Background Art

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system and the leading cause of a progressive dementia in the elderly population. Its clinical symptoms are impairment of memory, cognition, temporal and local orientation, judgment and reasoning but also severe emotional disturbances. There are currently no treatments available which can prevent the disease or its progression or stably reverse its clinical symptoms. AD has become a major health problem in all societies with high life expectancies and also a significant economic burden for their health systems.

AD is characterized by 2 major pathologies in the central nervous system (CNS), the occurrence of amyloid plaques and neurofibrillar tangles (Hardy 1 2

et al. and Selkoe ). Both pathologies are also commonly observed in patients with Down's syndrome (trisomy 21), which also develop AD-like symptoms in early life. Genetic ablation of the BACE1 gene in mice has clearly shown that its activity is essential for the processing of APP which leads to the generation of Αβ-peptides, in the absence of BACE1 no Αβ-peptides are produced (Luo et al ³ and Roberds et al. ⁴ ). Mice which have been genetically engineered to express the human APP gene and which form extensive amyloid plaques and Alzheimer' s disease like pathologies during aging fail to do so when β-secretase activity is reduced by genetic ablation of one of the BACE1 alleles (McConlogue et al. ⁵ ). It is thus presumed that inhibitors of BACE1 activity can be useful agents for therapeutic intervention in Alzheimer's disease (AD). Furthermore, the formation, or formation and deposition, of β-amyloid peptides in, on or around neurological tissue (e.g., the brain) are inhibited by the present compounds, i.e. inhibition of the Αβ-production from APP or an APP fragment.

Inhibitors of BACE1 can in addition be used to treat the following diseases: IBM (inclusion body myositis) (Vattemi G. et al. ⁶ ), Down's Syndrome (Barbiero L. et al. ⁷ ), Wilson's Disease (Sugimoto I. 8 isease (Desnues B. 9

et al. ), Whipple's d et al. ), Spinocerebellar Ataxia 1 and Spinocerebellar Ataxia 7 (Gatchel J.R. et al. ¹⁰ Dermatomyositis (Greenberg S.A. et al ¹¹ and Greenberg S.A. et al. ¹² ), Kaposi Sarcoma (Lagos D. et al. ¹³ ), Glioblastoma multiforme ¹⁴ , Rheumatoid arthritis (Ungethuem U. et al. ¹⁵ ), Amyotrophic lateral sclerosis (Koistinen H. et al. ¹⁶ and Li Q.X. 17 Huntington's Disease (Kim Y.J. 18 19

et al. ), et al. and Hodges A. et al. ), Multiple Mieloma (Kihara Y. 20

al. ), Malignant melanoma (Talantov D. 21

et et al. ) Sjogren syndrome

(Basset C. 22 wal P.K. 23

et al. ), Lupus erythematosus (Gre et al. ), Macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, Breast cancer (Hedlund M. 24 et al. and Kondoh K. et al. ²⁵ ), Gastrointestinal diseases (Hoffmeister A. et al. ²⁶ ),

Autoimmune/inflammatory diseases (Woodard-Grice A.V. 27

et al. ), Rheumatoid Arthritis (Toegel S. 28 atory reactions (Lichtenthaler S.F. 29

et al. ), Inflamm et al. ), Arterial Thrombosis (Merten M. et al. ), Cardiovascular diseases such as Myocardial infarction and stroke (Maugeri

N. et al. 31 and Graves disease (Kiljanski J. et al.32 ).

BACE1 inhibitors have been described in the art, e.g. in WO 2011/058763, WO 2011/071135 and WO 2012/156284 ³³ . The present invention provides novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as Alzheimer's disease. Furthermore the use of compounds of formula I in the treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease and Wilson's Disease. The novel compounds of formula I have improved pharmacological properties.

Field of the Invention

The present invention provides amidines having BACE1 inhibitory properties, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

Summary of the Invention

The present invention provides a compound of formula I,

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

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

Detailed Description of the Invention

The present invention provides a compound of formula I and its pharmaceutically acceptable salts thereof, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the therapeutic and/or prophylactic treatment of diseases and disorders which are associated with inhibition of BACEl, such as Alzheimer's disease. Furthermore, the formation, or formation and deposition, of β-amyloid plaques in, on or around neurological tissue (e.g., the brain) are inhibited by the present compounds by inhibiting the Αβ production from APP or an APP fragment.

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

The term "Ci_6-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (ie/t-butyl), isopentyl,

2- ethyl -propyl (2-methyl -butyl), 1,2-dimethyl -propyl and the like. Particular "Ci_6-alkyl" are "Ci_

3- alkyl". A specific group is methyl. The term "halogen-Ci_6-alkyl", alone or in combination with other groups, refers to C _1-6 - alkyl as defined herein, which is substituted by one or multiple halogen, particularly 1-5 halogen, more particularly 1-3 halogen. Particular halogen is fluoro. Particular "halogen-Ci_6-alkyl" is fluoro-Ci_6-alkyl and a particular "halogen-Ci_3 -alkyl" is fluoro-Ci_3-alkyl. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and the like. The term "Ci_6-alkoxy-Ci_6-alkyl", alone or in combination with other groups, refers to Ci_

6-alkyl as defined herein, which is substituted by one or multiple Ci_6-alkoxy, as defined herein, particularly 1 Ci_6-alkoxy. Particular "Ci_6-alkoxy-Ci_6-alkyl" is methoxy-Ci_6-alkyl. Examples are methoxymethyl, methoxyethyl and the like.

The term "cyano", alone or in combination with other groups, refers to N≡C-(NC-). The term "amino", alone or in combination with other groups, refers to -NH ₂ .

The term "halogen", alone or in combination with other groups, denotes chloro (CI), iodo (I), fluoro (F) and bromo (Br). Particular "halogen" is CI and F. A specific group is F. The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring, in particular 5 to 8, or multiple condensed rings comprising 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms individually selected from N, O and S, in particular IN or 2N, in which group at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl, lH-benzoimidazolyl, benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, lH-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), lH-pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[l]pyrindinyl and the like. Particular "heteroaryl" are pyridinyl, oxazolyl and pyrazinyl. Specific "heteroaryl" are pyridin-2-yl, oxazol-4-yl and pyrazin-2-yl.

The term "C ₃ _6-cycloalkyl" refers to a 3 to 8 membered carbon ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl. Particular are cycloalkyl groups having a 3, 4, 5 or 6 membered carbon ring. Specific is cyclopropyl.

The term "C ₃ _6-cycloalkyl-Ci_6-alkoxy", alone or in combination with other groups, refers to a "C ₃ _6-cycloalkyl" as defined herein linked via "Ci_6-alkoxy" as defined herein. Specific is cyclopropylmethoxy.

The term "Ci_6-alkoxy", alone or in combination with other groups, stands for an -0-C _1-6 - alkyl radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy), 2-butoxy (sec- butoxy), t-butoxy (ie/t-butoxy), isopentyloxy (i-pentyloxy) and the like. Particular "Ci-6-alkoxy" are groups with 1 to 4 carbon atoms. Specific are ethoxy and methoxy. The term "halogen-Ci-6-alkoxy", alone or in combination with other groups, refers to C _1-6 - alkoxy as defined herein, which is substituted by one or multiple halogens, in particular fluoro. Particular "halogen-Ci_6-alkoxy" are fluoro-Ci_6-alkoxy. Specific "halogen-Ci_6-alkoxy" are 2,2- difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3, 3,3-pentafluoropropoxy and difluoromethoxy.

The term ''C ₂ -6-alkynyl-Ci_6-alkoxy", alone or in combination with other groups, refers to Ci_6-alkoxy as defined herein, which is substituted by one or multiple C ₂ -6-alkynyl as defined herein, in particular 1 C ₂ -6-alkynyl. Specific is but-2-ynyloxy.

The term "C ₂ -6-alkynyl", alone or in combination with other groups, denotes a monovalent linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms, and comprising one, two or three triple bonds. Examples of C ₂ -6-alkynyl include ethynyl, propynyl, and n-butynyl. The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Specific "aryl" is phenyl.

The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid.

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

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

The term "inhibitor" denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein. The term "half maximal inhibitory concentration" (IC ₅₀ ) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC ₅₀ values can be converted logarithmically to pIC ₅ o values (-log IC ₅₀ ), in which higher values indicate exponentially greater potency. The IC ₅₀ value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC ₅₀ value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation ³⁴ . The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to pKi values (-log Ki), in which higher values indicate exponentially greater potency. "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The term "as defined herein" and "as described herein" when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any. The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

The terms "protecting group" or "protection group" denote the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" (here also P ¹ ) denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9- fluorenylmethoxycarbonyl (FMOC), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, iert-butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of these groups are found in several books. 35. The term "protected amino group" refers to an amino group substituted by an amino-protecting groups. A particular amino-protecting group is di-tert-butyl dicarbonate (Boc ₂ 0).

The term "leaving group" denotes the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include halogen, in particular bromo, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, and acyloxy.

The term "aromatic" denotes the conventional idea of aromaticity as defined literature ³⁶ . The term "pharmaceutically acceptable excipient" denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof.

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

All separate embodiments may be combined.

One embodiment of the invention provides a compound of formula I,

wherein

R ¹ is selected from the group consisting of

i) aryl,

ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci_6-alkyl, halogen-Ci_6-alkoxy, Ci_6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C ₂ _ 6-alkynyl-Ci_6-alkoxy, C ₂ _6-alkynyl, Ci_6-alkyl, C ₃ _6-cycloalkyl and C ₃ _6-cycloalkyl-Ci_6- alkoxy;

iii) heteroaryl, and

iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci_6-alkyl, halogen-Ci_6-alkoxy, Ci_6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C ₂ _ 6-alkynyl-Ci_6-alkoxy, C ₂ _6-alkynyl, Ci_6-alkyl, C ₃ _6-cycloalkyl and C ₃ _6-cycloalkyl-Ci_6- alkoxy;

R is halogen;

R is selected from the group consisting of

i) Ci_6-alkyl, and

ii) halogen-Ci_6-alkyl;

R ⁴ is selected from the group consisting of

i) halogen, and ii) hydrogen;

R ⁵ is selected from the group consisting of

i) halogen, and

ii) hydrogen; or pharmaceutically acceptable salts thereof.

A certain embodiment relates to a compound a compound of formula I, wherein

R ¹ is selected from the group consisting of

i) aryl,

ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci_6-alkyl, halogen-Ci_6-alkoxy, Ci_6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C ₂ _ 6-alkynyl-Ci_6-alkoxy, C ₂ _6-alkynyl, Ci_6-alkyl, C ₃ _6-cycloalkyl and C ₃ _6-cycloalkyl-Ci_6- alkoxy;

iii) heteroaryl, and

iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-Ci_6-alkyl, halogen-Ci_6-alkoxy, Ci_6-alkoxy, Ci_6-alkoxy-Ci_6-alkyl, C ₂ _ 6-alkynyl-Ci_6-alkoxy, C ₂ _6-alkynyl, Ci_6-alkyl, C ₃ _6-cycloalkyl and C ₃ _6-cycloalkyl-Ci_6- alkoxy;

R is halogen;

R is selected from the group consisting of

i) Ci_6-alkyl, and

ii) halogen-Ci_6-alkyl;

R ⁴ is hydrogen, and

R ⁵ is hydrogen; or pharmaceutically acceptable salts thereof.

A certain embodiment relates to a compound of formula la as described herein,

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. A certain embodiment relates to a compound of formula I as described herein, wherein R is heteroaryl substituted by 1-2 substituents individually selected from cyano, halogen, halogen- Ci_6-alkoxy, Ci_6-alkoxy, C ₂ -6-alkynyl-Ci_6-alkoxy, Ci_6-alkyl, and C ₃ _6-cycloalkyl-Ci_6-alkoxy.

A certain embodiment relates to a compound of formula I as described herein, wherein R ¹ is pyridinyl, pyrazinyl or oxazolyl, substitued by 1-2 substituents individually selected from the group consisting of cyano, halogen, halogen-Ci_6-alkoxy, Ci_6-alkoxy, C ₂ -6-alkynyl-Ci_6-alkoxy, Ci_6-alkyl, and C ₃ _6-cycloalkyl-Ci_6-alkoxy.

A certain embodiment relates to a compound of formula I as described herein, wherein R ¹ is 2-methyloxazol-4-yl, 3,5-dichloropyridin-2-yl, 5-(2,2,2-trifluoroethoxy)pyridin-2-yl, 5- (2,2,3,3, 3-pentafluoropropoxy)pyrazin-2-yl, 5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl, 5-(2,2- difluoroethoxy)pyridin-2-yl, 5-(but-2-ynyloxy)pyrazin-2-yl, 5-(but-2-ynyloxy)pyridin-2-yl, 5- (cyclopropylmethoxy)pyrazin-2-yl, 5-(cyclopropylmethoxy)pyridin-2-yl, 5-(difluoromethoxy)-2- pyridyl, 5-(difluoromethoxy)pyrazin-2-yl, 5-(difluoromethoxy)pyridin-2-yl, 5- (trifluoromethoxy)pyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloropyridin-2-yl, 5- cyanopyridin-2-yl, 5-ethoxypyridin-2-yl, 5-methoxypyrazin-2-yl.

A certain embodiment relates to a compound of formula I as described herein, wherein R ¹ is 2-methyloxazol-4-yl, 3,5-dichloropyridin-2-yl, 5-(2,2,2-trifluoroethoxy)pyridin-2-yl, 5- (2,2,3,3, 3-pentafluoropropoxy)pyrazin-2-yl, 5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl, 5-(2,2- difluoroethoxy)pyrazin-2-yl, 5-(2,2-difluoroethoxy)pyridin-2-yl, 5-(but-2-ynyloxy)pyrazin-2-yl, 5-(but-2-ynyloxy)pyridin-2-yl, 5-(cyclopropylmethoxy)pyrazin-2-yl, 5-

(cyclopropylmethoxy)pyridin-2-yl, 5-(difluoromethoxy)pyrazin-2-yl, 5-

(difluoromethoxy)pyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 5-chloropyridin-2-yl, 5- cyanopyridin-2-yl or 5-ethoxypyridin-2-yl.

A certain embodiment relates to a compound of formula I as described herein, wherein R is F.

A certain embodiment relates to a compound of formula I as described herein, wherein R is Ci_6-alkyl.

A certain embodiment relates to a compound of formula I as described herein, wherein R is methyl. A certain embodiment relates to a compound of formula I as described herein, wherein R is -CH ₂ F.

A certain embodiment relates to a compound of formula I as described herein, wherein R ⁴ is H. A certain embodiment relates to a compound of formula I as described herein, wherein R ⁵ is H.

A certain embodiment relates to a compound of formula I as described herein, wherein R ¹ is pyridinyl, pyrazinyl or oxazolyl, substitued by 1-2 substituents individually selected from the group consisting of cyano, halogen, halogen-Ci_6-alkoxy, Ci_6-alkoxy, C2-6-alkynyl-Ci_6-alkoxy, Ci_6-alkyl, and C3_6-cycloalkyl-Ci_6-alkoxy, R ² is F, R ³ is methyl and R ⁴ and R ⁵ are both H

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

(4S,6S)-4-(2-(3,5-dichloropyridin-2-yl)-6-fluoro-3,4-dihy droquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(but-2-ynyloxy)pyrazin-2-yl)-6-fluoro-3,4 -dihydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(but-2-ynyloxy)pyridin-2-yl)-6-fluoro-3,4-di hydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(cyclopropylmethoxy)pyrazin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(cyclopropylmethoxy)pyridin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(difluoromethoxy)pyrazin-2-yl)-6-fluoro-3,4- dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-chloro-3-methylpyridin-2-yl)-6-fluoro-3,4-di hydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-chloropyridin-2-yl)-6-fluoro-3,4-dihydroquin azolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-ethoxypyridin-2-yl)-6-fluoro-3,4-dihydroquin azolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(2-methyloxazol-4-yl)-3,4-dihydroquina zolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, (4S,6S)-4-(6-fluoro-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl )-3,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(5-(2,2,3,3,3-pentafluoropropoxy)pyraz in-2-yl)-3,4-dihydroquinazolin-7- yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2 -amine,

(4S,6S)-4-(6-fluoro-2-(5-(trifluoromethoxy)pyridin-2-yl)- 3,4-dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(fluoromethyl)-4-[6-fluoro-2-(2-methyloxazol-4-yl) -3,4-dihydroquinazolin-7-yl]-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[2-(5-chloro-2-pyridyl)-6-fluoro-3,4-dihydroquinaz olin-7-yl]-4-(fluoromethyl)-6- (trifluoromethyl)-5,6-dihydro-l,3-oxazin-2-amine,

(4S,6S)-4-[2-[5-(difluoromethoxy)-2-pyridyl]-6-fluoro-3,4-di hydroquinazolin-7-yl]-4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-l,3-oxazin-2- amine,

(4S,6S)-4-[6-fluoro-2-(5-methoxypyrazin-2-yl)-3,4-dihydroqui nazolin-7-yl]-4-methyl-6- (trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

(4S,6S)-4-[6-fluoro-2-[5-(2,2,3,3-tetrafluoropropoxy)pyri din-2-yl]-3,4-dihydroquinazolin-7-yl]- 4-methyl-6-(trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

6-(7-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-4-yl)-6-fluoro- 3,4-dihydroquinazolin-2-yl)nicotinonitrile, and

6-[7-[(4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5 ,6-dihydro-l,3-oxazin-4-yl]-6- fluoro-3,4-dihydroquinazolin-2-yl]pyridine-3-carbonitrile,

or a pharmaceutical acceptable salt thereof.

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

(4S,6S)-4-(2-(5-chloropyridin-2-yl)-6-fluoro-3,4-dihydroq uinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

6-(7-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-4-yl)-6-fluoro- 3,4-dihydroquinazolin-2-yl)nicotinonitrile,

(4S,6S)-4-(2-(5-(cyclopropylmethoxy)pyridin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(2-methyloxazol-4-yl)-3,4-dihydroqu inazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3,4- dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(but-2-ynyloxy)pyrazin-2-yl)-6-fluoro-3,4-di hydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine, (4S,6S)-4-(2-(5-ethoxypyridin-2-yl)-6-fluoro-3,4-dihydroquin azolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(but-2-ynyloxy)pyridin-2-yl)-6-fluoro-3,4-di hydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(5-(2,2,2-trifluoroethoxy)pyridin-2 -yl)-3,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(3,5-dichloropyridin-2-yl)-6-fluoro-3,4-dihydro quinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-chloro-3-methylpyridin-2-yl)-6-fluoro-3,4-di hydroquinazolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(difluoromethoxy)pyrazin-2-yl)-6-fluoro-3,4- dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(5-(trifluoromethoxy)pyridin-2-yl)-3,4 -dihydroquinazolin-7-yl)-4-methyl- 6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluor o-3,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(6-fluoro-2-(5-(2,2,3,3,3-pentafluoropropoxy)pyraz in-2-yl)-3,4-dihydroquinazolin-7- yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine,

(4S,6S)-4-(2-(5-(cyclopropylmethoxy)pyrazin-2-yl)-6-fluoro-3 ,4-dihydroquinazolin-7-yl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1 ,3-oxazin-2-amine, and

(4S,6S)-4-[6-fluoro-2-[5-(2,2,3,3-tetrafluoropropoxy)pyridin -2-yl]-3,4-dihydroquinazolin-7-yl]- 4-methyl-6-(trifluoromethyl)-5,6-dihydro- 1 ,3-oxazin-2-amine,

or a pharmaceutical acceptable salt thereof.

A certain embodiment of the invention relates to a process to synthesize a compound of formula I as described herein, which process comprises reacting a compound of formula 7 to a compound of formula I.

7 I herein PG, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined as herein. A certain embodiment of the invention relates to a compound of formula I as described herein, whenever prepared by a process as defined above.

A certain embodiment of the invention relates to a compound of formula I as described herein for use as therapeutically active substance. A certain embodiment of the compound of formula I as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β- amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the compound of formula I as described herein for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral scleros is (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson's Disease.

A certain embodiment of the invention provides a pharmaceutical composition comprising a compound of formula I as described herein and 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 the use in inhibition of 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 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 manufacture 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 manufacture of a medicament for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, Spinocerebellar Ataxia 1, Spinocerebellar Ataxia 7, Whipple's Disease or Wilson's Disease.

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

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

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

The skilled person in the art will recognize that the compounds of formula I can exist in tautomeric form

All tautomeric forms are encompassed in the present invention. The compounds of formula I may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. Stereoisomers of compounds of formula I are compounds of formula la or compounds of formula lb, in particular compounds of formula la, wherein the residues have the meaning as described in any of the embodiments.

In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

The compounds of formula I may be prepared in accordance with the following schemes. The starting material may be prepared in accordance with known methods. Any previously defined residues and variables will continue to have the previously defined meaning unless otherwise indicated.

7

Scheme 1

Compounds of formula I can be prepared according to reaction scheme 1. Aromatic amines of structure 1 are halogenated, for instance, iodinated, to give 2. This transformation can be achieved by treatment of 1 with iodine and silver sulfate, among other methods. Treatment of 2 with a suitable cyanide, such as zink cyanide, in the presence of a catalyst, such as Pd ₂ (dba)3 /dppf, gives nitrile 3. At this point it may be advantageous to protect the oxazin motif of 3 by a suitable protection group (PG), which renders the oxazin motif less reactive in 4. This may be achieved for instance by treating 3 with Boc ₂ 0 and a suitable base, such as DIPEA, to give Boc- protected oxazin 4. Compound 4 is then reduced by a reducing agent such as NiCl ₂ / NaBH ₄ to give 5, which is coupled with a heteroarylcarboxylic acid, 6, in the presence of a coupling reagent such as EDC to give 7. In a final step, 7 is transformed into I by suitable conditions to achieve condensation, for instance, by heating in acetic acid.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a suitable solvent such as e.g. dioxane or THF and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or by chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base. One possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g. M(OH) _n , wherein M = metal or ammonium cation and n = number of hydroxide anions, to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilization.

Insofar as their preparation is not described in the examples, the compounds of formula I as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

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

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 inhibition of BACE1 activity. The compounds were investigated in accordance with the test given hereinafter. Cellular Αβ-lowering assay:

The Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells were seeded in 96 well Microtiter plates in cell culture medium (Iscove's, plus 10% (v/v) fetal bovine serum, penicillin/streptomycin ) to about 80% confluency and the compounds were added at a 3x concentration in 1/3 volume of culture medium ( final DMSO concentration was kept at 1 % v/v). After 18-20 hrs incubation at 37°C and 5% C0 ₂ in a humidified incubator, the culture supernatants were harvested for the determination of Αβ 40 concentrations using Perkin-Elmer Human Amyloid beta 1-40 ( high specificity ) Kit ( Cat# AL275C ).

In a Perkin-Elmer White Optiplate-384 ( Cat# 6007290 ), 2ul culture supernatants were combined with 2μ1 of a 10X AlphaLISA Anti-ΙιΑβ Acceptor beads + Biotinylated Antibody Anti-Αβ 1-40 Mix ( 50 μg/mL / 5nM ). After 1 hour room temperature incubation, 16μ1 of a 1.25 X preparation of Streptavidin (SA) Donor beads (25μg/mL ) were added and incubated for 30 minutes in the Dark. Light Emission at 615 nm was then recorded using En Vision- Alpha Reader. Levels of Αβ 40 in the culture supernatants were calculated as percentage of maximum signal (cells treated with 1% DMSO without inhibitor). The IC ₅₀ values were calculated using the Excel XLfit software.

Table 1 : IC ₅₀ values of selected examples

Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, 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 can also contain still other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which 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 will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1- 500 mg, particularly 1-100 mg, of a compound of formula I. Examples of compositions according to the invention are: Example A Tablets of the following composition are manufactured in the usual manner:

Table 2: possible tablet composition

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

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

Example B-l

Capsules of the following composition are manufactured:

Table 3: possible capsule ingredient composition Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Fill into a suitable capsule. The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured:

Table 5: possible soft gelatin capsule composition

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example C

Suppositories of the following composition are manufactured:

Table 6: possible suppository composition Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Example D

Injection solutions of the following composition are manufactured:

Table 7: possible injection solution composition Manufacturing Procedure

The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. Example E

Sachets of the following composition are manufactured:

Table 8: possible sachet composition

Manufacturing Procedure The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

Experimental Part The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

Example 1

(4S,6S)-4-(2-(5-chloropyridin-2-yl)-6-fluoro-3,4-dihydroquin azolin-7-yl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine Step 1: (4S,6S)-4-(5-amino-2-fluoro-4-iodophenyl)-4-methyl-6-(triflu oromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine

Under an atmosphere of argon, (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine (3 g, 10.3 mmol, CAS: 1432511-78-8, prepared according to Hilpert et al ³⁷ ) was combined with acetic acid (50 ml) to give a light yellow solution. Ammonium iodide (1.49 g, 10.3 mmol) and hydrogen peroxide (1.17 g, 1.3 ml, 10.3 mmol) were added. The reaction mixture was stirred for 3 days at room temperature. The reaction mixture was poured into satd. Na ₂ 0 ₃ S ₂ (60 ml) and extracted with EtOAc (3 x 60ml). The organic layers were combined and washed with satd. NaHC0 ₃ (50 ml). The organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (EtOAc/MeOH/heptane as eluent) to yield the title compound as a yellow foam (3.07 g, 71.4 %, MS (m/e) = 418.1 [M+H] ⁺ ).

Step 2: 2-amino-4-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3- oxazin-4-yl) -5 -fluorobenzonitrile

In a sealed glass tube, (4S,6S)-4-(5-amino-2-fluoro-4-iodophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine (3.07 g, 7.36 mmol) was combined with DMF (80 ml) to give a yellow solution. Zinc cyanide (1.73 g, 14.7 mmol), 1,1'- bis(diphenylphosphino)ferrocene (408 mg, 736 μηιοι) and zinc (120 mg, 1.84 mmol) were added. Argon was bubbled through the raction mixture for 10 min. Tris(dibenzylidenaceton)- dipalladium (337 mg, 368 μπιοΐ) was added and argon was again bubbled through the reaction mixture for 10 min. The reaction mixture was heated to 110 °C and stirred over night. The reaction mixture was cooled to room temperature and filtered.The filtered reaction mixture was poured into 200 ml H ₂ 0 and extracted with EtOAc (3 x 100 ml). The organic layers were combined and washed with satd. NaCl (1 x 150 mL). The aqueous layer was back-extracted with DCM (2 x 200 ml). The organic layers were dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel to yield the title compound as a dark brown viscous oil (2.77 g, 100 %, MS (m/e) = 317.1 [M+H] ⁺ ).

Step 3: tert-butyl (4S,6S)-4-(5-amino-4-cyano-2-fluorophenyl)-4-methyl-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate Under an atmosphere of argon, 2-amino-4-((4S,6S)-2-amino-4-methyl-6-

(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4-yl)-5-fluor obenzonitrile (2.77 g, 7.37 mmol) was combined with THF (140 ml) to give a light brown solution. Di-tert-butyl dicarbonate (3.22 g, 14.7 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.9 g, 2.51 ml, 14.7 mmol) were added. The reaction was stirred for a week at room temperature. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (0% to 40% EtOAc in heptane as eluent) to yield the title compound as a yellow solid (1.88 g, 59.0 %, MS (m/e) = 417.2 [M+H] ⁺ ).

Step 4: tert-butyl (4S,6S)-4-(5-amino-4-(aminomethyl)-2-fluorophenyl)-4-methyl- 6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcarbamate Under an atmosphere of argon, tert-butyl (4S,6S)-4-(5-amino-4-cyano-2-fiuorophenyl)-4- methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylcar bamate (1.88 g, 4.52 mmol) was combined with MeOH (60 ml) to give a yellow solution. The reaction mixture was cooled to 0°C. Nickel(II) chloride hexahydrate (107 mg, 452 μηιοι) and sodium tetrahydroborate (683 mg, 18.1 mmol) were added at 0°C. Th reaction mixture was stirred for 30 min at 0°C, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with satd. NH ₄ C1 (25 ml). The reaction mixture was extracted with DCM (50 ml) .The aqueous layer was back- extracted with DCM (2 x 50 ml). The organic layers were dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (0% to 10% MeOH in DCM as eluent) to yield the title compound as a light yellow foam (1.74 g, 85.9 %, MS (m/e) = 421.3 [M+H] ⁺ ).

Step 5: tert-butyl (4S,6S)-4-(5-amino-4-((5-chloropicolinamido)methyl)-2-fluoro phenyl)- 4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-ylc arbamate

Under an atmosphere of argon, tert-butyl (4S,6S)-4-(5-amino-4-(aminomethyl)-2- fiuorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l, 3-oxazin-2-ylcarbamate (100 mg, 223 μηιοι) was combined with DMF (2 ml) to give a yellow solution. 5-Chloropicolinic acid (35.1 mg, 223 μηιοι), Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (64.1 mg, 334 μηιοι), lH-benzo[d] [l,2,3]triazol-l-ol (45.2 mg, 334 μηιοι), and N- ethyl-N-isopropylpropan-2-amine (57.6 mg, 75.8 μΐ, 446 μηιοι) were added. The reaction mixture was stirred for 2 hr at room temperature, and was then purified by preparative HPLC (column: Zorbax Eclipse XDB-C18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) =95%-5% to 596-95%) to give a light yellow foam (67.9 mg, 54.4 %, MS (m/e) = 560.3 [M+H] ⁺ ).

Step 6: (4S,6S)-4-(2-(5-chloropyridin-2-yl)-6-fiuoro-3,4-dihydroquin azolin-7-yl)-4- methyl-6-(trifiuoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine Under an atmosphere of argon, in a sealed glass tube, tert-butyl (4S,6S)-4-(5-amino-4-((5- chloropicolinamido)methyl)-2-fiuorophenyl)-4-methyl-6-(trifi uoromethyl)-5,6-dihydro-4H-l,3- oxazin-2-ylcarbamate (67.9 mg, 121 μηιοΐ) was combined with acetic acid (2 ml) to give a yellow solution. The reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was taken up with EtOAc (10 ml) and washed with satd. NaHC0 ₃ (2 x 10 ml). The organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to yield the title compound as a light yellow solid (25.5 mg, 41.4 %, MS (m/e) = 442.11 [M+H] ⁺ ).

Preparation in analogy to MS

Ex. Name

example 1, educt used in step 5: (M+H ⁺ )

6-(7-((4S,6S)-2-amino-4-methyl-6-

(trifluoromethyl)-5,6-dihydro-4H-

2 l,3-oxazin-4-yl)-6-fluoro-3,4- 5-cyanopicolinic acid 433.14

dihydroquinazolin-2- yl)nicotinonitrile

(4S,6S)-4-(2-(5-

(cyclopropylmethoxy)pyridin-2-yl)-

5-(cyclopropylmethoxy)picolinic

3 6-fluoro-3,4-dihydroquinazolin-7- 478.19

acid

yl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine

(4S,6S)-4-(6-fluoro-2-(2- methyloxazol-4-yl)-3,4-

2-methyloxazole-4-carboxylic

4 dihydroquinazolin-7-yl)-4-methyl- 412.14

acid

6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-

(difluoromethoxy)pyridin-2-yl)-6-

5 fluoro-3,4-dihydroquinazolin-7-yl)- 5-(difluoromethoxy)picolinic acid 474.14

4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-(but-2-

5-(but-2-ynyloxy)pyrazine-2-

6 ynyloxy)pyrazin-2-yl)-6-fluoro-3,4- 477.17

carboxylic acid

dihydroquinazolin-7-yl)-4-methyl- Preparation in analogy to MS

Ex. Name

example 1, educt used in step 5: (M+H ⁺ )

6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-ethoxypyridin-2- yl)-6-fluoro-3,4-dihydroquinazolin-

7 5-ethoxypicolinic acid 452.17 7-yl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine

(4S,6S)-4-(2-(5-(but-2- ynyloxy)pyridin-2-yl)-6-fhioro-3,4-

8 dihydroquinazolin-7-yl)-4-methyl- 5-(but-2-ynyloxy)picolinic acid 476.17 6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(6-fluoro-2-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)-3,4-

5-(2,2,2-trifluoroethoxy)picolinic

9 dihydroquinazolin-7-yl)-4-methyl- 506.14 acid

6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(3,5-dichloropyridin- 2-yl)-6-fluoro-3,4-

10 di ydroquinazolin-7-yl)-4-methyl- 3,5-dichloropicolinic acid 476.1 6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-chloro-3- methylpyridin-2-yl)-6-fluoro-3,4-

11 di ydroquinazolin-7-yl)-4-methyl- 5-chloro-3-methylpicolinic acid 456.12 6-(trifluoromethyl)-5,6-dihydro- 4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-

(difluoromethoxy)pyrazin-2-yl)-6-

5 - (difhioromethoxy)pyrazine-2-

12 fluoro-3,4-dihydroquinazolin-7-yl)- 475.13 carboxylic acid

4-methyl-6-(trifluoromethyl)-5,6- di ydro-4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(6-fluoro-2-(5- (trifluoromethoxy)pyridin-2-yl)-

13 3,4-dihydroquinazolin-7-yl)-4- 5-(trifluoromethoxy)picolinic acid 492.13 methyl-6- (trifluoromethyl)-5 ,6- di ydro-4H- 1 ,3-oxazin-2-amine

14 (4S,6S)-4-(2-(5-(2,2- 5-(2,2-difluoroethoxy)picolinic 488.15 Preparation in analogy to MS

Ex. Name

example 1, educt used in step 5: (M+H ⁺ ) difluoroethoxy)pyridin-2-yl)-6- acid

fluoro-3,4-dihydroquinazolin-7-yl)- 4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-(2,2- difluoroethoxy)pyrazin-2-yl)-6-

5-(2,2-difluoroethoxy)pyrazine-2-

15 fluoro-3,4-dihydroquinazolin-7-yl)- 489.15

carboxylic acid

4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(6-fluoro-2-(5-(2,2,3,3,3- pentafluoropropoxy)pyrazin-2-yl)- 5-(2,2,3,3,3-

16 3,4-dihydroquinazolin-7-yl)-4- pentafluoropropoxy)pyrazine-2- 556.14

methyl-6-(trifluoromethyl)-5,6- carboxylic acid

dihydro-4H- 1 ,3-oxazin-2-amine

(4S,6S)-4-(2-(5-

(cyclopropylmethoxy)pyrazin-2-

5-(cyclopropylmethoxy)pyrazine-

17 yl)-6-fluoro-3,4-dihydroquinazolin- 479.18

2-carboxylic acid

7-yl)-4-methyl-6-(trifluoromethyl)- 5,6-dihydro-4H-l,3-oxazin-2-amine

(4S,6S)-4-[6-fluoro-2-[5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl]-

6-(2,2,3,3-

18 3,4-dihydroquinazolin-7-yl]-4- 538.14

tetrafluoropropoxy)nicotinic acid

methyl-6-(trifluoromethyl)-5,6- dihydro- 1 ,3-oxazin-2-amine

(4S,6S)-4-(6-fluoro-2-(5- methoxypyr azin - 2-yl)-3,4-

5-methoxypyrazine-2-carboxylic

19 dihydroquinazolin-7-yl)-4-methyl- 439.15

6 - (trifiuoromethyl) - 5 ,6 - dihydro - acid

4H-l,3-oxazin-2-amine

Table 9: Preparation of selected example

Example 20

(4S,6S)-4-(2-(5-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3,4- dihydroquinazolin-7-yl)-4- (fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin -2-amine The title compound was prepared in analogy to Example 1, using (4S,6S)-4-(5-amino-2- fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-2-amine (CAS: 1432511-78-8, prepared by the method of Hilpert et. aV ⁷ ) in step 1, and 5- (difiuoromethoxy)picolinic acid in step 5. MS: 492.2 (M+H ⁺ ). Example 21

(4S,6S)-4-(2-(5-chloropyridin-2-yl)-6-fluoro-3,4-dihydroquin azolin-7-yl)-4-(fluoromethyl)

(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

The title compound was prepared in analogy to Example 1, using (4S,6S)-4-(5-amino-2- fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-2-amine (CAS: 1432511-78-8, prepared by the method of Hilpert et. al. ³⁷ ) in step 1, and 5-chloropicolinic acid in step 5. MS: 460.2 (M+H ⁺ ).

Example 22

6-(7-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5 ,6-dihydro-4H-l,3-oxazin-4-yl)-6- fluoro-3,4-dihydroquinazolin-2-yl)nicotinonitrile

The title compound was prepared in analogy to Example 1, using (4S,6S)-4-(5-amino-2- fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-2-amine (CAS: 1432511-78-8, prepared by the method of Hilpert et. al. ³⁷ ) in step 1, and 5-cyanopicolinic acid in step 5. MS: 451.3 (M+H ⁺ ).

Example 23

(4S,6S)-4-(6-fluoro-2-(2-methyloxazol-4-yl)-3,4-dihydroquina zolin-7-yl)-4-(fluoromethyl)-6- (trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-2-amine

The title compound was prepared in analogy to Example 1, using (4S,6S)-4-(5-amino-2- fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihyd ro-4H-l,3-oxazin-2-amine (CAS: 1432511-78-8, prepared by the method of Hilpert et. al. ³⁷ ) in step 1, and 2-methyloxazole-4- carboxylic acid in step 5. MS: 430.2 (M+H ⁺ ).

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