HK1191941A

HK1191941A - Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors

Info

Publication number: HK1191941A
Application number: HK14105118.0A
Authority: HK
Inventors: 罗伯特．纳尔基齐昂; 伊曼纽尔．皮纳德; 沃尔夫冈．沃斯特
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2011-05-27
Filing date: 2012-05-24
Publication date: 2014-08-08

Description

Spiro- [1,3] -oxazines and spiro- [1,4] -oxazepines as BACE1 and/or BACE2 inhibitors

Background

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

AD is characterized by 2 major pathological features in the Central Nervous System (CNS): the appearance of amyloid plaques and neurofibrillary tangles (Hardy et al, The amyloid hypothesisis of Alzheimer's disease: progression and schemes on The road to therapeutics, Science (Science) 2002Jul 19; 297(5580) 353-6, Selkoe, Cell biology of The amyloid β -protein precursor and The mechanism of Alzheimer's disease, AnnuRev 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. Gene excision of the BACE1 gene in Mice clearly shows that its activity is important for APP processing leading to the production of A β -peptide, without BACE1 producing A β -peptide (Luo et al, Mice discovery in BACE1, the Alzheimer's beta-secretase, ha normal genotype and extracted beta-amino generation, Nat neurosci.2001Mar; 4 (3): 231-2, robers et al, knockdown microwave enzyme activity in amplification of the primer beta-amino reactivity in braine: experiments for Alzheimer's diseases therapeutics, Hum Genet (human molecular genetics) 1; 10-13112). Mice that have been genetically engineered to express the human APP gene and develop extensive amyloid plaques and Alzheimer's pathology during aging no longer exhibit this when the beta-secretase activity is reduced by excision of one of the BACE1 alleles (McConlogue et al, Partial reduction of BACE1ha targeting on Alzheimer's disease and synthetic pathology in APP Transgenic Rice.J Biol Chem. (J. Biol. Chem.) 2007Sep 7; 282 (36): 26326). It is therefore speculated that inhibitors of BACE1 activity may be agents useful in the therapeutic intervention of Alzheimer's Disease (AD).

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

Beta cell failure and the resulting marked decrease in insulin secretion and hyperglycemia marked the onset of T2D. Most of the current treatments do not prevent the loss of the beta cell population characteristic of T2D. However, recent studies with the GLP-1 analog gastrin and other drugs have shown that it is possible to achieve preservation and proliferation of beta cells, leading to improved glucose tolerance and slowing progression to overt T2D (LL Baggio and DJ Drucker, "Therapeutic profiling approach diabetes in type2 diabetes", annu. rev. med.2006,57, 265. sup. 281).

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

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

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

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

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

The present invention provides novel compounds of formula I, their manufacture, medicaments based on compounds according to the invention and their manufacture as well as the use of compounds of formula I in the control or prevention of diseases such as alzheimer's disease and type II diabetes. The novel compounds of formula I have improved pharmacological properties.

Technical Field

The present invention provides spiro- [1,3] having BACE1 and/or BACE2 inhibitory properties]-Azines and spiro- [1,4]-oxazaThe preparation thereof, 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 endonuclease of 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, in particular alzheimer's disease. And/or the compounds of the present invention have BACE2 inhibitory activity and may therefore be used in the therapeutic and/or prophylactic treatment of diseases and disorders such as type II diabetes and other metabolic diseases.

Detailed Description

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

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

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

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

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

The term "halo-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl substituted with one or more halogens, in particular 1-5 halogens, more in particular 1-3 halogens, most in particular 1 halogen or 3 halogens. The term "halo-C_1-3-alkyl ", alone or in combination with other groups, means C as defined herein_1-3-alkyl substituted with one or more halogens, in particular 1-5 halogens, more in particular 1-3 halogens, most in particular 1 halogen or 3 halogens. A particular halogen is fluorine. Particular "halo-C_1-6-alkanesThe radical "being fluorine-C_1-6-alkyl and in particular "halo-C_1-3-alkyl "is fluoro-C_1-3-an alkyl group. Examples are difluoromethyl, chloromethyl, fluoromethyl and the like. A specific example is trifluoromethyl.

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

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

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 specific "halogen" 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 independently selected from N, O and S, especially N and O, in which at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include: benzofuranyl, benzimidazolyl, 1H-benzimidazolyl, benzoAzinyl radicals, benzoOxazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolyl, isothiazolylAzolyl group,Azolyl, pyrazinyl, pyrazolyl, 1H-pyrazolyl, pyrazolo [1, 5-a ]]Pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6, 7-dihydro-5H- [1]Azoindenyl, and the like. Particular "heteroaryl" groups are pyridyl, pyrimidinyl and 1H-pyrazolyl. Specific groups are pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl and 1H-pyrazole 5-yl.

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 particular "aryl" group is phenyl.

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

The term "C_1-6-alkoxy ", alone or in combination with other groups, denotes-O-C which may be linear or branched, with single or multiple branches_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. Specific examples are methoxy and ethoxy.

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

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

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts 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. Specific examples are formic acid, trifluoroacetic acid and hydrochloric acid. In particular hydrochloric acid, trifluoroacetic acid and fumaric acid.

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

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

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

The term "half maximal inhibitory concentration" (IC)₅₀) Representing the concentration of the particular compound required to obtain 50% inhibition of the biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted into pIC₅₀Value (-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 "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor for a receptor. It is measured using a competitive binding assay and, if no competing ligand (e.g., a radioligand) is present, is equal to the concentration at which 50% of the receptor is occupied by that particular inhibitor. Ki values can be logarithmically converted to pKi values (-log Ki), where higher values indicate a greater exponential increase in potency.

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

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

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

The term "protecting group" means a group that, in the meaning conventionally associated therewith in synthetic chemistry, selectively blocks one reactive site in a polyfunctional compound such that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group may be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" denotes a group intended to protect an amino group and includes benzyl, benzyloxycarbonyl (benzyloxyformyl, CBZ), 9-Fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-Butoxycarbonyl (BOC), trityl (Tr), 4-monoethoxytrityl (MMTr), 4, 4-dimethoxy-trityl (DMTr), 4, 4', 4 "-trimethoxytrityl and trifluoroacetyl. Further examples of such Groups are found in t.w.greene and p.g.m.wuts, "Protective Groups in organic synthesis", 2 nd edition, John Wiley & Sons, inc., New York, NY, 1991, chapter 7; haslam, "Protective Groups in Organic Chemistry", edited by J.G.W.McOmie, Plenum Press, New York, NY, 1973, Chapter 5, and T.W.Greene, "Protective Groups in Organic Synthesis", John 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, and also thienyloxy, dihalophosphonoxy, optionally substituted benzyloxy, isopropoxy and acyloxy groups.

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

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

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

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

All individual embodiments may be combined.

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

wherein

V is-CR^7aR^7b-；

W is-CR^2aR^2b-；

X is-CR^1aR^1b-, - (O-, -S-or-SO)₂-；

Y-NH-C=O-：

Z is selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

ii) heteroaryl substituted with 1-4 substituents independently selected from R⁸，

iii) an aryl group, and

iv) aryl substituted with 1-4 substituents independently selected from R⁸，

R^1aSelected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^1bselected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^2aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^2bselected from the group consisting of:

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

ii) an aryl group, and

iii)C_1-6-an alkyl group;

or R^2aAnd R^2bTogether with C to which they are attached form a heterocyclic group;

R³selected from the group consisting of:

i) hydrogen, and

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

R⁴selected from the group consisting of:

i) hydrogen, and

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

R⁵selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R⁶selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R^7aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^7bselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-alkanesA group;

R⁸selected from the group consisting of:

i) the cyano group(s),

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

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

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

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

vi)C_1-6-an alkoxy group,

vii)C_1-6-alkoxy-C_1-6-an alkyl group,

viii)C_2-6-alkynyl, and

ix)C_1-6-an alkyl group;

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

A particular embodiment is a compound as described herein, wherein

V is-CR^7aR^7b-；

W is-CR^2aR^2b-；

X is-CR^1aR^1b-, - (O-, -S-or-SO)₂-；

Y-NH-C=O-；

Z is selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

ii) heteroaryl substituted with 1-2 substituents independently selected from R⁸And are and

iii) aryl substituted with 1-2 substituents independently selected from R⁸，

R^1aSelected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^1bselected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^2aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^2bselected from the group consisting of:

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

ii) phenyl, and

iii)C_1-6-an alkyl group;

or R^2aAnd R^2bTogether with the C to which they are attached form a tetrahydropyranyl group;

R³is halogen;

R⁴is halogen;

R⁵is hydrogen;

R⁶is hydrogen;

R^7ais hydrogen;

R^7bis hydrogen;

R⁸selected from the group consisting of:

i) the cyano group(s),

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

iii) halo-C_1-6-alkyl, and

iv)C_1-6-an alkoxy group,

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

A particular embodiment is a compound as described herein, wherein

V is-CR^7aR^7b-；

W is-CR^2aR^2b-；

X is-CR^1aR^1b-；

Y-NH-C=O-：

Z is selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

iii) aryl substituted with 1-2 substituents independently selected from R⁸，

R^1aSelected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^1bselected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^2aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^2bselected from the group consisting of:

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

ii) phenyl, and

iii)C_1-6-an alkyl group;

R³is halogen;

R⁴is halogen;

R⁵is hydrogen;

R⁶is hydrogen;

R^7ais hydrogen;

R^7bis hydrogen;

R⁸selected from the group consisting of:

i) the cyano group(s),

ii) halogen, and

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

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

A particular embodiment is a compound as described herein, wherein

X is-CR^1aR^1b-；

Y-NH-C=O-；

Z is by R⁸(ii) a substituted heteroaryl group, wherein,

R^1ais hydrogen;

R^1bis hydrogen;

R³is halogen;

R⁴is halogen;

R⁵is hydrogen;

R⁶is hydrogen;

R^7ais hydrogen;

R^7bis hydrogen;

R⁸selected from the group consisting of:

i) cyano radicals, and

ii) halogen, and

n is 0;

m is 1;

p is 0;

or a pharmaceutically acceptable salt thereof.

A particular embodiment are compounds as described herein, wherein n is 0.

A particular embodiment are compounds as described herein, wherein n is 1.

A particular embodiment are compounds as described herein, wherein m is 0.

A particular embodiment are compounds as described herein, wherein m is 1.

A particular embodiment are compounds as described herein, wherein p is 0.

A particular embodiment is a compound as described herein, wherein p is 1.

A particular embodiment is a compound as described herein, wherein X is-CR^1aR^1b-and R^1aAnd R^1bAre all hydrogen.

A particular embodiment is a compound as described herein, wherein X is-CR^1aR^1b-。

A particular embodiment are compounds as described herein, wherein R^1aIs hydrogen.

A particular embodiment are compounds as described herein, wherein R^1aIs a halogen.

A particular embodiment are compounds as described herein, wherein R^1aIs F.

A particular embodiment are compounds as described herein, wherein R^1aIs C_1-6-an alkyl group.

A particular embodiment are compounds as described herein, wherein R^1aIs methyl.

A particular embodiment are compounds as described herein, wherein R^1bIs hydrogen.

A particular embodiment are compounds as described herein, wherein R^1bIs a halogen.

A particular embodiment are compounds as described herein, wherein R^1bIs F.

A particular embodiment are compounds as described herein, wherein R^1bIs C_1-6-an alkyl group.

A particular embodiment are compounds as described herein, wherein R^1bIs methyl.

A particular embodiment is a compound as described herein, whereinR^2aIs C_1-6-an alkyl group.

A particular embodiment are compounds as described herein, wherein R^2aIs methyl.

A particular embodiment are compounds as described herein, wherein R^2aIs hydrogen.

A particular embodiment are compounds as described herein, wherein R^2bIs C_1-6-an alkyl group.

A particular embodiment are compounds as described herein, wherein R^2bIs methyl.

A particular embodiment are compounds as described herein, wherein R^2bIs hydrogen.

A particular embodiment are compounds as described herein, wherein R^2bIs an aryl group.

A particular embodiment are compounds as described herein, wherein R^2bIs phenyl.

A particular embodiment are compounds as described herein, wherein R^2aAnd R^2bTogether with the C to which they are attached form a heterocyclic group.

A particular embodiment are compounds as described herein, wherein R^2aAnd R^2bTogether with the C to which they are attached form a tetrahydropyranyl group.

A particular embodiment is a compound as described herein, wherein X is-O-.

A particular embodiment is a compound as described herein, wherein X is-S-.

A particular embodiment are compounds as described herein, wherein X is-SO₂-。

A particular embodiment is a compound as described herein, wherein p is 1 and W is-CR^2aR^2b-and R^2aAnd R^2bAre all hydrogen.

A particular embodiment is a compound as described herein, wherein V is-CR^7aR^7b-and R^7aAnd R^7bAre all hydrogen.

A particular embodiment is a compound as described herein, wherein V is-CR^7aR^7b-。

A particular embodiment are compounds as described herein, wherein R^7aIs hydrogen.

A particular embodiment are compounds as described herein, wherein R^7bIs hydrogen.

A particular embodiment is a compound as described herein, wherein W is-CR^2aR^2b-。

A particular embodiment are compounds as described herein, wherein R³Is a halogen.

A particular embodiment are compounds as described herein, wherein R³Is F.

A particular embodiment are compounds as described herein, wherein R⁴Is a halogen.

A particular embodiment are compounds as described herein, wherein R⁴Is F.

A particular embodiment are compounds as described herein, wherein R⁵Is hydrogen.

A particular embodiment are compounds as described herein, wherein R⁶Is hydrogen.

A particular embodiment is a compound as described herein, wherein Y is-NH-C = O-.

A particular embodiment are compounds as described herein, wherein Z is heteroaryl substituted with halo or cyano.

A particular embodiment are compounds as described herein, wherein Z is 2-chloropyridyl, 3, 5-dichlorophenyl, 3, 5-dichloropyridyl, 3-cyano-phenyl, 4-chloro-1H-pyrazolyl, 5-chloropyridyl, 5-cyanopyridyl, 5-fluoropyridyl, 5-methoxypyridyl, 5-trifluoromethylpyridyl or pyrimidinyl.

A particular embodiment are compounds as described herein, wherein Z is 2-chloropyridin-4-yl, 3, 5-dichlorophenyl, 3, 5-dichloropyridin-2-yl, 3-cyano-phenyl, 4-chloro-1H-pyrazol-5-yl, 5-chloropyridin-2-yl, 5-chloropyridin-3-yl, 5-cyanopyridin-2-yl, 5-cyanopyridin-3-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-trifluoromethylpyridin-2-yl, or pyrimidin-5-yl.

A particular embodiment are compounds as described herein, wherein Z is 5-cyanopyridin-2-yl, 5-chloropyridin-3-yl, or 5-fluoropyridin-2-yl.

A particular embodiment are compounds as described herein, wherein Z is heteroaryl.

A particular embodiment is a compound as described herein, wherein Z is pyrimidinyl.

A particular embodiment are compounds as described herein, wherein Z is heteroaryl substituted with 1-2 substituents independently selected from R⁸。

A particular embodiment are compounds as described herein, wherein Z is 1H-pyrazolyl, pyridinyl, or pyrimidinyl.

A particular embodiment are compounds as described herein, wherein Z is 1H-pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5-yl.

A particular embodiment are compounds as described herein, wherein Z is aryl.

One particular embodimentIs a compound as described herein, wherein Z is aryl substituted with 1-4 substituents independently selected from R⁸。

A particular embodiment are compounds as described herein, wherein Z is phenyl substituted with 1-2 substituents independently selected from chloro and cyano.

A particular embodiment are compounds as described herein, wherein R⁸Is cyano.

A particular embodiment are compounds as described herein, wherein R⁸Is a halogen.

A particular embodiment are compounds as described herein, wherein R⁸Is chlorine.

A particular embodiment are compounds as described herein, wherein R⁸Is fluorine.

A particular embodiment are compounds as described herein, wherein R⁸Is halo-C_1-6-an alkyl group.

A particular embodiment are compounds as described herein, wherein R⁸Is trifluoromethyl.

A particular embodiment are compounds as described herein, wherein R⁸Is C_1-6-alkoxy groups.

A particular embodiment are compounds as described herein, wherein R⁸Is methoxy.

A particular embodiment is a compound as described herein, selected from the group consisting of:

(R) -7- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(2 ' R, 4R) -6 ' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-a salt of 2-amine formic acid,

(2RS, 4R) -5 ', 5 ' -difluoro-2-phenyl-6- (pyrimidin-5-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(2RS, 4R) -6- (3, 5-dichlorophenyl) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]Oxazines]-a 2' -amine of the group consisting of,

(2RS, 4R) -6- (3, 5-dichlorophenyl) -6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-a 3' -amine of the group consisting of,

(2RS, 4R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chromane-4, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(2RS, 4R) -6- (5-Chloropyridin-3-yl) -6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4 ' ] -]Oxazazem]-a 3' -amine of the group consisting of,

(2RS, 4R) -6 ', 6' -difluoro-2-phenyl-6- (pyrimidin-5-yl) -6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-a 3' -amine of the group consisting of,

(2 ' S, 4R) -6 ' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-a salt of 2-amine formic acid,

(R) -3- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) benzonitrile,

(R) -4, 4, 5 ', 5 ' -tetrafluoro-7- (5-fluoropyridin-3-yl) -3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -5- (2 '-amino-4, 4, 5', 5 '-tetrafluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile,

(R) -5- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) nicotinonitrile,

(R) -5- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile,

(R) -5 ', 5' -difluoro-6- (5-methoxypyridin-3-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]Oxazines]-a 2' -amine of the group consisting of,

(R) -5 ', 5 ' -difluoro-6- (pyrimidin-5-yl) -2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -5 ', 5 ' -difluoro-6- (pyrimidin-5-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (2-Chloropyridin-4-yl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (3, 5-dichlorophenyl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (3, 5-dichlorophenyl) -5 ', 5' -difluoro-5 ', 6' -dihydrospiro [ chroman-4, 4 '- [1, 3' ]]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (3, 5-dichlorophenyl) -6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]Oxazazem]-a 3' -amine of the group consisting of,

(R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -6' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-a (2-amine) of a (meth) acrylic acid,

(R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -6- (5-Chloropyridin-3-yl) -6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-a 3' -amine of the group consisting of,

(R) -7- (5-Chloropyridin-3-yl) -4, 4, 5 ', 5 ' -tetrafluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 2-dimethyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 2-dimethyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-fluoropyridyl amide,

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5- (trifluoromethyl) picolinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-chloropyridyl amide,

(R) -N- (2 ' -amino-5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetra-fluoro-3Hydrogen-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-4, 4-dimethyl-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-cyanopyridinamide,

(R) -N- (2-amino-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-6' -yl) -5-chloropyridyl amide,

(R) -N- (2-amino-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-6' -yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide,

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -4-chloro-1H-pyrazole-5-carboxamide，

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4]]Oxazazem]-7-yl) -5-cyanopyridinamide,

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4]]Oxazazem]-7-yl) -5-chloropyridyl amide,

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-cyanopyridinamide,

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-chloropyridyl amide,

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -3, 5-dichloropyridyl amide,

3- ((2RS, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) benzonitrile,

3- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -diHydrogen-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-6-yl) benzonitrile,

3- [ (2' R, 4R) -2-amino-5, 5-difluoro-5, 5", 6, 6" -tetrahydro-4 "H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-6' -yl]The formate salt of a benzonitrile,

5- ((2RS, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) nicotinonitrile,

5- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) nicotinonitrile,

n- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide,

n- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamide,

n- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-fluoropyridyl amide,

n- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5- (trifluoromethyl) picolinamide,

n- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5- (trifluoromethyl) picolinamide,

n- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-cyanopyridinamide,

n- [ (2 'R, 4R) -2-amino-5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-6' -yl]-5-cyanopyridine-2-carboxamide,

n- [ (4R) -2-amino-5, 5-difluoro-1 ', 1' -dioxo-2 ', 3', 5, 6-tetrahydrospiro [1, 3-Oxazine-4, 4' -thiochromenes]-6' -yl]-5-chloropyridine-2-carboxamide, and

n- [ (4R) -2-amino-5, 5-difluoro-1 ', 1' -dioxo-2 ', 3', 5, 6-tetrahydrospiro [1, 3-Oxazine-4, 4' -thiochromenes]-6' -yl]-5-cyanopyridine-2-carboxamide,

or a pharmaceutically acceptable salt thereof.

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide, and

or a pharmaceutically acceptable salt thereof.

Particular embodiments of the present invention provide methods as described below,

wherein V, W, Y, Z, n, p, R¹、R²、R³、R⁴、R⁵And R⁶As defined herein and m is 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A certain embodiment of the present invention provides a method for the inhibition of BACE1 and/or BACE2 activity, in particular for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, alzheimer's disease, diabetes or type II diabetes, comprising administering a compound of formula I as described herein to a human being or animal.

A certain embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, diabetes or type II diabetes, which method comprises administering a compound of formula I as described herein to a human being or animal.

A certain embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, which method comprises administering a compound of formula I as described herein to a human being or animal.

A certain embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of diabetes, which method comprises administering a compound of formula I as described herein to a human being or animal.

A certain embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of type II diabetes, which method comprises administering a compound of formula I as described herein to a human being or animal.

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

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

all tautomeric forms are included in the invention.

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

Wherein X is-CR^1aR^1b(R^1a、R^1bIs hydrogen, lower alkyl or fluorine) and W is-CR^2aR^2b(wherein p =1, R^2a、R^2bIs hydrogen) the sulfenimide of the formula A2 can be prepared as follows: similar to t.p.tang&Ellman, j.org.chem.1999,64,12, by condensation of aryl ketones a1 with a sulfinamide, e.g. an alkyl sulfinamide, most particularly (R) - (+) -tert-butyl sulfinamide, in the presence of a lewis acid, such as e.g. a titanium (IV) alkoxide, more particularly a titanium (IV) ethoxide, in a solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.

The conversion of sulfinylimine a2 to sulfinamide ester A3 proceeds stereoselectively via a chiral directing group as described by Tang & Ellman. The sulfinimide A2 can be reacted in a Levomato reaction with a zinc enolate produced from, for example, an alkyl bromodifluoroacetate, especially ethyl bromodifluoroacetate, and a reactive zinc dust, at ambient to elevated temperatures, especially at 23 to 60 ℃ in a solvent such as an ether, for example diethyl ether or especially tetrahydrofuran.

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

Hydrolysis of the chiral directing group in the sulfinylamine alcohol of formula A4 gives the aminoalcohol of formula A5, which can be carried out with 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-bisIn an alkane.

Amino of the formula A6Oxazines may be prepared by reaction of an amino alcohol of formula a5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.

Reduction of derivatives of formula a6 wherein Q is nitro gives anilines of formula a7, which can be achieved by hydrogenation using a catalyst such as palladium on charcoal in protic solvents such as alcohols, especially ethanol or methanol.

Scheme A: synthesis of compounds of formulae i.1 and i.2.

The target amines of the formula I.1 can be prepared by reacting compounds of the formula A6 with compounds of the formula Z-R^aIs prepared by palladium-catalyzed cross-coupling (Suzuki-Miyaura-coupling) between derivatives of (a), wherein R is^aHas the meaning of boric acid or ester.

The target amides of the formula I.2 can be prepared by reacting an aniline of the formula A7 with a carboxylic acid of the formula Z-COOH in the presence of 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholinium chlorideHydrates (DMTMM) as condensationSelective coupling preparation in the case of reagents in solvents such as methanol.

Another typical procedure for the preparation of the aniline of formula a7 via the N-protected intermediate is shown in scheme a.1.

The protection of the amino group in the compound of formula A6 wherein Q is bromine for the preparation of aryl bromides of formula a6.1 can be carried out as follows: with triarylmethyl chlorides 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), in particular DMTr-Cl, under basic conditions, for example in the presence of amines such as triethylamine or diisopropylethylamine in chlorinated solvents such as dichloromethane or chloroform, at temperatures between 0 ℃ and ambient temperature.

The aryl bromides of formula A6.1 can be reacted with an ammonia equivalent such as benzophenone imine in a suitable transition metal catalyst such as bis (dibenzylideneacetone) palladium (O) ((dba)₂Pd) or tris (dibenzylideneacetone) dipalladium (O) [ (dba)₃Pd₂]And a suitable ligand such as rac-2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (t-Bu X-PHOS) in the presence of a base such as sodium tert-butoxide, potassium phosphate or cesium carbonate in a suitable solvent such as toluene or 1, 4-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (t-Bu X-PHOS)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 6.2.

Deprotection of the two amino groups in the compound of formula a6.2 can be accomplished as follows: by a one-pot procedure, it is first reacted with a strong organic acid, such as trifluoroacetic acid, in a chlorinated solvent, such as dichloromethane or chloroform, under anhydrous conditions, at a temperature between 0 ℃ and ambient temperature, to cleave P¹-a group. Water is then added to cleave the benzophenone imine and the reaction proceeds to the diamine of formula A7 at ambient temperature.

Scheme a.1: an alternative synthesis of an intermediate aniline of formula a7.

Sulfenimides of the formula B2, where X is O or S and W is-CR^2aR^2b(wherein p =1, R^2a，R^2bIs hydrogen, lower alkyl, phenyl, or forms a heterocyclic group together with the C to which they are attached) may form a heterocycloalkyl group), may form a heterocyclic group with T.P.Tang&J.a. ellman, j.org.chem.1999,64,12 are similarly prepared by condensation of aryl ketone B1 with a sulfenamide, such as an alkyl sulfenamide, most particularly (R) - (+) -tert-butyl sulfenamide, in a lewis acid such as a titanium (IV) alkoxide, more particularly titanium (IV) ethoxide, in a solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.

The conversion of sulfenimide B2 to sulfenamide ester B3 proceeds stereoselectively through a chiral directing group as described by Tang & Ellman. The sulfinimide B2 can be reacted in a Levomato reaction with a zinc enolate produced from, for example, an alkyl bromodifluoroacetate, especially ethyl bromodifluoroacetate, and a reactive zinc dust, at ambient to elevated temperatures, especially at 23 to 60 ℃ in a solvent such as an ether, for example diethyl ether or more especially tetrahydrofuran.

The alcohol of formula B4 can be prepared by reduction of the ethyl ester of formula B3 with a basic hydride, in particular lithium borohydride or lithium aluminum hydride, in a solvent such as an ether, for example diethyl ether or more particularly tetrahydrofuran.

Hydrolysis of the chirally directing group in the sulfinylamine alcohol of formula B4 affords the aminoalcohol of formula B5, which may be reacted with a mineral acid, such as sulfuric acid or, in particular, hydrochloric acid, in a solvent such as an ether, for example diethyl ether, tetrahydrofuran or, more in particular, 1, 4-bisIn alkane go to completionAnd (4) obtaining.

Amino of the formula B6Oxazines may be prepared by reaction of an amino alcohol of formula B5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.

The reduction of the derivative of formula B6 wherein Q is nitro for the aniline of formula B7 can be accomplished by hydrogenation using a catalyst, such as palladium on charcoal, in a protic solvent, such as an alcohol, especially ethanol or methanol.

Scheme B: synthesis of compounds of formulae i.3 and i.4.

The target amines of the formula I.3 can be prepared by reacting compounds of the formula B6 with compounds of the formula Z-R^aIn which R is R, under conditions known to the person skilled in the art, by palladium-catalyzed cross-coupling (Suzuki-Miyaura coupling)^aHas the meaning of boric acid or ester.

The target amides of the formula I.4 can be prepared by reacting an aniline of the formula B7 with a carboxylic acid of the formula Z-COOH with 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholinium chlorideSelective coupling preparation of hydrate (DMTMM) as condensing agent in solvent such as methanol.

Target amides of the formula I.3 or I.4, wherein X is SO₂It can be prepared from compounds of formula i.3 or i.4, wherein X is S, by oxidation in an inert solvent at a temperature between 0 ℃ and ambient temperature using, for example, potassium monopersulfate as the oxidizing agent.

Alternatively, as shown in scheme b.1, anilines of formula B7 can be prepared via N-protected intermediates.

Protection of the amino group in the compound of formula a6, wherein Q is bromine, gives an aryl bromide of formula B6.1, which 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), in particular 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 a temperature between 0 ℃ and ambient temperature.

The aryl bromides of formula B6.1 can be reacted with an ammonia equivalent such as benzophenone imine in a suitable transition metal catalyst such as bis (dibenzylideneacetone) palladium (O) ((dba)₂Pd) or tris (dibenzylideneacetone) dipalladium (O) [ (dba)₃Pd₂]And a suitable ligand such as rac-2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (rac-BINAP), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (t-Bu X-PHOS) in the presence of a base such as sodium tert-butoxide, potassium phosphate or cesium carbonate in a suitable solvent such as toluene or 1, 4-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (t-Bu X-PHOS)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 B6.2.

Deprotection of the two amino groups in the compound of formula B6.2 can be accomplished as follows: by a one-pot procedure, it is first reacted with a strong organic acid, such as trifluoroacetic acid, in a chlorinated solvent, such as dichloromethane or chloroform, under anhydrous conditions, at a temperature between 0 ℃ and ambient temperature, to cleave P¹-a group. Water is then added to cleave the benzophenone imine and the reaction proceeds to the diamine of formula B7 at ambient temperature.

Scheme B.1: an alternative synthesis of an intermediate aniline of formula B7.

Alkylation of an alcohol of formula a4 or B4 to a nitrile of formula C1 can be accomplished with a suitable mild base, particularly silver (I) oxide, in a solvent such as tetrahydrofuran or dichloromethane, more particularly dichloromethane, in the presence of an alkylation catalyst such as tetra-butylammonium iodide.

Hydrolysis of the chirally directing group in a nitrile of formula C1 gives an aminonitrile of formula C2, which can be reacted with a mineral acid, such as sulfuric acid or especially hydrochloric acid, in a solvent such as an ether, for example diethyl ether or more especially 1, 4-bisAnd (3) finishing in alkane.

An aminooxazepine of formula C3Can be prepared by reaction of an aminonitrile of the formula C2 with trimethylaluminum in a solvent such as xylene or toluene, in particular toluene.

The reduction of the derivative of formula C3, wherein Q is nitro, gives the aniline of formula C4, which can be accomplished by hydrogenation using a catalyst, such as palladium on charcoal, in a protic solvent, such as an alcohol, in particular ethanol or methanol.

Scheme C: synthesis of compounds of formulae i.5 and i.6.

The target amines of the formula I.5 can be prepared by reacting compounds of the formula C3 with compounds of the formula Z-R^aIs prepared under palladium-catalyzed cross-coupling conditions (Suzuki-Miyaura coupling) under conditions known to those skilled in the art, wherein R is^aHas the meaning of boric acid or ester.

The target amides of the formula I.6 can be prepared by reacting anilines of the formula C4 with carboxylic acids of the formula Z-COOH with 4- (4, 6)-dimethoxy [1.3.5]Triazin-2-yl) -4-methylmorpholinium chlorideSelective coupling preparation of hydrate (DMTMM) as condensing agent in solvent such as methanol.

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

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

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

Pharmacological testing

The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are associated with the inhibition of BACE1 and/or BACE2 activity. The compounds were investigated according to the tests given below.

Cellular a β reduction assay:

a) human HEK293 cells stably transfected with a vector expressing cDNA of the human APP wt gene (APP695) were used to assess potency of compounds in cellular assays. Cells were seeded in 96-well microtiter plates, in cell culture medium (Iscove, plus 10% (v/v) fetal calf serum, glutamine, penicillin/streptomycin) to about 80% confluency, and compounds were added at 10x concentration in 1/10 volumes of medium without FCS containing 8% DMSO (final concentration of DMSO is maintained at 0.8% v/v). In a humidified incubator at 37 ℃ and 5% CO₂After 18-20 hours of incubation, the culture medium supernatant was harvested for determination of the concentration of A.beta.40. 96-well ELISA plates (e.g., Nunc MaxiSorb) were coated with monoclonal antibodies that specifically recognize the C-terminal end of A.beta.40 (Brockhaus et al, NeuroReport9, 1481-1486; 1998). After blocking of non-specific binding sites with, e.g., 1% BSA and washing, the culture supernatant is added at an appropriate dilution with horseradish peroxidase-conjugated a β detection antibody (e.g., antibody 4G8, Senetek, Maryland Heights, MO) and incubated for 5 to 7 hours. The wells of the microtiter plate were then washed thoroughly with Tris buffered saline containing 0.05% Tween20 and the assay was washed with tetramethylbenzidine/H in citrate buffered saline₂O₂Color development (develoop). In the presence of a volume of 1NH₂SO₄After stopping the reaction, the reaction was measured at 450nm wavelength on an ELISA reader. The concentration of a β in the culture supernatant was calculated from a standard curve obtained with known amounts of pure a β peptide.

b) Alternatively, the a β 40AlphaLISA assay may be used. HEK293APP cells were seeded in 96-well microtiter plates, in cell culture medium (Iscove's plus 10% (v/v) fetal bovine serum, penicillin/streptomycin) to approximately 80% confluency, and compound was added at 3x concentration in 1/3 volumes of medium (final concentration of DMSO was maintained at 1% v/v). In a humidified incubator at 37 ℃ and 5% CO₂Incubation 18-2After 0 hours, the media supernatant was harvested for determination of A β 40 concentration using the Perkin-Elmer Human Amoloid 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 Excel XLfit software.

BACE inhibition assay by measuring cellular TMEM27 lysis:

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

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

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

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

Table 1: IC of selected embodiments₅₀The value of the one or more of,^a)and^b)indicates the corresponding cellular assay used.

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-liquid 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 l to 100mg, of a compound of the formula I. Examples of compositions according to the invention are:

example A

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

table 2: possible tablet compositions

Manufacturing process

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

2. The granules were dried at 50 ℃.

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

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

Example B-1

Capsules of the following composition were prepared:

table 3: possible capsule ingredient composition

Manufacturing process

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

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

3. Filling into suitable capsules.

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

Example B-2

Soft gelatin capsules of the following composition were prepared:

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

Table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		Karion83	8 (Dry matter)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 5: possible soft gelatin capsule compositions

Manufacturing process

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

Example C

Suppositories of the following composition were prepared:

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

Table 6: possible suppository composition

Manufacturing process

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

Example D

Injection solutions of the following composition were prepared:

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

Table 7: possible injection solution compositions

Manufacturing process

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

Example E

Sachets of the following composition were made:

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

Table 8: possible sachet composition

Manufacturing process

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

Experimental part

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

MS: mass Spectrometry (MS) was measured with either positive or negative ion spray (ISP or ISN) on a Perkin-Elmer SCIEX API300 or electron bombardment (EI, 70eV) on a Finnigan MAT SSQ7000 spectrometer.

Synthesis of intermediate sulfinylimine A2

General procedure

To a solution of (R) - (+) -tert-butylsulfinamide (66mmol) in tetrahydrofuran (350ml) were added successively ketone A1(72.6mmol) and titanium (IV) ethoxide (132mmol) and the solution was stirred at reflux temperature for 5 hours. The mixture was cooled to 22 ℃ and treated with brine (400 ml). The suspension was stirred for 10 minutes and then stirred atAnd (4) filtering. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate as eluent to give pure sulfinimide a2.

Intermediate A2.1(X=-CR^1a，R^1b；R^1a，R^1b=H；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 7-bromo-3, 4-dihydro-2H-naphthalen-1-one { CAS [32281-97-3 ]]} (intermediate A1.1) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ 7-bromo-3, 4-dihydro-2H-naphthalen- (1E) ylidene]Amide (64% yield) as yellow solid. Ms (isp): m/z =328.1[ M + H ]]⁺And 329.9[ M +2+ H]⁺。

Intermediate A2.2(X=-CR^1a，R^1b；R^1a，R^1b=H；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 7-nitro-3, 4-dihydro-2H-naphthalen-1-one { CAS [40353-34-2] } (intermediate a1.2), the product (R) -2-methyl-propane-2-sulfinic acid [ 7-nitro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene ] -amide was obtained (62% yield) as a yellow solid.

Intermediate A2.3(X=-CR^1a，R^1b；R^1a，R^1b=CH₃；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 4, 4-dimethyl-7-nitro-3, 4-dihydro-2H-naphthalen-1-one (WO03095430) (intermediate A1.3), the product (R) -2-methyl-propane-2-sulfinic acid [4, 4-dimethyl-7-nitro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene-1-ylidene-is obtained]Amide (66% yield) as yellow solid. Ms (isp): m/z =323.5[ M + H [ ]]⁺。

Intermediate A2.4(X=-CR^1a，R^1b；R^1a，R^1b=F；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen-1-one (intermediate A1.4), the product (R) -2-methyl-propane-2-sulfinic acid [ 7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene acid ] is obtained]Amide (97% yield) as a light brown solid. Ms (isp): m/z =365.9[ M + H [ ]]⁺。

7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen-1-one (intermediate A1.4) was obtained as follows:

a)6 ' -bromo-3 ', 4 ' -dihydro-2 ' H-spiro [ [1,3] dithiocyclopentane-2, 1 ' -naphthalene ]

A solution of 6-bromo-3, 4-dihydro-2H-naphthalen-1-one (CAS [66361-67-9]) (0.9g, 4.00mmol) in dichloromethane (8ml) was cooled to 0 ℃ and treated with 1, 2-ethanedithiol (769mg, 686. mu.l, 8.00mmol) and boron trifluoroacetate (284mg, 247. mu.l, 2.00 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 hours. For work-up, the reaction mixture was poured into a solution of sodium hydroxide (1N) and extracted with dichloromethane (40 ml). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using heptane/ethyl acetate = 100: 0 to 70: a gradient of 30 as eluent. 6 ' -bromo-3 ', 4 ' -dihydro-2 ' H-spiro [ [1,3] dithiocyclopentane-2, 1 ' -naphthalene ] (1.06g, 88% yield) was obtained as a pale red oil.

b) 6-bromo-1, 1-difluoro-1, 2,3, 4-tetrahydro-naphthalene

A suspension of N-iodosuccinimide (1.78g, 7.9mmol) in dichloromethane (15ml) was cooled to-70 ℃. Hydrogen fluoride-pyridine (1.57g, 1.42ml, 15.8mmol) was added dropwise. Adding 6 '-bromo-3', 4 '-dihydro-2' H-spiro [ [1,3] dropwise]Dithiocyclopentane-2, 1' -naphthalene]A cold solution (-70 ℃ C.) of (1.19g, 3.95mmol) in dichloromethane (10ml) and the white suspension turned brown. The mixture was stirred at-70 ℃ for 15 minutes. For work-up, the dark red solution was poured into a mixture of hexane (50ml) and dichloromethane (10 ml). The dark solution is passed through a silica gel layer first and then through silica-NH₂Harmonizing diatomaceous earth (dicalite)And (3) a layer. Will be provided withThe resulting colorless solution was evaporated and the crude product was purified by chromatography on silica gel using heptane/ethyl acetate = 100: 0 to 90: a gradient of 10 as eluent. 6-bromo-1, 1-difluoro-1, 2,3, 4-tetrahydro-naphthalene (668mg, 68% yield) was obtained as a pale yellow oil.

c) 7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen-1-one

A solution of 6-bromo-1, 1-difluoro-1, 2,3, 4-tetrahydro-naphthalene (691mg, 2.8mmol) in tert-butanol (7 ml). A solution of potassium dihydrogen phosphate (769mg, 5.59mmol) in water (2ml) and a solution of sodium phosphate heptahydrate (1.51g, 5.59mmol) in water (2ml) were added. Thereafter, potassium permanganate (670mg, 4.2mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. For work-up, the mixture was diluted with ethyl acetate (200ml), the organic layer was separated, washed with water (10ml) and brine (10ml), finally dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using heptane/ethyl acetate = 100: 0 to 80: a gradient of 20 as eluent. 7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen-1-one (515mg, 71% yield) was obtained as a colorless oil.

Intermediate A2.5(X=-CR^1a，R^1b；R^1a，R^1b=H；p=0)

Starting from 6-bromo-indan-1-one { CAS [14548-39-1 ]]} (intermediate A1.5) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-indan- (1E) -ylidene acid]Amide (34% yield) as yellow solid. Ms (isp): m/z =314.2[ M + H [ ]]⁺。

Intermediate A2.6(X=-CR^1a，R^1b；R^1a，R^1b=H；p=0)

Starting from 6-nitro-indan-1-one { CAS [24623-24-3 ]]} (intermediate A1.6), the product (R) -2-methyl-propane-2-sulfinic acid [ 6-nitro-indan- (1E) -ylidene acid is obtained]Amide (51% yield) as a dark semi-solid. Ms (isp): m/z =281.0[ M + H [ ]]⁺。

Synthesis of intermediate sulfonamido ester A3

General procedure (via the Lifomazki reaction)

In a dry apparatus, a suspension of freshly activated zinc powder (1.63g, 24.9mmol) in anhydrous tetrahydrofuran (70ml) was heated to reflux under an inert atmosphere. A solution of sulfinimide A2(24.9mmol) and bromo-acetate (24.9mmol) in anhydrous tetrahydrofuran (15ml) was added dropwise over a period of 15min, and the suspension was heated to reflux for 5h (5 h). The cooled mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate, the organic layer was dried and evaporated. The crude material was purified by flash chromatography using heptane/ethyl acetate as eluent to give the sulfonamido ester a3.

Intermediate A3.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 7-bromo-3, 4-dihydro-2H-naphthalen- (1E) -ylidene]Amide (intermediate a2.1) to give the product [ (R) -7-bromo-1- ((R) -2-methyl-propane-2-sulfinylamino) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (90% yield) as light brown oil. Ms (isp): m/z =452.1[ ]M+H]⁺And 454.1[ M +2+ H]⁺。

Intermediate A3.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 7-nitro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene]Amide (intermediate a2.2) to give the product difluoro- [ (R) -1- ((R) -2-methyl-propane-2-sulfinylamino) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Ethyl acetate (83% yield) as yellow oil. Ms (isp): m/z =419.2[ M + H%]⁺。

Intermediate A3.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [4, 4-dimethyl-7-nitro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene]Amide (intermediate a2.3) to give the product [ (R) -4, 4-dimethyl-1- ((R) -2-methyl-propane-2-sulfinylamino) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (73% yield) as yellow oil. Ms (isp): m/z =447.5[ M + H [ ]]⁺。

Intermediate A3.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 7-bromo-4, 4-difluoro-3, 4-dihydro-2H-naphthalen- (1E) -ylidene]-amide (intermediate A2.4) and ethyl 2-bromo-2, 2-difluoroacetate to obtain the product [ (R) -7-bromo-4, 4-difluoro-1- ((R) -2-methyl-propane-2-sulfinylamino) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (58% yield) as a brown solid. Ms (isp): m/z =488.1[ M + H [ ]]⁺And 490.0[ M + H]⁺。

Intermediate A3.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-indan- (1E) -ylidene]-amide (intermediate a2.5) to yield the product [ (R) -6-bromo-1- ((R) -2-methyl-propane-2-sulfinylamino) -indan-1-yl]Difluoro-ethyl acetate (43% yield) as a dark brown solid. Ms (isp): m/z =438.0[ M + H [ ]]⁺。

Intermediate A3.6

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-nitro-indan- (1E) -ylidene]-amide (intermediate a2.6) to obtain the product difluoro- [ (R) -1- ((R) -2-methyl-propane-2-sulfinylamino) -6-nitro-indan-1-yl]Ethyl acetate (60% yield) as a dark colored semi-solid. Ms (isp): m/z =405.0[ M + H [ ]]⁺。

Synthesis of intermediate sulfonamidol A4

General procedure

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

Intermediate A4.1

Starting from [ (R) -7-bromo-1- ((R) -2-methyl-propane-2-sulfinylamino) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (intermediate a3.1) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -7-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (45% yield) as white solid. Ms (isp): m/z =410.1[ M + H%]⁺And 412.1[ M +2+ H]⁺。

Intermediate A4.2

Starting from difluoro- [ (R) -1- ((R) -2-methyl-propane-2-sulfinylamino) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]-ethyl acetate (intermediate a3.2) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (92% yield) as brown solid. Ms (isp): m/z =377.4[ M + H ]]⁺。

Intermediate A4.3

Starting from [ (R) -4, 4-dimethyl-1- ((R) -2-methyl-propane-2-sulfinylamino) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (intermediate A3.3) to yield the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -4, 4-dimethyl-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (50% yield) as a light brown solid. Ms (isp): m/z =405.5[ M + H [ ]]⁺。

Intermediate A4.4

Starting from [ (R) -7-bromo-4, 4-difluoro-1- ((R) -2-methyl-propane-2-sulfinylamino) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Difluoro-ethyl acetate (intermediate a3.4) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -7-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -4, 4-difluoro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (100% yield) as a grey foam. Ms (isp): m/z =446.0[ M + H%]⁺And 447.9[ M + H ]]⁺。

Intermediate A4.5

Starting from [ (R) -6-bromo-1- ((R) -2-methyl-propane-2-sulfinylamino) -indan-1-yl]Difluoro-ethyl acetate (intermediate a3.5) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -indan-1-yl]Amide (77% yield) as a dark brown solid. Ms (isp): m/z =395.8[ M + H [ ]]⁺。

Intermediate A4.6

Starting from difluoro- [ (R) -1- ((R) -2-methyl)-propane-2-sulfinylamino) -6-nitro-indan-1-yl]-ethyl acetate (intermediate a3.6) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-indan-1-yl]Amide (84% yield) as a dark brown solid. Ms (isp): m/z =363.2[ M + H [ ]]⁺。

Synthesis of intermediate amino alcohol A5

General procedure:

a solution of sulfinamidol A4(10.3mmol) in methanol or tetrahydrofuran (30 to 60ml) was dissolved with hydrochloric acid in 1, 4-bisThe solution in alkane (4M, 10-13ml) was treated and stirring continued at 23 ℃ for 2 to 18 h. The mixture was partitioned between ethyl acetate and aqueous sodium carbonate (2M), the organic layer was dried over sodium sulfate, filtered and evaporated to give a residue which was purified by chromatography on silica using a mixture of n-heptane and ethyl acetate as eluent to give the pure amino alcohol a5.

Intermediate A5.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -7-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (intermediate a4.1) to give the product 2- ((R) -1-amino-7-bromo-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (25% yield) as a pale yellow gum. Ms (isp): m/z =306.0[ M + H [ ]]⁺And 308.1[ M +2+ H]⁺。

Intermediate A5.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (intermediate a4.2) to give the product 2- ((R) -1-amino-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (74% yield) as a light yellow solid. Ms (isn): m/z =271.3[ M-H]^-。

Intermediate A5.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -4, 4-dimethyl-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (intermediate a4.3) to give the product 2- ((R) -1-amino-4, 4-dimethyl-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (49% yield) as an off-white foam. Ms (isp): m/z =301.4[ M + H%]⁺。

Intermediate A5.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -7-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -4, 4-difluoro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]-amide (intermediate a4.4) to give the product 2- ((R) -1-amino-7-bromo-4, 4-difluoro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (44% yield) as a yellow oil. Ms (isp): m/z =342.0[ M + H ]]⁺And 344.0[ M +2+ H]⁺。

Intermediate A5.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-1- (1, 1-difluoro-2-hydroxy-ethyl) -indan-1-yl]-amide (intermediate a4.5) to give the product 2- ((R) -1-amino-6-bromo-indan-1-yl) -2, 2-difluoro-ethanol (81% yield) as a dark brown solid. Ms (isp): m/z =291.0[ M + H [ ]]⁺。

Intermediate A5.6

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-indan-1-yl]-amide (intermediate a4.6) to give the product 2- ((R) -1-amino-6-nitro-indan-1-yl) -2, 2-difluoro-ethanol (70% yield) as a dark brown solid. Ms (isp): m/z =258.9[ M + H%]⁺。

Intermediate amino group Synthesis of oxazine A6

General procedure

The dried tube was charged with a mixture of amino alcohol A5(18.8mmol), cyanogen bromide (33.9mmol) and ethanol (61 ml). The tube was sealed and heated at 90 ℃ for 16 hours. For work-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (150ml) and saturated aqueous sodium carbonate (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (2 × 50 ml). The organic layers were washed with brine (50ml) then combined, dried over sodium sulfate and evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate A6.1

Starting from 2- ((R) -1-amino-7-bromo-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (intermediate as.1), the product (R) -7-bromo-5 ', 5' -difluoro-3, 4, 5 ', 6' -tetrahydro-2H-spiro [ naphthalene-1, 4 '- [1, 3' ] -]Oxazines]-2' -amine (50% yield) as white solid. Ms (isp): m/z =331.0[ M + H [ ]]⁺And 333.0[ M +2+ H]⁺。

Intermediate A6.2

Starting from 2- ((R) -1-amino-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (intermediate a5.2), the product (R) -5 ', 5' -difluoro-7-nitro-3, 4, 5 ', 6' -tetrahydro-2H-spiro [ naphthalene-1, 4 '- [1, 3' ] -]Oxazines]-2' -amine (62% yield) as white solid. Ms (isp): m/z =298.2[ M + H [ ]]⁺。

Intermediate A6.3

Starting from 2- ((R) -1-amino-4, 4-dimethyl-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol(intermediate A5.3) to obtain the product (R) -5 ', 5 ' -difluoro-4, 4-dimethyl-7-nitro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2' -amine (51% yield) as pale yellow gum. Ms (isp): m/z =326.5[ M + H%]⁺。

Intermediate A6.4

Starting from 2- ((R) -1-amino-7-bromo-4, 4-difluoro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethanol (intermediate a5.4), the product (R) -7-bromo-4, 4, 5 ', 5 ' -tetrafluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2' -amine (65% yield) as white solid. Ms (isp): m/z =366.9[ M + H [ ]]⁺And 369.0[ M + H ]]⁺。

Intermediate A6.5

Starting from 2- ((R) -1-amino-6-bromo-indan-1-yl) -2, 2-difluoro-ethanol (intermediate a5.5), the product (R) -6-bromo-5 ', 5' -difluoro-2, 3, 5 ', 6' -tetrahydrospiro [ indene-1, 4 '- [1, 3' - [ is obtained]Oxazines]-2' -amine (64% yield) as off-white solid. Ms (isp): m/z =346.8[ M + H ]]⁺。

Intermediate A6.6

a) (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-indan-1-yl-cyanamide

A mixture of 2- ((R) -1-amino-6-nitro-indan-1-yl) -2, 2-difluoro-ethanol (intermediate A5.6), (1.6g, 6.2mmol) and sodium acetate (1.54g, 18.6mmol) in ethanol (30ml) was warmed to 40 ℃. The mixture was then treated with cyanogen bromide (724mg, 6.82mmol) and allowed to stir at 40 ℃ for 16 h. The crude material obtained after removal of the solvent under reduced pressure was purified by column chromatography on silica gel using 3: purification of the mixture of 2 as eluent yielded (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-indan-1-yl-cyanamide (800mg, 42% yield) as a colorless viscous solid. Ms (isp): m/z =284.0[ M + H [ ]]⁺。

b) (R) -5 ', 5 ' -difluoro-6-nitro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a tube, a solution of (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-indan-1-yl-cyanamide (1.0g, 3.55mmol) in methanol (10ml) was treated with ammonium hydroxide (25% solution in water, 3 ml). The tube was sealed and heated at 60 ℃ for 16 hours. For work-up, the reaction mixture was evaporated under reduced pressure. The crude material was purified by column chromatography (NH-biotage) using 95: 5 the mixture is purified as eluent. To obtain (R) -5 ', 5 ' -difluoro-6-nitro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (500mg, 50% yield) as a white solid. Ms (isp): m/z =283.4[ M + H [ ]]⁺。

Synthesis of intermediate aniline A7

General procedure

Nitro groups were reacted using palladium (10%, charcoal) (159mg, 150. mu. mol) as a catalystA solution of oxazine A6(3mmol) in ethanol (31ml) was hydrogenated at atmospheric pressure. The reaction was complete after 90 minutes. The reaction mixture was filtered over dicalite layer, which was washed with ethanol (3 × 20 ml). The combined ethanol solution was evaporated under reduced pressure. The product was used in step without further purification.

Intermediate A7.1

Starting from (R) -5 ', 5 ' -difluoro-7-nitro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2 '-amine (intermediate a6.2) to obtain the product (R) -5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]2', 7-diamine (58% yield) as a light brown solid. Ms (isp): m/z =268.3[ M + H [ ]]⁺。

Intermediate A7.2

Starting from (R) -5 ', 5' -difluoro-4, 4-dimethyl-7-nitro-3, 4, 5 ', 6'-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-2 '-amine (intermediate a6.3) to obtain the product (R) -5', 5 '-difluoro-4, 4-dimethyl-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]2', 7-diamine (88% yield) as a pale yellow foam. Ms (isp): m/z =296.4[ M + H [ ]]⁺。

Intermediate A7.3

Starting from (R) -5 ', 5 ' -difluoro-6-nitro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2 '-amine (intermediate a6.6) to obtain the product (R) -5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]2', 6-diamine (75% yield) as a yellow viscous liquid. Ms (isp): m/z =254.0[ M + H ]]⁺。

Example 1

(R) -7- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a tube, (R) -7-bromo-5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]A mixture of-2' -amine (intermediate A6.1) (35mg, 106. mu. mol), 5-chloropyridin-3-ylboronic acid (17mg, 106. mu. mol) and cesium carbonate (138mg, 423. mu. mol) in tetrahydrofuran (2.8ml) and water (1.4ml) was purged with argon for 5 minutes. Thereafter, [1, 1' -bis (diphenylphosphino) ferrocene ] was added]Palladium (II) dichloride (3.9mg, 5.3. mu. mol), the tube was sealed and the mixture was heated at 80 ℃ for 25 minutes. For work-up, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using heptane/ethyl acetate = 100: 0 to 0: a gradient of 100 as eluent. To obtain (R) -5- (2 '-amino-4, 4, 5', 5 '-tetrafluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile (24mg, 63% yield) as an off-white solid. Ms (isp): m/z =364.1[ M + H%]⁺。

Example 2

(R) -5- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile

In a similar manner to that described in example 1, (R) -7-bromo-5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate a6.1) with 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinonitrile yielded the title compound (72% yield) as an off-white solid. Ms (isp): m/z =355.2[ M + H [ ]]⁺。

Example 3

(R) -7- (5-chloro)Pyridin-3-yl) -4, 4, 5 ', 5 ' -tetrafluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -7-bromo-4, 4, 5 ', 5' -tetrafluoro-3, 4, 5 ', 6' -tetrahydro-2H-spiro [ naphthalene-1, 4 '- [1, 3' ] -]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate a6.4) with 5-chloropyridin-3-ylboronic acid yielded the title compound (28% yield) as a white solid. Ms (isp): m/z =399.9[ M + H [ ]]⁺。

Example 4

(R) -4, 4, 5 ', 5 ' -tetrafluoro-7- (5-fluoropyridin-3-yl) -3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -7-bromo-4, 4, 5 ', 5' -tetrafluoro-3, 4, 5 ', 6' -tetrahydro-2H-spiro [ naphthalene-1, 4 '- [1, 3' ] -]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate a6.4) with 5-fluoropyridin-3-ylboronic acid yielded the title compound (32% yield) as a pale yellow solid. Ms (isp): m/z =384.0[ M + H [ ]]⁺。

Example 5

(R) -5- (2 '-amino-4, 4, 5', 5 '-tetrafluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile

To and fromIn a similar manner to that described in example 1, (R) -7-bromo-4, 4, 5 ', 5' -tetrafluoro-3, 4, 5 ', 6' -tetrahydro-2H-spiro [ naphthalene-1, 4 '- [1, 3' ] -]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate a6.4) with 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinonitrile yielded the title compound (51% yield) as a yellow solid. Ms (isp): m/z =390.3[ M [ ]]⁺。

Example 6

(R) -6- (2-Chloropyridin-4-yl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with 5-chloropyridin-3-ylboronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound (25% yield) as an off-white solid. Ms (isp): m/z =349.8[ M + H [ ]]⁺。

Example 7

(R) -5 ', 5 ' -difluoro-6- (pyrimidin-5-yl) -2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with pyrimidin-5-ylboronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound (19% yield) as an off-white solid. Ms (isp): m/z =317.0[ M + H [ ]]⁺。

Example 8

(R) -6- (3, 5-dichlorophenyl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with 3, 5-dichlorophenyl boronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound (15% yield) as an off-white solid. Ms (isp): m/z =382.8[ M + H [ ]]⁺。

Example 9

(R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with 5-chloropyridin-3-ylboronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound (19% yield) as a white solid.MS(ISP)：m／z=349.8[M+H]⁺。

Example 10

(R) -3- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) benzonitrile

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with 3-cyanophenylboronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound (10% yield) as an off-white solid. Ms (isp): m/z =340.2[ M + H%]⁺。

Example 11

(R) -5- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) nicotinonitrile

In a similar manner to that described in example 1, (R) -6-bromo-5 ', 5' -difluoro-2, 3, 5 ', 6-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-2' -amine (intermediate a6.5) with 5-cyanopyridin-3-ylboronic acid in 3: 1 cross-coupling reaction in the mixture yielded the title compound as an off-white solid.

General procedure for the preparation of amides of formula i.2:

a solution of formic acid (0.23mmol) in methanol (5ml) was preparedThe solution was cooled to 0 ℃. Adding 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholinium chlorideHydrate (DMTMM) (80mg, 0.27mmol) and the solution was stirred at 0 ℃ for 30 min. Thereafter, a solution of intermediate diamine A8(0.21mmol) in methanol (5ml) was added dropwise via syringe at 0 ℃. The reaction mixture was stirred at 23 ℃ for 18-60 hours. For work-up, the reaction mixture was poured into a solution of sodium carbonate (1M) and then extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure, leaving a residue which is chromatographed on silica gel or on silica-NH₂The phases are purified using a mixture of dichloromethane and methanol (0-10%) to give the pure amide of formula I.

Example 12

(R) -N- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-chloropyridyl amide

(R) -5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 7-diamine (intermediate a7.1) and 5-chloropicolinic acid yielded the title compound (42% yield) as a white solid. Ms (isp): m/z =407.2[ M + H%]⁺。

Example 13

(R) -N- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 7-diamine (intermediate a7.1) and 5-cyanopicolinic acid yielded the title compound (38% yield) as a white solid. Ms (isp): m/z =398.2[ M + H ]]⁺。

Example 14

(R) -N- (2 '-amino-5', 5 '-difluoro-4, 4-dimethyl-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-4, 4-dimethyl-3, 4, 5 ', 6 ' -tetrahydro-2H-spiro [ naphthalene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 7-diamine (intermediate a7.2) and 5-cyanopicolinic acid yielded the title compound (65% yield) as a light yellow solid. Ms (isp): m/z =426.0[ M + H [ ]]⁺。

Example 15

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate a7.3) and 5-cyanopicolinic acid yielded the title compound (27% yield) as an off-white solid. Ms (isp): m/z =384.2[ M + H [ ]]⁺。

Example 16

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide

(R) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate a7.3) and 5-chloropicolinic acid yielded the title compound (16% yield) as an off-white solid. Ms (isp): m/z =393.0[ M + H ]]⁺。

Example 17

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5-fluoropyridyl amide

(R) -5 ', 5 ' -difluoro-2, 3, 5 ', 6 ' -tetrahydrospiro [ indene-1, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate a7.3) and 5-fluoropicolinic acid gave the title compound (17% yield) as an off-white solid. Ms (isp): m/z =377.2[ M + H [ ]]⁺。

Example 18

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 3, 5', 6 '-tetrahydrospiro [ indene-1, 4' - [1,3]]Oxazines]-6-yl) -5- (trifluoromethyl) picolinamide

(R) -5 ', 5 ' -difluoro-2, 3, 5 '6 '-Tetrahydropiro [ indene-1, 4' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate a7.3) and 5- (trifluoromethyl) picolinic acid gave the title compound (15% yield) as an off-white solid. Ms (isp): m/z =427.2[ M + H [ ]]⁺。

Synthesis of intermediate sulfinylimine B2

General procedure

To a solution of (R) - (+) -tert-butylsulfinamide (66mmol) in tetrahydrofuran (350ml) were added successively ketone B1(72.6mmol) and titanium (IV) ethoxide (132mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 ℃, treated with brine (400ml), the suspension stirred for 10 minutes and washed with celite (R) (K)) And (4) filtering. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate as eluent to give pure sulfinimide B2.

Intermediate B2.1(X=O；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 6-bromo-chroman-4-one { CAS [49660-57-3 ]]} (intermediate B1.1) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-chroman- (4E) -ylidene acid]Amide (69% yield) as light yellow oil. Ms (isp): m/z =332.0[ M + H ]]⁺。

Intermediate B2.2(X=O；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 6-nitro-chroman-4-one { CAS [68043-53-8 ]]} (intermediate B1.2) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ 6-nitro-chroman- (4E) -ylidene acid]Amide (85% yield) as yellow oil. Ms (isp): m/z =297.2[ M + H [ ]]⁺。

Intermediate B2.3(X=O；W=-CR^2a，R^2b；R^2a= phenyl, R^2b=H；p=1)

Starting from (RS) -6-bromo-2-phenyl-chroman-4-one { CAS [56414-11-0 ]](ii) a WO2010021680} (intermediate B1.3) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (RS) -6-bromo-2-phenyl-chroman- (4E) -ylidene]Amide (64% yield) as yellow solid. Ms (isp): m/z =407[ M + H ]]⁺。

Intermediate B2.4(X=O；W=-CR^2a，R^2b；R^2a= phenyl, R^2b=H；p=1)

Starting from (RS) -6-nitro-2-phenyl-chroman-4-one { CAS [3034-03-5 ]]} (intermediate B1.4) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (RS) -6-nitro-2-phenyl-chroman- (4E) -ylidene]Amide (43% yield) as a yellow solid. Ms (isp): m/z =373[ M + H ]]⁺。

Intermediate B2.5(X=O；W=-CR^2a，R^2b；R^2a，R^2b= methyl, R^2b=H；p=1)

Starting from 6-bromo-2, 2-dimethyl-chroman-4-one { CAS [99853-21-1 ]](ii) a WO2010021680} (intermediate B1.5) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-2, 2-dimethyl-chroman- (4E) -ylidene acid]Amide (55% yield) as yellow solid. Ms (isp): m/z =358.1[ M + H ]]⁺And 360.2[ M +2+ H ]]⁺。

Intermediate B2.6(X=O；W=-CR^2a，R^2b；R^2a，R^2b= methyl, R^2b=H；p=1)

Starting from 2, 2-dimethyl-6-nitro-chroman-4-one { CAS [111478-49-01 ]]} (intermediate B1.6), the product (R) -2-methyl-propane-2-sulfinic acid [2, 2-dimethyl-6-nitro-chroman- (4E) -ylidene acid is obtained]Amide (64% yield) as yellow solid. Ms (isp): m/z =325.2[ M + H [ ]]⁺。

Intermediate B2.7

Starting from 6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-one { CAS [1212017-68-9 ]](ii) a WO2010021680} (intermediate B1.7) to obtain the product (R, E) -N- (6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-ylidene) -2-methylpropane-2-sulfinamide (67% yield) as a yellow solidAnd (3) a body. Ms (isp): m/z =400.1[ M + H%]⁺And 402.2[ M + H ]]⁺。

Intermediate B2.8(X=S；W=-CR^2a，R^2b；R^2a，R^2b=H；p=1)

Starting from 6-bromo-thiochroman-4-one { CAS [13735-13-2 ]]} (intermediate B1.8), the product (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-thiochroman- (4E) -ylidene acid ] is obtained]Amide (73% yield) as yellow solid. Ms (isp): m/z =346.0[ M + H [ ]]⁺。

Synthesis of intermediate sulfonamido ester B3

General procedure (via the Lifomazki reaction)

In a drying apparatus, a suspension of fresh activated zinc powder (1.63g, 24.9mmol) in anhydrous tetrahydrofuran (70ml) was heated to reflux under an inert atmosphere. A solution of sulfinimide B2(24.9mmol) and bromo-acetate (24.9mmol) in anhydrous tetrahydrofuran (15ml) was added dropwise over a period of 15 minutes and the suspension was heated to reflux for 5 h. The cold mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate, the organic layer was dried and evaporated. The crude material was purified by flash chromatography using heptane/ethyl acetate as eluent to give sulfonamido ester B3.

Intermediate B3.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-chroman- (4E) -ylidene]Amide (intermediate B2.1) to give the product [ (R) -6-bromo-4- ((R) -2-methyl-propane)-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (63% yield) as yellow oil. Ms (isp): m/z =456.1[ M + H [ ]]⁺。

Intermediate B3.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-nitro-chroman- (4E) -ylidene ] -amide (intermediate B2.2), the product difluoro- [ (R) -4- ((R) -2-methyl-propane-2-sulfinylamino) -6-nitro-chroman-4-yl ] -acetic acid ethyl ester was obtained (52% yield) as a red oil.

Intermediate B3.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (RS) -6-bromo-2-phenyl-chroman- (4E) -ylidene]-amide (intermediate B2.3) to give the product [ (2RS, 4R) -6-bromo-4- ((R) -2-methyl-propane-2-sulfinylamino) -2-phenyl-chroman-4-yl)]Difluoro-ethyl acetate (82% yield) as a yellow solid. Ms (isp): m/z =532[ M + H%]⁺。

Intermediate B3.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (RS) -6-nitro-2-phenyl-chroman- (4E) -ylidene]-amide (intermediate B2.4) to give the product difluoro- [ (2RS, 4R) -4- ((R) -2-methyl-propane-2-sulfinylamino) -6-nitro-2-phenyl-chroman-4-yl)]Ethyl acetate (42% yield) as a yellow solid. MS (ISP))：m／z=497[M+H]⁺。

Intermediate B3.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-2, 2-dimethyl-chroman- (4E) -ylidene]Amide (intermediate B2.5) to give the product [ (R) -6-bromo-2, 2-dimethyl-4- ((R) -2-methyl-propane-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (53% yield) as a light yellow solid. Ms (isp): m/z =482.2[ M + H%]⁺And 484.3[ M +2+ H]⁺。

Intermediate B3.6

Starting from (R) -2-methyl-propane-2-sulfinic acid [2, 2-dimethyl-6-nitro-chroman- (4E) -ylidene]-amide (intermediate B2.6) to obtain the product [ (R) -2, 2-dimethyl-6-nitro-4- ((R) -2-methyl-propane-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (56% yield) as red oil. Ms (isp): m/z =449.2[ M + H [ ]]⁺。

Intermediate B3.7

Starting from (R, E) -N- (6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-ylidene) -2-methylpropane-2-sulfinamide (intermediate B2.7) to obtain the product 2- ((4R) -6-bromo-4- ((R) -1, 1-dimethylethylsulfonamido) -2 ', 4', 5 ', 6' -tetrahydrospiro [ chromane-2, 3' -pyrane]Ethyl-4-yl) -2, 2-difluoroacetate (58% yield) as a light yellow foam. Ms (isp): m/z =524.2[ M + H%]⁺And 526.1[ M + H]⁺。

Intermediate B3.8

Starting from (R) -2-methyl-propane-2-sulfinic acid [ 6-bromo-thiochroman- (4E) -ylidene]-amide (intermediate B2.8) to give the product [ (R) -6-bromo-4- ((R) -2-methyl-propane-2-sulfinylamino) -thiochroman-4-yl]Difluoro-ethyl acetate (77% yield) as yellow viscous oil. Ms (isp): m/z =470.2[ M + H%]⁺And 472.2[ M +2+ H]⁺。

Synthesis of intermediate sulfonamidol B4

General procedure

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

Intermediate B4.1

Starting from [ (R) -6-bromo-4- ((R) -2-methyl-propane-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (intermediate B3.1) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl acetate)Base) -chroman-4-yl]Amide (96% yield) as white solid. Ms (isp): m/z =414.1[ M + H [ ]]⁺。

Intermediate B4.2

Starting from difluoro- [ (R) -4- ((R) -2-methyl-propane-2-sulfinylamino) -6-nitro-chroman-4-yl]-ethyl acetate (intermediate B3.2) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-chroman-4-yl]Amide (78% yield) as red oil. Ms (isp): m/z =379.2[ M + H%]⁺。

Intermediate B4.3

Starting from [ (2RS, 4R) -6-bromo-4- ((R) -2-methyl-propane-2-sulfinylamino) -2-phenyl-chroman-4-yl]-difluoro-ethyl acetate (intermediate B3.3) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -6-bromo-4- (1, l-difluoro-2-hydroxy-ethyl) -2-phenyl-chroman-4-yl]Amide (78% yield) as white solid. Ms (isp): m/z =490[ M + H [ ]]⁺。

Intermediate B4.4

Starting from difluoro- [ (2RS, 4R) -4- ((R) -2-methyl-propane-2-sulfinylamino) -6-nitro-2-phenyl-chroman-4-yl]Ethyl acetate (intermediate B3.4) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-2-phenyl-chroman-4-yl]Amide (64% yield) as a yellow viscous liquid. Ms (isp): m/z =455[ M + H]⁺。

Intermediate B4.5

Starting from [ (R) -6-bromo-2, 2-dimethyl-4- ((R) -2-methyl-propane-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (intermediate B3.5) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -2, 2-dimethyl-chroman-4-yl]Amide (99% yield) as a white powder. Ms (isp): m/z =440.2[ M + H%]⁺And 442.2[ M +2+ H]⁺。

Intermediate B4.6

Starting from [ (R) -2, 2-dimethyl-6-nitro-4- ((R) -2-methyl-propane-2-sulfinylamino) -chroman-4-yl]Difluoro-ethyl acetate (intermediate B3.6) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -2, 2-dimethyl-6-nitro-chroman-4-yl]Amide (59% yield) as red oil. Ms (isp): m/z =407.3[ M + H [ ]]⁺。

Intermediate B4.7

Starting from 2- ((4R) -6-bromo-4- ((R) -1, 1-dimethylethylsulfonamido) -2 ', 4',5 ', 6 ' -Tetrahydropiro [ chroman-2, 3 ' -pyrans]Ethyl (4-yl) -2, 2-difluoroacetate (intermediate B3.7) to yield the product (R) -N- ((4R) -6-bromo-4- (1, 1-difluoro-2-hydroxyethyl) -2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-yl) -2-methylpropane-2-sulfinamide (98% yield) as a white solid. Ms (isp): m/z =482.2[ M + H%]⁺And 484.1[ M + H ]]⁺。

Intermediate B4.8

Starting from [ (R) -6-bromo-4- ((R) -2-methyl-propane-2-sulfinylamino) -thiochroman-4-yl)]Difluoro-ethyl acetate (intermediate B3.8) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -thiochroman-4-yl]Amide (94% yield) as white foam. Ms (isp): m/z =428.2[ M + H%]⁺And 430.2[ M +2+ H ]]⁺。

Synthesis of intermediate amino alcohol B5

General procedure:

a solution of sulfinamide alcohol B4(10.3mmol) in methanol or tetrahydrofuran (30 to 60ml) was dissolved with hydrochloric acid in 1, 4-bisThe solution in alkane (4M, 10-13ml) was treated and stirring was continued for 2 to 18h at 23 ℃. The mixture was partitioned between ethyl acetate and aqueous sodium carbonate (2M), the organic layer was dried over sodium sulfate, filtered and evaporated to give a residue which was purified by chromatography on silica using a mixture of n-heptane and ethyl acetate as eluent to give pure amino alcohol B5.

Intermediate B5.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -chroman-4-yl ] -amide (intermediate B4.1), the product 2- ((R) -4-amino-6-bromo-chroman-4-yl) -2, 2-difluoro-ethanol was obtained (73% yield) as a light yellow oil.

Intermediate B5.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-chroman-4-yl]-amide (intermediate B4.2) to give the product 2- ((R) -4-amino-6-nitro-chroman-4-yl) -2, 2-difluoro-ethanol (25% yield) as a yellow oil. Ms (isp): m/z =275.1[ M + H [ ]]⁺。

Intermediate B5.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -2-phenyl-chroman-4-yl ] -amide (intermediate B4.3), the product 2- ((2RS, 4R) -4-amino-6-bromo-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethanol is obtained (70% yield).

Intermediate B5.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-2-phenyl-chroman-4-yl]Amide (intermediate B4.4) to give the product 2- ((2RS, 4R) -4-amino-6-nitro-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethanol (50% yield) as a light yellow solid. Ms (isp): m/z =351.2[ M + H [ ]]⁺。

Intermediate B5.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -2, 2-dimethyl-chroman-4-yl]-amide (intermediate B4.5) to give the product 2- ((R) -4-amino-6-bromo-2, 2-dimethyl-chroman-4-yl) -2, 2-difluoro-ethanol (47% yield) as a viscous pale yellow oil. Ms (isp): m/z =319.0[ M + H [ ]]⁺And 321.0[ M +2+ H]⁺。

Intermediate B5.6

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -2, 2-dimethyl-6-nitro-chroman-4-yl]Amide (intermediate B4.6) to give the product 2- ((R) -4-amino-2, 2-dimethyl-6-nitro-chroman-4-yl) -2, 2-difluoro-ethanol (69% yield) as a red oil. Ms (isp): m/z =303.1[ M + H%]⁺。

Intermediates B5.7A and B5.7B

Starting from (R) -N- ((4R) -6-bromo-4- (1, 1-difluoro-2-hydroxyethyl) -2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-yl) -2-methylpropane-2-sulfinamide (intermediate B4.7), and reaction on silica gel using heptane/ethyl acetate = 100: 0 to =: after chromatography with a gradient of 100 as eluent, 2- ((2R, 4R) -4-amino-6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran is obtained]-4-yl) -2, 2-difluoroethanol (47% yield) (intermediate B5.7A) as the first eluting isomer as a white foam; ms (isp): m/z =378.0[ M + H [ ]]⁺And 380.0[ M +2+ H ]]⁺. A second eluting isomer, 2- ((2S, 4R) -4-amino-6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran, is also obtained]-4-yl) -2, 2-difluoroethanol (27% yield) (intermediate B5.7B) as a white foam; ms (isp): m/z =378.0[ M + H [ ]]⁺And 380.0[ M +2+ H ]]⁺。

Intermediate B5.8

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -thiochroman-4-yl]Amide (intermediate B4.8) to give the product 2- ((R) -4-amino-6-bromo-thiochroman-4-yl) -2, 2-difluoro-ethanol (85% yield) as a colorless viscous oil. Ms (isp): m/z =324.0[ M + H%]⁺。

Intermediate amino group Synthesis of oxazine B6

General procedure

The dried tube was charged with a mixture of amino alcohol B5(18.8mmol), cyanogen bromide (33.9mmol) and ethanol (61 ml). The tube was sealed and heated at 90 ℃ for 16 hours. For work-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (150ml) and saturated aqueous sodium carbonate (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (2 × 50 ml). The organic layers were washed with brine (50ml) then combined, dried over sodium sulfate and evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate B6.1

Starting from 2- ((R) -4-amino-6-bromo-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.1), the colorless product (R) -6-bromo-5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amine (15% yield). Ms (isp): m/z =331.1[ M + H [ ]]⁺。

Intermediate B6.2

Starting from 2- ((R) -4-amino-6-nitro-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.2), the product (R) -5 ', 5' -difluoro-6-nitro-5 ', 6' -dihydrospiro [ chroman-4, 4 '- [1, 3' ] -]Oxazines]-2' -amine (24% yield) as light yellow solid. Ms (isp): m/z =300.1[ M + H%]⁺。

Intermediate B6.3

Starting from 2- ((2RS, 4R) -4-amino-6-bromo-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.3), the product (2RS, 4R) -6-bromo-5 ', 5' -difluoro-2-phenyl-5 ', 6' -dihydrospiro [ chroman-4, 4 '- [1, 3' ] -]Oxazines]-2' -amine (30% yield).

Intermediate B6.4

Starting from 2- ((2RS, 4R) -4-amino-6-nitro-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.4), the product (2RS, 4R) -5 ', 5' -difluoro-6-nitro-2-phenyl-5 ', 6' -dihydrospiro [ chroman-4, 4 '- [1, 3' ] -]Oxazines]-2' -amines.

Intermediate B6.5

Starting from 2- ((R) -4-amino-6-bromo-2, 2-dimethyl-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.5), the product (R) -6-bromo-5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3] is obtained]Oxazines]-2' -amine (35% yield) as light yellow solid. Ms (isp):m／z=361.1[M+H]⁺and 363.1[ M +2+ H]⁺。

Intermediate B6.6

Starting from 2- ((R) -4-amino-2, 2-dimethyl-6-nitro-chroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.6), the product (R) -5 ', 5 ' -difluoro-2, 2-dimethyl-6-nitro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3] is obtained]Oxazines]-2' -amine (50% yield) as yellow oil. Ms (isp): m/z =328.1[ M + H ]]⁺。

Intermediate B6.7

Starting from 2- ((2R, 4R) -4-amino-6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-yl) -2, 2-difluoroethanol (intermediate B5.7A) to give the product (2 ' R, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]2-amine (49% yield) as a white foam; ms (isp): m/z =403.3[ M + H%]⁺And 405.2[ M +2+ H ]]⁺。

Intermediate B6.8

Starting from 2- ((2S, 4R) -4-amino-6-bromo-2 ', 4 ', 5 ', 6 ' -tetrahydrospiro [ chroman-2, 3 ' -pyran]-4-yl) -2, 2-difluoroethanol (intermediate B5.7B) to give the product (2 ' S, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]2-amine (47% yield) as a white foam; ms (isp): m/z =403.0[ M + H [ ]]⁺And 405.0[ M +2+ H]⁺。

Intermediate B6.9

Starting from 2- ((R) -4-amino-6-bromo-thiochroman-4-yl) -2, 2-difluoro-ethanol (intermediate B5.9), the product (R) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro [ [1,3] was obtained]Oxazine-4, 4' -thiochroman]2-amine (29% yield) as a colorless waxy solid. Ms (isp): m/z =349.1[ M + H%]⁺And 351.0[ M +2+ H ]]⁺。

Synthesis of intermediate Aniline B7 (Via the Nitro group) Reduction of oxazines

General procedure

Nitro groups were reacted using palladium (10%, charcoal) (159mg, 150. mu. mol) as a catalystSolution of oxazine B6(3mmol) in ethanol (31ml)Hydrogenation at atmospheric pressure. The reaction was complete after 90 minutes. The reaction mixture was filtered over dicalite layer, which was washed with ethanol (3 × 20 ml). The combined ethanol solution was evaporated under reduced pressure. The product was used in step without further purification.

Intermediate B7.1

Starting from (R) -5 ', 5 ' -difluoro-6-nitro-5 ', 6 ' -dihydrospiro [ chromane-4, 4 ' - [1,3]]Oxazines]-2 '-amine (intermediate B6.2) to obtain the product (R) -5', 5 '-difluoro-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]2', 6-diamine (67% yield) as a yellow solid. Ms (isp): m/z =270.3[ M + H [ ]]⁺。

Intermediate B7.2

Starting from (2RS, 4R) -5 ', 5 ' -difluoro-6-nitro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2 '-amine (intermediate B6.4) to obtain the product (2RS, 4R) -5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]2', 6-diamine (81% yield) brownA colored solid.

Intermediate B7.3

Starting from (R) -5 ', 5 ' -difluoro-2, 2-dimethyl-6-nitro-5 ', 6 ' -dihydrospiro [ chromane-4, 4 ' - [1,3]]Oxazines]-2 '-amine (intermediate B6.6) to obtain the product (R) -5', 5 '-difluoro-2, 2-dimethyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]2', 6-diamine (64% yield) as a yellow oil. Ms (isp): m/z =298.2[ M + H [ ]]⁺。

Synthesis of intermediate Aniline B7 (via Buchwald-Hartwig Cross-coupling reaction)

Intermediate B7.4

(R) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-2, 6' -diamine

a) (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro- [ [1, 3[ ]]Oxazine-4, 4' -thiochroman]-2-amine (intermediate B6.1)

Reacting (R) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]A solution of (E) -2-amine (intermediate B6.9) (460mg, 1.32mmol) and triethylamine (267mg, 2.63mmol) in dichloromethane (10ml) was cooled to 0 ℃ and 4, 4' -dimethoxytrityl chloride (469mg, 1.38mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 hours. For work-up, the reaction mixture was evaporated and the residue was purified by chromatography on silica gel using heptane/ethyl acetate = 0: 100 to 60: a gradient of 40 was purified directly as eluent. To obtain (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]2-amine (789mg, 92% yield) as a yellow foam. Ms (isp): m/z =651.0[ M + H [ ]]⁺And 353.0[ M +2+ H]⁺。

b) (R) -N2- (bis (4-methoxyphenyl) (phenyl) methyl) -N6' - (diphenylmethylene) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-2, 6' -diamine (intermediate B6.2)

To (R) -N- (bis (4-methoxyphenyl) (phenyl) methyl) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro [ [1,3] in a dry tube under an argon atmosphere]Oxazine-4, 4' -thiochroman]A solution of (789mg, 1.21mmol) of (E) -2-amine in toluene (10ml) was added continuously to benzophenone imine (439mg, 2.42mmol), sodium tert-butoxide (349mg, 3.63mmol), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl { CAS [564483-19-8 ]]Chloroform adduct of (51.4mg, 121. mu. mol) and tris (dibenzylideneacetone) dipalladium (O) { CAS [52522-40-4 ]]}(37.6mg，36.3μmol). The tube was sealed and the reaction mixture was stirred at 110 ℃ for 15 hours. For work-up, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel using heptane/ethyl acetate = 0: 100 to 70: a gradient of 30 as eluent. To obtain (R) -N2- (bis (4-methoxyphenyl) (phenyl) methyl) -N6' - (diphenylmethylene) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]2, 6' -diamine (613mg, 67% yield) as a yellow solid. Ms (isp): m/z =752.5[ M + H [ ]]⁺。

c) (R) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-2, 6' -diamine

Mixing (R) -N2- (bis (4-methoxyphenyl) (phenyl) methyl) -N6' - (diphenylmethylene) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]A solution of-2, 6' -diamine (613mg, 815. mu. mol) in dichloromethane (10ml) was treated with trifluoroacetic acid (930mg, 8.15 mmol). The orange solution was stirred at room temperature for 15 hours. Thereafter, the reaction mixture was diluted with dichloromethane (10ml) and washed with a 1M solution of sodium carbonate (5 ml). The organic layer was separated, dried over sodium sulfate and evaporated. Dissolving the obtained yellow oil in waterTo an alkane (8ml) followed by dropwise addition of hydrochloric acid (bis)4N solution in alkane, 2.04 ml). A precipitate is formed which is formed on addition of hydrochloric acid (II)4N solution in alkane, 2.0ml) was dissolved. The orange solution was stirred at room temperature for 15 hours. For work-up, the solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 ml). The organic layer was washed with hydrochloric acid (1N, 8ml), the aqueous layer was separated and adjusted to pH9 by the addition of sodium hydroxide (2N). Thereafter, the aqueous layer was extracted with ethyl acetate (3 × 30ml), the organic layers were combined and dried over sodium sulfate. After evaporation under reduced pressure, (R) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3] is obtained]Oxazine-4, 4' -thiochroman]2, 6' -diamine (230mg, 89% yield) as a yellow solid, pure enough to be used in the next step without further purification. Ms (isp): m/z =286.1[ M + H [ ]]⁺。

Intermediate B7.5

In close analogy to the procedure described for the synthesis of intermediate B7.4, (2 'R, 4R) -5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-2, 6' -diamine:

a) (2' R, 4R) -N- [ bis (4-methoxyphenyl) (phenyl) methyl]-6' -bromo-5, 5-difluoro-5, 5", 6, 6" -tetrahydro-4 "H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-2-amines

Starting from (2 ' R, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]2-amine (intermediate B6.7) to give the title compound (80% yield) as a white foam. Ms (isp): m/z =705.2[ M + H%]⁺And 707.2[ M +2+ H]⁺。

b) (2' R, 4R) -N-2- [ bis (4-methoxyphenyl) (phenyl) methyl]-N-6- '- (diphenylmethylene) -5, 5-difluoro-5, 5', 6,6 '-tetrahydro-' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-2, 6' -diamine

Starting from (2' R, 4R) -N- [ bis (4-methoxyphenyl) (phenyl) methyl]-6' -bromo-5, 5-difluoro-5, 5", 6, 6" -tetrahydro-4 "H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]2-amine to obtain the title compound (54% yield) as a yellow solid. Ms (isp): m/z =806.5[ M + H [ ]]⁺。

c) (2 'R, 4R) -5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-2, 6' -diamine

Starting from (2' R, 4R) -N-2- [ bis (4-methoxyphenyl) (phenyl) methyl]-N-6- '- (diphenylmethylene) -5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]2, 6' -diamine to give the title compound (34% yield) as a pale yellow solid. Ms (isp): m/z =340.1[ M + H%]⁺。

Example 19

(R) -6- (5-chloropyridin-3-yl) -5', 5-Difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amines

In a tube, (R) -6-bromo-5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]A mixture of-2' -amine (intermediate B6.1) (20mg, 60. mu. mol), 5-chloropyridin-3-ylboronic acid (11mg, 72. mu. mol) and cesium carbonate (78mg, 240. mu. mol) in tetrahydrofuran (1.2ml) and water (0.59ml) was purged with argon for 5 minutes. Thereafter, [1, 1' -bis (diphenylphosphino) ferrocene ] was added]Palladium (II) dichloride (2.2mg, 3.0. mu. mol), the tube was sealed and the mixture was heated at 80 ℃ for 30 minutes. For work-up, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica-NH₂Phase on heptane/ethyl acetate = 100: 0 to 0: a gradient of 100 as eluent. To obtain (R) -5- (2 '-amino-4, 4, 5', 5 '-tetrafluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) nicotinonitrile (12mg, 55% yield) as a pale yellow solid. Ms (isp): m/z =366.0[ M + H ]]⁺。

Example 20

(R) -6- (3, 5-dichlorophenyl) -5 ', 5' -difluoro-5 ', 6' -dihydrospiro [ chroman-4, 4 '- [1, 3' ]]Oxazines]-2' -amines

In a similar manner to that described in example 19, (R) -6-bromo-5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of-2' -amine (intermediate B6.1) with 3, 5-dichlorophenylboronic acid yielded the title compound (58% yield) as a pale yellow solid. Ms (isp): m/z =399.1[ M + H [ ]]⁺。

Example 21

(R) -5 ', 5 ' -difluoro-6- (pyrimidin-5-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 19, (R) -6-bromo-5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.1) with pyrimidin-5-yl boronic acid yielded the title compound (55% yield) as a light yellow solid. Ms (isp): m/z =333.1[ M + H [ ]]⁺。

Example 22

(R) -5 ', 5 ' -difluoro-6- (5-methoxypyridin-3-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 19, (R) -6-bromo-5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.1) with 5-methoxypyridin-3-ylboronic acid yielded the title compound (60% yield) as a pale yellow solid. Ms (isp): m/z =362.2[ M + H [ ]]⁺。

Example 23

(2RS, 4R) -6- (5-chloropyridine-3-yl) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amines

In a similar manner to that described in example 19, (2RS, 4R) -6-bromo-5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.3) with 5-chloropyridin-3-ylboronic acid gave the title compound (16% yield) as a grey solid. Ms (isp): m/z =442.3[ M + H%]⁺。

Example 24

5- ((2RS, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) nicotinonitrile

In a similar manner to that described in example 19, (2RS, 4R) -6-bromo-5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.3) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (16% yield) as a white solid. Ms (isp): m/z =433.3[ M + H ]]⁺。

Example 25

(2RS, 4R) -5 ', 5 ' -difluoro-2-phenyl-6- (pyrimidin-5-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-2' -amines

As described in example 19In a similar manner, (2RS, 4R) -6-bromo-5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.3) with pyrimidin-5-yl boronic acid yielded the title compound (22% yield) as a white solid. Ms (isp): m/z =409.3[ M + H [ ]]⁺。

Example 26

(2RS, 4R) -6- (3, 5-dichlorophenyl) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]Oxazines]-2' -amines

In a similar manner to that described in example 19, (2RS, 4R) -6-bromo-5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of-2' -amine (intermediate B6.3) with 3, 5-dichlorophenyl boronic acid yielded the title compound (17% yield) as a white solid. Ms (isp): m/z =475.0[ M + H [ ]]⁺。

Example 27

3- ((2RS, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) benzonitrile

In a similar manner to that described in example 19, (2RS, 4R) -6-bromo-5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Cross-coupling reaction product of (E) -2' -amine (intermediate B6.3) with 3-cyanophenylboronic acidThe title compound (13% yield) was produced as a white solid. Ms (isp): m/z =432.2[ M + H%]⁺。

Example 28

(R) -6- (5-Chloropyridin-3-yl) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]Oxazines]-2' -amines

In a similar manner to that described in example 19, (R) -6-bromo-5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]The cross-coupling reaction of the-2' -amine (intermediate B6.5) with 5-chloropyridin-3-ylboronic acid gave the title compound (78% yield) as a white powder. Ms (isp): m/z =394.1[ M + H [ ]]⁺。

Example 29

(2 ' R, 4R) -6 ' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 5 ', 6,6 "-tetrahydro-4" H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-2-Aminoformic acid salt

In a similar manner to that described in example 19, (2 ' R, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]Cross-coupling reaction of-2-amine (intermediate B6.7) with 5-chloropyridin-3-ylboronic acid and chromatography on preparative HPLC yielded the title compound (66% yield) as an off-white amorphous material. Ms (isp): m/z =436[ M + H]⁺And 438[ M +2+ H]⁺。

Example 30

3- [ (2 'R, 4R) -2-amino-5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' -H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-6' -yl]Benzonitrile formate salt

In a similar manner to that described in example 19, (2 ' R, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]The cross-coupling reaction of the-2-amine (intermediate B6.7) with 3-cyanophenylboronic acid and chromatography on preparative HPLC gave the title compound (25% yield) as a light yellow solid. Ms (isp): m/z =426.2[ M + H%]⁺。

Example 31

(2 'S, 4R) -6' - (5-chloropyridin-3-yl) -5, 5-difluoro-5, 5 ', 6, 6' -tetrahydro-4 '' H-dispiro [1, 3-Oxazine-4, 4 ' -chromene-2 ', 3 ' -pyrans]-2-Aminoformic acid salt

In a similar manner to that described in example 19, (2 ' S, 4R) -6 ' -bromo-5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]The cross-coupling reaction of the-2-amine (intermediate B6.8) with 5-chloropyridin-3-ylboronic acid and chromatography on preparative HPLC gave the title compound (66% yield) as an off-white amorphous material. Ms (isp): m/z =436[ M + H]⁺And 438[ M +2+ H]⁺。

Example 32

(R) -6' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-2-amines

In a similar manner to that described in example 19, (R) -6' -bromo-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]The cross-coupling reaction of the-2-amine (intermediate B6.9) with 5-chloropyridin-3-ylboronic acid gave the title compound (70% yield) as a white solid. Ms (isp): m/z =382.0[ M + H [ ]]⁺。

General procedure for the preparation of amides of formula i.4:

a solution of carboxylic acid (0.23mmol) in methanol (5ml) was cooled to 0 ℃. Adding 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholinium chlorideHydrate (DMTMM) (80mg, 0.27mmol) and the solution was stirred at 0 ℃ for 30 min. Thereafter, a solution of intermediate diamine B7(0.21mmol) in methanol (5ml) was added dropwise via syringe at 0 ℃. The reaction mixture was stirred at 23 ℃ for 18-60 hours. For work-up, the reaction mixture was poured into a solution of sodium carbonate (1M) and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure left a residue which was chromatographed on silica gel or on silica-NH₂The phases are purified using a mixture of dichloromethane and methanol (0-10%) to give the pure amide of formula I.

Example 33

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide

(R) -5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.1) and 5-chloropicolinic acid yielded the title compound (56% yield) as a white solid. Ms (isp): m/z =409.2[ M + H%]⁺。

Example 34

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.1) and 5-cyanopicolinic acid yielded the title compound (74% yield) as a yellow solid. Ms (isp): m/z =400.2[ M + H%]⁺。

Example 35

(R) -5 ', 5 ' -difluoro-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.1) and 4-chloro-1H-pyrazole-5-carboxylic acid gave the title compound (34% yield) as a light yellow solid. Ms (isp): m/z =398.1[ M + H ]]⁺。

Example 36

N- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide

(2RS, 4R) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.2) and 5-chloropicolinic acid yielded the title compound (21% yield) as an off-white solid. Ms (isp): m/z =485.1[ M + H]⁺。

Example 37

N- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamides

(2RS, 4R) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.2) and 5-cyanopicolinic acid yielded the title compound (33% yield) as an off-white solid. Ms (isp): m/z =476.1[ M + H [ ]]⁺。

Example 38

N- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5-fluoropyridyl amide

(2RS，4R)-5′，5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.2) and 5-fluoropicolinic acid gave the title compound (26% yield) as an off-white solid. Ms (isp): m/z =469.2[ M + H [ ]]⁺。

Example 39

N- ((2R or 2S, 4R) -2 '-amino-5', 5 '-difluoro-2-phenyl-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -5- (trifluoromethyl) picolinamide

(2RS, 4R) -5 ', 5 ' -difluoro-2-phenyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.2) and 5-fluoropicolinic acid gave the title compound (27% yield) as an off-white solid.

Example 40

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 2-dimethyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) -5-chloropyridyl amide

(R) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.3) and 5-chloropicolinic acid yielded the title compound (85% yield) as a white solid. Ms (isp): m/z =437.1[ M + H [ ]]⁺。

EXAMPLE 41

(R) -N- (2 '-amino-5', 5 '-difluoro-2, 2-dimethyl-5', 6 '-dihydrospiro [ chroman-4, 4' - [1,3]]Oxazines]-6-yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.3) and 5-cyanopicolinic acid gave the title compound (78% yield) as a yellow solid. Ms (isp): m/z =428.3[ M + H [ ]]⁺。

Example 42

(R) -N- (2-amino-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-6' -yl) -5-chloropyridyl amide

(R) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.4) and 5-chloropicolinic acid yielded the title compound (55% yield) as a white solid. Ms (isp): m/z =424.9[ M + H [ ]]⁺。

Example 43

(R) -N- (2-amino-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]-6' -yl) -5-cyanopyridinamides

(R) -5 ', 5 ' -difluoro-2, 2-dimethyl-5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]Condensation of-2', 6-diamine (intermediate B7.4) and 5-cyanopicolinic acid gave the title compound (57% yield) as a yellow solid. Ms (isp): m/z =415.9[ M + H [ ]]⁺。

Example 44

N- [ (2 'R, 4R) -2-amino-5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' -H-dispiro [1, 3-Oxazine-4, 4 ' -chromene-2 ', 3 ' -pyrans]-6' -yl]-5-cyanopyridine-2-carboxamide

(2 'R, 4R) -5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]Condensation of-2, 6' -diamine (intermediate B7.5) and 5-cyanopicolinic acid yielded the title compound (64% yield) as a yellow solid. Ms (isp): m/z =470.3[ M + H%]⁺。

Example 45

N- [ (4R) -2-amino-5, 5-difluoro-1 ', 1' -dioxo-2 ', 3', 5, 6-tetrahydrospiro [1, 3-Oxazine-4, 4' -thiochromenes]-6' -yl]-5-chloropyridine-2-carboxamide

Reacting (R) -N- (2-amino-5, 5-difluoro-5, 6-dihydrospiro [ [1,3]]Oxazine-4, 4' -thiochroman]A solution of (6' -yl) -5-chloropyridyl amide (example 42) (30mg, 70.6. mu. mol) in methanol (2ml) was treated with potassium monopersulfate (52.1mg, 84.7. mu. mol). The suspension was stirred at room temperature for 5 days. For working up, the reaction mixture is worked upEvaporating under reduced pressure and chromatographing the residue on silica-NH₂Phase on heptane/ethyl acetate = 100: 0 to 20: a gradient of 80 as eluent was purified directly. The title compound (30mg, 93% yield) was obtained as a white solid. Ms (isp): m/z =457.2[ M + H]⁺。

Example 46

N- [ (4R) -2-amino-5, 5-difluoro-1 ', 1' -dioxo-2 ', 3', 5, 6-tetrahydrospiro [1, 3-Oxazine-4, 4' -thiochromenes]-6' -yl]-5-cyanopyridine-2-carboxamide

In a similar manner to that described in example 45, N- [ (2 'R, 4R) -2-amino-5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-6' -yl]Oxidation of-5-cyanopyridine-2-carboxamide (example 44) gave the title compound (74% yield) as a white solid. Ms (isp): m/z =448.2[ M + H [ ]]⁺。

Synthesis of intermediate sulfinamide nitrile C1

General procedure

A solution of sulfonamidol A4(4.1mmol) in dichloromethane (23ml) was treated successively at 22 ℃ with 2-bromoacetonitrile (6.2mmol), silver (I) oxide (1.9g) and tetrabutylammonium iodide (0.30g) and stirring was continued for 2 h. For the work-up, the suspension was filtered and the filtrate was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and evaporated to give crude sulfinamide nitrile C1, which was used without further purification.

Intermediate C1.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (1, 1-difluoro-2-hydroxy-ethyl) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (intermediate a4.2) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (2-cyanomethoxy-1, 1-difluoro-ethyl) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (68% yield) as a brown oil. Ms (isp): m/z =416.3[ M + H%]⁺。

Intermediate C1.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -chroman-4-yl]-amide (intermediate B4.1) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -chroman-4-yl]Amide (64% yield) as an off-white waxy solid. Ms (isp): m/z =451.0[ M + H [ ]]⁺And 453.0[ M +2+ H]⁺。

Intermediate C1.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-chroman-4-yl]Amide (intermediate B4.2) to obtain the product (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -6-nitro-chroman-4-yl]Amide (79% yield) as brown oil. Ms (isp): m/z =418.2[ M + H%]⁺。

Intermediate C1.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -6-bromo-4- (1, 1-difluoro-2-hydroxy-ethyl) -2-phenyl-chroman-4-yl ] -amide (intermediate B4.3), the product (R) -2-methyl-propane-2-sulfinic acid [ (2S, 4R) -6-bromo-4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -2-phenyl-chroman-4-yl ] -amide was obtained (79% yield) as a white solid.

Intermediate C1.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -4- (1, 1-difluoro-2-hydroxy-ethyl) -6-nitro-2-phenyl-chroman-4-yl ] -amide (intermediate B4.4), the product (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -6-nitro-2-phenyl-chroman-4-yl ] -amide was obtained (76% yield) as a viscous yellow liquid.

Synthesis of intermediate aminonitrile C2

General procedure

Sulfinamide nitrile C1(4.25mmol) in 1, 4-bisSolution in alkane (20ml) with hydrochloric acid in 1, 4-bisThe solution in alkane (4M, 5.3ml) was treated and stirring was continued for 1 hour at 22 ℃. For work-up, the mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium carbonate. The organic layer was dried and evaporated. The crude material was purified on silica using n-heptaneAnd ethyl acetate as eluent to give pure aminonitrile C2.

Intermediate C2.1

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -1- (2-cyanomethoxy-1, 1-difluoro-ethyl) -7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl]Amide (intermediate C1.1) to obtain the product [2- ((R) -1-amino-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethoxy]Acetonitrile (76% yield) as a light brown oil. Ms (isp): m/z =312.1[ M + H [ ]]⁺。

Intermediate C2.2

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -6-bromo-4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -chroman-4-yl]Amide (intermediate C1.2) to obtain the product [2- ((R) -4-amino-6-bromo-chroman-4-yl) -2, 2-difluoro-ethoxy- ]]Acetonitrile (50% yield) as off-white oil. Ms (isp): m/z =347.0[ M + H [ ]]⁺And 349.2[ M +2+ H]⁺。

Intermediate C2.3

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (R) -4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -6-nitro-chroman-4-yl]Amide (intermediate C1.3) to obtain the product [2- ((R) -4-amino-6-nitro-chroman-4-yl) -2, 2-difluoro-ethoxy]Acetonitrile (87% yield) as yellow oil. Ms (isp): m/z =313.9[ M + H [ ]]⁺。

Intermediate C2.4

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -6-bromo-4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -2-phenyl-chroman-4-yl ] -amide (intermediate C1.4), the product [2- ((2RS, 4R) -4-amino-6-bromo-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethoxy ] -acetonitrile was obtained (62% yield) as a light yellow solid.

Intermediate C2.5

Starting from (R) -2-methyl-propane-2-sulfinic acid [ (2RS, 4R) -4- (2-cyanomethoxy-1, 1-difluoro-ethyl) -6-nitro-2-phenyl-chroman-4-yl ] -amide (intermediate C1.5), the product [2- ((2RS, 4R) -4-amino-6-nitro-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethoxy ] -acetonitrile was obtained (63% yield) as a brown solid.

Intermediate 1, 4-oxaza Synthesis of C3

General procedure

A solution of aminonitrile C2(2.20mmol) in toluene (38ml) was treated with a solution of trimethylaluminum in toluene (2M, 1.2ml) at 22 ℃ and the mixture was heated to 80 ℃ for 1 hour. For the work-up, the mixture was cooled to 0 ℃ and diluted with a saturated aqueous solution of sodium carbonateAnd (5) releasing. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, dried and evaporated. The residue was chromatographed on silica-NH₂Purification on phase using a mixture of n-heptane and ethyl acetate as eluent to give pure 1, 4-oxazaC3。

Intermediate C3.1

Starting from [2- ((R) -1-amino-7-nitro-1, 2,3, 4-tetrahydro-naphthalen-1-yl) -2, 2-difluoro-ethoxy]-acetonitrile (intermediate C2.1) to obtain the product (R) -6 ', 6 ' -difluoro-7-nitro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4 ' ] -]Oxazazem]-3' -amine (70% yield) as light brown foam. Ms (isp): m/z =312.1[ M + H [ ]]⁺。

Intermediate C3.2

Starting from [2- ((R) -4-amino-6-bromo-chroman-4-yl) -2, 2-difluoro-ethoxy]Acetonitrile (intermediate C2.2) to obtain the product (R) -6-bromo-6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4] in quantitative yield]Oxazazem]-3' -amine as off-white foam. Ms (isp): m/z =347.1[ M + H%]⁺And 349.1[ M +2+ H]⁺。

Intermediate C3.3

Starting from [2- ((R) -4-amino-6-nitro-chroman-4-yl) -2, 2-difluoro-ethoxy]-acetonitrile (intermediate C2.3) to obtain the product (R) -6 ', 6' -difluoro-6-nitro-6 ', 7' -dihydro-2 'H-spiro [ chromane-4, 5' - [1,4]]Oxazazem]-3' -amine (98% yield) as red oil. Ms (isp): m/z =313.9[ M + H [ ]]⁺。

Intermediate C3.4

Starting from [2- ((2RS, 4R) -4-amino-6-bromo-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethoxy]-acetonitrile (intermediate C2.4) to obtain the product (2RS, 4R) -6-bromo-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4 ' ] -]Oxazazem]-3' -amine (67% yield) as a yellow semi-solid. Ms (isp): m/z =422.9[ M + H [ ]]⁺。

Intermediate C3.5

Starting from [2- ((2RS, 4R) -4-amino-6-nitro-2-phenyl-chroman-4-yl) -2, 2-difluoro-ethoxy]-acetonitrile (medium)Intermediate C2.5) to obtain the product (2RS, 4R) -6 ', 6' -difluoro-6-nitro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-3' -amine (37% yield) as a brown solid. Ms (isp): m/z =390.0[ M + H ]]⁺。

Synthesis of intermediate Aniline C4 (via the Nitro group 1.4-Oxazahetero) Reduction of (2)

General procedure

NitroxazepinesA solution of C3(3mmol) in ethanol (31ml) was hydrogenated at atmospheric pressure using palladium (10%, on charcoal) (159mg, 150. mu. mol) as a catalyst. After 90 minutes, the reaction was complete. The reaction mixture was filtered over a dicalite layer, which was washed with ethanol (3 × 20 ml). The combined ethanol solution was evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate C4.1

Starting from (R) -6 ', 6' -difluoro-7-nitro-3, 4, 6 ', 7' -tetrahydro-2H, 2 'H-spiro [ naphthalene-1, 5' - [1,4]]Oxazazem]-3 ' -amine (intermediate C3.1) to obtain the product (R) -6 ', 6 ' -difluoro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4] in quantitative yield]Oxazazem]3', 7-diamine as a yellow foam. Ms (isp): m/z =282.2[ M + H ]]⁺。

Intermediate C4.2

Starting from (R) -6 ', 6' -difluoro-6-nitro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-3 ' -amine (intermediate C3.3) to obtain the product (R) -6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]3', 6-diamine (95% yield) as a yellow solid. Ms (isp): m/z =284.1[ M + H%]⁺。

Intermediate C4.3

Starting from (2RS, 4R) -6 ', 6' -difluoro-6-nitro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chromane-4, 5' - [1,4]Oxazazem]-3 '-amine (intermediate C3.5) to obtain the product (2RS, 4R) -6', 6 '-difluoro-2-phenyl-6', 7 '-dihydro-2' H-spiro [ chroman-4, 5 '- [1, 4' ] -]Oxazazem]3', 6-diamine (54% yield) as a brown solid. Ms (isp): m/z =360.0[ M + H%]⁺。

In analogy to the general procedure used for the preparation of the amides of formula I, the intermediate aniline of formula C4 was passed with acid through 4- (4, 6-dimethoxy [1.3.5 ]]Triazin-2-yl) -4-methylmorpholinium chlorideThe reaction of hydrate (DMTMM) as a condensing agent yields the following compound:

example 47

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4]]Oxazazem]-7-yl) -5-cyanopyridinamides

(R) -6 ', 6' -difluoro-3, 4, 6 ', 7' -tetrahydro-2H, 2 'H-spiro [ naphthalene-1, 5' - [1,4]]Oxazazem]Condensation of-3', 7-diamine (intermediate C4.1) and 5-cyanopicolinic acid yielded the title compound (37% yield) as an off-white solid. Ms (isp): m/z =412.2[ M + H [ ]]⁺。

Example 48

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-3, 4, 6 ', 7 ' -tetrahydro-2H, 2 ' H-spiro [ naphthalene-1, 5 ' - [1,4]]Oxazazem]-7-yl) -5-chloropyridyl amide

(R) -6 ', 6' -difluoro-3, 4, 6 ', 7' -tetrahydro-2H, 2 'H-spiro [ naphthalene-1, 5' - [1,4]]Oxazazem]-3', 7-diamine (intermediate)C4.1) and 5-chloropicolinic acid gave the title compound (45% yield) as an off-white solid. Ms (isp): m/z =421.1[ M + H [ ]]⁺。

Example 49

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-cyanopyridinamides

(R) -6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4 ' ]]Oxazazem]Condensation of-3', 6-diamine (intermediate C4.2) and 5-cyanopicolinic acid yielded the title compound (51% yield) as a yellow solid. Ms (isp): m/z =414.3[ M + H [ ]]⁺。

Example 50

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-chloropyridyl amide

(R) -6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4 ' ]]Oxazazem]Condensation of-3', 6-diamine (intermediate C4.2) and 5-chloropicolinic acid yielded the title compound (54% yield) as a light yellow solid. Ms (isp): m/z =423.2[ M + H [ ]]⁺。

Example 51

(R) -N- (3 ' -amino-6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -3, 5-dichloropyridyl amide

(R) -6 ', 6 ' -difluoro-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4 ' ]]Oxazazem]Condensation of-3', 6-diamine (intermediate C4.2) and 3, 5-chloropicolinic acid yielded the title compound (38% yield) as a light yellow solid. Ms (isp): m/z =457.2[ M + H]⁺And 459.2[ M +2+ H]⁺。

Example 52

N- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5- (trifluoromethyl) picolinamide

(2RS, 4R) -6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]Condensation of-3', 6-diamine (intermediate C4.3) and 5-trifluoromethyl-pyridine-2-carboxylic acid gave the title compound (7% yield) as a light brown solid. Ms (isp): m/z =532.8[ M + H%]⁺。

Example 53

N- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-cyanopyridinamides

(2RS, 4R) -6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]Condensation of-3', 6-diamine (intermediate C4.3) and 5-cyanopicolinic acid yielded the title compound as an off-white solid. Ms (isp): m/z =490.2[ M + H [ ]]⁺。

In a similar manner to that described in example 19, the following compound was obtained:

example 54

(R) -6- (5-Chloropyridin-3-yl) -6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-3' -amines

(R) -6-bromo-6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]The cross-coupling reaction of the-3' -amine (intermediate C3.2) with 5-chloropyridin-3-ylboronic acid yielded the title compound (35% yield) as a light brown amorphous material. Ms (isp): m/z =380.2[ M + H [ ]]⁺。

Example 55

(R) -6- (3, 5-dichlorophenyl) -6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]Oxazazem]-3' -amines

(R) -6-bromo-6 ', 6' -difluoro-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]The cross-coupling reaction of-3' -amine (intermediate C3.2) with 3, 5-dichlorophenyl boronic acid yielded the title compound (40% yield) as a light brown foam. Ms (isp): m/z =413.2[ M + H ]]⁺And 415.2[ M +2+ H]⁺。

Example 56

(2RS, 4R) -6- (5-Chloropyridin-3-yl) -6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4 ' ] -]Oxazazem]-3' -amines

(2RS, 4R) -6-bromo-6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]The cross-coupling reaction of the-3' -amine (intermediate C3.4) with 5-chloropyridin-3-ylboronic acid yielded the title compound (7% yield) as a white solid.

Example 57

(2RS, 4R) -6- (3, 5-dichlorophenyl) -6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-3' -amines

(2RS, 4R) -6-bromo-6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]The cross-coupling reaction of-3' -amine (intermediate C3.4) with 3, 5-dichlorophenyl boronic acid yielded the title compound (8% yield) as a white solid. Ms (isp): m/z =489.4[ M + H ]]⁺。

Example 58

(2RS, 4R) -6 ', 6' -difluoro-2-phenyl-6- (pyrimidin-5-yl) -6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]-3' -amines

(2RS, 4R) -6-bromo-6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]Cross-coupling reaction of the-3' -amine (intermediate C3.4) with pyrimidin-5-yl boronic acid gave the title compound (12% yield). Ms (isp): m/z =423.0[ M + H [ ]]⁺。

Example 59

5- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1,4]]Oxazazem]-6-yl) nicotinonitrile

(2RS, 4R) -6-bromo-6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]The cross-coupling reaction of the-3' -amine (intermediate C3.4) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (15% yield) as a colorless solid. Ms (isp): m/z =447.4[ M + H [ ]]⁺。

Example 60

3- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1, 4)]Oxazazem]-6-yl) benzonitrile

(2RS, 4R) -6-bromo-6 ', 6' -difluoro-2-phenyl-6 ', 7' -dihydro-2 'H-spiro [ chroman-4, 5' - [1,4]]Oxazazem]Cross-coupling reaction of the (3' -amine) (intermediate C3.4) with 3-cyanophenylboronic acid gave the title compound (10% yield)Rate) as a colorless solid. Ms (isp): m/z =446.0[ M + H%]⁺。

Claims

1. A compound of the formula I,

wherein

V is-CR^7aR^7b-；

W is-CR^2aR^2b-；

X is-CR^1aR^1b-, - (O-, -S-or-SO)₂-；

Y-NH-C=O-：

Z is selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

iii) an aryl group, and

iv) aryl substituted with 1-4 substituents independently selected from R⁸，

R^1aSelected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^1bselected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^2aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^2bselected from the group consisting of:

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

ii) an aryl group, and

iii)C_1-6-an alkyl group;

R³selected from the group consisting of:

i) hydrogen, and

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

R⁴selected from the group consisting of:

i) hydrogen, and

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

R⁵selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R⁶selected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group,

R^7aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^7bselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R⁸selected from the group consisting of:

i) the cyano group(s),

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

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

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

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

vi)C_1-6-an alkoxy group,

vii)C_1-6-alkoxy-C_1-6-an alkyl group,

viii)C_2-6-alkynyl, and

ix)C_1-6-an alkyl group;

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

V is-CR^7aR^7b-；

W is-CR^2aR^2b-；

X is-CR^1aR^1b-, - (O-, -S-or-SO)₂-；

Y-NH-C=O-：

Z is selected from the group consisting of:

i) (ii) a heteroaryl group, wherein,

iii) aryl substituted with 1-2 substituents independentlyIs selected from R⁸，

R^1aSelected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^1bselected from the group consisting of:

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

ii) halogen, and

iii)C_1-6-an alkyl group;

R^2aselected from the group consisting of:

i) hydrogen, and

ii)C_1-6-an alkyl group;

R^2bselected from the group consisting of:

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

ii) phenyl, and

iii)C_1-6-an alkyl group;

R³is halogen;

R⁴is halogen;

R⁵is hydrogen;

R⁶is hydrogen;

R^7ais hydrogen;

R^7bis hydrogen;

R⁸selected from the group consisting of:

i) the cyano group(s),

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

iii) halo-C_1-6-alkyl, and

iv)C_1-6-an alkoxy group,

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1-2, wherein n is 0.

4. The compound of any one of claims 1-3, wherein X is-CR^1aR^1b-and R^1aAnd R^1bAre all hydrogen.

5. The compound of any one of claims 1-4, wherein p is 0.

6. A compound according to any one of claims 1-3, wherein X is-O-.

7. The compound of claims 1-2 and 6, wherein p is 1 and W is-CR^2aR^2b-and R^2aAnd R^2bAre all hydrogen.

8. The compound of any one of claims 1-7, wherein R³Is a halogen.

9. The compound of any one of claims 1-8, wherein R³Is F.

10. The compound of any one of claims 1-9, wherein R⁴Is a halogen.

11. The compound of any one of claims 1-10, wherein R⁴Is F.

12. The method according to any of claims 1-11The compound of any one of, wherein R⁵Is hydrogen.

13. The compound of any one of claims 1-12, wherein R⁶Is hydrogen.

14. The compound of any one of claims 1-13, wherein m is 0.

15. The compound of any one of claims 1-13, wherein m is 1.

16. The compound of any one of claims 1-15, wherein Z is heteroaryl substituted with halo or cyano.

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

(2 ' R, 4R) -6 ' - (5-Chloropyridin-3-yl) -5, 5-difluoro-5, 5 ', 6,6 ' -tetrahydro-4 ' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2'3' -pyrans]-a salt of 2-amine formic acid,

(R) -5 ', 5 ' -difluoro-6- (5-methoxypyridin-3-yl) -5 ', 6 ' -dihydrospiro [ chroman-4, 4 ' - [1,3]]Oxazines]-a 2' -amine of the group consisting of,

(R) -N- (2 '-amino-5', 5 '-difluoro-3, 4, 5', 6 '-tetrahydro-2H-spiro [ naphthalene-1, 4' - [1,3]]Oxazines]-7-yl) -5-cyanopyridinamide,

(R) -N- (2 '-amino-5', 5 '-difluoro-5', 6 '-dihydrospiro [ chromane-4, 4' - [1,3]]Oxazines]-6-yl) -4-chloro-1H-pyrazole-5-carboxamide,

(R) -N- (3 '-amino-6', 6 '-difluoro-6'7 ' -dihydro-2 ' H-spiro [ chroman-4, 5 ' - [1,4]]Oxazazem]-6-yl) -5-cyanopyridinamide,

3- ((2RS, 4R) -3 ' -amino-6 ', 6 ' -difluoro-2-phenyl-6 ', 7 ' -dihydro-2 ' H-spiro [ chromane-4, 5 ' - [1, 4)]Oxazazem]-6-yl) benzonitrile,

3- [ (2 'R, 4R) -2-amino-5, 5-difluoro-5, 5', 6,6 '-tetrahydro-4' H-dispiro [1, 3-Oxazine-4, 4 '-chromene-2', 3 "-pyrans]-6' -yl]The formate salt of a benzonitrile,

n- ((2RS, 4R) -3 '-amino-6', 6 '-difluoro-2-phenyl-6', 7 '-dihydro-2' H-spiro [ chroman-4,5′-[1，4]oxazazem]-6-yl) -5-cyanopyridinamide,

or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1-17, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 16, which process comprises: reacting a compound of formula I' to a compound of formula I,

wherein V, W, Y, Z, n, p, R¹，R²，R³，R⁴，R⁵And R⁶As defined in any one of claims 1 to 16 and m is 1.

20. A compound of formula I according to any one of claims 1 to 18, when manufactured by a process as defined in claim 19.

21. Compounds of formula I according to any one of claims 1 to 18 for use as therapeutically active substances.

22. A compound of formula I according to claims 1-18 for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β -amyloid levels and/or β -amyloid oligomers and/or β -amyloid plaques and further deposits, or alzheimer's disease.

23. Compounds of formula I according to claims 1-18 for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of diabetes or type II diabetes.

24. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 18, together with a pharmaceutically acceptable carrier and/or pharmaceutically acceptable auxiliary substances.

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

26. The use of a compound of formula I according to any one of claims 1 to 18 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of diabetes.

27. A method for the therapeutic and/or prophylactic treatment of alzheimer's disease, which method comprises administering a compound of formula I according to any of claims 1-18 to a human being or animal.

28. A method for the therapeutic and/or prophylactic treatment of diabetes or type II diabetes, which method comprises administering a compound of formula I according to any of claims 1 to 18 to a human being or animal.

29. The invention as hereinbefore described.