TW201307307A - 1,3-oxazines as BACE1 and/or BACE2 inhibitors - Google Patents

Abstract

The present invention provides 4-(3-Amino-phenyl)-5, 6-dihydro-4H-[1, 3]oxazin-2-ylamines of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes.

Description

1,3- as a BACE1 and/or BACE2 inhibitor

The present invention provides 4-(3-amino-phenyl)-5,6-dihydro-4H-[1,3] having BACE1 and/or BACE2 inhibitory properties. The use of a -2-ylamine, a pharmaceutical composition thereof, and the like, and the like as a therapeutic active.

Alzheimer's disease (AD) is a major cause of neurodegenerative diseases of the central nervous system and progressive dementia in the elderly population. Its clinical symptoms are memory, cognition, time and location orientation, judgment and understanding disorders, as well as severe emotional disorders. Treatment to prevent the disease or its deterioration or stable reversal of its clinical symptoms has not yet been achieved. AD has become a major health problem in all populations that affects high life expectancy and also imposes a significant financial burden on its health systems.

AD is characterized by two major pathologies in the central nervous system (CNS): appearance of amyloid plaques and neurofibrillary tangles (Hardy et al, The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics , Science. 2002 Jul 19; 297(5580): 353-6, Selkoe, Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994; 10: 373-403 ). These two pathologies are also common in patients with Down's syndrome (21st trisomy), which also exhibit AD-like symptoms early in life. Neurofibrillary tangles are intracellular agglutination of microtubule-associated protein τ (MAPT). Amyloid-like plaques appear in the extracellular space; their major components are Aβ-peptides. The Aβ-peptide system obtains one of the proteolytic fragments from the β-amyloid precursor protein (APP) via a series of proteolytic steps. Several APP forms have been identified, the largest of which are proteins of 695, 751 and 770 amino acid lengths. They are all produced by differential splicing of a single gene. The Aβ-peptide is produced from the same domain of APP, but its N- and C-termini are different, and the main species has 40 and 42 amino acid lengths. There are several evidences that strongly suggest that agglutinating Aβ-peptide is an essential molecule in the pathology of AD: 1) amyloid plaques formed by Aβ-peptide are always part of the AD pathology; 2) Aβ-peptide is toxic to nerves; 3) In familial Alzheimer's disease (AD), mutations in the disease genes APP, PSN1, and PSN2 lead to increased Aβ-peptide concentration and early cerebral amyloidosis; 4) transgenes expressing these FAD genes Mice develop pathologies that share many similar aspects to human disease. The Aβ-peptide is produced from APP in sequence via the action of two proteolytic enzymes called β- and γ-secretase. The β-secretase first cleaves about 28 amino acids outside the transmembrane domain (TM) in the extracellular domain of APP to produce an APP C-terminal fragment (CTFβ) containing TM- and cytoplasmic domains. The CTFβ is a matrix of γ-secretase that cleaves several adjacent positions within the TM to produce Aβ peptides and cytoplasmic fragments. The γ-secretase is a complex of at least four different proteins whose catalytic subunits resemble premature aging proteins (PSEN1, PSEN2). --secretase (BACE1, Asp2; BACE stands for β-site APP-lyase) is an aspartame-based protease anchored to the membrane by the transmembrane domain (Vassar et al., Beta-secretase cleavage of Alzheimer's amyloid) Precursor protein by the transmembrane aspartic protease BACE, Science. 1999 Oct 22;286(5440):735 ). It will behave in many tissues of human organs, but its concentration is particularly high in the CNS. The genetic excision of the mouse BACE1 gene has clearly shown that its activity is required for the processing of APP produced by Aβ-peptide, and in the absence of BACE1, no Aβ-peptide is produced (Luo et al., Mice deficient in BACE1, the Alzheimer's beta- Secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci . 2001 Mar; 4(3): 231-2 ; Roberds et al, BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain:implications for Alzheimer's Disease therapeutics, Hum Mol Genet . 2001 Jun 1;10(12):1317-24 ). When the β-secretase activity is reduced by genetically excising one of the BACE1 dual genes, it is genetically engineered to express the human APP gene and form a large number of amyloid plaques and Alzheimer's disease during aging. Type-pathological mice will not exhibit the above results (McConlogue et al, Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep 7;282(36):26326 ). Therefore, it is hypothesized that BACE1 activity inhibitors are useful drugs for therapeutic intervention in Alzheimer's disease (AD).

Type 2 diabetes mellitus (T2D) is caused by insulin resistance and insufficient insulin secretion from pancreatic β-cells, leading to poor glycemic control and hyperglycemia (M Prentki & CJ Nolan, "Islet beta-cell failure in type 2 diabetes." .Clin. Investig. 2006, 116(7), 1802-1812). Patients with T2D have a higher risk of developing microvascular and macrovascular diseases and a range of related complications, including diabetic nephropathy, retinopathy and blood Tube disease. In 2000, 17.1 million people have been confirmed to have the condition, and it is expected that this number will double in 2030 (S Wild, G Roglic, A Green, R. Sicree & H King, "Global prevalence of Diabetes, Diabetes Care 2004, 27(5), 1047-1053), making the disease a major health problem. The rise in T2D epidemics is associated with increasing sedentary lifestyles and high-energy food intake in the world's population (P Zimmet, KGMM Alberti & J Shaw, "Global and societal implications of the diabetes epidemic" Nature 2001, 414, 782-787 ).

Β-cell failure and subsequent rapid decline in insulin secretion and markers of hyperglycemia T2D onset. Most existing treatments do not prevent loss of beta-cell mass and form dominant T2D. However, recent developments in GLP-1 analogues, gastrin and other drugs have shown that maintenance and proliferation of β-cells can result in improved glucose tolerance and slowing of dominant T2D progression (LL Baggio & DJ Drucker, Therapeutic approaches to preserve islet mass in type 2 diabetes", Annu. Rev. Med. 2006, 57, 265-281).

Tmem27 has been shown to promote β-cell proliferation (P Akpinar, S Kuwajima, J Krützfeldt, M Stoffel, "Tmem 27: A cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation", Cell Metab. 2005, 2, 385-397) and Insulin secretion (K Fukui, Q Yang, Y Cao, N Takahashi et al, "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", Cell Metab. 2005, 2, 373-384) protein. Tmem27 is a 42 kDa membrane glycoprotein that is structurally detached from the surface of β-cells due to degradation of full-length cell Tmem27. Overexpression of Tmem27 in transgenic mice increased the number of β-cells and improved glucose tolerance in the dietary-induced obesity DIO model of diabetes. Furthermore, in rodent beta-cell proliferation assays (eg, using INS1e cells), siRNA knockdown of Tmem27 reduces proliferation rates, indicating the effect of Tmem27 on controlling the number of beta cells.

In the same proliferation assay, BACE2 inhibitors also increased proliferation. However, inhibition of BACE2 in combination with Tmem27 siRNA knockdown resulted in a low rate of proliferation. Therefore, it was concluded that BACE2 is a protease responsible for the degradation of Tmem27. Furthermore, in vitro, BACE2 cleaves the peptide based on the sequence of Tmem27. The closely related protease BACE1 does not cleave this peptide and the selective inhibition of BACE1 alone does not enhance the proliferation of β-cells.

The close homolog BACE2 membrane binds to aspartame chymotrypsin and is co-located with Tmem27 in human pancreatic β-cells (G Finzi, F Franzi, C Placidi, F Acquati et al., "BACE2 is stored in secretory granules Of mouse and rat pancreatic beta cells", Ultrastruct Pathol. 2008, 32(6), 246-251). Also known as degradable APP (I Hussain, D Powell, D Howlett, G Chapman et al, "ASP1 (BACE2) cleaves the amyloid precursor protein at the β-secretase site" Mol Cell Neurosci. 2000, 16, 609-619), IL- 1R2 (P Kuhn, E Marjaux, A Imhof, B De Strooper et al., "Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma- Secretase" J. Biol. Chem. 2007, 282 (16), 11982-11995) and ACE2. The ability to degrade ACE2 illustrates the potential role of BACE2 in controlling hypertension.

Therefore, inhibition of BACE2 is recommended as a T2D treatment to maintain and restore the number of β-cells and stimulate insulin secretion in pre-diabetes and diabetic patients. Accordingly, it is an object of the present invention to provide selective BACE2 inhibitors. These compounds are useful as therapeutic actives, particularly for the treatment and/or prevention of diseases associated with inhibition of BACE2.

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

BACE1 and/or BACE2 inhibitors can also be used to treat the following diseases: IBM (Inclusion Body Myositis) (Vattemi G. et al., Lancet. 2001 Dec 8; 358 (9297): 1962-4), Down Syndrome (Barbiero L) Et., Exp Neurol. 2003 Aug; 182(2): 335-45), Wilson's Disease (Sugimoto I. et al., J Biol Chem. 2007 Nov 30; 282(48): 34896 -903), Whipple's disease (Desnues B. et al., Clin Vaccine Immunol. 2006 Feb; 13(2): 170-8), spinal cerebellar disorder 1 and spinocerebellar disorders 7 (Gatchel JR et al. , Proc Natl Acad Sci USA 2008 Jan 29;105(4):1291-6), Dermatomyositis (Greenberg SA et al, Ann Neurol. 2005 May; 57(5): 664-78 and Greenberg SA et al, Neurol 2005 May; 57(5): 664-78), Kaposi Sarcoma (Lagos D. et al., Blood, 2007 Feb 15; 109(4): 1550-8), glioblastic glioblasts Tumor (E-MEXP-2576, http://www.ebi.ac.uk/microarray-as/aer/result? queryFor=PhysicalArrayDesign&aAccession=A-MEXP-258), rheumatoid arthritis (Ungethuem U. et al.) , GSE2053), amyotrophic lateral sclerosis (Koistinen H. et al. Muscle Nerve. 2006 Oct; 34(4): 444-50 and Li QX et al, Aging Cell. 2006 Apr; 5(2): 153-65), Huntington's disease (Kim YJ et al, Neurobiol Dis.2006 May;22(2):346-56.Epub 2006 Jan 19 and Hodges A. et al., Hum Mol Genet.2006 Mar 15;15(6):965-77.Epub 2006 Feb 8), multiple Sexual myeloma (Kihara Y. et al, Proc Natl Acad Sci US A. 2009 Dec 22; 106(51): 21807-12), malignant melanoma (Talantov D. et al, Clin Cancer Res. 2005 Oct 15; 11 (20): 7234-42), dry syndrome (Basset C. et al., Scand J Immunol. 2000 Mar; 51(3): 307-11), lupus erythematosus (Grewal PK et al., Mol Cell Biol. 2006, Jul ;26(13):4970-81), macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, breast cancer (Hedlund M. et al., Cancer Res. 2008 Jan 15;68(2) : 388-94 and Kondoh K. et al., Breast Cancer Res Treat. 2003 Mar; 78(1): 37-44), Gastrointestinal diseases (Hoffmeister A. et al., JOP. 2009 Sep 4; 10(5): 501 -6) Autoimmune/inflammatory disease (Woodard-Grice AV et al, J Biol Chem. 2008 Sep 26; 283(39): 263 64-73.Epub 2008 Jul 23), rheumatoid arthritis (Toegel S. et al., Osteoarthritis Cartilage. 2010 Feb; 18(2): 240-8. Epub 2009 Sep 22), inflammatory response (Lichtenthaler SF et al. J Biol Chem. 2003 Dec 5; 278(49):48713-9.Epub 2003 Sep 24), Arterial Thrombosis (Merten M. et al., Z Kardiol. 2004 Nov; 93(11): 855-63), Cardiovascular diseases such as myocardial infarction and stroke (Maugeri N. et al., Srp Arh Celok Lek. 2010 Jan; 138 Suppl 1:50-2) and Graves' disease (Kilja) Ski J. et al., Thyroid. 2005 Jul; 15(7): 645-52).

The present invention provides novel compounds of formula I, their manufacture, agents based on the compounds of the invention, and the like, and compounds of formula I for controlling or preventing diseases such as Alzheimer's disease and type 2 diabetes use. Further, the use of a compound of formula I for the treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancers such as breast cancer, such as myocardial infarction and stroke is provided. Cardiovascular disease, dermatomyositis, Down syndrome, gastrointestinal disease, glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM) , inflammatory response, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignant melanoma, multiple bone marrow Tumor, rheumatoid arthritis, Sjogren syndrome, spinocerebellar disorders 1, spinocerebellar disorders 7, Whipple's disease, and Wilson's Disease. The novel compounds of formula I have the pharmacological properties of Whipple's Disease.

The present invention provides a compound of formula I, Wherein the substituents and variables are as described below and in the scope of the patent application; or a pharmaceutically acceptable salt thereof.

The compounds of the present invention have Asp2 (β-secretase, BACE1 or membrane-bound aspartate-2) inhibitory activity and are therefore useful for the therapeutic and/or prophylactic treatment of diseases and conditions characterized by: Elevated beta-amyloid protein concentrations and/or beta-amyloid oligos and/or beta-amyloid plaques and further deposition, in particular, Alzheimer's disease. And/or the compounds of the invention have BACE2 inhibitory activity and are therefore useful in the therapeutic and/or prophylactic treatment of diseases and conditions such as type 2 diabetes and other metabolic disorders.

The present invention provides a compound of the formula I and a pharmaceutically acceptable salt thereof, a preparation of the above compound, an agent containing the above compound, and the like, and the therapeutic and/or prophylactic treatment of the above compound with BACE1 and/or BACE2 activity Use in inhibiting related diseases and conditions such as Alzheimer's disease and type 2 diabetes. Furthermore, the inhibition of Aβ-production from APP or APP fragments by the compounds of the invention inhibits the formation, formation and deposition of β-amyloid plaques in, on or around nerve tissues (eg, the brain).

Applying the following definitions of the basic terms used in the present invention regardless of the The term appears alone or in combination with other groups.

Unless otherwise stated, the following terms in this application (including the specification and the scope of the patent application) have the definitions indicated below. It should be noted that the singular forms "a" and "the"

The term "C _1-6 -alkyl", alone or in combination with other groups, represents a hydrocarbyl group, which may be straight-chain or branched, and has one or more branches, wherein the alkyl group generally comprises from 1 to 6 Carbon atom, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl ( Second butyl), t-butyl (t-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, represents a hydrocarbyl group, which may be straight or branched, wherein the alkyl group contains from 1 to 3 carbon atoms. The specific "C _1-6 -alkyl" is "C _1-3 -alkyl". Specifically, it is a methyl group and an ethyl group. The most specific one is methyl.

The term "cyano-C _1-6 -alkyl", alone or in combination with other groups, means one or more cyano groups, in particular, 1 to 5 cyano groups, more specifically 1 cyano group. The group is substituted with a C _1-6 -alkyl group as defined herein. Examples are cyano-methyl and the like.

The term "halogen atom -C _1-6 -alkyl", alone or in combination with other groups, means one or more halogen atoms, in particular, 1 to 5 halogen atoms, more specifically, 1 to 3 A halogen atom, most specifically, a C _1-6 -alkyl group as defined herein, substituted by 1 halogen atom or 3 halogen atoms. The term "halogen atom -C _1-3 -alkyl", alone or in combination with other groups, means one or more halogen atoms, in particular, 1 to 5 halogen atoms, more specifically, 1 to 3 A halogen atom, most specifically, a C _1-3 -alkyl group as defined herein, substituted with 1 halogen atom or 3 halogen atoms. The specific halogen atom is fluorine. The specific "halogen atom-C _1-6 -alkyl group" is a fluorine-C _1-6 -alkyl group and a specific "halogen atom -C _1-3 -alkyl group" is a fluorine-C _1-3 -alkyl group. Examples are difluoromethyl, chloromethyl, fluoromethyl and the like. Specifically, it is a trifluoromethyl group, -CH ₂ -CHF ₂ and -CH ₂ -CH ₂ F.

The term "C _1-6 -alkoxy-C _1-6 -alkyl", alone or in combination with other groups, means substituted by one or more C _1-6 -alkoxy groups as defined herein. C _1-6 -alkyl. Examples are MeO-CH ₂ -, 1MeO-Et, 2MeO-Et, 1MeO-2EtO-propyl and the like.

The term "C _3-6 -cycloalkyl-C _1-6 -alkyl", alone or in combination with other groups, means substituted by one or more C _3-6 -cycloalkyl groups as defined herein. C _1-6 -alkyl. Examples are cyclopropyl-methyl and the like.

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

The term "hydroxy", alone or in combination with other groups, refers to HO-.

The term "halogen atom", alone or in combination with other groups, means chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). Specific "halogen atoms" are Cl and F. Specifically, it is F.

The term "heteroaryl", alone or in combination with other groups, refers to a fused ring having a single 4 to 8 membered ring or a plurality of containing 6 to 14, in particular 6 to 10 ring atoms, and containing 1, 2 Or three aromatic carbocyclic groups independently selected from N, O and S, in particular, a hetero atom of N and O, in which at least one heterocyclic aromatic ring. Examples of "heteroaryl" include benzofuranyl, benzimidazolyl, 1H-benzimidazolyl, benzo Base, benzo Azolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, oxazolyl, 1H-carbazolyl, fluorenyl, isoquinolyl, Isothiazolyl, different Azolyl, Azyl, pyrazinyl, pyrazolyl, 1H-pyrazolyl, pyrazolo[1,5-a]pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolyl, tetrazolyl , thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[1]pyridinyl and the like. Particular "heteroaryl" is pyridinyl, pyrazinyl, furyl, thiazolyl, 2H-pyrazolyl and 1H-pyrazolyl. Specifically, it is pyridin-2-yl, pyrazin-2-yl, furan-3-yl, thiazol-5-yl, 2H-pyrazol-3-yl and 1H-pyrazol-3-yl.

The term "heterocyclyl", alone or in combination with other groups, denotes a ring heteroatom containing 1, 2 or 3 selected from N, O and S, and the remaining ring atoms are saturated with a monovalent of 4 to 9 ring atoms of carbon. Or partially unsaturated single or double loop systems. Bicyclic means consisting of two rings having two shared ring atoms, i.e., a chain separating the two bonds of the two rings or one or two ring atoms. Examples of monocyclic saturated heterocyclic groups are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazolidinyl, Zymididine Zyridinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thio Morpholin-4-yl, azepanyl, diazepanyl, homohexahydropyrazinyl or oxazepine. Examples of bicyclic saturated heterocyclic groups are 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-thio-9-aza-bicyclo[3.3.1]fluorenyl. Examples of partially unsaturated heterocyclic groups are dihydrofuranyl, imidazolinyl, dihydro- Azolyl, tetrahydro-pyridyl or dihydropyranyl.

The term "C _1-6 -alkoxy", alone or in combination with other groups, represents -OC _1-6 -alkyl, which may be straight-chain or branched, having one or more branches, wherein the alkyl group Generally containing from 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i -butoxy (isobutoxy), 2-butoxy (second butoxy), t-butoxy (t-butoxy), isopentyloxy (i-pentyloxy) and the like By. The specific "C _1-6 -alkoxy group" is a group having 1 to 4 carbon atoms. Specifically, it is a methoxy group and an ethoxy group.

The term "halogen atom -C _1-6 -alkoxy", alone or in combination with other groups, means C _1-6 as defined herein, via one or more halogen atoms, in particular, fluorine. Alkoxy. The specific "halogen atom -C _1-6 -alkoxy group" is a fluorine-C _1-6 -alkoxy group. Specifically, it is a difluoromethoxy group and a trifluoromethoxy group.

The term "C _3-6 -cycloalkyl-C _1-6 -alkoxy", alone or in combination with other groups, means one or more "C _3-6 -cycloalkyl groups as defined herein. Specifically, a cyclopropyl group is substituted with a C _1-6 -alkoxy group as defined herein. Specific "C _3-6 -cycloalkyl-C _1-6 -alkoxy" is cyclopropyl-C _1-6 -alkoxy. Specifically, it is a cyclopropyl-methoxy group and a cyclopropyl-ethoxy group.

The term "C _3-6 -cycloalkyl-C _2-6 -alkynyl", alone or in combination with other groups, refers to a link "C _2-6 -alkynyl" as defined herein, as used herein. The definition of "C _3-6 -cycloalkyl". Specifically, it is a cyclopropyl-ethynyl group.

The term "C _3-6 -cycloalkyl", alone or in combination with other groups, denotes a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing from 3 to 6 ring carbon atoms, in particular containing from 3 to 5 ring carbon atoms. Monovalent saturated monocyclic hydrocarbon group. Bicyclic means consisting of two saturated carbocycles having two carbon atoms in common, i.e., separating the bonds of the two rings from a single bond or a chain of one or two carbon atoms. Particular C _3-6 -cycloalkyl monocyclic. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl or adamantyl. A specific "C _3-6 -cycloalkyl group" is a cyclohexyl group.

The term "C _2-6 -alkynyl", alone or in combination with other groups, denotes a unitary unit of 2 to 6 carbon atoms, in particular 2 to 4 carbon atoms and containing one, two or three triple bonds. Chain or branched saturated hydrocarbon group. Examples of the C _2-6 -alkynyl group include an ethynyl group, a propynyl group, a prop-2-ynyl group, and an n-butynyl group. Specifically, it is an ethynyl group and a propynyl group.

Alone or with other combinations of the groups The term "C _2-6 - alkynyl -C _1-6 - alkoxy" as used herein refers to the connection of defined "C _1-6 - alkoxy," as used herein in the The definition of "C _2-6 -alkynyl". Specifically, it is 5-but-2-ynyloxy.

The term "pharmaceutically acceptable salt" means a salt suitable for use in contact with humans and animal tissues. Examples of suitable inorganic and organic acid salts are, but are 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, tartaric acid, trifluoroacetate and the like. Specifically, formic acid, trifluoroacetic acid and hydrochloride. Specific are hydrochloric acid, trifluoroacetic acid and fumarate.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary" mean carriers and auxiliary substances, such as diluents or excipients, which are compatible with the other ingredients in the formulation.

The term "pharmaceutical composition" encompasses a specified ingredient containing a predetermined amount or ratio. A product, and any product obtained directly or indirectly by combining a specified amount of the specified ingredients. In particular, it encompasses products comprising one or more active ingredients and optionally a carrier comprising inert ingredients, and directly or indirectly, by combining, merging or agglomerating any two or more ingredients, or dissociating one Or a plurality of ingredients, or any product obtained by other types of reactions or interactions of one or more ingredients.

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

The term "half maximum inhibitory concentration" (IC ₅₀₎ required to represent the concentration of a particular compound at 50% inhibition of in vitro biological process. The IC ₅₀ value can be converted to a log-value pIC ₅₀ value (-log IC ₅₀ ), and among the pIC ₅₀ values, a higher value indicates an exponential level of potency. The IC ₅₀ value is not an absolute value, but varies depending on the experimental conditions (eg, the concentration employed). The IC ₅₀ value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff formula (Biochem. Pharmacol. (1973) 22: 3099). The term "inhibition constant" (Ki) indicates the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor occupies 50% of the receptor in the absence of a competitive ligand (eg, a radioligand). The Ki value can be converted to a logarithmic value pKi value (-log Ki), where a higher value indicates a greater exponential efficiency.

By "therapeutically effective amount" is meant an amount of a compound that is sufficient to effect such treatment for a disease state when administered to an individual for the treatment of a disease state. "Therapeutically effective amount" means the compound, the condition of the disease to be treated, the severity of the condition being treated, the age and relative health of the individual, the route and form of administration, and the attending physician Or the judgment of the veterinarian and other factors.

When referring to a variable, the terms "as defined herein" or "as described herein" are used to refer to the broad definition of the variable, and the preferred, better, and best definitions that may exist.

When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" mean adding or mixing two or more reactants under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction to produce the indicated and/or desired product is not necessarily directly achieved by the combination of the two reagents added at the beginning, that is, one or more intermediates may be produced from the mixture, which ultimately form the indicated / or the desired product.

The term "protecting group", in the context of conventional and synthetic chemistry, means selectively blocking a reactive site in a polyfunctional compound such that the chemical reaction is selected at another unprotected reactive site, and In the group. The protective group at the appropriate point can be removed. Exemplary protecting groups are amine protecting groups, carboxy protecting groups or hydroxy protecting groups. The term "amino protecting group" denotes a group for protecting an amine group and includes a benzyl group, a benzyloxycarbonyl group (carbobenzyloxy group, CBZ), a 9-fluorenylmethoxycarbonyl group (FMOC), a p-methoxy group. Benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroethylidene. For further examples of such groups, see TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd Edition, John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, "Protective Groups in Organic Chemistry", JGW McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and TW Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amine group" refers to an amine group substituted with an amine protecting group. Particular amine protecting groups are tert-butoxycarbonyl, bis(dimethoxyphenyl)-benzyl and dimethoxytrityl.

The term "leaving group" means a group having the meaning associated with its conventional knowledge in synthetic organic chemistry, i.e., an atom or group that is removable under the conditions of the substitution reaction. Examples of the leaving group include a halogen atom, specifically, a bromine; an alkane- or an arylsulfonyloxy group such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a thiomethyl group, or a benzenesulfonyloxy group. a benzyloxy group, an isopropoxy group, and a decyloxy group.

The term "aromatic" means a conventional aroma concept as defined in the literature, as specifically defined in IUPAC-Compendium of Chemical Terminology, 2nd, A.D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" means any ingredient that is not therapeutically active and non-toxic, such as disintegrants, binders, fillers, solvents, buffers, penetrants, stabilizers, antioxidants used in the formulation of pharmaceutical products. , surfactant or lubricant.

When a palmitic carbon is present in the chemical structure, the structure encompasses all stereoisomers associated with the palmitic carbon.

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

All separate embodiments can be combined.

An embodiment of the invention is a compound of formula I, Wherein R ¹ is selected from the group consisting of i) hydrogen, ii) a halogen atom, and iii) a C _1-6 -alkyl group; and R ² is selected from the group consisting of: i) hydrogen, ii C _1-6 -alkyl, and iii) halogen atom -C _1-3 -alkyl, R ³ is selected from the group consisting of: i) hydrogen, and ii) C _1-6 -alkyl, R ⁴ is selected from the group consisting of: i) a halogen atom, and ii) a C _1-6 -alkyl group, iii) a halogen atom - a C _1-6 -alkoxy group, and a R ⁵ system-C (=O) -R ⁶ , R ⁶ is selected from the group consisting of: i) a heteroaryl group, ii) a heteroaryl group optionally substituted with from 1 to 4 substituents of the group: cyano, cyanide -C _1-6 -alkyl, halogen atom, halogen atom -C _1-6 -alkoxy, halogen atom -C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 - alkoxy-C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-6 -alkoxy, C _3-6 -cycloalkyl-C _{1 -6} -alkyl, C _3-6 -cycloalkyl-C _2-6 -alkynyl, C _2-6 -alkynyl-C _1-6 -alkoxy and C _1-6 -alkyl, iii) C _3-6 - cycloalkyl, IV) by a group independently selected from 1-4 of substituents of C _3-6 - cycloalkyl: cyano, cyanoalkyl, -C _1-6 - Group, a halogen atom, a halogen atom, -C _1-6 - alkoxy group, halogen atom, -C _1-6 - alkyl, hydroxy, C _1-6 - alkoxy, C _1-6 - alkoxy, -C _{1 -6} -alkyl and C _1-6 -alkyl, v)heterocyclyl, and vi)heterocyclyl substituted with from 1 to 4 substituents selected from the group consisting of cyano, cyano-C _{1 -6} -alkyl, halogen atom, halogen atom -C _1-6 -alkoxy, halogen atom -C _1-6 -alkyl, C _1-6 -alkoxy, C _{1-6 -alkoxy-} C _1-6 -alkyl and C _1-6 -alkyl; or a pharmaceutically acceptable salt thereof.

A particular embodiment of the invention provides a compound of formula Ia as described herein, Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ are as defined herein.

A particular embodiment of the invention provides a compound as described herein, wherein R ¹ is a halogen atom, R ² is C _1-6 -alkyl, and R ³ is selected from the group consisting of: i) hydrogen, and Ii) C _1-6 -alkyl, R ⁴ is selected from the group consisting of the following groups: i) a halogen atom, and ii) a halogen atom - a C _1-6 -alkoxy group, R ⁵ -C(=O) -R ⁶ , R ⁶ is selected from the group consisting of i) heteroaryl, ii) heteroaryl optionally substituted with from 1 to 4 substituents of the group: cyano, halogen atom, Halogen atom-C _1-6 -alkoxy group, halogen atom-C _1-6 -alkyl group, C _1-6 -alkoxy group, C _1-6 -alkyl group, C _3-6 -cycloalkyl group, C _3-6 -cycloalkyl-C _1-6 -alkoxy, C _2-6 -alkynyl-C _1-6 -alkoxy and C _3-6 -cycloalkyl-C _2-6 -alkynyl , iii) C _3-6 - cycloalkyl, and iv) over 1 are independently selected from a halogen atom and a cyano group to 4 of substituents of C _3-6 - cycloalkyl, or a pharmaceutically acceptable salt thereof.

One particular embodiment of the present invention provides a compound as described herein, the halogen atom in which R ¹ lines.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ¹ F.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ¹ hydrogen.

One particular embodiment of the present invention provides a compound as described herein, the wherein, R ¹ Department of C _1-6 - alkyl.

A particular embodiment of the invention provides a compound as described herein, wherein R ² is C _1-6 -alkyl.

A particular embodiment of the invention provides a compound as described herein, wherein R ² is Me.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ² hydrogen.

A particular embodiment of the invention provides a compound as described herein, wherein R ² is - halogen atom - C _1-3 -alkyl.

A particular embodiment of the invention provides a compound as described herein, wherein R ² is -CH ₂ -CHF ₂ .

A particular embodiment of the invention provides a compound as described herein, wherein R ² is -CH ₂ -CH ₂ F.

One particular embodiment of the present invention provides a compound as described herein, the hydrogen based wherein R ^3.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ³ C _1-6 - alkyl.

One particular embodiment of the present invention provides a compound as described herein, the halogen atom in which R ⁴ system.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁴ F.

Embodiment provides a compound as described herein specific embodiments of the present invention, one, a halogen atom wherein R ⁴ based -C _1-6 - alkoxy.

A particular embodiment of the invention provides a compound as described herein, wherein R ⁴ is -OCH ₂ CF ₃ .

Embodiment provides a compound as described herein, of one particular embodiment of the present invention, wherein R ⁴ line C _1-6 - alkyl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁵ -C (= O) -R ^6.

One particular embodiment of the present invention provides a compound as described herein, the R ⁶ wherein the heteroaryl system.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 1H- pyrazol-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 2H- pyrazol-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ furan-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ thiazol-5-yl.

A particular embodiment of the invention provides a compound as described herein, wherein R ⁶ is pyridin-2-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, pyrazin-2-yl , furan-3-yl or thiazol-5-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ is independently selected from a halogen atom and a cyano group 1 to 2 substituents of the substituents of the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 3-chloro-5-cyano - pyridin-2-yl.

A particular embodiment of the invention provides a compound as described herein, wherein R ⁶ is heteroaryl optionally substituted with from 1 to 2 substituents of a halogen atom -C _1-6 -alkyl and a halogen atom .

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 3-fluoro-5-trifluoromethyl - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 3-chloro-5-trifluoromethyl - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 4-chloro-1- (2,2-difluoro - ethyl) lH-pyrazol-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ substituted with 1 to 2 halogen atoms heteroaryl.

One particular embodiment of the present invention provides a compound as described herein, the 5-fluoro lines wherein R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which 3,5-difluoro-R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-fluoro-5-methyl} - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ chloro-3-fluoro - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the 3,5-dichloro-based wherein R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system 5-chloro wherein R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 2-Chloro - thiazol-5-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ -1H- pyrazol-4-chloro-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the R ⁶ wherein the heteroaryl system cyano-substituted aryl group.

One particular embodiment of the present invention provides a compound as described herein, the system 5-cyano wherein R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which the halogen atom R ⁶ -C _1-6 - alkoxy substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-methoxy-5-fluoro} - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-methoxy-5-fluoro} - pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the wherein R ^{6 is} 5-difluoromethoxy-based group - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 5- (2,2,2-trifluoro - ethoxy) - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 5- (2,2,3,3,3-pentafluoro-propoxy) - - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 5- (2,2,3,3-tetrafluoro-propoxy) - - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 5- (2,2-difluoro - ethoxy) - pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _1-6 - alkyl substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which 2,5-dimethyl-R ⁶ - furan-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ -1H- pyrazol-1,5-dimethyl-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _3-6 - cycloalkyl, -C _1-6 - alkyl substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which 5-cyclopropyl R ⁶ - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _3-6 - cycloalkyl, -C _2-6 - alkynyl substituents of the heteroaryl.

One particular embodiment of the present invention provides a compound as described herein, the R ⁶ wherein 5-cyclopropyl-ethynyl-based - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _2-6 - alkynyl -C _1-6 - alkoxy substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the Department of 5- wherein R ⁶ but-2-ynyloxy - pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _3-6 - cycloalkyl, -C _1-6 - alkoxy substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-methoxy-5-cyclopropyl} - pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-methoxy-5-cyclopropyl} - pyridin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which the halogen atom R ⁶ -C _1-6 - alkyl substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ^{6-fluoro-5-methyl} - pyrazin-2-yl.

One particular embodiment of the present invention provides a compound as described herein, the system in which the halogen atom R ⁶ -C _1-6 - alkyl and C _1-6 - alkyl substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the R ⁶ wherein 2-methyl-5-trifluoromethyl-based -2H- pyrazol-3-yl.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ⁶ C _1-6 - alkoxy substituted with the heteroaryl group.

One particular embodiment of the present invention provides a compound as described herein, the system in which R ⁶ 5-methoxy - pyridin-2-yl.

A particular embodiment of the invention provides a compound as described herein, wherein R ⁶ is independently selected from the group consisting of a cyano group, a halogen atom, and a C _3-6 -cycloalkyl-C _2-6 -alkynyl group. A heteroaryl group substituted with two substituents.

One particular embodiment of the present invention provides a compound as described herein, the system through which R ² is independently selected from cyano, chloro, ethynyl, and cyclopropyl 1-2 substituents of the pyridyl substituent.

A particular embodiment of the invention provides a compound as described herein selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-3-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-methoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro -4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyclopropyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-chloro-thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-methyl-5-trifluoromethyl- 2H -pyrazole-3-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4 -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6- Dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1-cyano-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5 ,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro -4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 4-chloro-1-difluoromethyl-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4,5-dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-fluoro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4S,5R)-2-amino-5-fluoro-4-fluoromethyl) Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4S,5S)-2-amino-5-fluoro-4-fluoromethyl) Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)- or (4R,5S)-2-amino-4 -difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4-methyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-guanamine, 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid {3-[(4R,5R)-2 -amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)) 2-amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1,5-dimethyl-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1-(2,2-difluoro-ethyl)-1 H -pyrazole-3-carboxylic acid [3-((4R ,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,2-difluoro-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,5-dimethyl-furan-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-difluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4, 5-dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, and 3,5-dichloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl- 5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, or a pharmaceutically acceptable salt thereof.

A particular embodiment of the invention provides a compound as described herein selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1-cyano-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5 ,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,2-difluoro-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,5-dimethyl-furan-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-chloro-thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4, 5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5 -(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 3,5-difluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid {3-[(4R,5R)-2 -amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)) 2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-3-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro -4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyclopropyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-methoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro -4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6- Dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, and 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino)- 5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, or a pharmaceutically acceptable salt thereof.

A particular embodiment of the invention provides a compound as described herein selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, and 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, or a pharmaceutically acceptable salt thereof.

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

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

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

A particular embodiment of the invention provides a compound as described herein which is 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5- (2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine.

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

A particular embodiment of the invention provides a compound as described herein, the process of which comprises reacting a compound of formula C4 with a compound of formula I Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

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

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active.

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

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

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

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active for therapeutic and/or prophylactic treatment with elevated beta-amyloid protein concentration and/or beta - Amylopectin-like and/or beta-amyloid plaques and other diseases and conditions characterized by deposition or Alzheimer's disease.

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

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.

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

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active for the therapeutic and/or prophylactic treatment of Alzheimer's disease, diabetes or type 2 diabetes.

A particular embodiment of the invention provides a compound of formula I as described herein for use as a therapeutic active for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis , autoimmune/inflammatory diseases, cancers such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal diseases, glioblastoma multiforme, Graves' disease, Henry Dington's disease, inclusion body myositis (IBM), inflammatory response, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis , malignant melanoma, multiple myeloma, rheumatoid arthritis, dry syndrome, spinal cerebellar disorders 1, spinal cerebellar disorders 7, Whipple's disease or Wilson's disease.

A particular 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.

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

A particular 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 particular 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 particular embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for therapeutic and/or prophylactic treatment with elevated beta-amyloid protein concentration and/or A disease or condition characterized by β-amyloid-like oligomers and/or β-amyloid plaques and other deposits or Alzheimer's disease.

A particular 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 particular 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 diabetes or type 2 diabetes.

A particular 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 diabetes.

A particular 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 diabetes or type 2 diabetes.

A particular embodiment of the invention provides a method of formula I as described herein Use of a compound for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancers such as breast cancer, such as myocardial infarction And stroke cardiovascular disease, dermatomyositis, Down syndrome, gastrointestinal disease, glioblastoma multiforme, Graves' disease, Huntington's disease, inclusion body myositis (IBM), inflammatory response, card Posey sarcoma, Kostmann disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, dryness Syndrome, spinal cerebellar disorders 1, spinal cerebellar disorders 7, Whipple's disease or Wilson's disease.

A particular 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, diabetes or type 2 diabetes.

A particular 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 particular 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 diabetes or type 2 diabetes.

A particular 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 diabetes.

A particular embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for therapeutic and/or prophylactic Treat type 2 diabetes.

A particular 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 Symptoms, autoimmune/inflammatory diseases, cancers such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal diseases, glioblastoma multiforme, Graves' disease, Huntington's disease, inclusion body myositis (IBM), inflammatory response, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous joints Inflammation, malignant melanoma, multiple myeloma, rheumatoid arthritis, dry syndrome, spinocerebellar disorders 1, spinal cerebellar disorders 7, Whipple's disease or Wilson's disease.

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

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

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

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

A particular embodiment of the invention provides a compound of formula I as described herein for use in therapeutic and/or prophylactic treatment with elevated beta-amyloid protein concentration and/or beta-amyloid oligo Polymers and/or beta-amyloid plaques and other diseases and conditions characterized by deposition or Alzheimer's disease.

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

A particular embodiment of the invention provides a compound of formula I as described herein for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.

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

A particular embodiment of the invention provides a compound of formula I as described herein for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.

A particular embodiment of the invention provides a compound of formula I as described herein for the therapeutic and/or prophylactic treatment of Alzheimer's disease, diabetes or type 2 diabetes.

A particular embodiment of the invention provides a compound of formula I as described herein for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/ Inflammatory diseases, cancers 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 response, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignant melanoma, Multiple myeloma, rheumatoid arthritis, dry syndrome, spinocerebellar disorders 1, spinocerebellar disorders 7, Whipple's disease or Wilson's disease.

A specific embodiment of the present invention provides a method for inhibiting BACE1 and/or BACE2 activity, in particular, therapeutic and/or prophylactic treatment with elevated β-amyloid protein concentration and/or β-amyloid protein oligomer And/or beta-amyloid plaques and other methods of depositing diseases and conditions, Alzheimer's disease, diabetes or type 2 diabetes, the method comprising, as described herein, Formula I The compound is administered to humans or animals.

A particular embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of Alzheimer's disease, diabetes or type 2 diabetes, the method comprising administering a compound of formula I as described herein With humans or animals.

A particular embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of Alzheimer's disease, comprising administering a compound of formula I as described herein to a human or animal.

A particular embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of diabetes comprising administering a compound of formula I as described herein to a human or animal.

A particular embodiment of the invention provides a method for the therapeutic and/or prophylactic treatment of type 2 diabetes comprising administering a compound of formula I as described herein to a human or animal.

A specific embodiment of the present invention provides a method for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory disease, such as breast cancer Cancer, cardiovascular disease such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal disease, glioblastoma multiforme, Graves' disease, Huntington Disease, inclusion body myositis (IBM), inflammatory response, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignancy Melanoma, multiple myeloma, rheumatoid arthritis, dry syndrome, spinal cerebellar disorder 1, spinal cerebellar disorder 7, Whipple's disease or Wilson's disease, the method comprising as described herein A compound of formula I is administered to a human or animal.

Furthermore, the invention includes all optical isomers of the compound of formula I, ie, diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding isomers and/or Isomers, as well as their solvates.

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

The invention encompasses all tautomeric forms.

A compound of formula I may contain one or more asymmetric centers and thus may exist as racemates, racemic mixtures, single mirror isomers, diastereomeric mixtures and individual diastereomers. There are other asymmetric centers for the properties of the substituents on the visible molecule. Each of these asymmetric centers independently produces two optical isomers and all possible optical isomers and diastereomers in the mixture And pure or partially purified compounds are included in the present invention. The invention is intended to cover all such isomeric forms of such compounds. The independent synthesis of such diastereomers or their isochrome separation can be accomplished by appropriate modification of the methods disclosed herein, as is known in the art. Their absolute stereochemistry can be determined by x-ray crystallographic analysis of the crystalline product or the derived crystalline intermediate (if desired) using a reagent containing an asymmetric center of known absolute configuration. If desired, the racemic mixture of the compounds can be separated to separate individual image isomers. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of the compound to the image-isomerically pure compound to form a mixture of diastereomers, followed by separation by standard methods (eg, fractional crystallization or chromatography). Individual diastereomers. Specific examples of isomers of the compounds of formula I are compounds of formula Ia or compounds of formula Ib, Ia-I, Ia-II, Ib-I or Ib-II, in particular, compounds of formula Ia Wherein the residue has the meaning as described in any of the embodiments.

In the examples of providing optically pure mirror image isomers, optically pure isomers means that the compound contains >90% by weight of the desired isomer, in particular, >95% by weight of the desired isomer, Or more specifically, >99% by weight of the desired isomer, based on the total weight of the isomer of the compound. A pure or palm-enriched compound can be prepared by palm-selective synthesis or by separation of the mirror image isomer. The mirror image isomer separation can be carried out on the final product or on a suitable intermediate.

Compounds of formula I can be prepared according to the following reaction schemes. The starting materials are commercially available or can be prepared according to known methods. Unless otherwise stated, any previously defined residues and variables will continue to have the previously defined meaning.

It can be modeled by TPTang & JAEllman, J. Org. Chem. 1999, 64, 12, by aryl ketone A1 with sulfinamide (for example, alkyl sulfinamide, most specifically, (R)-( +) - tert-butylsulfinamide) in the presence of a Lewis acid (eg, titanium (IV) alkoxide, more specifically, titanium oxychloride (IV)) in a solvent The sulfinimide of the formula A2 is prepared by condensation in an ether such as diethyl ether or, more specifically, tetrahydrofuran.

The conversion of sulfinimide A2 to sulfinamide A3 is carried out in a stereoselective manner by a palmitoyl targeting group as described by Tang & Ellman. The sulfinimide A2 can be combined with the zinc enolate, the active zinc powder at ambient temperature to high temperature (specifically, at 23 to 60 ° C), such as an ether (for example, diethyl ether or, more specifically, tetrahydrofuran). The Reformatsky reaction was carried out in a solvent. The zinc enolate is produced from acetic acid or an alkyl propionate substituted by a halogen atom (for example, specifically, bromo-fluoro-ethyl acetate or ethyl 2-bromo-2-fluoro-propionate). The sulfinimide A2 may also be an alkyl acetate (for example, ethyl 2-(2,2,2-trifluoroethoxy)) substituted with a halogen atom-alkoxy group, such as n-butyl lithium. In the presence of a strong base, it is reacted in an inert solvent such as an ether (for example, diethyl ether or, more specifically, tetrahydrofuran) at 0 to -78 °C.

The ethyl ester of formula A3 can be reduced by using an alkali hydride, in particular lithium borohydride or lithium aluminum hydride, in a solvent such as an ether (for example, diethyl ether or, more specifically, tetrahydrofuran). An alcohol of formula A4 is prepared.

A solvent such as an ether (for example, diethyl ether, tetrahydrofuran or, more specifically, 1,4-dioxane) may be used by a mineral acid (for example, sulfuric acid or, in particular, hydrochloric acid). The palmitoyl locating group in the sulfinamide of formula A4 is hydrolyzed to obtain an amino alcohol of formula A5 .

It may be by amine groups with cyanogen bromide as an alcohol of formula A5 such as alcohols, certain words, prepared in a solvent such as ethanol in the reaction of the amine group in formula A6 .

Standard process for purifying sulfuric acid and fuming nitric acid without solvent The preparation of nitrated A6 A7 nitro derivatives of formula, wherein R ^{7 is} hydrogen system.

The nitro group in the compound of formula A7 can be reduced to obtain an aniline of formula A8 by hydrogenation using a catalyst such as palladium-coated carbon in a protic solvent such as an alcohol (specifically, ethanol or methanol).

Alternatively, the derivative such as the formula A6 (wherein the R ⁷ nitro group) can be hydrogenated in a protic solvent such as an alcohol (specifically, ethanol or methanol) using a catalyst such as palladium-coated carbon to obtain a formula A8. Aniline.

A solution of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmethyloxalin guanidine (DMTMM) hydrate in a solvent such as methanol A selective reaction of an aniline of formula A8 with a carboxylic acid of the formula R ⁶ -COOH is carried out to give the guanamine of formula I.

Another common process for preparing a compound of formula A8 is illustrated in Reaction Scheme B.

By triarylmethyl chloride, such as triphenylmethyl chloride (Tr-Cl), p-methoxyphenyl diphenylmethyl chloride (MMTr-Cl), di(p-methoxyphenyl)benzene Methyl chloride (DMTr-Cl) or tris(p-methoxyphenyl)methyl chloride (TMTr-Cl), in particular, DMTr-Cl, under basic conditions, for example, in triethylamine Protecting the amine group in the compound of formula A6 in the presence of an amine of diisopropylethylamine in a chlorinated solvent (eg, dichloromethane or chloroform) at a temperature between 0 ° C and ambient temperature (wherein R ⁷ is bromine) to produce an aryl bromide of formula B1 .

The aryl bromide of formula B1 can be combined with an ammonia equivalent (eg, benzophenone imine) in a suitable transition metal catalyst (eg, bis(dibenzylideneacetone)palladium(0)((dba) ₂ Pd) or ginseng (dibenzylideneacetone) dipalladium(0)((dba) ₃ Pd ₂ )) and a suitable ligand (racemic-2,2'-bis(diphenylphosphino-)-1, 1'-binaphthyl (rac-BINAP), 2-biscyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (X-PHOS) or 2-di-tert-butylphosphine-2' In the presence of 4',6'-triisopropylbiphenyl (t-Bu X-PHOS) in the presence of a base such as sodium tributoxide, potassium phosphate or cesium carbonate in a suitable solvent such as toluene Or 1,4-dioxane, reacting at a temperature between 80 and 110 ° C under an inert atmosphere such as nitrogen or argon to produce a compound of formula B2 .

The two amine groups of the compound of formula B2 can be deprotected by a one-pot process by reacting a compound of formula B2 with a strong organic acid (eg, trifluoroacetic acid) in a chlorinated solvent (eg, dichloromethane or chloroform). In the absence of water, the reaction is carried out at a temperature between 0 ° C and ambient temperature to cleave the P ¹ - group to obtain an intermediate product of the formula B3 . Water is then added to cleave the benzophenone imine and react at room temperature to produce a diamine of formula A8 .

Another process for preparing a compound of formula I is illustrated in Reaction Scheme C.

By allowing a compound of the formula A7 and ditributyl dicarbonate to be in a solvent such as tetrahydrofuran under basic conditions, for example, in the presence of an amine such as triethylamine or diisopropylethylamine. Reacting at a temperature between 0 ° C and ambient temperature and in the presence of 4-dimethylamino-pyridine as a catalyst to protect the amine group (wherein the R ⁷ nitro group) in the compound of formula A7 to give A compound of the formula C1 .

One of the third butoxycarbonyl groups of the compound of formula C1 can be selectively cleaved by an acid such as trifluoroacetic acid to yield a compound of formula C2 and a minor amount of a compound of formula A7 .

The protected amine group of formula C2 can be reduced by hydrogenation using a catalyst such as palladium-coated carbon in a protic solvent such as an alcohol, in particular ethanol or methanol. The nitro group to produce a protected aniline of formula C3 .

It can be used in a solvent such as methanol by 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-chloromethylmorpholine hydrazine hydrate (DMTMM) or other a condensing agent (such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium quinone (HBTU) or O-(7-azabenzene) hexafluorophosphate And triazol-1-yl)-N,N,N',N'-tetramethyluronium (HATU), in the presence of an amine such as triethylamine or diisopropylethylamine, such as In a solvent of acetonitrile or N,N-dimethylformamide, the aniline of formula C3 is coupled with a carboxylic acid of formula R ⁶ -COOH at a temperature between 0 ° C and ambient temperature to give a formula C4 The amine.

The protective third butoxycarbonyl group in the compound of formula C4 can be cleaved by an acid such as trifluoroacetic acid in an inert solvent such as dichloromethane at a temperature between 0 ° C and ambient temperature to give Compound of I.

Alternatively, a compound of the formula A6' can be obtained by a chloro-methane alkyl derivative (eg, tert-butyl-chlorodimethyl-decane or tert-butyl-chlorodiphenyl-decane), Under alkaline 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 ° C and ambient temperature The mono-alcohol in the compound of formula A5 is selectively protected in the presence of 4-dimethylamino-pyridine as a catalyst.

The isothiocyanate is selected depending on the reactivity of the amine functional group to form a thiourea of formula D2 . Preferably, a solution of benzamidine isocyanate in an inert solvent (e.g., acetone) is used to prepare a deuterated thiourea of formula D2 at a temperature between 0 and 100 °C.

By chlorination using an alkyl oxonium salt (for example, trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate) in an inert solvent such as, for example, dichloromethane or chloroform In a solvent, the thiourea of formula D2 is treated at a temperature between 0 ° C and the ambient temperature to cyclize under the simultaneous loss of the methylation group to form an N-fluorenyl group of formula D3 . .

The compound of formula A6' is obtained under basic conditions, for example, by cleavage of a thiol residue in a compound of formula D3 in a protic solvent such as an alcohol (e.g., methanol or ethanol) using an alkali carbonate.

Alternatively, by using an aryl bromide of formula D3 with an ammonia equivalent (eg, benzophenone imine) in a suitable transition metal catalyst (eg, bis(dibenzylideneacetone) palladium (0) ((dba) ₂ Pd) or ginseng (dibenzylideneacetone) dipalladium (0) ((dba) ₃ Pd ₂ )) and suitable ligands (eg racemic-2,2'-bis(diphenyl) Phosphine-)-1,1'-binaphthyl (rac-BINAP), 2-biscyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (X-PHOS) or 2-di-third In the presence of butylphosphine-2',4',6'-triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base such as sodium butoxide, potassium phosphate or cesium carbonate, In a suitable solvent (such as toluene or 1,4-dioxane), it is reacted in an inert atmosphere (such as nitrogen or argon) at a temperature between 80 and 110 ° C to obtain a formula B3 . Imine (see Reaction Scheme B).

The compound of formula I can be dissolved in a suitable solvent (e.g., dioxane or tetrahydrofuran (THF)) and added in an appropriate amount by standard methods known to those skilled in the art. Corresponding to the acid, the corresponding pharmaceutically acceptable acid salt is obtained. The products can generally be isolated by filtration or by chromatography. The compound of formula I can be converted to a pharmaceutically acceptable base salt by treating the compound with a base. One of the possible methods of forming such a salt is, for example, adding 1/n equivalent of a base salt (such as, for example, M(OH) _n , wherein M = metal or ammonium cation and n = hydroxide anion amount) to the compound The solvent is removed in a suitable solvent (e.g., ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and by evaporation or lyophilization. Particularly preferred salts are the hydrochloride, formate and trifluoroacetate salts.

If the process is not illustrated in the examples, the compounds and intermediates of formula I can be prepared in a similar manner or in accordance with the methods described herein. The starting materials are commercially available, are known in the art or can be prepared by methods known in the art or the like.

It will be appreciated that a compound of formula I in the present invention may be derivatized at a functional group to provide a derivative which can be converted back to the original compound in vivo.

Pharmacological test

The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It has been found that the compounds of the invention inhibit BACE1 and/or BACE2 activity. The compounds were studied according to the tests given below.

Cell Aβ-Descent Detection Method:

Human HEK293 cells stably transfected with a vector expressing the cDNA of the human APP wt gene (APP695) were used to evaluate the potency of these compounds in cell assays. The cells were seeded in a cell culture medium (Iscove, +10% fetal bovine serum, amidoxime, penicillin/streptomycin) in a 96-well microtiter plate to about 80% confluency and in the absence of FCS and containing 8 1/10 volume of a 10x concentration compound was added to the % DMSO medium (the final DMSO concentration was maintained at 0.8% by volume). After incubation for 18 to 20 hours in a humidified incubator at 37 ° C and 5% CO ₂ , the culture supernatant was collected for determination of Aβ40 concentration. A 96-well ELISA plate (e.g., Nunc MaxiSorb) was coated with a monoclonal antibody that specifically recognizes the C-terminus of A?40 (Brockhaus et al., NeuroReport 9, 1481-1486; 1998). After blocking the non-specific binding site by, for example, 1% BSA and washing, the appropriately diluted culture supernatant and horseradish peroxidase-coupled Aβ detection antibody are added (for example, antibody 4G8, Senetek) , Maryland Heights, MO) and culture for 5 to 7 hours. The wells of the microtiter wells were then thoroughly washed by Tris buffered saline containing 0.05% Tween 20 and the assay was developed by tetramethylbenzidine/H ₂ O ₂ in citric acid buffer. After a volume by 1 NH ₂ SO ₄ to terminate the reaction, the reaction was determined at wavelength of 450 nm in an ELISA reader. The concentration of A[beta] in the culture supernatant was calculated from a standard curve obtained from a known amount of pure A[beta] peptide.

BACE inhibition assay by measuring cell TMEM27 cleavage:

This assay utilizes the principle that human TMEM27 cleaves the inhibition of endogenous BACE2 in the Ins1e mouse cell line and detaches from the cell surface into the culture medium, followed by detection in an ELISA assay. Inhibition of BACE2 prevented lysis and shedding in a dose-dependent manner.

The stable cell line "INS-TMEM27" indicates an INS1e-derived cell strain of full length hTMEM27 induced by a deoxytetracycline-dependent manner (using the TetOn system). The cells were subjected to RPMI 1640 + glutamate dipeptide (Invitrogen) penicillin/streptomycin, 10% fetal bovine serum, 100 mM pyruvate, 5 mM β-mercaptoethanol, 100 μg/ml G418 and 100 μg throughout the experiment. /ml hygromycin was cultured and grown in adherent culture at 37 ° C in a standard CO ₂ cell incubator.

INS-TMEM27 cells were seeded in 96-well plates. After 2 days of culture, the BACE2 inhibitor was added at the concentration range required for the assay and after a further 2 hours, deoxytetracycline was added to a final concentration of 500 ng/ml. The cells were incubated for an additional 46 hours and the supernatant was collected for detection of exfoliated TMEM27.

An ELISA assay (using a pair of mouse anti-human TMEM27 antibodies against the extracellular domain of TMEM27) was used to detect TMEM27 in the culture medium. By standard curve fitting software (such as, for Excel spreadsheet program of the XLFit) using an ELISA reader and the concentrations of each inhibitor is calculated BACE2 inhibition EC _50.

Pharmaceutical composition

The compound of formula I and a pharmaceutically acceptable salt can be used, for example, as a therapeutic active in the form of a pharmaceutical preparation. Such pharmaceutical preparations can be administered orally, for example, in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, it can also be administered rectally, for example, in the form of a suppository, or parenterally, for example, in the form of an injectable solution.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutical inert inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as carriers for, for example, lozenges, coated lozenges, dragees and hard gelatin capsules. Suitable carrier agents for soft gelatin capsules, for example, vegetable oils, waxes, fats, semi-solids and liquids Body polyols and the like. However, depending on the nature of the active ingredient, the carrier is generally not required in the case of soft gelatin capsules. Suitable carrier systems for the manufacture of solutions and syrups, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

The present invention also provides an agent comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier, and a process for the manufacture thereof, which comprises one or more compounds of formula I and/or pharmaceutically acceptable salts thereof And (if desired) one or more other therapeutically valuable substances are combined with one or more therapeutically inert carriers to form a galenic dosage form.

The dosage can be varied over a wide range and, of course, adjusted for individual requirements in each particular case. In the case of oral administration, the dosage for an adult may be from about 0.01 mg to about 1000 mg of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof per day. The daily dose can be administered in a single dose or in separate doses, and in addition, when indicated, this upper limit can also be exceeded.

The following examples are illustrative of the invention and are not intended to limit the invention, and are merely exemplary of the invention. Pharmaceutical preparations usually contain from about 1 to 500 mg, in particular from 1 to 100 mg of a compound of formula I. Examples of compositions of the invention are:

Example A

Tablets having the following composition are manufactured in the usual manner:

Process

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

2. Dry the granules at 50 °C.

3. Pass the particles through a suitable grinding apparatus.

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

Example B-1

Manufacture capsules with the following composition:

Process

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

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

3. Fill into suitable capsules.

The compound of formula I, lactose and corn starch are first mixed in a mixer and subsequently mixed in a pulverizer. The mixture was returned to the mixer; talc was added to the mixer and thoroughly mixed. The mixture is filled into suitable capsules (eg, hard gelatin capsules) by a machine.

Example B-2

A soft gelatin capsule having the following composition is produced:

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 are processed according to common processes.

Example C

A suppository having the following composition is manufactured:

Process

The suppository base was melted in a glass or steel vessel, thoroughly mixed and cooled to 45 °C. The fine powder of the compound of formula I is immediately added to the vessel and stirred until completely dispersed. The mixture is poured into a suppository mold of suitable size and allowed to cool; the suppository is then removed from the film and individually encapsulated in wax paper or metal foil.

Example D

An injection solution having the following composition is produced:

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 1.0 ml by adding the remaining amount of water. The solution was filtered, filled into vials with appropriate additional items and sterilized.

Example E

Produce a sachet with the following composition:

Process

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated by a mixture of polyvinylpyrrolidone and water. The granules are mixed with magnesium stearate and flavoring additives and filled into the sachet.

Experimental part

The following examples are provided to illustrate the invention. These examples are not to be considered as limiting the scope of the invention, but are merely intended to be exemplary of the invention.

Intermediate sulfinimide A2.1 (R ⁷ =H) synthesis

Treatment of 1-(2-fluorophenyl)ethanone (20 g, 145 mmol) by (R)-(+)-t-butylsulfinamide (21.1 g, 174 mmol) in EtOAc A solution of tetrahydrofuran (250 ml) followed by titanium (IV) ethoxide (66.1 g, 290 mmol). The solution was stirred at 50 ° C for 15 hours. For the treatment, the dark brown solution was allowed to cool to room temperature and then poured into a saturated ammonium chloride solution. After the addition of ethyl acetate, the mixture was stirred vigorously for 15 minutes. After the layer separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulfate and evaporated. The crude product was purified by silica gel chromatography using a 4: 1 mixture of cyclohexane and ethyl acetate to afford (R)-EN (1-(2-fluorophenyl)-ethyl)-2- Propane-sulfinamide (25.9 g, 74% of theory). MS (ISP): m/z =242.3 [M+H] ⁺ .

Intermediate product A2.2

The reaction of 2-fluoro-1-(2-fluoro-phenyl)-ethanone with (R)-t-butylsulfinamide will be produced in a manner similar to that described for the preparation of sulfinimide A2.1. (R)-2-methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-extended ethyl-(Z)-yl]-decylamine in the form of an orange oil (52% of theory). MS (ISP): m/z = 260.2 [M+H] ⁺ .

2-Fluoro-1-(2-fluoro-phenyl)-ethanone was obtained as follows:

By triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and nonafluoro-n-butanesulfonium fluoride (8.48 g, 26.9 mmol) at 0 °C A solution of 1-(2-fluorophenyl)-2-hydroxyethanone [CAS 218771-68-7; WO 9857925, Example 16] (2.77 g, 18.0 mmol) in dichloromethane (42 ml). The tube was sealed and the reaction mixture was stirred at room temperature overnight. For the treatment, the dark red solution was poured onto a saturated solution of saturated sodium hydrogen carbonate and ice, and then extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate and evaporated. The crude material was purified by flash chromatography using dichloromethane as a dissolvant (Telos Flash Silica) to obtain 2-fluoro-1-(2-fluoro-phenyl)-ethanone (1.23 g, in the form of a yellow semi-solid). 61% of the value).

Intermediate product A2.3

1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (CAS 1262858-97-8; WO 2011009943) in a manner similar to that described for the preparation of sulfinimide A2.1 Reaction with (R)-t-butylsulfinamide will yield (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2-fluoro) in the form of a yellow oil -Phenyl)-2,2-difluoro-extended ethyl-(E)-yl]-decylamine (77% of theory). MS (ISP): m/z = 356.1 [M+H] ⁺ and 358.0 [M+2+H] ⁺ .

Synthesis of intermediate product sulfinamide A3

Basic process (by Restatsky reaction)

A suspension of fresh active zinc powder (1.63 g, 24.9 mmol) in anhydrous tetrahydrofuran (70 ml) was heated to reflux in a dry apparatus under an inert atmosphere. A solution of sulfinamide A2 (24.9 mmol) and bromoacetate (24.9 mmol) in dry tetrahydrofuran (15 ml) was added dropwise over 15 min. For the treatment, the cooled mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The crude material was purified by flash chromatography using a mixture of heptane and ethyl acetate as a dissolving agent to obtain the sulfinamide A3.

Intermediates A3.1 and A3.2

[R--2-methyl-propane-2-sulfinic acid [1-(2-fluorophenyl)-(E)-extended ethyl]-decylamine (intermediate product A2.1) and 2-bromo Starting with -2-fluoroacetic acid, a small amount of isomer (2S,3R)-2-fluoro-3-(2-fluoro-phenyl)-3-(R) which is rapidly dissolved in the form of a dark brown oil is obtained. )-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (intermediate product A3.1). MS (ISP): m/z = 348.2 [M+H] ⁺ .

The second fraction contains a relatively slow-dissolved large isomer (2R,3R)-2-fluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl group in the form of a brown oil. - Propane-2-sulfinylamino)-butyric acid ethyl ester (intermediate product A3.2). MS (ISP): m/z = 348.2 [M+H] ⁺ .

Synthesis of intermediate product sulfinamide A3.3 and A3.4

A solution of diisopropylamine (3.35 g, 101 mmol) in tetrahydrofuran (25 ml) was treated with n-butyllithium (1.6 M in hexanes, 20.7 ml). The solution was stirred at -7 ° C for 40 minutes. Then, the solution was cooled to -75 ° C and a solution of ethyl 2-fluoropropanoate (3.98 g, 33.2 mmol) in tetrahydrofuran (5 ml) was added dropwise. After 40 minutes, a solution of triisopropanol chlorotitanium (8.64 g, 33.2 mmol) in tetrahydrofuran (15 ml) was slowly added dropwise. After 40 minutes, (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluorophenyl)-(E)-extended ethyl]-decylamine (-) at -72 °C A solution of the intermediate product A2.1) (4.0 g, 16.6 mmol) in tetrahydrofuran (5 ml) was added dropwise to an orange solution. Stirring was continued at -72 °C for 4 hours, after which the reaction mixture was maintained at -20 °C for 17 hours. For the treatment, the reaction mixture was quenched by aqueous ammonium chloride (13%, 100 ml). The precipitate formed was diluted with water and the mixture obtained by extraction with ethyl acetate was three times. The organic layer was washed with brine, then combined, dried and evaporated. The 5:2-mixture of heptane and ethyl acetate was used as a dissolving agent to purify the crude product by gelatin chromatography to give (2S,3R)-2-fluoro-3-(2-fluoro-phenyl) as a pale yellow oil. )-2-methyl-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (A3.3) and (2R,3R)-2-fluoro- 1-(2-Fluoro-phenyl)-2-methyl-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (A3.4) : 2-mixture (4.43 g, 74%). MS (ISP): m/z = 362.2 [M+H] ⁺ .

Synthesis of intermediate product sulfinamide A3.5 and A3.6

The diisopropylamine (1.19 g, 11.8 mmol) of tetrahydrofuran was slowly treated with n-butyllithium (1.6 M in hexanes, 7.34 ml) at -20 ° C under an inert atmosphere. Ml) solution. The solution was stirred at 0 ° C for 30 minutes. The freshly prepared lithium diisopropylamide amide solution was added dropwise to ethyl 2-(2,2,2-trifluoroethoxy)acetate (2.19 g) at -78 ° C over 20 minutes under an inert atmosphere. , 11.8 mmol) in tetrahydrofuran (45 ml). The colorless clear solution was stirred at -78 °C for 30 minutes. Then, a solution of (R)-EN (1-(2-fluorophenyl)exetyl)-2-methylpropane-sulfinamide (1.13 g, 4.7 mmol) in tetrahydrofuran (4 ml) was added. The mixture was allowed to warm to -20 ° C and stirring was continued for 30 minutes. For the treatment, the reaction mixture was hydrolyzed by a half-saturated solution of ammonium chloride, followed by extraction three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The heptane/ethyl acetate gradient solution = 5/1 to 2:1 was used as a dissolving agent to purify the crude product by silica gel chromatography to obtain (2S,3R)-3-(2-fluoro-phenyl) as a yellow oil. 3-((R)-2-methyl-propane-2-sulfinylamino)-2-(2,2,2-trifluoro-ethoxy)-butyric acid ethyl ester (A3.5) And (2R,3R)-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-2-(2,2,2- 1:6-mixture of trifluoro-ethoxy)-butyric acid ethyl ester (A3.5) (1.35 g, 67% of theory). MS: m/z = 428.2 [M + H] ⁺ .

Ethyl 2-(2,2,2-trifluoroethoxy)acetate is obtained in a procedure analogous to that described for the corresponding methyl ester in EP0532178.

Synthesis of intermediate sulfonamides A3.7 and A3.8 (via Reformatsky reaction)

[R)-2-Methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-extended ethyl(Z)-yl]-decylamine (intermediate product A2.2 Starting with 2-bromo-2-fluoroacetic acid ethyl ester, obtained after chromatography with a gradient of heptane/ethyl acetate = 4:1 to 1:2 as a dissolving agent (Telos Flash Silica) Faster isomer (2R,3S)-2,4-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-arylene Sulfonamide)-butyric acid ethyl ester. MS (ISP): m/z = 366.2 [M+H] ⁺ .

A second elution of a small amount of isomer (2S,3S)-2,4-difluoro in the form of a yellow oil is obtained after preparative chromatography on a chiral HPLC (Chiralpak AD; elutant: 40% isopropanol / heptane). 3-(2-Fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (intermediate product A3.8). MS (ISP): m/z = 366.2 [M+H] ⁺ .

Synthesis of intermediate sulfonamides A3.9 and A3.10 (via Rayforth reaction)

[R--2-methyl-propane-2-sulfinic acid [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-extension-(E)-yl]- Start with decylamine (intermediate product A2.3) and 2-bromo-2-fluoroacetic acid ethyl ester as a dissolving agent in a gradient solution of heptane/ethyl acetate = 100:0 to 60:30 (Telos Flash) Silica) 2 diastereomer (2R,3R)-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro in the form of a pale yellow viscous oil -3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester and (2S,3R)-3-(5-bromo-2-fluoro-phenyl)- A mixture of 2,4,4-trifluoro-3-((R)-2-methyl-propane-2-sulfinylamido)-butyric acid ethyl ester (1 main component). MS (ISP): m/z = 462.2 [M+H] ⁺ and 464.2 [M+2+H] ⁺ .

Synthesis of intermediate product sulfinamide A4

Basic process

A solution of sulfinamide A3 (12.7 mmol) in dry tetrahydrofuran (50 ml) was taken from <RTI ID=0.0>> The reaction mixture was quenched by EtOAc (EtOAc)EtOAc. The mixture of n-heptane and ethyl acetate was used as a dissolving agent to purify the residue by gel chromatography to obtain the pure intermediate sulfinamide A4.

Intermediate product A4.1

(2S,3R)-2-fluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester ( Starting with intermediate product A3.1), 2-methyl-propane-2-sulfinic acid [(1R,2S)-2-fluoro-1-(2-fluoro-phenyl)- in the form of a colorless viscous oil is obtained. 3-hydroxy-1-methyl-propyl]-guanamine. MS (ISP): m/z = 306.1 [M+H] ⁺ .

Intermediate product A4.2

(2R,3R)-2-fluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester ( Starting with intermediate product A3.2), 2-methyl-propane-2-sulfinic acid [(1R, 2R)-2-fluoro-1-(2-fluoro-phenyl)-3 was obtained in the form of a light red crystal. -Hydroxy-1-methyl-propyl]-guanamine. MS (ISP): m/z = 306.1 [M+H] ⁺ .

Alternatively, the two isomers A4.1 and A4.2 can be obtained by reducing the mixture as described below, followed by separation from Chirapak AD, wherein A4.1 is the second isolating epimer, A4.2 is the first isolating isomer.

Intermediate product A4.3

From (2S,3R)-2-fluoro-3-(2-fluoro-phenyl)-2-methyl-3-((R)-2-methyl-propane-2-sulfinylamino)- Ethyl butyrate (intermediate product A3.3) and (2R,3R)-2-fluoro-3-(2-fluoro-phenyl)-2-methyl-3-((R)-2-methyl- Starting with a 1:2-mixture of propane-2-sulfinamido)-butyric acid ethyl ester (intermediate product A3.4), 2-methyl-propane-2-sulfinic acid was obtained as a white solid [ 1R, 2R)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1,2-dimethyl-propyl]-guanamine (A4.3). MS (ISP): m/z = 320.1 [M+H] ⁺ . A small amount of isomers were not isolated.

Intermediate product A4.4

From (2S,3R)-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-2-(2,2,2- Ethyl trifluoro-ethoxy)-butyrate (intermediate product A3.5) and (2R,3R)-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane Starting with a 1:6-mixture of ethyl 2-sulfinamide)-2-(2,2,2-trifluoro-ethoxy)-butyrate (A3.6), obtained as a light yellow oil (R)-N-((2R)-2-(2-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethoxy)butan-2-yl)-2- Methylpropane-2-sulfinamide (A4.4). MS (ISP): m/z = 386.1 [M+H] ⁺ . A small amount of isomers were not isolated.

Intermediate product A4.5

From (2R,3S)-2,4-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid Ethyl ester (intermediate product A3.7) was started to obtain (2R)-methyl-propane-2-sulfinic acid [(1S, 2R)-2-fluoro-1-fluoromethyl- in the form of a viscous colorless oil. 1-(2-Fluoro-phenyl)-3-hydroxy-propyl]-guanamine. MS (ISP): m/z = 324.3 [M+H] ⁺ .

Intermediate product A4.6

From (2S,3S)-2,4-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid Starting with ethyl ester (intermediate product A3.8), (2R)-methyl-propane-2-sulfinic acid [(1S,2S)-2-fluoro-1-fluoromethyl-1-) was obtained as a colorless oil. (2-Fluoro-phenyl)-3-hydroxy-propyl]-guanamine. MS (ISP): m/z = 324.3 [M+H] ⁺ .

Intermediates A4.7 and A4.8

From (2S,3R)- and (2R,3R)-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro-3-((R)-2-methyl- Starting with a mixture of propane-2-sulfinamido)-butyric acid ethyl ester (intermediate products A3.9 and A3.10) to obtain (R)-2-methyl-propane-2 in the form of a white foam - sulfinic acid [(1R, 2R)- and (1R, 2S)-1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-2-fluoro-3-hydroxy-propyl a mixture of guanamine. MS (ISP): m/z = 420.2 [M+H] ⁺ and 422.0 [M+2+H] ⁺ .

Synthesis of Intermediate Amino Alcohol A5

Basic process

A solution of sulfinamide A4 (3.4 mmol) in methanol (12 ml) was obtained from aq. The reaction mixture was allowed to warm and maintained at room temperature for 16 hours. For the treatment, the reaction mixture was evaporated under reduced pressure. The solid residue was partitioned between water (10 ml) The aqueous layer was separated and extracted again with ethyl acetate (25 ml). The combined organic layers were washed with water (5 ml), and the aqueous layer was combined and treated with aqueous sodium carbonate to adjust pH to 9-10. The aqueous layer was then extracted by ethyl ester (3 x 35 ml). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate amino alcohol A5.1

From 2-methyl-propane-2-sulfinic acid [(1R,2S)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-decylamine (Intermediate product A4.1) was started to obtain (2S,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-butan-1-ol (98% yield) as a colorless oil. rate). MS (ISP): m/z = 202.3 [M+H] ⁺ .

Intermediate product Alkyl alcohol A5.2

From 2-methyl-propane-2-sulfinic acid [(1R, 2R)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-decylamine (Intermediate product A4.2) begins with (2R,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-butan-1-ol (95%) as a light brown oil Yield). MS (ISP): m/z = 202.2 [M+H] ⁺ .

Intermediate product Amino A 5.3

From 2-methyl-propane-2-sulfinic acid [(1R, 2R)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1,2-dimethyl-propyl] Starting with decylamine (intermediate product A4.3) to give (2R,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-2-methyl-butyl as a colorless oil 1-propanol (A5.3). MS (ISP): m/z = 216.3 [M+H] ⁺ .

Intermediate product Alkyl alcohol A5.4

From (R)-N-((2R)-2-(2-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethoxy)butan-2-yl)-2- Starting with methylpropane-2-sulfinamide (intermediate product A4.4), (2R,3R)-3-amino-3-(2-fluoro-phenyl)-2-(2) is obtained as a colorless oil. 2,2,2-Trifluoro-ethoxy)-butan-1-ol (A5.4). MS (ISP): m/z = 282.3 [M+H] ⁺ .

Intermediate amino alcohol A5.5

From 2-methyl-propane-2-sulfinic acid [(1S, 2R)-2-fluoro-1-fluoromethyl-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-oxime Starting with the amine (intermediate product A4.5), (2R,3S)-3-amino-2,4-difluoro-3-(2-fluoro-phenyl)-butyl- in the form of a pale yellow viscous oil 1-alcohol. MS (ISP): m/z = 220.2 [M+H] ⁺ .

Intermediate amino alcohol A5.6

From 2-methyl-propane-2-sulfinic acid [(1S,2S)-2-fluoro-1-fluoromethyl-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-oxime Starting with the amine (intermediate product A4.6), (2S,3S)-3-amino-2,4-difluoro-3-(2-fluoro-phenyl)-but-1- alcohol. MS (ISP): m/z = 220.3 [M+H] ⁺ .

Intermediates A5.7 and A5.8

From (R)-2-methyl-propane-2-sulfinic acid [(1R,2R)- and (1R,2S)-1-(5-bromo-2-fluoro-phenyl)-1-difluoro Starting with a mixture of methyl-2-fluoro-3-hydroxy-propyl]-nonylamine (intermediate products A4.7 and A4.8), (2R, 3R)- and (2S) are obtained in the form of a viscous light yellow oil. , 3R)-3-Amino-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro-butan-1-ol. MS (ISP): m/z = 315.9 [M+H] ⁺ and 317.9 [M+2+H] ⁺ .

Intermediate amine group Synthesis of A6

Basic process

A mixture of amino alcohol A5 (18.8 mmol), cyanogen bromide (33.9 mmol) and ethanol (61 ml) was placed in a drying tube. The tube was sealed and heated at 90 ° C for 16 hours. For the treatment, the reaction product was cooled and evaporated under reduced pressure. The residue was partitioned between EtOAc (EtOAc)EtOAc. The aqueous layer was separated and re-extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 ml), then evaporated, dried over sodium sulfate and evaporated. The product was used in the next step without further purification.

Intermediate amine group A6.1

Starting from (2S,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-butan-1-ol (intermediate product A5.1), obtained in the form of a colorless viscous oil ( 4R,5S)-5-fluoro-4-(2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] 2-ylamine (85% yield). MS (ISP): m/z = 227.2 [M+H] ⁺ .

Intermediate amine group A6.2

Starting from (2R,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-butan-1-ol (intermediate product A5.2), quantitatively obtained as a pale yellow solid ( 4R,5R)-5-fluoro-4-(2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 227.2 [M+H] ⁺ .

Intermediate amine group A6.3

Starting from (2R,3R)-3-amino-2-fluoro-3-(2-fluoro-phenyl)-2-methyl-butan-1-ol (intermediate product A5.3), obtained as a white solid Form (4R,5R)-5-fluoro-4-(2-fluoro-phenyl)-4,5-dimethyl-5,6-dihydro-4H-[1,3] 2-ylamine (A6.3). MS (ISP): m/z = 241.2 [M+H] ⁺ .

Intermediate amine group A6.4

From (2R,3R)-3-amino-3-(2-fluoro-phenyl)-2-(2,2,2-trifluoro-ethoxy)-butan-1-ol (intermediate product A5. 4) Starting, (4R,5R)-4-(2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 is obtained as a colorless oil. ,6-dihydro-4H-[1,3] 2-ylamine (A6.4). MS (ISP): m/z = 307.2 [M+H] ⁺ .

Intermediate amine group A6.5

Starting from (2R,3S)-3-amino-2,4-difluoro-3-(2-fluoro-phenyl)-butan-1-ol (intermediate product A5.5), obtained as a white solid (4S,5R)-5-fluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z =245.2 [M+H] ⁺ .

Intermediate amine group A6.6

Starting from (2S,3S)-3-amino-2,4-difluoro-3-(2-fluoro-phenyl)-butan-1-ol (intermediate product A5.6), obtained as a white solid (4S,5S)-5-fluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z =245.2 [M+H] ⁺ .

N-decylamino group Intermediate product of D3 Another synthesis of A6'

Basic process

Treatment of N-decylamino by potassium carbonate (383 mg, 2.74 mmol, 3.6 eq) A solution of D3 (761 μmol) in methanol (12 ml). The reaction mixture was stirred at 50 ° C overnight then evaporated. The crude material was purified by chromatography using a gradient solution of heptane and ethyl acetate as a dissolving agent, direct gelatin (Telos Flash Silica).

Intermediate amine group A6'.1 and A6'.2

From N-[(4R,5R)- and (4R,5S)-4-(5-bromo-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-dihydro- 4H-[1,3] Starting with 2-yl]-benzamide (intermediate products D3.1 and D3.2), (4R,5R)- and (4R,5S)-4-(5-bromo- 2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 341.1 [M+H] ⁺ , 343.3 [M+2+H] ⁺ .

Intermediate nitro Synthesis of A7

Basic process

Amine group The dispersion of A6 (2.8 mmol) in sulfuric acid (22.1 g, 216 mmol) was cooled to 0 ° C and stirring was continued until a homogeneous solution was obtained. Tobacco nitric acid (300 mg, 214 μl, 4.29 mmol) was added dropwise at 4 °C at 0 °C. After the addition was completed, the ice bath was removed and stirring was continued for 30 minutes at room temperature. For the treatment, the solution was added dropwise to a mixture of crushed ice (50 g) and water (50 g). The pH was adjusted to 7-8 by aqueous sodium hydroxide solution. The aqueous layer was extracted twice with ethyl acetate, and then the combined organic layer was washed with brine, then dried over sodium sulfate and evaporated. The product was used in the next step without further purification.

Intermediate nitro A7.1

From (4R,5S)-5-fluoro-4-(2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A6.1), (4R,5S)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4 was obtained as a pale yellow foam. -methyl-5,6-dihydro-4H-[1,3] 2-ylamine (86% yield). MS (ISP): m/z =272.1 [M+H] ⁺ .

Intermediate nitro A7.2

From (4R,5R)-5-fluoro-4-(2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A6.2), (4R,5R)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4- is obtained as a white foam Methyl-5,6-dihydro-4H-[1,3] 2-ylamine (75% yield). MS (ISP): m/z = 272.3 [M+H] ⁺ .

Intermediate nitro A7.3

From (4R,5R)-5-fluoro-4-(2-fluoro-phenyl)-4,5-dimethyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A6.3), (4R,5R)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4,5 was obtained as a light yellow oil. -Dimethyl-5,6-dihydro-4H-[1,3] 2-ylamine (A7.3). MS (ISP): m/z = 286.1 [M+H] ⁺ .

Intermediate nitro A7.4

From (4R,5R)-4-(2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[ 1,3] Starting with 2-ylamine (intermediate product A6.4), (4R,5R)-4-(2-fluoro-5-nitro-phenyl)-4-methyl- in the form of a pale yellow foam 5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 2-ylamine (A7.4). MS (ISP): m/z = 352.2 [M+H] ⁺ .

Intermediate nitro A7.5

From (4S,5R)-5-fluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3] Starting with -2-ylamine (intermediate product A6.5), (4S,5R)-5-fluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-benzene was obtained as a pale yellow solid Base)-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 290.1 [M+H] ⁺ .

Intermediate nitro A7.6

From (4S,5S)-5-fluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A6.6), (4S,5S)-5-fluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-benzene was obtained as a pale yellow solid Base)-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 290.1 [M+H] ⁺ .

Synthesis of intermediate aniline A8

Basic process

Palladium (10% carbon monoxide) (159 mg, 150 μmol) was used as a catalyst at atmospheric pressure to make the nitro group A7 (3 mmol) in ethanol (31 ml) was hydrogenated. After 90 minutes, the reaction was complete. The reaction mixture was filtered through a Dicalit layer and washed with ethyl alcohol (3×20 ml). The combined ethanol solution was evaporated under reduced pressure. The product was used in the next step without further purification.

Intermediate aniline A8.1

From (4R,5S)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A7.1), (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4- is obtained as a white foam. Methyl-5,6-dihydro-4H-[1,3] 2-ylamine (98% yield). MS (ISP): m/z =242.2 [M+H] ⁺ .

Intermediate aniline A8.2

From (4R,5R)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A7.2), (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4- is obtained as a white foam. Methyl-5,6-dihydro-4H-[1,3] 2-ylamine (97% yield). MS (ISP): m/z =242.3 [M+H] ⁺ .

Intermediate aniline A8.3

From (4R,5R)-5-fluoro-4-(2-fluoro-5-nitro-phenyl)-4,5-dimethyl-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A7.3), (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5- was obtained as a white solid. Dimethyl-5,6-dihydro-4H-[1,3] 2-ylamine (A8.3). MS (ISP): m/z = 265.2 [M+H] ⁺ .

Intermediate aniline A8.4

From (4R,5R)-4-(2-fluoro-5-nitro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-di Hydrogen-4H-[1,3] Starting with 2-ylamine (intermediate product A7.4), (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5- was obtained as a pale yellow solid. (2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 2-ylamine (A8.4). MS (ISP): m/z = 322.2 [M+H] ⁺ .

Intermediate aniline A8.5

From (4S,5R)-5-fluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A7.5), (4S,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl was obtained as an off-white solid Base-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 260.2 [M+H] ⁺ .

Intermediate aniline A8.6

From (4S,5S)-5-fluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-4H-[1,3] Starting with 2-ylamine (intermediate product A7.5), (4S,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4- is obtained as a white foam. Fluoromethyl-5,6-dihydro-4H-[1,3] -2-ylamine. MS (ISP): m/z = 260.2 [M+H] ⁺ .

Another synthesis of the intermediate aniline A8

Basic process

A solution of DMTr-imine B2 (219 μmol) in dichloromethane (3 ml) was obtained by trifluoroacetic acid (171 μl, 2.19 mmol, 10 eq). After 30 minutes (after the reaction was carried out, followed by TLC), the solution was evaporated. Then, hydrochloric acid (1 M; 2.19 ml, 10 eq) was added to the crude intermediate imine B3. After 30 minutes at room temperature (after the reaction was carried out, followed by TLC), the reaction mixture was poured into a cold sodium carbonate solution (1 M; 14 ml). The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated. A gradient solution of heptane and ethyl acetate was used as a dissolving agent to remove the residue from the chlorobenzene-NH ₂ (Telos Flash NH ₂ ) chromatography.

Intermediates aniline A8.7 and A8.8

From {(4R,5R)- and (4R,5S)-4-[5-(diphenylmethylene-amino)-2-fluoro-phenyl]-4-difluoromethyl-5-fluoro- 5,6-dihydro-4H-[1,3] Starting with 2-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (intermediate products B2.1 and B2.2), a pale yellow crystalline material is obtained ( 4R,5R)- and (4R,5S)-4-(5-Amino-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[1 , 3] -2-ylamine. MS (ISP): m/z =278.4 [M+H] ⁺ .

Intermediate product DMTr- Synthesis of B1

Basic process

By N-ethyldiisopropylamine (195 μl, 1.15 mmol, 2 eq) and 4,4'-dimethoxytriphenylmethyl chloride (292 mg, 861 μmol, 1.5) at 0 °C Eq) treatment of amine groups A6' (574 μmol) in dichloromethane (8 ml). After 16 hours at 22 ° C, the reaction mixture was washed with water and then organic layer was evaporated, evaporated and evaporated. The gradient was purified by chromatography using a gradient of heptane and ethyl acetate as a solvent (Telos Flash Silica).

Intermediate products B1.1 and B1.2

From (4R,5R)- and (4R,5S)-4-(5-bromo-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[ 1,3] Starting with 2-ylamine (intermediate products A6'.1 and A6'.2), [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R) was obtained as a white solid. ,5R)- and (4R,5S)-4-(5-bromo-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3 ] -2-yl]-amine. R _f : 0.52 (SiO ₂ ; heptane: ethyl acetate = 2:1; detection: UV, 254 nm).

Synthesis of intermediate product imine B2

Basic process

Sodium terbutyrate (131 mg, 1.36 mmol, 3 eq), 2-di-tert-butylphosphine-2', 4', 6'-three different in sequence under argon at 22 °C Propylbiphenyl (28.9 mg, 68.1 μmol, 0.15 eq), ginseng (diphenylmethyleneacetone) dipalladium (0) chloroform adduct (24.2 mg, 22.7 μmol, 0.05 eq) and benzophenone imine (170 mg, 157 μl, 908 μmol, 2 eq) for DMTr- A solution of B1 (454 μmol) in toluene (6 ml). The tube was sealed and heated to 105 ° C for 60 hours. The mixture was cooled to 22 ° C, evaporated under reduced pressure and a gradient of heptane and ethyl acetate was used as chromatographic amine phase (Telos Flash NH ₂ ).

Intermediate products B2.1 and B2.2

From [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)- and (4R,5S)-4-(5-bromo-2-fluoro-phenyl) -4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3] Starting with -2-yl]amine (intermediate products B1.1 and B1.2), {(4R,5R)- and (4R,5S)-4-[5-(diphenyl) are obtained in the form of a pale yellow foam. Methylene-amino)-2-fluoro-phenyl]-4-difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3] -2-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine. MS (ISP): m/z = 744.5 [M+H] ⁺ , 442.4 [M-DMTr+H] ⁺ .

Synthesis of intermediate O-protected amino alcohol D1

Treated with triethylamine (4.35 ml, 31.3 mmol), 4-dimethylaminopyridine (868 mg, 7.11 mmol) and butyl-chloro-dimethyl-decane (4.51 g, 28.4 mmol) 2R,3R)- and (2S,3R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2,4,4-trifluoro-butan-1-ol (4.49 g, A solution of 14.2 mmol) (Intermediate A5.7 and A5.8) in dichloromethane (120 ml) For the treatment, the reaction mixture was extracted with a saturated sodium hydrogen carbonate solution (40 ml), water (40 ml) and brine (40 ml). The aqueous bicarbonate solution was extracted with dichloromethane, then the organic layers were combined, dried over sodium sulfate and evaporated. The crude product was purified by chromatography using a gradient of heptane / ethyl acetate = 100:0 to 90:10 as eluting solvent (Telos Flash Silica). Obtaining (1R,2R)- and (1R,2S)-1-(5-bromo-2-fluoro-phenyl)-3-(t-butyl-dimethyl-decaneoxy) in the form of a viscous colorless oil Base)-1-difluoromethyl-2-fluoro-propylamine (2.05 g, 85% of theory). MS (ISP): m/z = 430.3 [M+H] ⁺ and 432.2 [M+2+H] ⁺ .

Synthesis of intermediate O-protected isothiocyanate adduct D2

(1R,2R)- and (1R,2S)-1-(5-bromo-2-fluoro-phenyl)-3-(3-tert-butyl-dimethyl-decane in a microwave tube Oxy)-1-difluoromethyl-2-fluoro-propylamine (intermediate products D1.1 and D1.2) (2.4551 g, 5.7 mmol) and benzamidine isothiocyanate (1.12 g, 6.85) Methyl) was dissolved in acetone (25 ml). The tube was sealed and heated at 70 ° C overnight. For the treatment, the reaction mixture was evaporated under reduced pressure and a gradient mixture of heptane / ethyl acetate = 100:0 to 80:20 was used as a solvent to dissolve the residue by chromatography (Telos Flash Silica). 1-Benzylmercapto-3-[(1R,2R)- and (1R,2S)-1-(5-bromo-2-fluoro-phenyl)-3- (in the form of a pale yellow foam) Third butyl-dimethyl-decyloxy)-1-difluoromethyl-2-fluoro-propyl]-thiourea (2.05 g, 61% of theory). MS (ISP): m/z = 623.0 [M+H] ⁺ and 625.1 [M+2+H] ⁺ .

mid product Synthesis of D3

1-Benzylmercapto-3-[(1R,2R)- and (1R,2S)-1-(5-bromo-2-fluoro-phenyl)-3-(t-butyl-dimethyl -decyloxy)-1-difluoromethyl-2-fluoro-propyl]-thiourea (intermediate D2.1 and D2.2) (2.021 g, 3.41 mmol) in dichloromethane (100 ml) The solution was cooled to 0 ° C and trimethyloxonium tetrafluoroborate (557 mg, 3.58 mmol) was added in one portion. The reaction mixture was stirred at 0 ° C for 40 minutes and then at room temperature for 3 hours. To complete the reaction, another equivalent of trimethyloxonium tetrafluoroborate (557 mg, 3.58 mmol) was added and stirring was continued overnight. For the treatment, the reaction mixture was evaporated and the residue was purified using a gradient of heptane / ethyl acetate = 100:0 to 0:100 as a solvent. Obtaining N-[(4R,5R)- and (4R,5S)-4-(5-bromo-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro in the form of a white foam 5,6-dihydro-4H-[1,3] -2-yl]-benzamide (962 mg, 63.5% of theory). MS (ISP): m/z = 445.4 [M+H] ⁺ and 447.3 [M+2+H] ⁺ .

Synthesis of guanamine as in formula I

Basic Process I:

A solution of the carboxylic acid (0.23 mmol) in methanol (5 ml) was cooled to 0. Add 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-chloromethylmorpholine hydrazine hydrate (DMTMM) (80 mg, 0.27 mmol) and at 0 The solution was stirred at ° C for 30 minutes. Thereafter, a solution of the intermediate product diamine A8 (0.21 mmol) in methanol (5 ml) was added dropwise at 0 °C. The reaction mixture was stirred at 23 ° C for 18-60 hours. For the treatment, the reaction mixture was poured into a sodium carbonate solution (1 M) and then extracted with dichloromethane. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to leave a light brown oil, which was purified using a mixture of dichloromethane and methanol (0-10%) to obtain the pure amines of formula I.

The following examples have a basic group. Depending on the reaction and the purification conditions, they are isolated as a free base form, or a salt form, or a free base and a salt form.

Example 1

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-chloro-pyridine-2-carboxylic acid gave the title compound as a white crystalline solid. MS (ISP): m/z = 381.2 [M+H] ⁺ .

Example 2

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 3,5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) afforded the title compound as a white crystalline solid. MS (ISP): m/z = 415.1 [M+H] ⁺ and 417.1 [M+2+H] ⁺ .

Example 3

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 3,5-difluoro-pyridine-2-carboxylic acid (CAS 745784-04-7) gave the title compound as a white solid. MS (ISP): m/z = 383.3 [M+H] ⁺ .

Example 4

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) is condensed with 5-cyano-pyridine-2-carboxylic acid (CAS 53234-55-2) to give the title compound as a white solid. MS (ISP): m/z = 372.2 [M+H] ⁺ .

Example 5

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS 1174321-03-9) to give the title compound as a white foam. MS (ISP): m/z = 395.1 [M+H] ⁺ .

Example 6

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS 1174323-34-2) to give the title compound as a white foam. MS (ISP): m/z = 413.3 [M+H] ⁺ .

Example 7

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) gave the title compound as a white solid. MS (ISP): m/z = 406.2 [M+H] ⁺ .

Example 8

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-chloro-3-fluoro-pyridine-2-carboxylic acid (CAS 207994-08-9) to give the title compound as a white solid. MS (ISP): m/z = 399.1 [M+H] ⁺ .

Example 9

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[ 1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS 80194-68-9) to give the title compound as white powder. MS (ISP): m/z = 449.1 [M+H] ⁺ .

Example 10

5-fluoromethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3 ] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-fluoromethoxy-pyrazine-2-carboxylic acid (CAS 1174321-00-6) to give the title compound as a white foam. MS (ISP): m/z = 396.2 [M+H] ⁺ .

Example 11

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-difluoromethyl-pyridine-2-carboxylic acid afforded the title compound as a white foam. MS (ISP): m/z = 397.3 [M+H] ⁺ .

Starting from 5-methyl-pyridine-2-carboxylic acid in a manner very similar to that described for the preparation of 5-difluoromethyl-pyrazine-2-carboxylic acid described in US 2009209757, 5-difluoromethyl-pyridine- 2-carboxylic acid (CAS 859538-41-3).

Example 12

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS 89402-28-8) to give the title compound as a white foam. MS (ISP): m/z = 433.3 [M+H] ⁺ .

Example 13

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) is condensed with 5-methoxy-pyridine-2-carboxylic acid (CAS 29082-92-6) to give the title compound as a white solid. MS (ISP): m/z = 377.3 [M+H] ₊ .

Example 14

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS 1174322-62-3; WO2009091016) to give the title compound as a white foam. MS (ISP): m/z = 411.3 [M+H] ⁺ .

Example 15

5-difluoromethyl-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3 ] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 5-difluoromethyl-pyrazine-2-carboxylic acid (CAS 1174321-06-2, US200909757) to give the title compound as a pale yellow solid. MS (ISP): m/z = 398.2 [M+H] ⁺ .

Example 16

5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1 , 3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 418.3 [M+H] ⁺ .

Obtain 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid according to the following basic procedure:

Treatment of 5-chloro-pyrazine-2-carboxylic acid (1.50 g, 9.46 mmol) by cyclopropyl-methanol (1.02 g, 14.1 mmol) and potassium hydroxide powder (2.12 g, 37.4 mmol) at 25 ° C A solution of anhydrous dimethyl hydrazine (5 ml). The mixture was heated at 80 ° C for 90 minutes in a microwave oven. For the treatment, the reaction mixture was quenched with aqueous citric acid (10%) then extracted with ethyl acetate (5×30 ml) and then extracted with a 4:1 mixture of dichloromethane and methanol. The combined organic layers were washed with brine (200 mL) dried and evaporated. After lyophilization, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (34% yield) was obtained as a white solid. MS (ISP): m/z = 195.0 [M+H] ⁺ .

Example 17

5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6- Dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 445.3 [M+H] ⁺ .

5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid was obtained as follows:

a) methyl 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylate

N-N-N of methyl 5-hydroxy-pyridine-2-carboxylate (200 mg, 1.31 mmol) was treated with sodium hydride (55% oil dispersion, 64 mg) at room temperature under nitrogen. Methylformamide (2 ml) solution. After the gas formation was terminated, the suspension was cooled to 0 ° C and 2,2,2-trifluoroethyl trifluoromethanesulfonate (364 mg, 1.57 mmol) was added. After stirring at room temperature for 2 hours, about 50% of the starting material remained. Another portion of 364 mg of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester was added and after 30 minutes the reaction was complete. For the treatment, the reaction mixture was treated with a saturated solution of sodium carbonate and then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The 3:1 mixture of heptane and ethyl acetate was used as a dissolving agent to purify the crude product. Methyl 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylate (216 mg, 70% of theory) was obtained as a white solid. MS (ISP): m/z = 236.3 [M+H] ⁺ .

b) 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid

Treatment of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid by a solution of lithium hydroxide monohydrate (78 mg, 1.84 mmol) in methanol (0.1 ml) A solution of methyl ester (216 mg, 0.92 mmol) in methanol (1 ml). After stirring for 2 hours, the reaction mixture was evaporated under reduced pressure. The residue was treated with hydrochloric acid (1N), the solid material was filtered, then washed with water and then dried under high vacuum. 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid (125 mg, 61% of theory) was obtained as a white solid.

Example 18

2,5-Dimethyl-furan-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3 ] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 2,5-dimethyl-furan-3-carboxylic acid (CAS 636-44-2) gave the title compound as a white solid. MS (ISP): m/z = 364.3 [M+H] ⁺ .

Example 19

5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-di Hydrogen-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 2-ylamine (intermediate product A8.2) is condensed with 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid (CAS 1174323-38-6; WO2009091016) to give a white solid The title compound of the form. MS (ISP): m/z = 428.2 [M+H] ⁺ .

Example 20

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-fluoro-pyridine-2-carboxylic acid afforded the title compound as a white solid. MS (ISP): m/z = 365.2 [M+H] ⁺ .

Example 21

5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro) -4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 2-ylamine (intermediate product A8.2) is condensed with 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 1097730-45-4; WO2009091016) to obtain a white foam The title compound in bulk form. MS (ISP): m/z = 427.2 [M+H] ⁺ .

Example 22

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) is condensed with 5-cyclopropyl-pyridine-2-carboxylic acid (CAS 1174322-66-7; WO 2009091016) to give the title compound as a white solid. MS (ISP): m/z = 387.3 [M+H] ⁺ .

Example 23

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 5-cyclopropylmethoxy-pyridine-2-carboxylic acid afforded the title compound as a white foam. MS (ISP): m/z = 417.3 [M+H] ⁺ .

5-Cyclopropylmethoxy-pyridine was prepared in a microwave oven at 90 ° C for 90 minutes in a similar manner to the preparation of 5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 16). -2-carboxylic acid. 5-Cyclopropylmethoxy-pyridine-2-carboxylic acid (25% yield) was obtained as an off white solid. MS (ISP): m/z = 194.0 [M+H] ⁺ .

Example 24

5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5, 6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of 2-ylamine (intermediate product A8.2) with 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid gave the title compound as a white foam. MS (ISP): m/z = 477.1 [M+H] ⁺ .

5-(2,2,3,3-Tetrafluoro-propoxy)-pyridine-2-carboxylic acid was prepared as follows:

a) methyl 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylate

Treatment of methyl 5-hydroxy-pyridine-2-carboxylate (2.0 g, 13.1 mmol) with potassium carbonate (5.415 g, 39.2 mmol) and 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (40 ml) solution. After stirring at room temperature for 4 hours, the suspension was diluted with diethyl ether. After filtration, the solution was evaporated and a gradient of heptane / ethyl acetate = 100:0 to 30:70 was used as a solvent. Methyl 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylate (3.49 g, 76% of theory) was obtained as a pale yellow solid. MS (ISP): m/z = 468.1 [M+H] ⁺ .

b) 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid

The methyl 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylate was hydrolyzed by lithium hydroxide in a manner similar to that described in Example 17b) to give a pale yellow solid. The title compound (yield 94% of theory). MS (ISP): m/z = 253 [M] ⁺ .

Example 25

5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of 2-ylamine (intermediate product A8.2) with 5-(2,2,3,3,3-pentafluoro-phenoxy)-pyridine-2-carboxylic acid to give the title in the form of a white foam Compound. MS (ISP): m/z = 495.2 [M+H] ⁺ .

5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid was obtained as follows:

a) Methyl 5-hydroxy-pyridine-2-carboxylate by potassium carbonate and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate in a manner similar to that described in Example 24a) Alkylation afforded methyl 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylate as a light yellow oil. MS (ISP): m/z = 285 [M] ⁺ .

b) obtained by hydrolysis of methyl 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylate by lithium hydroxide in a manner similar to that described in Example 17b) 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid as a white solid. MS (ISP): m/z = 271 [M+H] ⁺ .

Example 26

2-Chloro-thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.2) with 2-chloro-thiazole-5-carboxylic acid (CAS 101012-12-8) gave the title compound as a white solid. MS (ISP): m/z = 387.2 [M+H] ⁺ .

Example 27

2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro -4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of 2-methylamine (intermediate product A8.2) with 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (CAS 128694-63-3) gave the title as a white solid Compound. MS (ISP): m/z = 418.3 [M+H] ⁺ .

Example 28

4-Chloro-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 4-chloro-1H-pyrazole-3-carboxylic acid (CAS 84547-87-5) to give the title compound as a white solid. MS (ISP): m/z = 370.1 [M+H] ⁺ .

Example 29

Thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the -2-ylamine (intermediate product A8.2) with thiazole-5-carboxylic acid (CAS 14527-41-4) gave the title compound as a white solid. MS (ISP): m/z = 353.2 [M+H] ⁺ .

Example 30

1,5-Dimethyl-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[ 1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 5744-59-2) to give the title compound as a white solid. MS (ISP): m/z = 364.3 [M+H] ⁺ .

Example 31

1-cyano-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) was condensed with 1-cyano-cyclopropanecarboxylic acid (CAS 6914-79-0) to give the title compound as a white foam. MS (ISP): m/z = 335.3 [M+H] ⁺ .

Example 32

Cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] The -2-ylamine (intermediate product A8.2) is condensed with cyclopropanecarboxylic acid to give the title compound as a white foam. MS (ISP): m/z = 310.2 [M+H] ⁺ .

Example 33

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

According to Process I, (4R,5S)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.1) with 5-cyano-pyridine-2-carboxylic acid afforded the title compound as a white solid. MS (ISP): m/z = 372.2 [M+H] ⁺ .

Example 34

5-Chloro-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5S)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.1) with 5-chloro-pyridine-2-carboxylic acid afforded the title compound as a white solid. MS (ISP): m/z = 381.1 [M+H] ⁺ .

Example 35

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

According to Process I, (4R,5S)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (intermediate product A8.1) with 3-chloro-5-cyano-pyridine-2-carboxylic acid afforded the title compound as a white powder. MS (ISP): m/z = 406.2 [M+H] ⁺ .

Example 36

3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[ 1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5S)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] Condensation of 2-ylamine (Intermediate A8.1) with 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid afforded the title compound as a white solid. MS (ISP): m/z = 449.2 [M+H] ⁺ .

Example 37

3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5 ,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of 2-ylamine (A8.3) with 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 1250130-41-6) gave the title as a white solid Compound. MS (ISP): m/z = 459.2 [M+H] ⁺ .

3-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid was prepared according to the following:

a) Add sodium hydride (55% oil solution, 64 mg) to methyl 3-hydroxy-pyridine-2-carboxylate (200 mg, 1.3 mmol) of N,N-dimethylformamide at 22 °C ( 2.0 ml) solution and continue to stir until gas evolution ceases. The suspension was cooled to 0 ° C and treated with trifluoroethyl trifluoromethanesulfonate (728 mg) and stirred at 22 ° C for 2 h. The mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and dried and evaporated. The n-heptane and ethyl acetate (3:1) were used as the dissolving agent to purify the residue by vermiculite chromatography to obtain 3-(2,2,2-trifluoro-ethoxy)-pyridine as a light green oil. Methyl-2-carboxylate. MS (ISP): m/z = 236 [M+H] ⁺ .

b) Treatment of methyl 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylate (216 mg, by a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) 0.9 mmol) in methanol (1 ml) and stirring was continued at 22 °C for 2 hours. The evaporated solution and the residue were triturated with a 1N aqueous solution of hydrochloric acid. The suspension was filtered, and the residue was washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. MS (ISN): m/z = 220 [MH] ^- .

Example 38

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

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 5-cyano-pyridine-2-carboxylic acid afforded the title compound as a colorless solid. MS (ISP): m/z = 386.2 [M+H] ⁺ .

Example 39

3,5-difluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 3,5-dichloro-pyridine-2-carboxylic acid gave the title compound as a colorless solid. MS (ISP): m/z = 429.2 [M+H] ⁺ and 431.1 [M+2+H] ⁺ .

Example 40

4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6- Dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 434.2 [M+H] ⁺ .

4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was prepared as follows:

a) methyl 1-difluoromethyl-1H-pyrazole-3-carboxylate

A solution of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid (CAS925179-02-8) (500 mg, 3.1 mmol) in methanol (18 ml) was cooled to 0 ° C and with sulfuric acid (98%, 0.2) Ml, 3.1 mmol) treatment. The mixture was heated to reflux and held for 2 hours. For the treatment, the solution was cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc (EtOAc) (EtOAc) The organic layer was separated and washed with water until the aqueous phase exhibited a neutral pH. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure. Methyl 1-difluoromethyl-1H-pyrazole-3-carboxylate (535 mg, 99% of theory) was obtained as a colourless liquid, which was pure enough for the next step without further purification. MS (ISP): m/z = 177.1 [M+H] ⁺ .

b) 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester

Methyl 1-difluoromethyl-1H-pyrazole-3-carboxylate (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N, N at 50 ° The mixture in dimethylformamide (5 ml) was heated overnight. The reaction mixture was cooled, poured into water (20 ml) The organic layer was separated, washed with water, dried over sodium sulfate and evaporated. The 3:1-mixture of cyclohexane and ethyl acetate was used as a dissolving agent to purify the yellow-green crude material by gel chromatography. Methyl 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylate (540 mg, 84% of theory) was obtained as a white solid. MS (ISP): m/z = 209.9 [M] ⁺ .

c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid

Treatment of 4-chloro-1-difluoromethyl-1H-pyrazole by a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1 mixture of water and methanol (12 ml) A solution of methyl 3-formate (540 mg, 2.6 mmol) in tetrahydrofuran (18 mL). After 1 hour, the reaction was completed and the solvent was evaporated under reduced pressure. The residue was dissolved in water (10 ml) and acidified (2M). The organic layer was dried with EtOAc (EtOAc)EtOAc. The solid material was filtered, washed and dried with pentane. After drying under reduced pressure, 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid (477 mg, 95% of theory) was obtained as white solid. MS (ISP): m/z = 195.0 [MH] ^- .

Example 41

5-Chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 5-chloro-pyridine-2-carboxylic acid gave the title compound as a colorless solid. MS (ISP): m/z = 395.1 [M+H] ⁺ .

Example 42

5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 5-fluoro-pyridine-2-carboxylic acid gave the title compound as a colorless solid. MS (ISP): m/z = 379.3 [M+H] ⁺ .

Example 43

4-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]decylamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of 2-ylamine (A8.3) with 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid (CAS 1006486-42-5) gives white The title compound in solid form. MS (ISP): m/z = 448.2 [M+H] ⁺ .

Example 44

2,2-Difluoro-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3 ] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] Condensation of the 2-ylamine (A8.3) with 2,2-difluoro-cyclopropanecarboxylic acid (CAS 107873-03-0) gave the title compound as a white solid. MS (ISP): m/z = 360.3 [M+H] ⁺ .

Example 45

5-Chloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6- Dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine

(4R,5R)-4-(5-Amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 according to Process I ,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (A8.4) with 5-chloro-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 461.2 [M+H] ⁺ .

Example 46

5-fluoro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6- Dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine

(4R,5R)-4-(5-Amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 according to Process I ,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (A8.4) with 5-fluoro-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 445.3 [M+H] ⁺ .

Example 47

5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6 -dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine

(4R,5R)-4-(5-Amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 according to Process I ,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (A8.4) with 5-cyano-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 452.1 [M+H] ⁺ .

Example 48

3,5-Dichloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 ,6-dihydro-4H-[1,3] 4-yl] -4-fluoro - phenyl} - Amides

(4R,5R)-4-(5-Amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 according to Process I ,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (A8.4) with 3,5-dichloro-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 495.1 [M+H] ⁺ and 497.2 [M+H] ⁺ .

Example 49

5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2 -trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine

(4R,5R)-4-(5-Amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5 according to Process I ,6-dihydro-4H-[1,3] Condensation of the 2-ylamine (A8.4) with 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 525.2 [M+H] ⁺ .

Example 50

5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro -4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4R,5R)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1 , 3] 2-ylamine (A8.3) is condensed with 5-but-2-ynyloxy-pyridine-2-carboxylic acid (prepared as described in Tamura Y. et al., WO 2010/113 848) to obtain The title compound is in the form of a white solid. MS (ISP): m/z = 430.3 [M+H] ⁺ .

Example 51

5-cyano-pyridine-2-carboxylic acid [3-((4S,5R)-2-amino-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to the procedure I, (4S,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3 ] Condensation of the 2-ylamine (A8.5) with 5-cyano-pyridine-2-carboxylic acid gave the title compound as a pale yellow solid. MS (ISP): m/z = 390.2 [M+H] ⁺ .

Example 52

5-cyano-pyridine-2-carboxylic acid [3-((4S,5S)-2-amino-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to Process I, (4S,5S)-4-(5-Amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3 ] Condensation of the 2-ylamine (A8.6) with 5-cyano-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 390.4 [M+H] ⁺ .

Example 53

5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)- or (4R,5S)-2-amino-4-difluoromethyl-5-fluoro-5,6-dihydro- 4H-[1,3] -4-yl)-4-fluoro-phenyl]-guanamine

According to the procedure I, (4R,5R)- and (4R,5S)-4-(5-amino-2-fluoro-phenyl)-4-difluoromethyl-5-fluoro-5,6-di Hydrogen-4H-[1,3] Condensation of the 2-ylamine with 5-cyano-pyridine-2-carboxylic acid gave the title compound as a white solid. MS (ISP): m/z = 408.4 [M+H] ⁺ . A small amount of isomers were not isolated.

Claims (27)

a compound of formula I, Wherein R ¹ is selected from the group consisting of i) hydrogen, ii) a halogen atom, and iii) a C _1-6 -alkyl group; and R ² is selected from the group consisting of: i) hydrogen, ii C _1-6 -alkyl, and iii) halogen atom -C _1-3 -alkyl, R ³ is selected from the group consisting of: i) hydrogen, and ii) C _1-6 -alkyl, R ⁴ is selected from the group consisting of i) a halogen atom, ii) a C _1-6 -alkyl group, and iii) a halogen atom - a C _1-6 -alkoxy group, and a R ⁵ system-C (=O) -R ⁶ , R ⁶ is selected from the group consisting of: i) a heteroaryl group, ii) a heteroaryl group optionally substituted with from 1 to 4 substituents of the group: cyano, cyanide -C _1-6 -alkyl, halogen atom, halogen atom -C _1-6 -alkoxy, halogen atom -C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 - alkoxy-C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-6 -alkoxy, C _3-6 -cycloalkyl-C _{1 -6} -alkyl, C _3-6 -cycloalkyl-C _2-6 -alkynyl, C _2-6 -alkynyl-C _1-6 -alkoxy and C _1-6 -alkyl, iii) C _3-6 - cycloalkyl, IV) by a group independently selected from 1-4 of substituents of C _3-6 - cycloalkyl: cyano, cyanoalkyl, -C _1-6 - Group, a halogen atom, a halogen atom, -C _1-6 - alkoxy group, halogen atom, -C _1-6 - alkyl, hydroxy, C _1-6 - alkoxy, C _1-6 - alkoxy, -C _{1 -6} -alkyl and C _1-6 -alkyl, v)heterocyclyl, and vi)heterocyclyl optionally substituted with from 1 to 4 substituents of the group: cyano, cyano- C _1-6 -alkyl group, halogen atom, halogen atom-C _1-6 -alkoxy group, halogen atom-C _1-6 -alkyl group, C _1-6 -alkoxy group, C _1-6 -alkoxy group a base-C _1-6 -alkyl group and a C _1-6 -alkyl group; or a pharmaceutically acceptable salt thereof. A compound of formula Ia, as claimed in claim 1, Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. The compound of any one of claims 1 to 2, wherein R ¹ is a halogen atom, R ² is a C _1-6 -alkyl group, and R ³ is selected from the group consisting of: i) hydrogen, and ii) C _1-6 -alkyl, R ⁴ is selected from the group consisting of: i) a halogen atom, and ii) a halogen atom - C _1-6 -alkoxy, R ⁵ -C(=O)-R ⁶ R ⁶ is selected from the group consisting of i) a heteroaryl group, ii) a heteroaryl group optionally substituted with 1 to 4 substituents selected from the group consisting of a cyano group, a halogen atom, a halogen atom - C _1-6 -alkoxy, halogen atom-C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-6 -alkoxy, C _2-6 -alkynyl-C _1-6 -alkoxy and C _3-6 -cycloalkyl-C _2-6 -alkynyl, iii) C _3-6 - cycloalkyl, and iv) over 1 are independently selected from a halogen atom and a cyano group to 4 of substituents of C _3-6 - cycloalkyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 2, wherein R ¹ is a halogen atom. The compound of any one of claims 1 to 2, wherein R ¹ is F. The compound of any one of claims 1 to 2, wherein R ² is C _1-6 -alkyl. The compound of any one of claims 1 to 2, wherein R ² is Me. The compound of any one of claims 1 to 2, wherein R ³ is hydrogen. The compound of any one of claims 1 to 2, wherein R ⁴ is a halogen atom. The compound of any one of claims 1 to 2, wherein R ⁴ is F. The compound of any one of claims 1 to 2, wherein R ⁴ is a halogen atom-C _1-6 -alkoxy group. The compound of any one of claims 1 to 2, wherein R ⁴ is -OCH ₂ CF ₃ . The compound of any one of claims 1 to 2, wherein R ⁶ is independently substituted with 1 to 2 substituents selected from the group consisting of a cyano group, a halogen atom and a C _3-6 -cycloalkyl-C _2-6 -alkynyl group. a heteroaryl group substituted by a group. The compound of any one of claims 1 to 2, wherein R ² is a pyridyl group substituted independently with 1 to 2 substituents selected from the group consisting of cyano, chloro and cyclopropylethynyl. The compound according to any one of claims 1 to 2, which is selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-3-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-methoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro -4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyclopropyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-chloro-thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-methyl-5-trifluoromethyl- 2H -pyrazole-3-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4 -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6- Dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1-cyano-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5 ,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro -4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 4-chloro-1-difluoromethyl-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4,5-dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-fluoro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4S,5R)-2-amino-5-fluoro-4-fluoromethyl) Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4S,5S)-2-amino-5-fluoro-4-fluoromethyl) Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)- or (4R,5S)-2-amino-4 -difluoromethyl-5-fluoro-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4-methyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid {3-[(4R,5R)-2 -amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)) 2-amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1,5-dimethyl-1 H -pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5 -fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1-(2,2-difluoro-ethyl)-1 H -pyrazole-3-carboxylic acid [3-((4R ,5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4 H- [1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,2-difluoro-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,5-dimethyl-furan-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-difluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4, 5-dimethyl-5,6-dihydro-4 H -[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, and 3,5-dichloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl- 5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4 H -[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 2, which is selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 1-cyano-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5 ,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,2-difluoro-cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2,5-dimethyl-furan-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-chloro-thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4, 5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5 -(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 3,5-difluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-- Fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 4-chloro-1H-pyrazole-3-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2) -amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid {3-[(4R,5R)-2 -amino-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R, 5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [3-((4R,5R)) 2-amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [3-((4R,5R)-2- Amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((4R,5R)-2-amine) 5--5-fluoro-4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-3-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4 -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-chloro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5- Dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5S)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro -4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyclopropylmethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, 5-cyclopropyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-difluoromethyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoromethoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl- 5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4,5-di Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-fluoro-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-(2 , 2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-methoxy-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl Base-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, cyclopropanecarboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro -4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, and thiazole-5-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl-5,6 -dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 2, which is selected from the group consisting of 5-chloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro- 4-methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 3,5-dichloro-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4- Methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4-methyl) -5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-nonylamine, 5-cyano-pyridine-2-carboxylic acid {3-[(4R,5R)-2-amino-4-methyl-5-( 2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3] 4-yl]-4-fluoro-phenyl}-decylamine, 5-cyclopropylethynyl-pyridine-2-carboxylic acid [3-((4R,5R)-2-amino-5-fluoro-4) -methyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-decylamine, and 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((4R,5R)-2-amino)- 5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3] 4-yl)-4-fluoro-phenyl]-guanamine, or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 17, which comprises reacting a compound of formula C4 with a compound of formula I Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in any one of claims 1 to 14. A compound of formula I according to any one of claims 1 to 2, which is prepared by the method of claim 18. A compound of formula I as claimed in any one of claims 1 to 2 for use as a therapeutic active. A compound of formula I according to any one of claims 1 to 2 for use as a therapeutic active for therapeutic and/or prophylactic treatment with elevated beta-amyloid protein concentration and/or beta-class Amyloid oligo and/or beta-amyloid plaques and other diseases and conditions characterized by deposition or Alzheimer's disease. A compound of formula I according to any one of claims 1 to 2 for use as a therapeutic active for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes. A compound of formula I according to any one of claims 1 to 2 for use as a therapeutic active for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, self Immunity/inflammatory diseases, cancers such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal disease, glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory response, Kaposi's sarcoma (Kaposi Sarcoma), Kostmann Disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome, spinocerebellar disorders 1, spinocerebellar disorders 7, Whipple's Disease, and Wilson's Disease. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary. Use of a compound of formula I according to any one of claims 1 to 17 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease. Use of a compound of formula I according to any one of claims 1 to 17 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes. Use of a compound of formula I according to any one of claims 1 to 17 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, Autoimmune/inflammatory diseases, cancers such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal diseases, glioblastoma multiforme, Graves' disease, Hunting Down's disease, inclusion body myositis (IBM), Inflammation, Kaposi's sarcoma, Cox's disease, lupus erythematosus, macrophage myofascial inflammation, juvenile congenital arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, dryness Syndrome, spinal cerebellar disorders 1, spinal cerebellar disorders 7, Whipple's disease and Wilson's disease.