass spectrometer (API150) from Applied biosystems or electron bombardment (EI, 70eV) on a Finnigan MAT SSQ7000 spectrometer.

Synthesis of intermediate A4

A4 a: (RS) -5- (3-bromo-phenyl) -5-methyl-imidazolidine-2, 4-dione

A mixture of 3-bromo-acetophenone (10.0g, 50mmol), potassium cyanide (4.96g, 75mmol) and ammonium carbonate (33.45g, 348mmol) in ethanol (65ml) was heated in an autoclave at 120 ℃ for 16 h. For work-up, the reaction mixture was cooled to room temperature and subsequently treated with water (250ml) and ethyl acetate (500 ml). The aqueous layer was separated and re-extracted with ethyl acetate (250 ml). The combined organic layers were washed twice with saturated sodium chloride solution (2 × 250ml), then dried over sodium sulfate and evaporated under reduced pressure. 13.2g (98.6% of theory) of (RS) -5- (3-bromo-phenyl) -5-methyl-imidazolidine-2, 4-dione are obtained as a white solid. The purity of the product allows its use in the next step without further purification. Mass (calculated value) C₁₀H₉BrN₂O₂[269.099](ii) a (found value) [ M-H]^-＝267，269。

A4 b: (RS) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-imidazolidine-2, 4-dione

Commercially available 1- (5-bromo-2-fluoro-phenyl) -ethanone was reacted with potassium cyanide and ammonium carbonate in ethanol in an autoclave at 120 ℃ for 16h to yield the title compound as a light yellow solid. Mass (calculated value) C₁₀H₈BrFN₂O₂[287.087](ii) a (found value) [ M-H]^-＝285，287。

A4 c: (RS) -5- (2-fluoro-phenyl) -5-methyl-imidazolidine-2, 4-dione

A mixture of freshly distilled 1- (2-fluorophenyl) ethanone (27.6g, 24.6ml, 200mmol, Eq: 1.00), potassium cyanide (15.6g, 240mmol, Eq: 1.20), ammonium carbonate (96.1g, 1.00mol, Eq: 5.00), and ammonium hydroxide (25%) (130g, 145ml, 931mmol, Eq: 4.65) in ethanol (250ml) and water (200ml) was stirred at 60 ℃ for 5.5 h. The ethanol was removed in vacuo, then cooled to 0 ℃, the residue was carefully acidified to pH1, the precipitate was filtered off, washed with dilute HCl and dried at 50 ℃ first on a rotary evaporator followed by high vacuum to give 5- (2-fluorophenyl) -5-methylimidazolidine-2, 4-dione as a white solid (40.4g, 194mmol, 97.0% yield). Ms (isn): m/z 207.5[ M-H ]]^-。

Synthesis of intermediate A6

A6 a: (RS) -2-amino-2- (3-bromo-phenyl) -propionic acid methyl ester

A dispersion of (RS) -5- (3-bromo-phenyl) -5-methyl-imidazolidine-2, 4-dione (12.81g, 48mmol) in 6N sodium hydroxide solution (95.23ml) was heated to reflux for 48 h. For the work-up, the reaction mixture was cooled with ice and treated with hydrochloric acid (36.5%) until a pH of 1 was reached. The mixture was evaporated to dryness under reduced pressure. Crude (RS) -2-amino-2- (3-bromo-phenyl) -propionic acid hydrochloride was dispersed in methanol (500ml) and cooled to 0 ℃. Thionyl chloride (18.02ml, 246mmol) was added dropwise over 12 minutes and under ice cooling. After the addition was complete, the reaction mixture was heated to reflux for 60 h. For work-up, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The white residue was treated with a mixture of ice and water (200ml), triethylamine (16.5ml) and diethyl ether (500 ml). The resulting suspension was filtered through a celite pad (dicalite); the aqueous layer was then separated and re-extracted with diethyl ether (250 ml). The combined organic layers were washed with saturated sodium chloride solution (250ml),dried over sodium sulfate and evaporated under reduced pressure. 9.39g (76.7% of theory) of (RS) -2-amino-2- (3-bromo-phenyl) -propionic acid methyl ester were obtained as a light yellow oil. The purity of the product allows its use in the next step without further purification. Mass (calculated value) C₁₀H₁₂BrNO₂[258.117](ii) a (found value) [ M + H [)]⁺＝258，260。

A6 b: (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propionic acid methyl ester

Hydrolysis of (RS) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-imidazolidine-2, 4-dione with 6N sodium hydroxide solution and esterification of the Resulting (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propionic acid with methanol and thionyl chloride yielded (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propionic acid methyl ester as a light yellow oil. The purity of the product allows its use in the next step without further purification. Mass (calculated value) C₁₀H₁₁BrFNO₂[276.107](ii) a (found value) [ M + H [)]⁺＝276，278。

A6 c: (RS) -2-amino-2- (2-fluoro-phenyl) -propionic acid methyl ester

Hydrolysis of (RS) -5- (2-fluoro-phenyl) -5-methyl-imidazolidine-2, 4-dione with 3N sodium hydroxide solution and esterification of the Resulting (RS) -2-amino-2- (2-fluoro-phenyl) -propionic acid with methanol and thionyl chloride yielded (RS) -2-amino-2- (2-fluoro-phenyl) -propionic acid methyl ester as a light yellow liquid. The purity of the product allows its use in the next step without further purification. Ms (isp): 198.2[ M + H ] M/z]⁺。

A6 d: (R) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propionic acid methyl ester

A mixture of (R) -N- ((R) -1- (5-bromo-2-fluorophenyl) -1-cyanoethyl) -2-methylpropane-2-sulfinamide (8.869g, 25.54mmol) in concentrated hydrochloric acid (90ml, 1078mmol) was stirred at 23 ℃ for 4h, then cooled to 0 ℃ and treated with 32% sodium hydroxide solution (120ml, 1277mmol), diluted with water (100ml) and extracted with ethyl acetate (1x300ml and 2x200 ml). The combined organic layers were passed over Na₂SO₄Dried, filtered, and the solvent removed in vacuo to leave the amide as an off-white solid. Dissolved in methanol (100ml) and concentrated sulfuric acid (21.39ml, 383mmol) was added carefully, the mixture was stirred at reflux for 40h, cooled to 0 ℃ and saturated Na₂CO₃-solution neutralization until pH9 is reached. Extraction with ethyl acetate (3 × 100ml), combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to afford methyl (R) -2-amino-2- (5-bromo-2-fluorophenyl) propionate (5.17g, 73%) as a light yellow oil, which was used without further purification. Ms (isp): 276.1[ M + H ] M/z]⁺And 278.0[ M +2+ H]⁺。

Synthesis of intermediate A7

A7 a: (RS) -2-amino-2- (3-bromo-phenyl) -propan-1-ol

A solution of (RS) -2-amino-2- (3-bromo-phenyl) -propionic acid methyl ester (9.39g, 36mmol) in tetrahydrofuran (360ml) was treated with lithium aluminium hydride (1.41g, 36 mmol; 282mg/2min) in portions at-5 ℃. After the addition was complete, stirring was continued for 30 minutes at 0-5 ℃. For work-up, the reaction mixture was cooled to-7 ℃ and water (9ml) was added dropwise. Thereafter, 2N sodium hydroxide solution (9ml) was added and stirring was continued at room temperature for 15 minutes. The grey suspension was filtered through a plug of celite, which was washed with tetrahydrofuran (200 ml). The filtrate was evaporated under reduced pressure.8.67g of crude (RS) -2-amino-2- (3-bromo-phenyl) -propan-1-ol were obtained as a colorless oil. The purity of the product allows its use in the next step without further purification. Mass (calculated value) C₉H₁₂BrNO[230.106](ii) a (found value) [ M + H [)]⁺＝230，232。

A7 b: (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propan-1-ol

Reduction of (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propionic acid methyl ester with lithium aluminium hydride in tetrahydrofuran yielded (RS) -2-amino-2- (5-bromo-2-fluoro-phenyl) -propan-1-ol as a light yellow oil. The purity of the product allows its use in the next step without further purification. Mass (calculated value) C₉H₁₁BrFNO[248.097](ii) a (found value) [ M + H [)]⁺＝248，250。

A7 c: (RS) -2-amino-2- (2-fluoro-phenyl) -propan-1-ol

Reduction of (RS) -2-amino-2- (2-fluoro-phenyl) -propionic acid methyl ester with lithium aluminium hydride in diethyl ether yielded (RS) -2-amino-2- (2-fluoro-phenyl) -propan-1-ol as a light yellow oil. The purity of the product allows its use in the next step without further purification. Ms (isp): m/z 170.3[ M + H ]]⁺。

A7 d: (R) -2-amino-2- (5-bromo-2-fluorophenyl) propan-1-ol

To a solution of methyl (R) -2-amino-2- (5-bromo-2-fluorophenyl) propionate (3.95g, 14.3mmol, Eq: 1.00) in diethyl ether (120ml) was addedLithium aluminium hydride (652mg, 17.2mmol, Eq: 1.2) was added in five portions at 0 ℃. The ice bath was removed and stirring was continued at room temperature for 2 hours. Water (652mg, 652. mu.l, 36.2mmol, Eq: 2.53), NaOH (15% in water) (572mg, 652. mu.l, 14.3mmol, Eq: 1.00) and water (1.96g, 1956. mu.l, 109mmol, Eq: 7.59) (1: 3 system) were added dropwise via syringe to the cooled reaction mixture and the mixture was stirred for 20min until a white suspension appeared. Mixing three small spoons with Na₂SO₄Added to the mixture, which was filtered after 5 min. The colorless ether solution was evaporated to give (R) -2-amino-2- (5-bromo-2-fluorophenyl) propan-1-ol (3.2g, 12.9mmol, 90.2% yield) as a white solid, which was used in the next step without further purification. Ms (isp): 248.1[ M + H ] M/z]⁺And 250.0[ M +2+ H ]]⁺。

Synthesis of intermediate A8

A8 a: (R) -2- (5-bromo-2-fluoro-phenyl) -2- (4-methoxy-benzylamino) -propan-1-ol

To a solution of (R) -2-amino-2- (5-bromo-2-fluorophenyl) propan-1-ol (9.2g, 37.1mmol, Eq: 1.00) in 1, 2-dichloroethane (145ml) was added 2, 4-dimethoxybenzaldehyde (6.16g, 37.1mmol, Eq: 1) at 23 ℃ followed by sodium triacetoxyborohydride (15.7g, 74.2mmol, Eq: 2.0). The reaction mixture was stirred at 23 ℃ overnight. The reaction mixture was washed with saturated NaHCO₃/CH₂Cl₂The extraction was performed twice. The combined organic layers were passed over Na₂SO₄Dried, filtered off and evaporated completely. The residue was purified by silica gel chromatography with 0-50% EtOAc in heptane to give (R) -2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propan-1-ol as a light brown oil (14.1g, 35.4mmol, 95.5% yield). Mass (calculated value) C₁₈H₂₁BrFNO₃[398.27](ii) a (found value) [ M + H [)]⁺＝398.0，400.0。

Synthesis of intermediate A9

A9 a: (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]Thiazolidine 2-oxide

To a solution of (R) -2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propan-1-ol (14.1g, 35.4mmol, Eq: 1.00) and pyridine (14.0g, 14.3ml, 177mmol, Eq: 5.0) in dichloromethane (258ml) was added thionyl chloride (5.05g, 3.1ml, 42.5mmol, Eq: 1.2) dropwise at-78 deg.C, stirring was continued for 5min at-78 deg.C, the cooling bath was removed, and the mixture was slowly warmed to 23 deg.C and stirring was continued for 20 min. With 5% citric acid and saturated NaHCO₃Solution extraction, passing the organic layer over Na₂SO₄Dried, filtered off and evaporated completely to give (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3 as a light yellow oil]Thiazolidine 2-oxide (15.7g, 35.3mmol, 99.8% yield), which did not require further purification. Ms (isp): 444.1[ M + H ] M/z]⁺And 446.0[ M +2+ H ]]⁺。

Synthesis of intermediate A10

A10 a: (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]Thiazolidine 2, 2-dioxide

To (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]To a mixture of thiazolidine 2-oxide (15.7g, 35.3mmol, Eq: 1.00) and sodium periodate (8.31g, 38.9mmol, Eq: 1.1) in ethyl acetate (120ml), acetonitrile (120ml) and cold water (192ml) was added ruthenium (III) chloride (73.3mg, 353. mu. mol, Eq: 0.01) at 23 ℃ and the reaction mixture was stirred vigorously for 30 minutes at 23 ℃. With saturated NaHCO₃Extracting with ethyl acetate, and passing the organic layer through Na₂SO₄Dried, filtered off and evaporated completely. The residue was purified by silica gel column chromatography with heptane/ethyl acetate to give the title. The product fractions were collected and evaporated completely, dried in HV to give (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3 as a white solid]Thiazolidine 2, 2-dioxide (15.6g, 33.9mmol, 95.9% yield). Ms (isn): 458.0[ M-H ] M/z]^-And 460.0[ M +2-H ]]^-。

Synthesis of intermediate A11

A11 a: (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetonitrile

a)2-mercaptoacetonitrile:to a commercially available S-cyanomethyl thioacetate [59463-56-8 ]](28.4g, 247mmol, Eq: 1.00) in methanol (280ml) under argon15(10.7g, 247mmol, Eq: 1.00). The mixture was stirred at reflux (70 ℃ C.) overnight. Will cool downThe mixture is filtered to a content of 2g for stabilization15 round bottom flask. The solvent was then evaporated in vacuo at ambient temperature leaving 2-mercaptoacetonitrile (14.35g, 196mmol, 79.6% yield) as a dark brown liquid.

b) To (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]2-mercaptoacetonitrile (1.22g, 16.6mmol, Eq: 1.5) was added dropwise to a solution of thiazolidine 2, 2-dioxide (5.1g, 11.1mmol, Eq: 1.00) and 1, 1, 3, 3-tetramethylguanidine (1.91g, 2.09ml, 16.6mmol, Eq: 1.5) in DMF (77.3ml) at 23 ℃. The reaction mixture was stirred at 23 ℃ for 16 hours. All volatiles were evaporated under high vacuum and the resulting residue was stirred vigorously between 60ml of dichloromethane and 20% (v/v) sulfuric acid solution (60ml) for 40 hours. Saturated NaHCO₃The solution was added slowly (pH 8) followed by extraction twice with dichloromethane. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetonitrile (5.2g, 10.9mmol, 98.3% yield) as a light brown oil. Ms (isp): 453.0[ M + H ] M/z]⁺And 455.2[ M +2+ H]⁺。

Synthesis of intermediate A12

A12 a: (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -N- (2, 4-dimethoxybenzyl) -2, 2, 2-trifluoroacetamide

To (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzyl)Amino) propylthio) acetonitrile (5.2g, 11.5mmol, Eq: 1.00) and triethylamine (2.32g, 3.2ml, 22.9mmol, Eq: 2.0) in dichloromethane (30ml), trifluoroacetic anhydride (3.61g, 2.43ml, 17.2mmol, Eq: 1.5). The reaction mixture was stirred at 0 ℃ for 20min, followed by 23 ℃ for 2 h. Extracting with water and dichloromethane, and passing the organic layer over Na₂SO₄Dried, filtered off and evaporated completely. The residue was purified by silica gel column chromatography with 0 to 50% ethyl acetate in heptane to give (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -N- (2, 4-dimethoxybenzyl) -2, 2, 2-trifluoroacetamide as a brown oil (5.9g, 10.7mmol, 93.6% yield). Ms (isp): 566.1[ M + NH ] M/z₄]⁺And 568.2[ M +2+ NH ]₄]⁺。

Synthesis of intermediate A13

A13 a: (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -2, 2, 2-trifluoroacetamide

A mixture of (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -N- (2, 4-dimethoxybenzyl) -2, 2, 2-trifluoroacetamide (5.9g, 10.7mmol, Eq: 1.00) and trifluoroacetic acid (73.5g, 49.6ml, 644mmol, Eq: 60) was stirred at 23 ℃ for 16 hours to give a dark red solution. Pouring saturated NaHCO₃-in solution and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel column chromatography with 0 to 50% ethyl acetate in heptane to give (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -2, 2, 2-trifluoroacetamide (3.1g, 6.99mmol, 65.1% yield) as a light brown oil. Ms (isn): 396.7[ M-H ] M/z]^-And 399.0[ M +2-H ]]^-。

Synthesis of intermediate A14Become into

A14 a: (R) -2- (2-amino-2- (5-bromo-2-fluorophenyl) propylthio) acetonitrile

To a solution of (R) -N- (2- (5-bromo-2-fluorophenyl) -1- (cyanomethylthio) propan-2-yl) -2, 2, 2-trifluoroacetamide (3g, 6.76mmol, Eq: 1.00) in ethanol (30ml) was added sodium borohydride (1.02g, 27.1mmol, Eq: 4.0), and the mixture was stirred at 23 ℃ for 16 hours. Pouring in ice-cold saturated NH₄C1-solution, stirred for 10min and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel column chromatography with 0 to 50% ethyl acetate in heptane to give (R) -2- (2-amino-2- (5-bromo-2-fluorophenyl) propylthio) acetonitrile (1.1g, 3.63mmol, 53.6% yield) as a light yellow oil. Ms (isp): 303.0[ M + H ] M/z]⁺And 304.9[ M +2+ H]⁺。

Synthesis of intermediate A15

A15 a: (R) -5- (5-bromo-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine

To a solution of (R) -2- (2-amino-2- (5-bromo-2-fluorophenyl) propylthio) acetonitrile (1.08g, 3.56mmol, Eq: 1.00) in toluene (20ml) was added dropwise trimethylaluminum (2M in toluene) (1.96ml, 3.92mmol, Eq: 1.1) at 23 ℃. The reaction mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was carefully quenched by addition of water at 0 ℃ followed by 1M Na₂CO₃The solution and ethyl acetate were extracted twice. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated to give 1.5g of a brown oil (139%). Passing the residue through siliconColumn chromatography on gel was purified with dichloromethane + dichloromethane/methanol/ammonium hydroxide 110: 10: 1 to give (R) -5- (5-bromo-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (720mg, 2.37mmol, 66.7% yield) as a pale brown gel. Ms (isp): 303.0[ M + H ] M/z]⁺And 305.0[ M +2+ H]⁺。

Synthesis of intermediate A16

A16 a: (R) -ethyl 2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetate

To (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]To a solution of thiazolidine 2, 2-dioxide (10g, 21.7mmol, Eq: 1.00) and ethyl thioglycolate (3.92g, 3.57ml, 32.6mmol, Eq: 1.5) in DMF (134ml) at 23 ℃ was added 1, 1, 3, 3-tetramethylguanidine (3.75g, 4.09ml, 32.6mmol, Eq: 1.5). The reaction mixture was stirred at 23 ℃ for 16 hours. The solution was evaporated in HV. The resulting residue was stirred vigorously between 100ml of dichloromethane and 20% (v/v) sulfuric acid solution (100ml) overnight. Saturated NaHCO₃The solution was added slowly (pH 8) followed by extraction twice with dichloromethane. The combined organic layers were dried over Na₂SO₄Filtered and evaporated to give the crude product (14.4g, 132%). The residue was chromatographed on 70g silica gel with 0-50% ethyl acetate in heptane to give ethyl (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetate as a light yellow oil (10.9g, 21.8mmol, 100% yield). Ms (isp): m/z 500.2[ M + H ]]⁺And 502.2[ M +2+ H ]]⁺。

A16 b: (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) -2-methylpropionic acid ethyl ester

a)Ethyl 2- (acetylthio) -2-methylpropionate:to a solution of ethyl 2-bromo-2-methylpropionate (5g, 3.81ml, 25.6mmol, Eq: 1.00) in acetone (150ml) was added potassium thioacetate (3.22g, 28.2mmol, Eq: 1.10) at 23 ℃. The mixture was stirred at 60 ℃ for 2.5 hours. The solvent was removed in vacuo, the orange solid was redissolved in dichloromethane, washed with water, and the organic layer was passed over Na₂SO₄Dried and filtered off. The solvent was removed in vacuo to leave ethyl 2- (acetylthio) -2-methylpropionate (5.01g, 25.0mmol, 97.6% yield) as a yellow oil. The crude product was used in the next step without further purification.

b)Ethyl 2-mercapto-2-methylpropionate:to a solution of ethyl 2- (acetylthio) -2-methylpropionate (3.02g, 15.9mmol, Eq: 1.00) in methanol (150ml) at 23 ℃ was added sodium methoxide (858mg, 15.9mmol, Eq: 1.00). The mixture was stirred at 23 ℃ for 4 hours. The solvent was removed in vacuo, redissolved in dichloromethane, washed with water, and passed over Na₂SO₄Dried and filtered off. The solvent was removed in vacuo to leave the product as a light brown oil, which was a mixture of ethyl 2-mercapto-2-methylpropionate and the corresponding disulfide (1.77g), which was used without further purification.

c) To (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]To a solution of thiazolidine 2, 2-dioxide (2g, 4.34mmol, Eq: 1.00) and ethyl 2-mercapto-2-methylpropionate (966mg, 966. mu.l, 6.52mmol, Eq: 1.5) in DMF (20ml) at 23 ℃ were added 1, 1, 3, 3-tetramethylguanidine (751mg, 819. mu.l, 6.52mmol, Eq: 1.5) and tri-n-butylphosphine (1.32g, 1.61ml, 6.52mmol, Eq: 1.5), and the reaction mixture was stirredStirred at 23 ℃ for 16 hours. The solution was evaporated in HV. The resulting residue was vigorously stirred overnight between 50ml of dichloromethane and 20% (v/v) sulfuric acid solution (50 ml). Saturated NaHCO₃-solution and 1M Na₂CO₃The solution was added slowly (pH 9) followed by extraction twice with dichloromethane. The combined organic layers were dried over Na₂SO₄Filtered and evaporated to give a yellow oil (3.51 g). The residue was chromatographed on 70g silica gel with 0-50% ethyl acetate in heptane to give ethyl (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) -2-methylpropionate (2.3g, 4.35mmol, 100% yield) as a colorless oil. Ms (isp): 528.2[ M + H ] M/z]⁺And 530.2[ M +2+ H]⁺。

A16 c: (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylic acid ethyl ester

a)1- (acetylthio) cyclobutanecarboxylic acid ethyl ester:to a commercially available solution of ethyl 1-bromocyclobutanecarboxylate (5g, 24.1mmol, Eq: 1.00) in acetone (48.3ml) at 23 ℃ was added potassium thioacetate (3.03g, 26.6mmol, Eq: 1.1) and the reaction mixture was stirred at reflux for another 30 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with diethyl ether and water. Separating the organic layer, passing over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed twice on 70g silica gel with 0-10% ethyl acetate in heptane to give ethyl 1- (acetylthio) cyclobutanecarboxylate (1.4g, 6.3mmol, 26.1% yield) as a brown liquid.

b)1-mercaptocyclobutanecarboxylic acid ethyl ester:to a solution of ethyl 1- (acetylthio) cyclobutanecarboxylate (1.4g, 6.92mmol, Eq: 1.00) in methanol (70ml) at 23 ℃ was added sodium methoxide (374mg, 6.92mmol, Eq: 1.00). The mixture was stirred at 23 ℃ for 16 hours. Dissolving with water and saturated NaClDiluting, extracting with dichloromethane, and passing the organic layer over Na₂SO₄Dried and filtered off. The solvent was removed in vacuo leaving a brown oil. The crude product was used in the next step without further purification.

c) To (R) -4- (5-bromo-2-fluoro-phenyl) -3- (2, 4-dimethoxy-benzyl) -4-methyl- [1, 2, 3]To a solution of thiazolidine 2, 2-dioxide (2g, 4.34mmol, Eq: 1.00) and ethyl 1-mercaptocyclobutanecarboxylate (1.04g, 6.52mmol, Eq: 1.5) in DMF (21.7ml) were added 1, 1, 3, 3-tetramethylguanidine (751mg, 819. mu.l, 6.52mmol, Eq: 1.5) and tri-n-butylphosphine (1.32g, 1.61ml, 6.52mmol, Eq: 1.5) at 23 ℃ and the reaction mixture was stirred for 20 h at 23 ℃. The solution was evaporated in HV. The resulting residue was vigorously stirred overnight between 40ml of dichloromethane and 20% (v/v) sulfuric acid solution (40 ml). Saturated NaHCO₃-solution and 1M Na₂CO₃The solution was added slowly (pH 10) followed by extraction twice with dichloromethane. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated to give a brown oil (3.32 g). The residue was chromatographed on 70g silica gel with 0-50% ethyl acetate in heptane to give ethyl (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylate (1.98g, 3.66mmol, 84.3% yield) as a light yellow oil. Ms (isp): m/z 540.2[ M + H ]]⁺And 542.3[ M +2+ H]⁺。

Synthesis of intermediate A17

A17 a: (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetic acid

To (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio)To a solution of ethyl acetate (3g, 5.99mmol, Eq: 1.00) in tetrahydrofuran (20ml), methanol (10ml), water (5ml) was added lithium hydroxide (287mg, 12.0mmol, Eq: 2.0) at 23 ℃. The colorless reaction solution was stirred at 23 ℃ for 2 hours. The reaction mixture was neutralized (pH 5-6) with 1N HCl (12.0ml, 12.0mmol, Eq: 2.0) and evaporated. The residue was triturated with dichloromethane/methanol 9: 1 and solid Na was added₂SO₄. The solid was filtered off and the filtrate evaporated to dryness to give crude (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetic acid as a white foam (3.2g, 6.1mmol, 102% yield), which was used without further purification. Ms (isn): 470.6[ M-H ] M/z]^-And 472.5[ M +2-H ]]^-。

A17 b: (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) -2-methylpropionic acid

To a solution of ethyl (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) -2-methylpropionate (3g, 5.68mmol, Eq: 1.00) in ethanol (35.7ml) was added 3N NaOH (3.78ml, 11.4mmol, Eq: 2.0). The reaction mixture was stirred at 70 ℃ for 2 hours. To the reaction mixture, 1N HCl (11.4ml, 11.4mmol, Eq: 2.0) was added (pH 5-6) at 23 ℃, and evaporated. The residue was triturated with dichloromethane/methanol 9: 1 and solid Na was added₂SO₄. The mixture was filtered off. The filtrate was evaporated to dryness to give crude (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylsulfanyl) -2-methylpropanoic acid (2.6g, 5.2mmol, 91.5% yield) as an off-white foam, which was used without further purification. Ms (isp): m/z 500.0[ M + H ]]⁺And 502.3[ M +2+ H ]]⁺。

A17 c: (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylic acid

To a solution of ethyl (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylate (2g, 3.7mmol, Eq: 1.00) in ethanol (50ml) was added 3N NaOH (2.47ml, 7.4mmol, Eq: 2.0). The reaction solution was stirred at 70 ℃ for 2 hours. To the reaction mixture, 1N HCl (7.4ml, 7.4mmol, Eq: 2.0) was added (pH 5-6) at 23 ℃. After evaporation, the residue was triturated with dichloromethane/methanol 9: 1 and solid Na was added₂SO₄. The solid was filtered off and the filtrate was evaporated to dryness to give crude (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylic acid as a white foam (1.8g, 3.51mmol, 94.9% yield), which was used without further purification. Ms (isp): 512.4[ M + H ] M/z]⁺And 514.4[ M +2+ H ]]⁺。

Synthesis of intermediate A18

A18 a: (R) -5- (5-bromo-2-fluorophenyl) -4- (2, 4-dimethoxybenzyl) -5-methylthiomorpholin-3-one

To a solution of (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) acetic acid (3.3g, 6.99mmol, Eq: 1.00) and N, N-diisopropylethylamine (2.71g, 3.66ml, 21.0mmol, Eq: 3.0) in ethyl acetate (194ml) was added 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (6.67g, 6.23ml, 10.5mmol, Eq: 1.5) at 23 deg.C, and the colorless reaction solution was stirred at 23 deg.C for 2 hours. The reaction mixture was washed with saturated NaHCO₃-solution, water and brine washes. Subjecting the organic layer to Na₂SO₄Dried, filtered and evaporated to give almost pure (R) -5- (5-bromo-2-fluorophenyl) -4-propanoic acid as a colorless oil(2, 4-Dimethoxybenzyl) -5-methylthiomorpholin-3-one (2.95g, 6.49mmol, 92.9% yield), which is crystallized in the refrigerator and used without further purification. Ms (isp): 454.0[ M + H ] M/z]⁺And 456.1[ M +2+ H]⁺。

A18 b: (R) -5- (5-bromo-2-fluorophenyl) -4- (2, 4-dimethoxybenzyl) -2, 2, 5-trimethylthiomorpholin-3-one

To a solution of (R) -2- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) -2-methylpropanoic acid (2.6g, 5.2mmol, Eq: 1.00) and diisopropylethylamine (2.01g, 2.72ml, 15.6mmol, Eq: 3.0) in ethyl acetate (104ml) was added 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (4.96g, 4.63ml, 7.79mmol, Eq: 1.5) at 23 ℃. The colorless reaction solution was stirred at 23 ℃ for 2 hours. The reaction mixture was washed with saturated NaHCO₃-solution, water and brine washes. Subjecting the organic layer to Na₂SO₄Dried, filtered and evaporated to give crude and almost pure (R) -5- (5-bromo-2-fluorophenyl) -4- (2, 4-dimethoxybenzyl) -2, 2, 5-trimethylthiomorpholin-3-one (2.45g, 5.08mmol, 97.7% yield) as a colorless oil which crystallized in the refrigerator. Ms (isp): 482.0[ M + H ] M/z]⁺And 484.3[ M +2+ H]⁺。

A18 c: (R) -7- (5-bromo-2-fluorophenyl) -8- (2, 4-dimethoxybenzyl) -7-methyl-5-thia-8-azaspiro [3.5] non-9-one

To a solution of (R) -1- (2- (5-bromo-2-fluorophenyl) -2- (2, 4-dimethoxybenzylamino) propylthio) cyclobutanecarboxylic acid (1.8g, 3.51mmol, Eq: 1.00) and diisopropylethylamine (1.36g, 1.84ml, 10.5mmol, Eq: 3.0) in ethyl acetate (70.3ml) was added1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (3.35g, 3.08ml, 5.27mmol, Eq: 1.5) was added at 23 ℃. The colorless reaction solution was stirred at 23 ℃ for 16 hours. The reaction mixture was washed with saturated NaHCO₃-solution, water and brine washes. Subjecting the organic layer to Na₂SO₄Dried, filtered and evaporated to give crude and pure (R) -7- (5-bromo-2-fluorophenyl) -8- (2, 4-dimethoxybenzyl) -7-methyl-5-thia-8-azaspiro [3.5] as a white foam]Nonan-9-one (1.75g, 3.54mmol, 101% yield). Ms (isp): 494.0[ M + H ] M/z]⁺And 496.4[ M +2+ H]⁺。

Synthesis of intermediate A19

A19 a: (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one

To a solution of (R) -5- (5-bromo-2-fluorophenyl) -4- (2, 4-dimethoxybenzyl) -5-methylthiomorpholin-3-one (2.95g, 6.49mmol, Eq: 1.00) in methanol (100ml) at 23 ℃ was added(7.98g, 13.0mmol, Eq: 2.00). The reaction mixture was stirred at 23 ℃ for 16 hours. The reaction mixture was carefully quenched by addition of water at 0 ℃ followed by addition of 10ml of dilute NaHSO₃-solution, saturated NaHCO₃-solution and ethyl acetate. Stirring vigorously for 10 min. The organic layer was separated and washed with water, then over Na₂SO₄Dried, filtered and evaporated to give a yellow oil which was chromatographed on 20g silica gel with 0-50% ethyl acetate in heptane to give (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1 λ 6-thiomorpholin-3-one (3g, 6.17mmol, 95.0% yield) as a white foam. Ms (isp): 486.2[ M + H ] M/z]⁺And 488.1[ M +2+ H]⁺。

A19 b: (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one

To a solution of (R) -5- (5-bromo-2-fluorophenyl) -4- (2, 4-dimethoxybenzyl) -2, 2, 5-trimethylthiomorpholin-3-one (2.45g, 5.08mmol, Eq: 1.00) in methanol (60ml) at 23 ℃ was added(6.24g, 10.2mmol, Eq: 2.00). The reaction mixture was stirred at 23 ℃ for 16 hours. The reaction mixture was carefully quenched by the addition of water at 0 ℃.10 ml of dilute NaHSO are added₃Solution, saturated NaHCO₃Solution and ethyl acetate. Stirring vigorously for 10 min. The organic layer was separated and washed with water, then dried over Na₂SO₄Filtered and evaporated to give crude and almost pure (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -2, 2, 5-trimethyl-1, 1-dioxo-1 λ 6-thiomorpholin-3-one (2.47g, 4.80mmol, 94.5% yield) as an orange foam. Ms (isp): 514.2[ M + H ] M/z]⁺And 516.3[ M +2+ H]⁺。

A19 c: (R) -2, 2-diallyl-5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one

To a solution of (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (1g, 2.06mmol, Eq: 1.00) in acetone (8ml) was added allyl bromide (547mg, 391. mu.l, 4.52mmol, Eq: 2.2), followed by additionPotassium carbonate (853mg, 6.17mmol, Eq: 3.0) was added. The reaction suspension was stirred in a sealed tube for 4 days. Extracting with water and ethyl acetate, separating the organic layer, and passing through Na₂SO₄Dried, filtered and evaporated to dryness. The residue was chromatographed on 20g silica gel with 0% to 50% ethyl acetate in heptane to give (R) -2, 2-diallyl-5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1 λ 6-thiomorpholin-3-one (620mg, 1.09mmol, 53.2% yield) as a white foam. Ms (isp): 566.2[ M + H ] M/z]⁺And 568.1[ M +2+ H]⁺。

A19 d: (R) -8- (5-bromo-2-fluoro-phenyl) -9- (2, 4-dimethoxy-benzyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] dec-2-en-10-one

To a solution of (R) -2, 2-diallyl-5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (610mg, 1.08mmol, Eq: 1.00) in dichloromethane (20.3ml) under argon was added [1, 3-bis- (2, 4, 6-trimethylphenyl) -2-imidazolidinylidene]Dichloro (phenylmethylene) (tricyclohexylphosphine) ruthenium (Grubbs II catalyst) (45.7mg, 53.8. mu. mol, Eq: 0.05). The reaction mixture was stirred at reflux for 4 hours. Evaporated and chromatographed on 20g silica gel with 0% to 50% ethyl acetate in heptane to give (R) -8- (5-bromo-2-fluoro-phenyl) -9- (2, 4-dimethoxy-benzyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] as a white foam]Dec-2-en-10-one (460mg, 854. mu. mol, 79.3% yield). Ms (isp): 538.2[ M + H ] M/z]⁺And 540.2[ M +2+ H ]]⁺。

A19 e: (R) -7- (5-bromo-2-fluoro-phenyl) -8- (2, 4-dimethoxy-benzyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] nonan-9-one

To (R) -7- (5-bromo-2-fluorophenyl) -8- (2, 4-dimethoxybenzyl) -7-methyl-5-thia-8-azaspiro [3.5]To a solution of non-9-one (1.7g, 3.44mmol, Eq: 1.00) in methanol (50ml) at 23 ℃ was added(4.23g, 6.88mmol, Eq: 2.00). The reaction mixture was stirred at 23 ℃ for 24 hours. The reaction mixture was carefully quenched by addition of water at 0 ℃ and 10ml of dilute NaHSO was added₃Solution, saturated NaHCO₃Solution and ethyl acetate. Stirring vigorously for 10 min. The organic layer was separated and washed with water, then over Na₂SO₄Dried, filtered and evaporated to give (R) -7- (5-bromo-2-fluoro-phenyl) -8- (2, 4-dimethoxy-benzyl) -7-methyl-5, 5-dioxo-5 λ 6-thia-8-aza-spiro [3.5] as an off-white foam]Nonan-9-one (1.9g, 3.25mmol, 94.5% yield). Ms (isp): 526.4[ M + H ] M/z]⁺And 528.3[ M +2+ H]⁺。

Synthesis of intermediate A20

A20 a: (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one

A mixture of (R) -5- (5-bromo-2-fluoro-phenyl) -4- (2, 4-dimethoxy-benzyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (251mg, 516. mu. mol, Eq: 1.00) and trifluoroacetic acid (5.88g, 3.98ml, 51.6mmol, Eq: 100) was stirred at 23 ℃ for 16 h. Pouring 1M Na₂CO₃-in solution and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. Chromatography of the residue on 5g silica gel with dichloromethane/ethyl acetate 9: 1 gave (R) -5- (5-bromo-2-fluoro-benzene as a white solidYl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (116mg, 345. mu. mol, 66.9% yield). Ms (isn): 334.0[ M-H ] M/z]^-And 336.0[ M +2-H ]]^-。

A20 b: (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one

A mixture of (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (2.1g, 4.08mmol, Eq: 1.00) and trifluoroacetic acid (46.5g, 31.5ml, 408mmol, Eq: 100) was stirred at 23 ℃. After 1 hour, trifluoromethanesulfonic acid (1.23g, 725. mu.l, 8.16mmol, Eq: 2.0) was added and stirring was continued for 2 hours. Pouring 1MNa₂CO₃-in solution and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed on 70g silica gel with heptane/ethyl acetate 1: 1 to give (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (1.4g, 3.84mmol, 94.2% yield) as an off-white solid. Ms (isp): 364.0[ M + H ] M/z]⁺And 366.3[ M +2+ H]⁺。

A20 c: (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] dec-2-en-10-one

Coupling (R) -8- (5-bromo-2-fluoro-phenyl) -9- (2, 4-dimethoxy-benzyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]Dec-2-en-10-one (450mg, 836. mu. mol, Eq: 1.00) and trifluoroacetic acid (9.53g, 6.44ml, 83.6mmol, Eq: 100) were stirred at 23 ℃. After 1h, trifluoromethanesulfonic acid (251mg, 148. mu.l, 1.67mmol, Eq: 2.0) was added and the dark red solution was stirred for 2 h. Falling downInto 1M Na₂CO₃-in solution and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed on 10g silica gel with heptane/ethyl acetate 1: 1 to give (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] as a white solid]Dec-2-en-10-one (340mg, 788. mu. mol, 94.3% yield). Ms (isp): 388.1[ M + H ] M/z]⁺And 390.2[ M +2+ H ]]⁺。

A20 d: (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] nonan-9-one

A mixture of RO6883781-000-001(1.9g, 3.25mmol, Eq: 1.00) and trifluoroacetic acid (29.6g, 20.0ml, 260mmol, Eq: 80) was stirred at 23 ℃. After 1 hour, trifluoromethanesulfonic acid (975mg, 577. mu.l, 6.5mmol, Eq: 2.0) was added and the dark red solution was stirred for an additional 2 hours. Pouring 1M Na₂CO₃To the solution and extracted twice with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed on 20g silica gel with heptane/ethyl acetate 1: 1 to give (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] as a pale red solid]Nonan-9-one (1.1g, 2.92mmol, 90.0% yield). Ms (isp): m/z 376.0[ M + H%]⁺And 378.4[ M +2+ H]⁺。

Synthesis of intermediate A21

A21 a: (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1 lambda 6-thiomorpholine-3-thione

To (R) -5- (5-bromo-2-)Fluoro-phenyl) -5-methyl-1, 1-dioxo-1 λ 6-thiomorpholin-3-one (3.11g, 9.25mmol, Eq: 1.00) inTo a solution in an alkane (72.3ml) was added Laowesson's reagent (2.99g, 7.4mmol, Eq: 0.8) at 23 ℃. The mixture was stirred at 80 ℃ for 2 hours. With saturated NaHCO₃Dilution of the solution, extraction with ethyl acetate, washing with brine, passage over Na₂SO₄Dried and filtered off. The solvent was removed in vacuo leaving a yellow oil (5.8g) which was purified by flash chromatography on 50g silica gel with 0-50% ethyl acetate in heptane to give (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1 λ 6-thiomorpholine-3-thione (2.7g, 7.67mmol, 82.9% yield) as a light yellow foam. Ms (isn): m/z 350.1[ M-H ]]^-And 352.2[ M +2-H ]]^-。

A21 b: (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholine-3-thione

To a solution of (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholin-3-one (1.4g, 3.84mmol, Eq: 1.00) in bisTo a solution in alkane (29.5ml) was added Laoweison's reagent (3.10g, 7.68mmol, Eq: 2.00). The reaction mixture was stirred at 80 ℃ for 10 hours. The reaction mixture was poured into saturated NaHCO₃-in solution and extracted twice with ethyl acetate. The organic layer was washed with brine, over Na₂SO₄Dried, filtered and evaporated to give a pale yellow oil. The residue was chromatographed on 20g silica gel with ethyl acetate in heptane to give (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1 λ 6-thiomorpholine-3-thione (1.3g, 3.4) as a pale yellow foam2mmol, 88.9% yield). Ms (isp): 380.0[ M + H ] M/z]⁺And 382.3[ M +2+ H]⁺。

A21 c: (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6 lambda 6-thia-9-aza-spiro [4.5] dec-2-ene-10-thione

Reacting (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]Dec-2-en-10-one (410mg, 1.06mmol, Eq: 1.00) and Laoweisen's reagent (427mg, 1.06mmol, Eq: 1.00) in twoIn an alkane (10ml) was stirred at 80 ℃ for 2 hours. More Laowerson's reagent (427mg, 1.06mmol, Eq: 1.00) was added and stirring continued at 85 ℃ for 16 h. More Laowerson's reagent (427mg, 1.06mmol, Eq: 1.00) was added and stirring continued at 95 ℃ for 6 h. The reaction mixture was poured into saturated NaHCO₃-in solution and extracted twice with ethyl acetate. The organic layer was washed with brine, over Na₂SO₄Dried, filtered and evaporated to give a pale yellow oil. The residue was chromatographed on 20g silica gel with dichloromethane/heptane to give (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] as a pale yellow foam]Dec-2-ene-10-thione (305mg, 754. mu. mol, 71.4% yield). Ms (isp): 404.1[ M + H ] M/z]⁺And 406.2[ M +2+ H]⁺。

A21 d: (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 lambda 6-thia-8-aza-spiro [3.5] nonane-9-thione

To (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5]]Nonan-9-one (1.1g, 2.92mmol, Eq: 1.00) in bisTo a solution in alkane (50ml) was added Laoweison's reagent (1.18g, 2.92mmol, Eq: 1.00). The reaction mixture was stirred at 80 ℃ for 2 hours. More Laowerson's reagent (1.55g, 3.84mmol, Eq: 1.00) was added and stirring continued at 80 ℃ for 8 h. The reaction mixture was poured into saturated NaHCO₃To the solution and extracted twice with ethyl acetate. The organic layer was washed with brine, over Na₂SO₄Dried, filtered and evaporated to give a pale yellow oil. The residue was chromatographed on 20g silica gel with 0-50% ethyl acetate in heptane to give (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] as a pale yellow foam]Nonane-9-thione (1.05g, 2.68mmol, 91.5% yield). Ms (isp): 392.0[ M + H ] M/z]⁺And 394.3[ M +2+ H]⁺。

Synthesis of intermediate A22

A22 a: (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

A mixture of (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1. lamda.6-thiomorpholine-3-thione (2.7g, 7.67mmol, Eq: 1.00) in ammonia (7M in MeOH) (47.2g, 60ml, 420mmol, Eq: 54.8) was stirred in a sealed tube at 60 ℃ for 5 h. The yellow solution was evaporated and then chromatographed on 20g silica gel with 0-80% ethyl acetate in heptane to give (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as a white foam]Thiazin-3-ylamine (1.78g, 5.31mmol, 69.3% yield). Ms (isp): 335.0[ M + H ] M/z]⁺And 337.0[ M +2+ H ]]⁺。

A22 b: (R) -5- (2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

To (R) -5- (5-bromo-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]Thiazin-3-ylamine (750mg, 2.24mmol, Eq: 1.00) in methanol (150ml) and 7M ammonia in methanol (959. mu.l, 6.71mmol, Eq: 3) Pd/C (238mg, 224. mu. mol, Eq: 0.1) was added at room temperature and the mixture was hydrogenated at room temperature for 2 hours. Extracted with dichloromethane and some 25% ammonium hydroxide solution. Subjecting the organic layer to Na₂SO₄Dried, filtered off and evaporated completely, dried in HV to give (R) -5- (2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as a white foam]Thiazin-3-ylamine (497mg, 1.94mmol, 86.7% yield). Ms (isp): 257.1[ M + H ] M/z]⁺。

A22 c: (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lambda.6- [1, 4] thiazin-3-ylamine

A mixture of (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1. lamda.6-thiomorpholine-3-thione (1.28g, 3.37mmol, Eq: 1.00) and ammonia (7N in MeOH) (38.5ml, 269mmol, Eq: 80) was stirred in a sealed tube at 60 ℃ for 20 h. With ethyl acetate/saturated NaHCO₃Solution extraction, passing the organic layer over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed with ethyl acetate to give (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1 λ 6- [1, 4] as a white solid]Thiazin-3-ylamine (1g, 2.75mmol, 81.8% yield). Ms (isp): 363.3[ M + H ] M/z]⁺And 365.3[ M +2+ H]⁺。

A22 d: (R) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

To (R) -5- (5-bromo-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]To a solution of thiazin-3-ylamine (1g, 2.75mmol, Eq: 1.00) in methanol (80ml) and ammonia (7M in MeOH) (1.18ml, 8.26mmol, Eq: 3.0) was added Pd/C10% (293mg, 275. mu. mol, Eq: 0.1) under an inert atmosphere at 23 ℃ and the suspension was placed under hydrogen (balloon) and stirred for 2h at 23 ℃. The catalyst was filtered off, washed three times with methanol and evaporated. The residue was taken up in dichloromethane/saturated NaHCO₃Extraction of the solution and passing the organic layer over Na₂SO₄Dried, filtered and evaporated to give pure (R) -5- (2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as a white solid]Thiazin-3-ylamine (760mg, 2.67mmol, 97.1% yield). Ms (isp): 285.4[ M + H ] M/z]⁺。

A22 e: (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] dec-2, 9-dien-10-ylamine

Reacting (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]A mixture of dec-2-ene-10-thione (300mg, 742. mu. mol, Eq: 1.00) and ammonia (7N in MeOH) (7.87g, 10ml, 70.0mmol, Eq: 94.3) was stirred in a sealed tube at 60 ℃ for 48 h. With ethyl acetate and saturated NaHCO₃Solution extraction, passing the organic layer over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed with ethyl acetate to give(R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] as a white foam]Dec-2, 9-dien-10-ylamine (249mg, 643. mu. mol, 86.7% yield). Ms (isp): m/z 387.3[ M + H ]]⁺And 389.3[ M +2+ H]⁺。

A22 f: (R) -8- (2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] dec-9-en-10-ylamine

To (R) -8- (5-bromo-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]Deca-2, 9-dien-10-ylamine (245mg, 633. mu. mol, Eq: 1.00) in a solution of methanol (10ml) and ammonia (7N in MeOH) (271. mu.l, 1.9mmol, Eq: 3.0) Pd/C10% (67.3mg, 63.3. mu. mol, Eq: 0.1) was added under an inert atmosphere at 23 ℃. The suspension was placed under hydrogen (balloon) and stirred at 23 ℃ for 2 hours. The catalyst was filtered off, washed three times with methanol and evaporated. The residue was taken up in dichloromethane and saturated NaHCO₃Solution extraction, organic layer over dried Na₂SO₄Filtered and evaporated to give pure (R) -8- (2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] as a white solid]Dec-9-en-10-ylamine (175mg, 564. mu. mol, 89.1% yield). Ms (isp): 311.5[ M + H ] M/z]⁺。

A22 g: (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 lambda 6-thia-8-aza-spiro [3.5] non-8-en-9-ylamine

Coupling (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5]]A mixture of nonane-9-thione (1.05g, 2.68mmol, Eq: 1.00) and ammonia (7N in MeOH) (19.1ml, 134mmol, Eq: 50) was stirred in a sealed tube at 60 ℃ for 40h. With ethyl acetate and saturated NaHCO₃Solution extraction, passing the organic layer over Na₂SO₄Dried, filtered and evaporated. The residue was chromatographed on 20g silica gel with ethyl acetate to give (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] as a white solid]Non-8-en-9-ylamine (560mg, 1.49mmol, 55.8% yield). Ms (isp): m/z 375.0[ M + H ]]⁺And 377.4[ M +2+ H]⁺。

A22 h: (R) -7- (2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 lambda 6-thia-8-aza-spiro [3.5] non-8-en-9-ylamine

To (R) -7- (5-bromo-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5]]To a solution of non-8-en-9-ylamine (555mg, 1.48mmol, Eq: 1.00) in methanol (50ml) and ammonia (7N in MeOH) (634. mu.l, 4.44mmol, Eq: 3.0) was added Pd/C10% (157mg, 148. mu. mol, Eq: 0.1) at 23 ℃ under an inert atmosphere. The suspension was placed under hydrogen (balloon) and stirred at 23 ℃ for 2 hours. The catalyst was filtered off, washed three times with methanol/dichloromethane (1: 1) and evaporated. The residue was taken up in dichloromethane and saturated NaHCO₃-solution extraction. Subjecting the organic layer to Na₂SO₄Dried, filtered and evaporated to give pure (R) -7- (2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 λ 6-thia-8-aza-spiro [3.5] as a white solid]Non-8-en-9-ylamine (385mg, 1.3mmol, 87.8% yield). Ms (isp): m/z 297.5[ M + H ]]⁺。

Synthesis of intermediate A23

A23 a: (R) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

To (R) -5- (2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]To a solution of thiazin-3-ylamine (497ng, 1.94mmol, Eq: 1.00) in concentrated sulfuric acid (14.8g, 8.06ml, 151mmol, Eq: 78) at 0 deg.C was added 100% nitric acid (189mg, 134. mu.l, 3.01mmol, Eq: 1.55), and the mixture was stirred at 0 deg.C for 1 hour. Pouring saturated NaHCO₃In solution, extraction with ethyl acetate and passage of the organic layer over Na₂SO₄And (5) drying. The solvent was removed in vacuo leaving (R) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as a pale yellow oil]Thiazin-3-ylamine (584mg, 1.94mmol, 100% yield). Ms (isp): m/z 302.1[ M + H ]]⁺。

A23 b: (R) -5- (2-fluoro-5-nitro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

Mixing (R) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1 lambda 6- [1, 4]]Thiazin-3-ylamine (760mg, 2.67mmol, Eq: 1.00) was dissolved in concentrated sulfuric acid (13.1g, 7.12ml, 134mmol, Eq: 50), followed by dropwise addition of fuming nitric acid (253mg, 179. mu.l, 4.01mmol, Eq: 1.5) at 0 ℃. The light brown solution was stirred at 0 ℃ for 2 hours. The reaction mixture was poured onto ice and basified with 3N NaOH, followed by extraction with dichloromethane. Separating the organic layer, passing over Na₂SO₄Dried, filtered and evaporated to dryness to give crude and pure (R) -5- (2-fluoro-5-nitro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1 λ 6- [1, 4] as a white foam]Thiazin-3-ylamine (950mg, 2.74mmol, 103% yield). Ms (isp): 328.4[ M + H ] M/z]⁺。

A23 c: (R) -8- (2-fluoro-5-nitro-phenyl) -8-methyl-6, 6-dioxo-6 lambda 6-thia-9-aza-spiro [4.5] dec-9-en-10-ylamine

Reacting (R) -8- (2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]Dec-9-en-10-ylamine (172mg, 554. mu. mol, Eq: 1.00) was dissolved in concentrated sulfuric acid (2.72g, 1.48ml, 27.7mmol, Eq: 50), followed by dropwise addition of fuming nitric acid (52.4mg, 37.1. mu.l, 831. mu. mol, Eq: 1.5) at 0 ℃. The light brown solution was stirred at 0 ℃ for 2 hours. The reaction mixture was poured onto ice and basified with 3N NaOH, followed by extraction with dichloromethane. Separating the organic layer, passing over Na₂SO₄Dried, filtered and evaporated to dryness to give crude and pure (R) -8- (2-fluoro-5-nitro-phenyl) -8-methyl-6, 6-dioxo-6 λ 6-thia-9-aza-spiro [4.5] as an off-white foam]Dec-9-en-10-ylamine (210mg, 591. mu. mol, 107% yield). Ms (isp): 356.5[ M + H ] M/z]⁺。

A23 d: (R) -7- (2-fluoro-5-nitro-phenyl) -7-methyl-5, 5-dioxo-5 lambda 6-thia-8-aza-spiro [3.5] non-8-en-9-ylamine

Reacting (R) -7- (2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5]]Non-8-en-9-ylamine (385mg, 1.3mmol, Eq: 1.00) was dissolved in concentrated sulfuric acid (6.37g, 3.46ml, 65.0mmol, Eq: 50). Fuming nitric acid (123mg, 87.1. mu.l, 1.95mmol, Eq: 1.5) was added dropwise at 0 ℃. The light brown solution was stirred at 0 ℃ for 2 hours. The reaction mixture was poured onto ice and basified with 3N NaOH, followed by extraction with dichloromethane. Separating the organic layer, passing over Na₂SO₄Dried, filtered and evaporated to dryness to give crude and pure (R) -7- (2-fluoro-5-nitro-phenyl) -7-methyl-5, 5-dioxo-5 λ 6-thia-8-aza-spiro [3.5] as a light brown foam]Non-8-en-9-ylamine (470mg, 1.38mmol, 106% yield). Ms (isp): m/z is 342.1[M+H]⁺。

Synthesis of intermediate A24

A24 a: (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

Mixing (R) -5- (2-fluoro-5-nitro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1 lambda 6- [1, 4]]A solution of thiazin-3-ylamine (584mg, 1.94mmol, Eq: 1.00) in ethanol (45ml), triethylamine (196mg, 270. mu.l, 1.94mmol, Eq: 1.00) and Pd/C (206mg, 194. mu. mol, Eq: 0.1) was hydrogenated at room temperature for 1 hour. The catalyst is filtered off, washed with ethanol, the filtrate is evaporated and dried in HV to give (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lambda.6- [1, 4] as an off-white foam]Thiazin-3-ylamine (460mg, 1.7mmol, 87.5% yield). Ms (isp): 272.4[ M + H ] M/z]⁺。

A24 b: (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-ylamine

To (R) -5- (2-fluoro-5-nitro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]Thiazin-3-ylamine (950mg, 2.88mmol, Eq: 1.00) in ethanol (50ml) was added triethylamine (292mg, 402. mu.l, 2.88mmol, Eq: 1.00) at 23 ℃ under an inert atmosphere and Pd/C10% (307mg, 288. mu. mol, Eq: 0.1) after inerting. The suspension was placed under hydrogen (balloon) and stirred at 23 ℃ for 1 hour. The catalyst was filtered off, washed three times with ethanol and a mixture of dichloromethane and methanol, and the combined filtrates were evaporated to give as an off-white solidCrude and almost pure (R) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4[ -l]Thiazin-3-ylamine (760mg, 2.54mmol, 88.0% yield). Ms (isp): m/z 300.3[ M + H ]]⁺。

A24 c: (R) -8- (5-amino-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6 lambda 6-thia-9-aza-spiro [4.5] dec-9-en-10-ylamine

To (R) -8- (2-fluoro-5-nitro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5]]Deca-9-en-10-ylamine (210mg, 591. mu. mol, Eq: 1.00) in ethanol (10ml) was added triethylamine (59.8mg, 82.4. mu.l, 591. mu. mol, Eq: 1.00) and Pd/C10% (62.9mg, 59.1. mu. mol, Eq: 0.1) after inerting at 23 ℃ under an inert atmosphere. The suspension was placed under hydrogen (balloon) and stirred at 23 ℃ for 1 hour. The catalyst was filtered off, washed three times with ethanol and evaporated to give crude and almost pure (R) -8- (5-amino-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6 λ 6-thia-9-aza-spiro [4.5] as an off-white foam]Dec-9-en-10-ylamine (182mg, 559 μmol, 94.7% yield). Ms (isp): 326.5[ M + H ] M/z]⁺。

A24 d: (R) -7- (5-amino-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 lambda 6-thia-8-aza-spiro [3.5] non-8-en-9-ylamine

To (R) -7- (2-fluoro-5-nitro-phenyl) -7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5]]To a solution of non-8-en-9-ylamine (470mg, 1.38mmol, Eq: 1.00) in ethanol (10ml), triethylamine (139mg, 192. mu.l, 1.38mmol, Eq: 1.00) was added under an inert atmosphere at 23 ℃, and Pd/C10% (62.9mg, 59.1. mu. mol) was added after inertingAnd Eq: 0.1). The suspension was placed under hydrogen (balloon) and stirred at 23 ℃ for 1 hour. The catalyst was filtered off, washed three times with ethanol and evaporated to give crude (R) -7- (5-amino-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5 λ 6-thia-8-aza-spiro [3.5] as a light brown solid]Non-8-en-9-ylamine (345mg, 1.11mmol, 80.5% yield). Ms (isp): 312.5[ M + H ] M/z]⁺。

Synthesis of intermediate A25

A25 a: (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -5- (5-bromo-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine

To a solution of (R) -5- (5-bromo-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (910mg, 3mmol, Eq: 1.00) and triethylamine (607mg, 836. mu.l, 6.00mmol, Eq: 2) in dichloromethane (30.0ml) was added 4, 4' -dimethoxytrityl chloride (1.12g, 3.3mmol, Eq: 1.1) at 23 ℃, and the mixture was stirred at 23 ℃ for 2H. The solution was concentrated in vacuo and directly subjected to flash chromatography on silica gel with N-heptane and ethyl acetate to afford (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -5- (5-bromo-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (1.67g, 2.76mmol, 91.9% yield) as an off-white foam. Ms (isp): 605.1[ M + H ] M/z]⁺And 607.2[ M +2+ H]⁺。

Synthesis of intermediate A26

A26 a: (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -5- (5- (diphenylmethyleneamino) -2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine

To a mixture of (R) -N- (bis (4-methoxyphenyl) (phenyl tom) methyl) -5- (5-bromo-2-fluorophenyl) -5-methyltom-5, 6-dihydro-2H-1, 4-thiazin-3-amine (1.67g, 2.76mmol, Eq: 1.00), sodium tert-butoxide (795mg, 8.27mmol, Eq: 3), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (85.6mg, 82.7. mu. mol, Eq: 0.03), and 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (117mg, 276. mu. mol, Eq: 0.1) in toluene (22.0ml), benzophenoketimine (1.00g, 926. mu.l, 5.52mmol, Eq: 2) was added at 23 ℃ and the reaction mixture was stirred at 105 ℃ for 5 hours under argon atmosphere. Extracting with water and ethyl acetate, and passing the organic layer over Na₂SO₄Dried, filtered off and evaporated completely. The crude material was purified by silica gel flash chromatography with N-heptane and ethyl acetate to afford (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -5- (5- (diphenylmethyleneamino) -2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (1.59g, 2.25mmol, 81.7% yield) as a yellow oil. Ms (isp): 706.3[ M + H ] M/z]⁺。

Synthesis of intermediate A27

A27 a: (R) -5- (5-amino-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine

To a solution of (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -5- (5- (diphenylmethyleneamino) -2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (1.59g, 2.25mmol, Eq: 1.00) in dichloromethane (80ml) at 23 ℃ was added dropwise TFA (12.8g, 8.68ml, 113mmol, Eq: 50), and the resulting red solution was stirred at 23 ℃ for 3 hours, followed by addition of bis (4-methoxyphenyl) (phenyl) methylAlkane (80ml) followed by 1M hydrochloric acid (2.25ml, 2.25mmol, Eq: 1.00) was added and stirring continued for 2h at 23 ℃. Pouring into 25% ammonium hydroxide solution, and extracting with dichloromethaneTwice, the combined organic layers were passed over Na₂SO₄Dried, filtered off and evaporated completely. The crude material was purified by silica gel column chromatography, first removing all non-polar by-products with ethyl acetate, followed by 7M ammonia in methanol, to obtain (R) -5- (5-amino-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (150mg, 627 μmol, 27.8% yield) as a light brown solid. Ms (isp): m/z 240.1[ M + H ]]⁺。

Synthesis of intermediate A31

A31 a: (R, E) -N- (1- (5-bromo-2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide

Commercially available 1- (5-bromo-2-fluorophenyl) ethanone (140g, 645mmol, Eq: 1.0) [ CAS No.477-89-3](R) -2-methylpropane-2-sulfinamide (78.2, 645mmol, Eq: 1.0) and titanium (IV) ethoxide (221g, 204ml, 968mmol, Eq: 1.5) were dissolved in tetrahydrofuran (1.191), and the mixture was heated to 75 ℃ and stirred at this temperature overnight. The mixture was cooled to 50 ℃, saturated sodium potassium tartrate solution (1.171, 2.58mol, Eq: 4) was added and the mixture was stirred at this temperature for 1.5 hours. The mixture was diluted with TBME, the layers were separated and the organic layer was washed with sulfuric acid (0.05M, 2.361, 118mmol, Eq: 0.183), saturated Na₂CO₃The solution (645ml, 645mmol, Eq: 1.00) was washed with brine, over Na₂SO₄Dried and the solvent evaporated, leaving a dark orange solid which was purified by trituration with n-heptane to give the first crop as an off-white solid (144.7 g). From the mother liquor, another batch (23.0g) was obtained by trituration with pentane and another batch was obtained by silica gel column chromatography with n-heptane/ethyl acetate. Total yield of (R, E) -N- (1- (5-bromo-2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide as an off-white solid (180.7g, 564mmol, 87.5% yield). Ms (isp): 320.3[ M + H ] M/z]⁺And 322.0[ M +2+ H]⁺。

Synthesis of intermediate A32

A32 a: (R) -N- ((R) -1- (5-bromo-2-fluorophenyl) -1-cyanoethyl) -2-methylpropane-2-sulfinamide

To a solution of diethylaluminum cyanide (1M in toluene, 45.25ml, 45.25mmol) at 23 ℃ was added isopropanol (2.314ml, 30.17mmol) and the mixture was stirred at 23 ℃ for 30 min. The resulting solution was added dropwise over 15min to a solution of (R, E) -N- (1- (5-bromo-2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide (9.66g, 30.17mmol) in tetrahydrofuran (452ml) at-78 deg.C, stirring was continued for 5min, followed by slow warming to-10 deg.C and stirring at-10 deg.C for 5.5 h. Pouring saturated NaHCO₃In solution, the precipitate is filtered off, washed with ethyl acetate, the organic layer is washed with brine and over Na₂SO₄And (5) drying. The solvent was removed in vacuo to leave a yellow oil (11.38g, d.r 9.9: 1) which was purified by crystallization from 2-methyltetrahydrofuran and n-heptane to give a first batch (4.80g) and purified by silica gel column chromatography with dichloromethane/TBME 95: 5(2.24g) A second batch was obtained from the mother liquor. Total yield of (R) -N- ((R) -1- (5-bromo-2-fluorophenyl) -1-cyanoethyl) -2-methylpropane-2-sulfinamide as an off-white solid (7.04g, 67%). Ms (isp): 347.1[ M + H ] M/z]⁺And 349.0[ M +2+ H ]]⁺。

Example 1

(R) -N- (3- (5-amino-3-methyl-3, 6-dihydro-2H-1, 4-thiazin-3-yl) -4-fluorophenyl) -5-cyanopyridinecarboxamide

To a solution of 5-cyanopyridine-2-carboxylic acid (28.8mg, 194. mu. mol, Eq: 1.00) in methanol (5ml) was added 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride at 0 deg.CHydrate (64.5mg, 233. mu. mol, Eq: 1.2). The colorless solution was stirred at 0 ℃ for 30 minutes, followed by dropwise addition via syringe of a solution of (R) -5- (5-amino-2-fluorophenyl) -5-methyl-5, 6-dihydro-2H-1, 4-thiazin-3-amine (50mg, 194. mu. mol, Eq: 1.00) in methanol (5 ml). The reaction mixture was stirred at 23 ℃ for 18 h. With saturated NaHCO₃Extraction of the solution with ethyl acetate and passage of the organic layer over Na₂SO₄Dried, filtered off and evaporated completely. The crude material was purified by silica gel column chromatography with ethyl acetate and methanol followed by ethyl acetate/methanol/ammonium hydroxide to give (R) -N- (3- (5-amino-3-methyl-3, 6-dihydro-2H-1, 4-thiazin-3-yl) -4-fluorophenyl) -5-cyanopyridinecarboxamide (64mg, 173.3 μmol, 89.1% yield) as a light yellow solid. Ms (isp): 370.0[ (M + H) ═ M/z⁺]。

Example 2

5-cyano-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

Method a): to a solution of (R) -N- (3- (5-amino-3-methyl-3, 6-dihydro-2H-1, 4-thiazin-3-yl) -4-fluorophenyl) -5-cyanopyridine-carboxamide (10mg, 27.1 μmol, Eq: 1.00) in dichloromethane (2ml) at 0 ℃ was added m-CPBA (80.1mg, 325 μmol, Eq: 4) and the reaction mixture was stirred at room temperature for 2 hours. All volatiles were removed in vacuo and the residue was purified by preparative HPLC to afford 5-cyano-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ 6- [1, 4] as a white solid]Thiazin-3-yl) -4-fluoro-phenyl]Amide (3mg, 28%, about 50% purity). Ms (isp): m/z 402.0[ (M + H)⁺]。

Method b): to a solution of 5-cyanopicolinic acid (69.1mg, 466 μmol, Eq: 1.1) in methanol (6ml) at 0 ℃ was added 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chlorideHydrate (187mg, 636. mu. mol, Eq: 1.5) and the mixture was stirred at 0 ℃ for 15 minutes. (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] in methanol (6ml) was added]Thiazin-3-ylamine (115mg, 424. mu. mol, Eq: 1.00) and stirred at 23 ℃ overnight. Pouring saturated NaHCO₃In solution, extraction with ethyl acetate and passage of the organic layer over Na₂SO₄And (5) drying. The solvent was removed in vacuo leaving a brown oil. The crude material was purified by silica gel flash chromatography (10 g): first washed with ethyl acetate, followed by the addition of a 5% solution of 7M ammonia in methanol to afford [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1 λ 6- [1, 4] 5-cyano-pyridine-2-carboxylic acid as a light yellow solid]Thiazin-3-yl) -4-fluoro-phenyl]Amide (63mg, 157. mu. mol, 37.0% yield). Ms (isp): m/z 402.4[ (M + H)⁺]。

Example 3

5-chloro-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

As described for example 2 (method b), starting from 5-chloropicolinic acid (73.5mg, 466. mu. mol, Eq: 1.1) and (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]Thiazin-3-ylamine (115mg, 424 μmol, Eq: 1.00) was prepared to give the title compound as a light yellow solid (80mg, 195 μmol, 45.9% yield). Ms (isp): 411.4[ (M + H) where M/z is equal to⁺]And 413.2[ (M +2+ H)⁺]。

Example 4

5-difluoromethoxy-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

As described for example 2 (method b), starting from 5- (difluoromethoxy) picolinic acid (69.7mg, 369. mu. mol, Eq: 1.00) and (R) -5- (5-amino-2-fluoro-phenyl) -5-methyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lambda.6- [1, 4]]Thiazin-3-ylamine (100mg, 369 μmol, Eq: 1.00) was prepared to give the title compound as a white foam (85mg, 192 μmol, 52.1% yield). Ms (isp): 443.4[ (M + H)⁺]。

Example 5

5-chloro-pyridine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

As described for example 2 (method b), starting from 5-chloropicolinic acid (60.8mg, 386. mu. mol, Eq: 1.1) and (R) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4]]Thiazin-3-ylamine (105mg, 351. mu. mol, Eq: 1.00) was prepared to give the title compound as a white foam (150mg, 342. mu. mol, 97.4% yield). Ms (isp): 439.3[ (M + H) M/z⁺]And 441.2[ (M +2+ H)⁺]。

Example 6

5-cyano-pyridine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

5-Cyanopicolinic acid (57.1mg, 386. mu. mol, Eq: 1.1) and (R) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as described for example 2 (method b)]Thiazin-3-ylamine (105mg, 351. mu. mol, Eq: 1.00) was prepared to give the title compound as a white foam (101mg, 235. mu. mol, 67.1% yield). Ms (isp): 430.3[ (M + H) where M/z is equal to⁺]。

Example 7

5-methoxy-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

Commercially available 5-methoxypyrazine-2-carboxylic acid (CAS-No.40155-42-8) (43.2mg, 281. mu. mol, Eq: 1.2) and (R) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as described for example 2 (method b)]Thiazin-3-ylamine (70mg, 234 μmol, Eq: 1.00) was prepared to give the title compound as a white foam (67mg, 154 μmol, 65.8% yield). Ms (isp): 436.5[ (M + H) where M/z is equal to⁺]。

Example 8

5-difluoromethyl-pyrazine-2-carboxylic acid [3- ((R) -5-amino-3, 6, 6-trimethyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1. lamda.6- [1, 4] thiazin-3-yl) -4-fluoro-phenyl ] -amide

Commercially available 5- (difluoromethyl) pyrazine-2-carboxylic acid (CAS-No.1174321-06-2) (48.9mg, 281. mu. mol, Eq: 1.2) and (R) -5- (5-amino-2-fluoro-phenyl) -2, 2, 5-trimethyl-1, 1-dioxo-1, 2, 5, 6-tetrahydro-1. lamda.6- [1, 4] as described for example 2 (method b)]Thiazin-3-ylamine (70mg, 234 μmol, Eq: 1.00) was prepared to give the title compound as a pale yellow foam (51mg, 112 μmol, 47.9% yield). Ms (isp): 456.5[ (M + H) M/z⁺]。

Example 9

5-cyano-pyridine-2-carboxylic acid [3- ((R) -10-amino-8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [4.5] dec-9-en-8-yl) -4-fluoro-phenyl ] -amide

From 5-cyanopyricolic acid (27.3mg, 184. mu. mol, Eq: 1.2) and (R) as described for example 2 (method b)8- (5-amino-2-fluoro-phenyl) -8-methyl-6, 6-dioxo-6. lamda.6-thia-9-aza-spiro [ 4.5%]Dec-9-en-10-ylamine (50mg, 154. mu. mol, Eq: 1.00) was prepared to give the title compound as a white foam (32mg, 70.3. mu. mol, 45.7% yield). Ms (isp): 456.5[ (M + H) M/z⁺]。

Example 10

5-chloro-pyridine-2-carboxylic acid [3- ((R) -9-amino-7-methyl-5, 5-dioxo-5 λ 6-thia-8-aza-spiro [3.5] non-8-en-7-yl) -4-fluoro-phenyl ] -amide

As described for example 2 (method b), starting from 5-chloropicolinic acid (48.6mg, 308. mu. mol, Eq: 1.2) and (R) -7- (5-amino-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lambda.6-thia-8-aza-spiro [3.5]]Non-8-en-9-ylamine (80mg, 257. mu. mol, Eq: 1.00) was prepared to give the title compound as a pale yellow foam (70mg, 155. mu. mol, 60.4% yield). Ms (isp): 451.4[ (M + H) where M/z is equal to⁺]And 453.2[ (M +2+ H)⁺]。

Example 11

5-cyano-pyridine-2-carboxylic acid [3- ((R) -9-amino-7-methyl-5, 5-dioxo-5. lamda.6-thia-8-aza-spiro [3.5] non-8-en-7-yl) -4-fluoro-phenyl ] -amide

5-Cyanopicolinic acid (33.1mg, 224. mu. nol, Eq: 1.2) and (R) -7- (5-amino-2-fluoro-phenyl) -7-methyl-5, 5-dioxo-5. lambda.6-thia-8-aza-spiro [3.5] as described for example 2 (method b)]Non-8-en-9-ylamine (58mg, 186. mu. mol, Eq: 1.00) was prepared to give the title compound as a pale yellow foam (39mg, 88.3. mu. mol, 47.4% yield). Ms (isp): 442.4[ (M + H)⁺]。

Claims

1. A compound of the formula I,

wherein

R¹Is 5-cyano-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-difluoromethoxy-pyridin-2-yl, 5-methoxy-pyrazin-2-yl or 5-difluoromethyl-pyrazin-2-yl;

R²selected from the group consisting of:

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

ii)C_1-6-alkyl, and

iii) halogen;

R³selected from the group consisting of:

i)C_1-6-alkyl, and

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

R⁴selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

R⁵selected from the group consisting of:

i)C_1-6-an alkyl group,

ii) halogen-C_1-6-alkyl, and

iii) a hydrogen atom in the presence of a hydrogen atom,

x is a number of 0 or 2,

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R²Is a halogen.

3. A compound according to any one of claims 1-2, wherein R²Is F.

4. A compound according to any one of claims 1-2, wherein R³Is C_1-6-an alkyl group.

5. A compound according to any one of claims 1-2, wherein R³Is methyl.

6. A compound according to any one of claims 1-2, wherein R⁴Is C_1-6-an alkyl group.

7. A compound according to any one of claims 1-2, wherein R⁴Is methyl.

8. A compound according to any one of claims 1-2, wherein R⁴Is hydrogen.

9. A compound according to any one of claims 1-2, wherein R⁵Is C_1-6-an alkyl group.

10. A compound according to any one of claims 1-2, wherein R⁵Is methyl.

11. A compound according to any one of claims 1-2, wherein R⁵Is hydrogen.

12. A compound according to any one of claims 1-2, wherein R⁴And R⁵Together form C_3-7-a cycloalkyl ring.

13. A compound according to claim 12, wherein R⁴And R⁵Together forming a cyclobutyl or cyclopentyl ring.

14. A compound according to any one of claims 1-2, wherein x is 2.

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

5-Difluoromethoxy-pyridine-2-carboxylic acid [3- ((R) -5-amino-3-methyl-1, 1-dioxo-1, 2, 3, 6-tetrahydro-1λ⁶-[1，4]Thiazin-3-yl) -4-fluoro-phenyl]-an amide of the formula (I),

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

or a pharmaceutically acceptable salt thereof.

16. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 14, which process comprises: reacting a compound of formula XI with a compound of formula XII to form a compound of formula I,

wherein x and R¹、R²、R³、R⁴And R⁵As defined in any one of claims 1 to 14.

17. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 15, together with a pharmaceutically acceptable carrier and/or pharmaceutically acceptable auxiliary substances.

18. The use of a compound of formula I according to any one of claims 1 to 15 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease.