TW201245162A - Novel substituted triazolyl piperazine and triazolyl piperidine derivatives as gamma secretase modulators - Google Patents

Abstract

The present invention is concerned with novel substituted triazolyl piperazine and triazolyl piperidine derivatives of Formula (I) wherein R1, R2, R3, R4a, R4b, R5, X, Y1, Y2, L1, and L2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

201245162, invention description: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel substituted triazolyl piperidin and triazolyl piperidine derivatives which are suitable for use as γ-secretase modulators. The present invention further relates to a method for preparing the compound of the above (4), a pharmaceutical composition containing the compound as an active ingredient, and the use of the compound as a medicine. [Prior Art] Arrhythmia (AD) is a progressive neurodegenerative disorder characterized by loss of memory, cognition, and behavioral stability. AD violates 6:10% of ethnic groups over 65 years of age and up to 5q% of ethnic groups over 85 years of age. It is the main cause of 40% loss of g, the third leading cause of death after cardiovascular disease and cancer. Upper eye 5 cannot effectively treat AD. The United States and the Eight Commandments "the net cost totals more than US$100 million per year. / There is an early pure etiology, which is associated with certain risks due to f age' (2) family history and (3) head trauma; other factors In the case of the brain and the financial quality, the lesions include intracellular nerves composed of hyperphosphorus h protein f, , , , , , , and amyloid β peptide fiber aggregates. (The main components of the amyloid plaques are powdery peptides of different lengths of 4-like protein β (Α_Ρ, Abeta or Aj3). One of the changes is Αβ1-42_peptide (Αβ·42), which is formed by salty letters. (4) The main component of the protein. Another type of arsenic is ΑβΜΟ-peptide (Αβ-40). Αβ is the precursor protein: _ powder protein precursor protein (4) or protein hydrolysis product of VIII (7). Also 201245162 familial early onset The chromosomal phenotype AD has been associated with the amyloid precursor protein (β-ΑΡΡ or APP) and the early-stage prostaglandin 丨盥2. In some patients, the late-type hair and the _peptone (Αρ〇Ε) gene Heart-to-is related genes, and recently found mutations in α2_macroglobulin, possibly Associated with at least 30% of the AD population. Despite this bifurcation, all AD types have similar pathological phenomena. Genetic analysis provides the best clue for rational logic therapy. All mutations found at present are quantitatively or qualitatively affected. The production of amyloid peptides (called peptides (Αβ), specifically Αβ42), and strongly supports the gossip "amyloid chain reaction hypothesis," (Tanzi and Bertram, 2005, Cell 120, 545). The possible correlation between the production of Αβ peptide and AD pathology emphasizes the need to better understand the manufacturing mechanism of Αβ and strongly guarantee the regulation of Αβ concentration. The release of Αβ peptide is regulated by at least two proteolytic activities, respectively The end of the Αβ peptide (Met-Asp bond) and the c-terminus (residue 37_42) β- and γ-secretase. In the secretory pathway, there is evidence that p_secretase is first cleaved 'to secrete s-APPp (sp ), a 11 kDa membrane-bound slow-end fragment (CTF) is retained. The latter can produce a Αβ peptide after being cleaved by a secretase, and a certain gene in a region encoding a specific protein (presenilin) Some sudden Patients will selectively increase the content of longer isotypes of 2, and these mutations are associated with early-onset familial Alzheimer's disease. Therefore, many researchers believe that Αβ42 is the main cause of Alzheimer's disease. Suspects. It is now known that γ-secretase activity is not attributable to a single specific protein, but is in fact associated with a combination of different proteins. 201245162 Multiple protein complexes contain gamma (γ)-secretase activity containing at least four components : Presenilin (PS) heterodimer, nicastrin, α-1 and pen-2. The ps heterodimerization system consists of an amino group- and a carboxy terminal PS fragment produced by hydrolysis of a precursor protein by endoprotein hydrolysis. The two aspartic acids at the catalytic site are located at the interface of the heterodimer. It has recently been discovered that dysprosium can act as a γ-secretase-substrate receptor. The function of other members of γ-secretase is not known, but is essential for activity (Steiner, 2004. Curr. Alzheimer Research 1(3): 175-181). Therefore, although the molecular mechanism of the second cleavage step has not yet been clarified, the γ-secretase-complex has become the main target for the study of compounds for the treatment of Alzheimer's disease. Various strategies have been proposed for γ-secretase of Alzheimer's disease, ranging from direct targeting of catalytic sites to the development of specific inhibitors and modulators of γ-secretase activity (Marjaux et al., 2004. Drug Discovery Today : Therapeutic Strategies, Volume 1, 1-6). Therefore, the literature has been described in various secreted enzyme-targeted compounds (Larner, 2004.) Secretases as therapeutic targets (increases in AD): Patent Case 2000 - 2004. Expert Opin. Ther. Patents 14, 1403-1420) Indeed, this finding has recently been supported by biochemical studies showing that certain non-steroidal anti-inflammatory drugs (NSAIDs) have an effect on γ-secretase (Weggen et al. (2001) Nature 414, 6860, 212 and WO 01/78721 and US 2002/0128319; Morihara et al. (2002) J. Neurochem. 83, 6 201245162 1009; Eriksen (2003) J. Clin. Invest. 112, 440). Using NSAIDs A possible limitation of the prevention or treatment of AD is its inhibitory activity against cyclooxygenase (COX) enzymes, which may cause undesirable side effects and low CNS permeability (Perett et al., 2005, J. Med. Chem. 48 5705- 5720). More recently NSAID R-flurbiprofen (an enantiomer without Cox-inhibitory activity and related gastric toxicity) failed in a large Phase III trial because the drug could not Let the patient think or do daily activities The ability is significantly improved compared with those who take placebo. WO-2009/103652 is related to ιΗ_ 1,2,4-triazol-3-amine derivatives as a modulator of Αβ; WO-2009/032277 is applicable. a heterocyclic compound which is a modulator of γ-secretase; w〇_2〇1〇/〇1〇188 is a related compound for the treatment of degenerative joint diseases and inflammatory diseases [丨, 2, 4 ] triazolo[1, 5- decidine compound; w〇_2〇1〇/〇98495 is a derivative of the sputum based on the ad medical agent; w〇_2〇〇8/〇9921 〇 related treatment of AD and related diseases The cultivating derivative; and w〇_2〇〇8/1〇〇412 provide compounds suitable for the treatment of diseases associated with β-amyloid peptide deposition in the brain. A novel novel for regulating γ-secretase activity is highly desirable. Compounds, in order to create another new opportunity to treat Alzheimer's disease. One of the objects of the present invention is to overcome at least the disadvantages of the prior art, or to provide alternatives. The compound of the invention or a part of the invention The compound may have a better improvement in the metabolism of the compound than the compound disclosed in the related art. Brain utilization, improve the solubility or to reduce the inhibitory CYP 201245162. It is therefore an object of the present invention to provide such novel compounds. SUMMARY OF THE INVENTION It has now been found that the compounds of the present invention are useful as modulators of broad secretase enzymes. The compounds according to the invention and their pharmaceutically acceptable compositions are suitable for the treatment or prevention of Alzheimer's disease. The present invention relates to novel compounds of formula (1):

R3 R5

丫2 Υ1 Ο) L2 R4b χκ> and its stereoisomers, wherein R and R are each independently selected from the group consisting of: a hydrohalyl group, a Cm alkyl group, a C!·4 alkoxy group, a Or an alkyl group substituted with a plurality of dentate substituents, and an a* alkoxy group substituted with one or more halo substituents; M especially L1 is NR6, 0, a carbonyl group or a covalent bond; wherein R6 is an alkyl group; / R3 represents a CN4 alkyl group; R4a and R4b are each independently selected from the group consisting of hydrogen and Cl-4 alkyl; 'X is N or CH; 8 201245162 L2 is hydrazine, CH2 or a covalent bond; The limitation is that when L2 is 〇, then X is CH; R5 is hydrogen or Cm alkyl; Υ is CH or Ν; Υ2 is CR7 or Ν; wherein R7 represents hydrazine or alkoxy; and it is pharmaceutically acceptable Addition salts, and their solvates. The invention also relates to a process for the preparation of a compound of formula (I) and a pharmaceutical composition therewith. The compounds of the present invention have been found to modulate γ-secretase activity in vivo and in vitro' and are therefore suitable for the treatment or prevention of Alzheimer's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), aging, Dementia, Lewy body dementia, amyloid angiopathy in the brain, multiple infarction, dementia, Down syndrome, dementia associated with Parkinson's disease, and loss associated with beta-amyloid Zhi' is preferably Alzheimer's disease and other diseases associated with β-amyloidosis (eg glaucoma). Based on the pharmacology of the above compound of formula (I), it is therefore suitable for use as a medicament. More specifically, the compound is useful for the treatment or prevention of AD, brain powdery vascular disease, multiple infarction, dementia, boxer dementia or Down syndrome. The invention also relates to a use of a compound according to formula (I), a stereoisomeric form thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof for the manufacture of a medicament for regulating γ-secretase activity . 201245162 = Formula _ _ _ _ secretase activity caused by the use of 2 forms of relative yield reduction is preferred. An advantage of the compound of the invention or a portion of the compound of the invention is that it enhances CNS-permeability. Shame too (four) in the step will be more detailed == same state. Unless otherwise stated herein, such 3f may be consistent with any other neon. The specific ° 壬 may not be a better feature or advantage. Any other 浐 为 较佳 较佳 较佳 I I I I I I I I I I I I I I I I I I I I I I I 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当f 戈 ”, unless otherwise stated or unless the atom or base H, _ finger _ "substituted" is preferably 1 to 3 hydrogen solid or eve: 11 'specifically 1 to 4 hydrogen, replacement, However, its __不^^:= should produce a chemically stable m positive reading from the specified group, and replace it to withstand the reflexive geese, °, that is, the compound should be sufficient to stabilize the medical agent. ^ ° + single _ into the purity type and formulated into a gas, the term "dental" is generally easy to see. " Unless otherwise stated herein or by the content of 10.201245162 as a group or a part of a group, the term "Cm 炫基" means a hydrocarbon group of the formula CnH2n + ,, where n is the range of i to 4 The number inside. ^ * Burning base g 1 to 4 slave atoms, preferably 5 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. The cM hospital base may be a straight chain or a branch and may be substituted as indicated herein. When a subscript is used after relaying a carbon atom, the subscript refers to the number of carbon atoms that the specified group may contain. The Cm alkyl group includes all straight-chain branched groups having 1 and 4 carbon materials, and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-decyl-ethyl, Butyl and its isomers (eg, n-butyl, isobutyl and tert-butyl); The term "Cl_4 alkoxy" as a part or a part of a group means a group of the formula ORb, wherein it is a Ci4 alkyl group. Suitable alkoxy groups, examples of which include methyloxy (also known as decyloxy), ethyloxy (also known as ethoxy), propyloxy, isopropyloxy, oxy, isobutyloxy, Second butyl oxygen and third butyl oxygen. The chemical name of this house is based on chemicai Abstracts

Service (CAS) agrees with the naming principle, using the name of Advanced Chemical Development, inc. (ACD/Labs system (10) this i2 〇〇

Product version 12.01 ; Build 33104, 27 May 2009). In the case of tautomeric forms, it should be understood that other tautomeric forms which are not shown are also included in the scope of the present invention. The following numbers are used to indicate the contact between Rl& R2 and the rest of the molecule: 11 201245162

: When the code number appears more than once in any composition, each definition is an independent stereoisomer. The term "compound of formula (1)", addition salts, solvates and stereoisomers used in this specification. 「 “Stereoisomers The terms “stereoisomer” or “stereochemically isomeric” above or below may be used interchangeably. All of the possible isoforms that may occur in the above-mentioned riding phrase "continuation of the isoform" scale. Unless otherwise stated: the chemical name of a substance refers to all possible stereochemical differences: this:, all stereoisomers of the compound of formula (1), regardless of the compound. The substance, whether as a pure stereoisomer or as two or more substances. A mixture of disc S4, 丄..___ isomers. The enantiomers are non-reciprocal \M: mirrored stereoisomers 12 201245162. A 1: 1 mixture of a pair of enantiomers is a racemate or a racemic mixture. Diastereomers are stereoisomers which are not enantiomers to each other, i.e., they are not mirror images of each other. More specifically, the stereocenter may be in the R- or S_ configuration; the substituent on the bivalent cyclic (partial) saturated group may be in a cis- or trans-configuration. If a compound contains a double bond, its substituent may be E or [configured on the double bond. Stereoisomers of the compounds of formula (1) are all included within the scope of the invention. Thus, if it is chemically feasible, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers. Instead of mixing p, the configuration is based on Cahn-Leng-Plolo (Cahn-lng0ld_, first decided. The configuration on the asymmetric atom is called R or S. It means that the stereoisomer is clearly stereoscopic In the case of a structure, θ, , and only other isomers (groups), that is, J: preferably less than 2%, more preferably less than, more preferably less than 5 〇/0. , 特宕古φ%丄因ΐ 'For example: when the formula σ) the compound specifies two: good things:: two =) different, the object; when, for example, the compound of formula (I) is specified as the formula (I) character two, 'Do not Substantially free of hydrazine isomers; when, for example, a finger isomer. ° m 其 匕 匕 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 实质上 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡 衡Silk, non-pharmaceutically acceptable acid 13 201245162 or a salt of a base can also be used, for example, to prepare or purify a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention. The pharmaceutically acceptable acid and base addition salts as described above or below are meant to include the medically active non-toxic acid and base addition salt forms which the compounds of formula (I) can form. A suitable method for pharmaceutically acceptable acid addition salts is to treat the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as: hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid , pyruvic acid, oxalic acid (also known as oxalic acid), malonic acid, succinic acid (also known as succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, sulfonic acid, ethyl sulfonate Acids, benzenesulfonic acid, p-toluene acid, cyclohexylamine sulfonic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form can be treated with a suitable base for conversion to a free-form test. The compound of formula (I) containing an acidic proton may also be converted to its non-toxic metal or amine addition salt form using suitable organic and non-computerized treatments. Suitable base salts include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as: lys, sodium, potassium, magnesium, calcium salts, and the like, and organic bases such as primary, secondary and tertiary lipids. And aromatic amines such as: mercaptoamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropyl Amine, diisopropylamine, di-n-butylamine, dipyridamole. Salts formed by Ding, slightly biting, morphine, tridecylamine, triethylamine, dipropylamine, quinuclidine, bite, sputum and isoindole 201245162 Forming H with amino acid Amine salts, and acids, and the like. Conversely, the salt type can be 'such as: arginine, off-body type. Treatment with hydrazine, conversion to free acid The term solvate includes the compounding of formula (1), and its salts. These types of hydrates and solvents alkoxides, and the like. A typical example is a hydrate, a racemic mixture of the formulas prepared as described below, and the AD can be synthesized by enantiomeric separation. The liquid chromatography method for separating the compound of the formula (1) from the known method for the solid phase is to use the corresponding stereochemistry from the appropriate starting material; the isomer may also be derived in a stereospecific manner. However, when the restriction condition is the structure, the compound should adopt stereo;; = the stereoisomerization method should adopt the pure enantiomeric starting material into the synthesis method. These methods are exemplified by the present invention, and the compound according to the present invention itself includes a combination of = two weights. In this application (4), two = and: according to the compound of formula (1), the chemical element includes this element = all of the same and isotope mixture. For example, when referring to nitrogen, salty understanding means 1Η, 2Η, 3Η and its mixture. - the compound according to the invention itself, ie comprising a compound having one or more ditopes and mixtures thereof, comprises a radioactive compound, also known as a labeled radioactive compound, wherein one or more non-radioactive atoms have been coated with it - The reduction active material is replaced. The term "label 15 201245162 radioactive compound" means any compound according to formula (I) or a pharmaceutically acceptable salt thereof, which comprises at least one radioactive atom. For example, the compound may label a positron or a radioactive isotope that emits gamma rays. In the technique of radioactive ligand binding, substitution to an atom or (2)^ atom can be selected. For development, the most commonly used radioactive isotopes (PET) are UC, 18F, 15A and 13N, all produced by an accelerator with a half-life of 20, 1 , 2 and 10 minutes. Since these radioactive isotopes have a short half-life, they can only be used in the research institutes where the accelerator itself can be produced by itself, thus limiting its use. The most commonly used are ίδρ Tcj T1 and 231. The method of operation of such radioactive isotope, its ', detachment method and method of incorporating into the molecule are related to this related art.

Pi Jin -daL Specifically, the radioactive atom may be selected from the group consisting of gas, carbon: white, and a group of elements. In particular, the radiation is rumored, and. 1 1. 玢, ,, and the application patents in this manual and the appendix "", "-" and "the" are also included: the early type - a compound. . The term "substance" refers to a compound or the above-mentioned terminology. The above terms are used in conjunction with other terms to describe the compound of the present invention. 201245162 In a specific embodiment, the invention relates to a novel compound of formula (i):

And stereoisomers thereof, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halo, Cm alkyl, Cm alkoxy, Cm alkane substituted with one or more halo substituents a Cm alkoxy group substituted with one or more halo substituents; L1 is NR6, fluorene, carbonyl or a covalent bond; wherein R6 is hydrogen or Cm hexyl; R3 represents Cm alkyl; R4a and R4b They are each independently selected from the group consisting of hydrogen and C!_4 alkyl, X is N or CH; L2 is 0, CH2 or a covalent bond; however, the constraint is that when L2 is 0, then X is CH; R5 is hydrogen or Cm alkyl; Y1 is CH or N; Y2 is CR7 or N; wherein R7 represents alkoxy; 17 201245162 and its pharmaceutically acceptable addition salts, and their solvates. In a specific embodiment, the invention relates to novel compounds of formula (I) and stereoisomers thereof, wherein R1 and R2 are each independently selected from the group consisting of: gas, dentate, fen, C !. 4 alkoxy, via one or more halo substituents, cM, and c-substituents substituted with one or more substituents; M gas L is NR6, Q, a carbonyl group or a covalent bond; wherein R6 is a hydroalkyl group; < Ci-4 r3 represents a Ci_4 hospital group; R4a#R4b is the same and each represents hydrogen or a C-4 alkyl group; x is N or CH; L2 is Ο, CH2 Or a covalent bond; however, the restriction is that when L2, X is CH; the horse 〇r5 is hydrogen or CV4 alkyl; γ1 is CH or N; Υ2 is CR7 or Ν; wherein R7 represents Η or Cm alkoxy And its pharmaceutically acceptable addition salts, and their solvates. In a specific embodiment, the present invention relates to a novel formula (E) and a stereoisomeric form thereof, wherein R is selected from the group consisting of: halo, cM, and CM alkoxy a q 4 alkyl group substituted with one or more halo substituents: a Cm alkoxy group substituted with one or more il group substituents; and 201245162 R2 is a group selected from the group consisting of hydrogen, a halogen group, a CV4 alkyl group, a Cm alkoxy group, a Cm alkyl group substituted with one or more halogen substituents, and a CN4 alkoxy group substituted with one or more substituents; L1 is NR6, hydrazine, a few Or a covalent bond; wherein R6 is hydrogen or Cm alkyl; R3 represents C1.4 alkyl; R4a is the same as R4b and both represent hydrogen or (^.4 alkyl; X is N or CH; L2 is Ο, CH2 Or a covalent bond; but the restriction is that when L2 is Ο, then X is CH; R5 is hydrogen or (^_4 alkyl; Y1 is CH or N; Y2 is CR7 or N; wherein R7 represents hydrazine or Cm alkane Oxyl; and pharmaceutically acceptable addition salts thereof, and solvates thereof. In one embodiment, the invention relates to novel compounds of formula (I) and stereoisomers thereof, wherein R1 and R2 are respectively Independently selected from the following In the group consisting of: a halogen group, a (^_4 alkyl group, a Cm alkoxy group, a C-alkyl group substituted with one or more ii group substituents, and a Cm alkane substituted with one or more substituent substituents氧基; L1 is NR6, hydrazine, carbonyl or a covalent bond; wherein R6 is hydrogen or Cm alkyl; R3 represents Cm alkyl; ^^ is the same as rule 415 and both represent hydrogen or (^_4 alkyl; X is N Or CH; 19 201245162 L2 is 〇, CH2 or a covalent bond; however, the restriction is that when L2 is 〇, then X is CH; r5 is hydrogen or Cm alkyl; Y is CH or N; Y2 is CR7 or N Wherein R7 represents H or a C 4 alkoxy group; and a pharmaceutically acceptable addition salt thereof, and a solvate thereof. In a specific embodiment, the present invention relates to a novel compound of the formula (1) and its stereoisomerism. And wherein R and R are each independently selected from the group consisting of hydrogen, halo, alkyl, ci 4 alkyl substituted with one or more halo substituents, and one or more _ groups a substituent substituted by a cN4 alkoxy group; L is NH or a covalent bond; R3 represents a CM alkyl group; R4a#R4b is the same and both represent nitrogen or

Cl-4 alkyl; x is N or CH; L2 is 〇, CH2 or a covalent bond; however, the restriction is that when L2 is 〇, then X is CH; r5 is hydrogen or CK4 alkyl; Y1 is CH or N; Y2 is cf or N; wherein R7 represents a ci4 alkoxy group; and a salt-acceptable addition salt thereof, and a solvent thereof. In a specific embodiment, the present invention is a compound of the formula (1) and a stereoisomer thereof, wherein 20 201245162 R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, sulfhydryl, a methyl group substituted with one or more halo substituents, and a methoxy group substituted with one or more halo substituents; L1 is NH or a covalent bond; R3 represents a fluorenyl group; R4a is the same as R4b and both represent Hydrogen or fluorenyl; X is N or CH; L2 is 0, CH2 or a covalent bond; however, the restriction is that when L2 is 〇, then X is CH; R5 is hydrogen or fluorenyl; Y1 is CH or N; Y2 is CR7 or N; wherein R7 represents a decyloxy group; and a pharmaceutically acceptable addition salt thereof, and a solvate thereof. In a specific embodiment, the present invention relates to novel compounds of formula (1) and stereoisomers thereof, wherein

R1 and R2 are each independently selected from the group consisting of: gas, gas, mercapto, trifluoromethyl' and trifluoromethoxy; L1 is NH or a covalent bond; R3 represents a methyl group; Han 415 is the same and both represent hydrogen or sulfhydryl; x is N or CH; L2 is Ο, CH 2 or a covalent bond; however, the limitation is when. For the time being, X is CH; R5 is gas or sulfhydryl; 21 201245162 Y is CH or N; Y2 is CR7 or N; wherein R7 represents methoxy; and its pharmaceutically acceptable addition salts are soluble Compound. In a specific embodiment, the substance and its stereoisomeric form, wherein the present invention relates to the novel formula (1) compounded trifluoromethylmethyl group, and R is selected from the group consisting of fluorine, methyl group, group and Trifluoromethyloxy; ^ R is selected from the group consisting of hydrogen, fluorine, and trifluoromethyl; L is NH or a covalent bond; r3 represents a methyl group; R is the same as R4b and represents Hydrogen or methyl; x is N or CH; + L is 〇, CH2 or a covalent bond; but the constraint is that when L2, then X is CH; R is hydrogen or sulfhydryl; Y is CH or N; γ2 Is CR7 or N; wherein R7 represents a decyloxy group; and a pharmaceutically acceptable addition salt thereof, and a solvate thereof. A particular embodiment of the invention pertains to any subgroup of the compound of formula (I) and its stereoisomeric form, or any other embodiment, wherein R1 is at the 2-position and R2 is at the 5-position. A particular embodiment of the invention pertains to the compound of formula (I) and its stereoisomers' or any other specific embodiment and any of its groups 22, 201245162, wherein R1 represents fluorine and is at the 5-position. And at the 2-position, and R2 represents a trifluorofluorene. A specific embodiment of the invention relates to a fish stereoisomer of the compound of the formula (I), or any other embodiment of the invention, Where R is at the 2-position and R2 is at the 4_ position. A specific embodiment of the invention relates to a compound of the formula (I) and to the stereoisomer 1' or any other specific embodiment thereof; wherein R1 represents a thiol group and is at the 2 position, R2 represents hydrogen or gas and a particular embodiment of the invention relates to a compound of formula (I) and its stereoisomeric form or any other specific embodiment thereof, wherein R1 is at the 2_ position and Is selected from the group consisting of: _ group, CM alkyl group, Cm alkoxy group, C1-4 alkyl group substituted by one or more halogen substituents, and substituted with one or more halogen groups a substituted Ci 4 alkoxy group and wherein R 2 is selected from the group consisting of hydrogen, halo, Ci. 4 alkyl, cM methoxy, substituted by one or more halo substituents a C-4 alkyl group and a Cm alkoxy group substituted with one or more halo substituents. A particular embodiment of the invention relates to a compound of the formula (I) and its stereoisomeric form, or any other embodiment thereof, and any subgroup thereof, wherein R1 is at the 2-position and wherein R2 is at any other position And R and R are each independently selected from the group consisting of: a halogenated Ci_4 alkyl group, a Cm alkoxy group, a Cm alkyl group substituted by one or more halogen substituents, and one or more The halo substituent is substituted for the heart 4 alkoxy group. 23 201245162 A specific embodiment of the invention relates to a compound of formula (i) and its stereoisomeric form or any other specific embodiment thereof, and any subgroup thereof, wherein R1 is at the 2-position and is selected from the following In the group of each substance: fluorine, methyl or trifluoromethyl. A particular embodiment of the invention relates to a compound of formula (1) and its stereoisomeric form, or any subgroup of any of the other embodiments and wherein at least one of R1 and R2 is not hydrogen. A particular embodiment of the invention pertains to the compounds of formula (I) and its stereoisomeric forms, or any other subgroup thereof, wherein R1 is at the 2' position. Further embodiments of the invention are related to one or more of the following constraints relating to the compound of the formula (I) and its stereoisomers' or any other specific complement thereof and any subgroup 1' thereof: (a) R represents a fluorenyl group and is at the 2_ position, and ft 2 represents hydrogen or fluorine and 4_(b) L1 is NH; (4) R3 represents a fluorenyl group; (4) R a is the same as R 4b and both represent a methyl group; And L2 is CH2 or a covalent bond; specifically (f) (g) (h) R5 is hydrogen; wherein R7 represents a decyloxy group. Y1 is CH; γ2 is CR7; 24 201245162 A specific embodiment of the invention relates to a compound of formula (i) and its stereoisomeric form, or any other specific embodiment thereof, and any subgroup thereof, wherein L1 is NR6 or covalent bond; specifically NR6; more specifically NH. A particular embodiment of the invention pertains to a compound of the formula (1) and its stereoisomeric form, or any other subgroup thereof, wherein R4a and R4b are the same and each represents a thiol group. A particular embodiment of the invention relates to a compound of formula (I) and its stereoisomers' or any other subgroup thereof having H compliant, wherein X is Ν' and L2 is ch2 or a covalent bond; In particular, N and L2 are covalent bonds. The stereoscopic embodiment relates to a compound of the formula (ι) and a group thereof, wherein X is a Pina group of any of its sub-systems received by other specific embodiments, wherein l2 is a covalent bond 1, any of which is described An I# silver macro-stereoisomeric form of the present invention, or any compound of the formula (1) and a group thereof, wherein L2 is 〇戋", and any of its specific examples, Then X is Cii; special, but the restriction condition is that when L2 is 0, the invention-specifically < L2 is CH2. The stereoisomeric type, or any of its examples, is related to the compound of the formula (1) and its specific implementation. And any of its sub-groups 25 201245162 group 'where Y1 is CH; and γ2 is CR7; wherein R7 represents a decyloxy group. A specific embodiment of the invention relates to a compound of the formula (I) and its stereoisomer ' or any of its other embodiments and any subgroup thereof' wherein at least one of γ1 and Y2 represents N. A particular embodiment of the invention relates to a compound of formula (I) and its stereoisomers' or any And any subgroup thereof according to other embodiments, wherein R7 represents a decyloxy group In a specific embodiment, the compound of formula (I) is selected from the group consisting of: 1·[5-(4-fluorophenyl) benzhydryl-1Η-1,2,4-triazole: Base]_4_(4 basic group)-pie σ well, Ν-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl_3-[4-[(2_methylπ ratio Ottomyl)oxy]-1-bunk bite base]_111-1,2,4-tris-7-amine, Ν-[2-fluoro-5-(-fluoromethyl)phenyl]-3-[4 -(4-methoxyphenyl)-3,3-dimethyl-1-piperinyl]-1-mercapto-1Η-1,2,4-triazole-5-amine, ' Ν·[ 2-fluoro-5-(trifluoromethyl)phenyl]-1-indenyl_3-[4_(4_.pyridylhydrazino)-1-pipedyl]-1H-1,2,4- Triazol-5-amine, N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-indenyl_3-[4-[(2_indolyl-4 〇pyridinyl) A -1_piperidinyl]-1H-1,2,4-triazole-5-amine, N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl_3 -['[(2_曱基^比其基基曱)]-1_派基基]-1Η-1,2,4-triazol-5·amine.HC1 .H2〇, N-[2- Gas _5_(trifluoromethyl)phenyl] sulfhydryl hydrazine (4) pyridin. base X 0 bottom 0 well base] -1H-1,2,4-tris-s--5-amine, 26 201245162 N-[2 -Fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4-decyloxyphenyl)_ι_π bottom well]-1_曱基_1Η-1,2 ,4-tris-5-amine, Ν-[2-gas-5-(trifluoromethyl)phenyl]-1-indenyl_3-[4-[(6-fluorenyl-4-» dense Oxygen]-1- ketone base]-1H-1,2,4-tris-π-s--5-amine, Ν-[2·fluoro-5-(trimethylsulfonyl)phenyl]-1-曱基_3-[4-(4-. 〇 基 基 ) ] ] ] ] ] ] -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 (4-methoxyphenyl)-3,3-dimercapto- 1-input σ well base]-1-methyl-1Η-1,2,4-tris-5-amine, Ν·( 4_fluoro·2_mercaptophenyl)_3_[4_(4-methoxyphenyl)3,3·diindolyl-1-pipelinyl]-1-mercapto-1Η-1,2,4 -Triazole-5-amine.1.2 HC1 .1.5 Η2〇, Ν-[3-fluoro-5-(trifluoromethyl)phenyl]·3-[4-(4-decyloxyphenyl)·3 , 3-dimercapto-1-0 bottom 13 well group]-1-methyl-1Η-1,2,4-tris-5-amine, fluorene-[3-fluoro-5-(trifluoromethyl) Phenyl]_3-[4-(4_nonyloxyphenyl)_3,3_didecyl-1-branches well base] small sulfhydryl _ih-1,2,4-tris--5 Amine.0.8 HC1, 3-[4-(4-decyloxyphenyl)-3,3-dimethyl-l-α bottom cultivating base] fluorenyl _N_(2-mercaptophenyl)-1Η_1 , 2,4-triazole-5-amine, 3-[4-(4-decyloxyphenyl)-3,3-dimethyl-1-propanyl] sulfhydryl _N_ [3-( Trifluoromethoxy)phenyl]-1H-1,2,4-triazole-5-amine, 3-[4-(4-decyloxyphenyl)-3,3-didecyl-1-旅耕基]小曱基_Ν·[3-(Trifluorodecyloxy)phenyl]-1Η-1,2,4-triazole-5-amine.HC1, Ν-[3-fluoro-2- (trifluoromethyl)phenyl]_3_[4-(4-decyloxyphenyl) )_3,3-dimercapto-1-L.0 well base]-1-mercapto-111-1,2,4-tris-quinone-5-amine, 3-[4-(4-decyloxybenzene) ))-3,3-dimercapto-l-π bottom cultivating base] bis(indolyl)-[2-(trifluoromethyl)phenyl]-1Η-1,2,4-triazole-5- Amine, and 27 201245162 3_[4-(5-Methoxy-2_acridinyl)-1-pipedyl]-bu-methyl-N-(2-methylphenyl)-1Η-1,2,4 a triazole 5-amine, a stereoisomeric form thereof, and a pharmaceutically acceptable addition salt thereof, and a solvate thereof. In a specific embodiment, the compound of formula (I) is selected from the group consisting of: 3-[4-(4.methoxyphenyl)-3,3-didecyl-1-pipeplin Base]_ι_曱基_ 曱基笨基)-1Η-1,2,4-triazole-5-amine, N-(4-fluoro-2-methylphenyl)·3-[4-(4 -Methoxyphenyl)_3,3-dimethylpiperidinyl]methyl-1H-1,2,4-triazole-5 amine, and methylphenyl)μ4#methoxyphenyl) 3,3 dimethyl isomeric form thereof, and its pharmaceutically acceptable addition _, and its solvate. In a specific embodiment, the compound of formula (I) is a 3-[4 dimethyl m-propenyl] small methyl group, a 2 methyl phenyl group, a decylamine or an N-(4|2• fluorenyl group) ) 3 _ hci.i.5H2 〇. - Alloamine. All possible combinations of the above-described specific embodiments are within the scope of the invention. 3 is now included in the preparation of compounds 28 201245162 The invention also encompasses a process for the preparation of compounds of formula (i) and subgroups thereof. In the illustrated reaction, it may be necessary to protect the reactive functional groups, such as hydroxyl, amine or carboxyl groups, where the final product requires such groups to avoid unnecessarily participating in the reaction. Commonly used protecting groups can be used according to standard operating methods, for example: see T. W Greene and p G M Wuts "Organic Chemistry Protection Base (pr〇tective GroUpS in 〇rganic

Chemistry) 1', John Wiley and Sons, 1999. The compound of formula (1) and its subgroups can be prepared in the sequential steps described below. The pass 4 is prepared from a starting material which can be prepared by standard methods known to those skilled in the art or by those skilled in the art. The compounds of the present invention can also be prepared by standard synthetic methods commonly used by those skilled in the art of organic chemistry. The general method for some typical examples is as follows: Experimental Process 1

(H-a1)

(la) Reaction Scheme 1 A compound of formula (1) wherein NR6 and R6 are hydrogen (referred to as (I a)) can be prepared by a coupling reaction between an intermediate of the formula (ΙΙ-al) and an appropriate aryl group of the formula (111). . In the reaction diagram 1, halo (halo) is defined as ci, Br or I, 29 201245162 All generations of soul are as defined above. This reaction can be carried out in the presence of a suitable test, for example, for example, Cs2C〇3 or sodium third butoxide. The reaction can be carried out in a reaction-inert solvent, for example, indene, #,#_dimercaptomethylamine (DMF), 1,2-dimethoxyethane (DME), third Alcohol or dioxane. The reaction typically involves the inclusion of a suitable catalyst (eg, saponin (PdJdbah, pd(OAc)2)) and a ligand (eg, (9,9-dimethyl) -9H-xanthene-4,5-diyl)bis[diphenylphosphine KXantphos), [1,1,-binaphthyl]_2,2,_diylbis[diphenylphosphine KBINAP), double ( 2-diphenylphosphinophenyl)-DpEph〇s), or dicyclohexyl[2',4,6,-paranium(1-methylethyl)[ι,Γ-biphenyl]-2-yl In the presence of a catalyst system of _phosphine (χ _ phos). This reaction is preferably carried out under an inert gas pressure such as nitrogen or argon pressure. Microwave-assisted heating can be used to enhance reaction rate and yield. The trace amount of palladium remaining after the operation reaction may be treated with a ruthenium-L-cysteine- or thiol-functionalized vermiculite to treat a suitable/paste or mixture of the compound containing the formula (1) (for example, DCM and The solution was removed after MeOH). Alternatively, the compound of the formula (I-a) can be prepared by a copper-catalyzed reaction of a formula (ΙΙ-al) intermediate with a suitable hydrazine halide of the formula (I-a) wherein all the codes are as defined above. The reaction can be carried out under protective gas pressure (for example, under N2 pressure). Stirring, warming (eg, 7 〇 _ 200 ° C) and/or pressurization may promote the reaction rate. The reaction is typically carried out in an organic solvent, for example, disulfoxide (DMS®) or dimercaptocaramine (DMF). The reaction may optionally be carried out in the presence of a base (for example, 30 201245162 D, for example: K2C〇3, CssCO3 or triethylamine (Et3)S〇) and/or in the presence of a ligand (eg dimethyl) Ethylenediamine or 1,10-morpholine is introduced into the group. The typical copper catalyst which can be used according to the amount of the catalyst or stoichiometric is copper salt cheek, for example, cuprous oxide (1), cuprous iodide. (1) or bromide steel (I). Experimental process 2

D-b2) Reaction Scheme 2 Compounds of formula (1) in which L1 is a covalent bond (referred to as (I-bl)) may be represented by the formula (IV-^ intermediates (wherein Han represents a substituent of the substituent) and the appropriate formula ( V) Derivative = The condensation reaction is carried out according to the inverse 2, which can be carried out in the reaction inert/mixing agent, for example, for example, a stupid, cis-dimethyl __F), 1 > 2_ Dimethoxy B-me), third butanol or akisaki

: Two and heating (for example: 7〇_12〇〇c) may promote the reaction rate. R combination: two groups such as thiol and ethyl. In this reaction, a positional isomer of the formula (I-b2) is usually also formed. 31 201245162 Experimental procedure 3 The intermediate of formula (Il-a 1) can be obtained by condensation reaction of the intermediate of formula (Vl-a) with an appropriate formula (v) anthracene derivative according to reaction scheme 3. The reaction can be carried out in a reaction-inert solvent, for example, toluene, dimethyl decylamine (DMF), 1,2-dimethoxyethane (DME), tert-butanol, iso Propylene or two π and so on. Stir and warm (for example: 7〇_12〇. The reaction rate is promoted. The positional isomer of formula (n_a2) is usually formed in this reaction.

Reaction Scheme 3 Experimental Process 4 The intermediate of formula (VI-a) can be obtained from the intermediate of formula (VII) and the appropriate formula (v imidate derivative (for example, r, for example: cyanimido phthalic acid diphenyl) The base vinegar is obtained by carrying out a nucleophilic substitution reaction according to the reaction scheme 4. The reaction can be carried out in a reaction inert solvent, for example, for example, B., propanol or dioxane. The reaction can be carried out as needed. The test (for example, Example 32 is carried out in the presence of K2C03, 7ν, ΛΑ-diisopropylethylamine (DIPEA) or Et3N).

201245162 Experimental procedure 5 Intermediates of formula (IV-b) wherein R represents an alkyl substituent can be obtained by alkylation of an intermediate of formula (IX-b) with an appropriate alkyl group of formula (X) according to reaction scheme 5 . The reaction can be carried out in the presence of a suitable test, for example, K2C03 or sodium hydride. The reaction can be carried out in a reaction-inert solvent such as, for example, dimercaptomethylamine (DMF), acetonitrile, ethanol or acetone. In the reaction scheme 5, halo is defined as Cl, Br or I.

(IX-b) (丨 V-b) Reaction Diagram 5 33 201245162 Experimental Process 6 The intermediate of formula (IX-b) can be prepared according to the reaction shown in Figure 6:

(IX-b) Reaction Scheme 6 Condensation of a compound of the formula (XI) with thiourea or 1,1'-thiocarbonyldiimidazole in a reaction inert solvent (for example, acetone) to give a formula (ΧΙΙΙ-b) ) Intermediates. Subsequently, the intermediate of formula (XIII-b) is replaced with an intermediate of formula (VII). The reaction is typically carried out in a reaction-inert solvent, for example, acetone, to produce an intermediate of formula (IX-b). In the reaction scheme 6, halo2 is defined as C1 or Br, and all other substituents are as defined above. 0 34 201245162 Experimental Process 7

Reaction Scheme 7 A compound of the formula (I) which is CO (referred to as (Ι-c)) can be obtained by oxidation of an intermediate of the formula (XIV-c). The reaction can be carried out in the presence of an oxidizing agent such as, for example, chlorodecanoic acid than biting the wrong salt or Dess-Martin reagent. The reaction can be carried out in a reaction-inert solvent, for example, dioxane, acetonitrile or tetrahydrofuran. In the reaction scheme 7, all the substituents are as defined above. Experimental process 8

Reaction Scheme 8 35 201245162 The intermediate of the formula (XIV-c) can be obtained by metallizing the intermediate of the formula (II-cl) with an appropriate formula (XV) acid according to the reaction scheme of FIG. The metallation reaction is preferably carried out in a suitable reaction solvent (for example, tetrahydrofurfuran) at _80oC to 0 ° C with a suitable base (eg, n-butyl chain) and a suitable electrophile (eg: The (XV) aldehyde) treats the intermediate of formula (Hd) for a period of time sufficient to complete the reaction. In Figure 8, halo 2 is defined as Br or I, and all other substituents are as defined above.

(XVI-c)

(H-c2) Reaction Scheme 9 The intermediate of the formula (II-cl) can be obtained by alkylating an intermediate of the formula (XVI-c) with an appropriate alkyl halide of the formula (XVII) according to the reaction scheme of Figure 9. This reaction can be carried out in the presence of a suitable base such as, for example, KfO3 or sodium hydride. The reaction can be carried out in a reaction inert solvent at the number of 2012 201245162, for example, dimethyl decylamine (DMF) or tetrahydrofuran. In the reaction diagram 9, halo is defined as Cl, Br or I. During the reaction, the positional isomer of formula (II-c2) is usually also formed. Experimental process 10 halo

(XVIII) • halo2

Reaction diagram ίο

The intermediate of formula (XVI-c) can be prepared by nucleophilic substitution reaction of an intermediate of formula (XVIII) with an intermediate of formula (VII). This reaction can be carried out in the presence of a suitable base, for example, K2C03 or DIPEA. The reaction can be carried out in a reaction-inert solvent, for example, n-butanol or acetonitrile. In the reaction scheme 10, halo2 is defined as C1 or Br, and all other substituents are as defined above. 37 201245162 Experimental Process 11

Reaction Scheme 11 A compound of the formula (I) wherein 1 is Ο (referred to as (fd)) can be obtained by a nucleophilic substitution reaction of an intermediate of the formula (n-cl) with an intermediate of the formula (XIX). The reaction can be carried out in the presence of a suitable base, for example, K2C〇3 or DIPEA. The reaction can be carried out in a reaction-inert solvent, for example, dioxane or acetonitrile. In Reaction Scheme 11, halo2 is defined as C1 or Br' and all other substituents are as defined above. Compounds of formula (III), (V), (VII), (VIII), (X), (XI), (XII), (XV), (XVII), (XVIII) and (XIX) may be obtained from commercial products or It can be prepared by those skilled in the art. The HC1 salt forms of the compounds can be prepared by several techniques known to those skilled in the art. In a typical process, for example, the free base is dissolved in DIPE or EbO, followed by dropwise addition of 6N HCl in 2-propanol or 1N HCl in EtzO. After the mixture is typically stirred for 1 minute, the product can be filtered off. The HC1 salt is typically dried under vacuum. 38 201245162 If necessary or necessary, proceed to the next step in any order: he may use compounds of formula (1), any subgroups thereof, addition salts, solvates and stereochemically isomeric methods known in the art. The form is converted to its compound according to the invention. Those skilled in the art know that the functional groups of the compounds in the above process may require the use of a protecting group to terminate the middle gate: when the functional group of the compound has been blocked with a protecting group, it can be removed after the reverse reaction. base. Shao Zhi Pharmacology It has been found that the compounds of the present invention can modulate γ-secretase activity. The compound of the invention and its pharmaceutically acceptable composition are therefore suitable for the treatment of 'ad, sputum, dementia, body, aging, dementia, dementia associated with Lewy bodies, powdery protein mites in the brain. Infarct dementia, Down's heterosis, and Parkinson's disease = loss; 2 β-amyloid-related dementia, preferably AD. g"" Therefore, the compound according to the present invention and its medicinal substance can be used for the treatment or prevention of a disease selected from the group consisting of: AD, ΤΒΙ, Μα, aging, dementia, or dementia, brain Department, 扒 扒 疋 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Loss of g and the term "regulating γ-secretase activity-secretase-complex affects the effect of sputum. The preferred effect is ^2^39 201245162 APP's overall rate of action is as if the compound was not used, but the change The relative amount of the action product is more preferably to reduce the Αβ42-peptide yield. For example, it is possible to produce different Αβ species (for example, Αβ-38 or other Αβ peptide species which are not shorter amino acid sequences of Αβ_42) or altered products. Relative yield (eg, changing (preferably increasing) the ratio of Αβ-40 to Αβ-42. It has been known that γ-secretase complexes also involve the processing of N〇tch_protein. Notch is a signal-transferring protein. development process Play a key role (see, for example, Schweisguth F (2〇〇4) Curr. Biol. 14, R129). A particular advantage of the therapeutic use of γ-secretase modulators seems to be that it does not interfere with 丫-secretase activity in the treatment of Notch. Activity to avoid potentially unwanted side effects. Although secretase inhibitors have side effects due to simultaneous inhibition of Notch, γ-secretase modulators may selectively reduce this highly prone to aggregating and neurotoxic type 6 That is, the advantage of Αβ42. Therefore, the preferred compound should not affect the Notch-acting activity of the γ-secretase complex. The “treatment” used herein includes all processes, which may be slowing, disturbing, stopping or blocking. He developed, but not - completely eliminates all symptoms. The monthly system is related to the compound of formula (1), its stereoisomers can be attached to the acid or test addition salts and solvates, 苴It is used as a medicine. 本 ” The present invention also relates to a compound according to formula (1), its stereoisomerism and its pharmaceutically acceptable acid or test addition salt and solvate for regulating γ-secretion 40 201245162 The invention also relates to a compound according to formula (i), a stereoisomeric form thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof, for use in the treatment or prevention selected from the group consisting of Disease or condition: AD, TBI, boxer dementia, MCI, aging, dementia, dementia associated with Lewy body, amyloid angiopathy in the brain, multiple infarction, dementia, Down syndrome, and Parkinson's Dementia associated with dementia and dementia associated with beta-amyloid. In one embodiment, the disease or condition is preferably AD. The invention also relates to a compound according to formula (I) The configuration is in combination with its pharmaceutically acceptable acid or base addition salts and solvates for the treatment of such diseases. The invention also relates to a compound according to formula (1), a stereoisomeric form thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof, for use in the treatment or prevention of such diseases. The invention also relates to a compound according to formula (I), a stereoisomeric form thereof and a pharmaceutically acceptable acid or base addition salt and a solvate thereof, which are used for the treatment or prevention, in particular for the treatment of γ-secretion A disease or condition mediated by an enzyme secretase. The invention also relates to the use of a compound according to formula (1), a stereoisomer thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof for the manufacture of a medicament. The invention also relates to the use of a compound according to formula (1), a stereoisomer thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof for the manufacture of a medicament for the modulation of gamma-secretase activity. 201245162 The present invention also relates to a medicament for the treatment or prophylaxis of any of the above conditions, according to a compound of the formula (1), a stereoisomeric form thereof and a pharmaceutically acceptable acid or an addition salt and a solvate thereof use. The invention also relates to the use of a compound according to formula (1), a stereoisomer thereof, and a pharmaceutically acceptable acid or base addition salt and solvate thereof for the manufacture of a medicament for the treatment of a condition as described above. In the present invention, according to the analysis method (for example, the analysis method used in the following examples), the compound (1) or any subgroup thereof is particularly effective in inhibiting the Αβ42-like production 1 (^5〇 value should be less than 1〇〇〇) nM, preferably less than 1 〇〇 nM 'more preferably less than 5 〇 nM, even more preferably less than 2 〇 nM. The compounds of the invention may be administered to mammals, preferably humans, for treatment or prevention. Any of the above diseases. A method for treating a warm-blooded animal (including a human) suffering from any of the above diseases or a method for preventing a warm-blooded animal (including a human) from suffering from any of the above diseases, based on the use of the compound of the formula (I). Administration (i.e., systemic or topical administration, preferably oral administration) to a warm-blooded animal (including human), an effective amount of a compound of the formula (1), a stereoisomer thereof, and a pharmaceutically acceptable addition salt thereof The present invention also relates to a use of a compound of formula (1) for modulating γ-secretase activity, resulting in a decrease in the relative yield of Αβ42-peptide. The compound of the present invention or a portion of the compound has the advantage that it enhances penetration of the CNS. " Those who are interested in treating these diseases can determine the effective medical daily dose from the test results presented below. The effective medical daily dose 42 201245162 will be about 0.005 mg/kg to 50 mg/kg body weight, in particular 〇〇1 mg/kg to 50 mg/kg body weight, more specifically 〇〇1 mg/kg to mg/kg body weight' is preferably from about 1 mg/kg to about 15 mg/kg body weight, more preferably It is from about 0. 01 mg/kg to about 10 mg/kg body weight, even more preferably from about 1 mg/kg to about i mg/kg body weight, most preferably from about 5 mg/kg to about 1 mg. /kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve medical efficacy will of course vary with each case, for example, the particular compound, the route of administration, the age and condition of the recipient, and the particular A treatment method also includes administering an active ingredient according to a course of administration 1 to 4 times a day. Among these treatment methods, the compound according to the present invention is preferably first formulated and then administered. As described below, conventionally used And easy to obtain ingredients to prepare suitable pharmaceutical formulations. Suitable for treatment or The compounds of the invention against Alzheimer's disease or a symptom thereof may be administered alone or in combination with one or more other medical agents. The combination therapy comprises administering a single pharmaceutical dose comprising a compound of formula (I) and one or more other medical agents. Formulations, and administration of a compound of formula (1) and various other medical agents in separate pharmaceutical dosage formulations, for example, a compound of formula (I) and a medical agent may be combined to form a single oral dosage composition such as an expectorant or capsule, or Each agent is administered separately as an oral dosage formulation. Although the active ingredient may be administered alone, it is preferably administered in a pharmaceutical composition. 43 201245162 骆J This 'the present invention provides a pharmaceutical composition, i contains = the material and the active ingredient as a medical ingredient. The carrier or diluent must be "acceptable" for use with the composition. The other ingredients are compatible and harmless to the recipient. ^ Convenient administration of the drug The compound can be formulated into various medical forms for administration. According to the compound of the present invention, in particular, the pharmaceutically acceptable acid or test addition salt, the stereochemically isomeric form thereof or any subgroup or combination thereof may be formulated for pharmaceutical use according to formula (1) & A variety of different medical types. A suitable composition can be any composition commonly used for systemic administration of a drug. In order to prepare the pharmaceutical composition of the present invention, a specific mixture of an effective amount of the specific compound (as needed 1 addition salt type) as an active ingredient and a pharmaceutically acceptable carrier can be formed, and the carrier can be formed into various types according to the preparation required for administration. . These pharmaceutical compositions are preferably in the form of a suitable unit, in particular, for oral, rectal, transdermal, parenteral injection or inhalation. For example, when preparing an oral dosage form composition, any conventional pharmaceutical medium can be used, for example, water, glycerin, oil, alcohol, etc., for oral liquid preparations, such as: suspension, syrup, achi Agents, emulsions and solutions; or solid carriers such as powders, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, and the like, for powders, pills, capsules and lozenges. Because tablets and capsules are convenient for administration, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are of course used. For parenteral administration, the carrier often contains two parts of sterile 44 201245162 ί, but other additives such as: can improve the solubility of 6 °, for example, can prepare an injection solution, wherein the _ includes a physiological saline solution a mixture of liquid or physiological food and (iv) sugar solution. For example, H recording liquid, wherein the _ includes a physiological saline solution, (4) a sugar solution or a mixture of physiological money water and a "5-glycol solution. The injection comprising the compound of the formula (I) can be formulated in an oil to extend the utility of the oil suitable for this purpose, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerin of long-chain fatty acid and Mixture with other oils. Injection (iv) floats can also be prepared, in which appropriate liquid carriers, suspending agents, and the like can be used. It also includes a solid (4) H-formed composition that is suitable for transdermal administration before use. It is required to contain a material plus _ and/or a suitable moisturizing agent, and it may be a suitable additive of any nature. By electroporation, the additive has a serious child effect on the skin. The additive can facilitate administration to the skin; and/or contribute to the preparation of the desired composition. These compositions may be administered in a variety of occasional manners, for example, in the form of a percutaneous patch, a drop, an ointment of an o(I) compound or an additive salt to increase the solubility of the corresponding acid or acid type. Suitable for the preparation of aqueous compositions. The above pharmaceutical compositions are particularly preferably formulated in unit dosage form for convenient administration of a homogeneous dose of one. The unit dosage form as used herein refers to a unit dosage, physical fraction, and each unit comprises a predetermined amount of active ingredient that is combined with the desired pharmaceutical carrier to produce the desired medical effect. Examples of such unit dosage forms are lozenges (including crepe or coated lozenges), capsules, pills 45 201245162, powder packs, sachets, suppositories, solutions or suspensions for injection, etc. dose. Since the compound according to the present invention is a potent oral compound, it is particularly advantageous to use a pharmaceutical composition comprising the compound for oral administration. In order to increase the solubility and/or stability of the compound of formula (I) in a pharmaceutical composition, it is preferred to use α-, β- or γ-cyclodextrin or a derivative thereof, specifically a hydroxyalkyl-substituted cyclodextrin, For example: 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Cosolvents (e.g., alcohols) may also be employed to improve the solubility and/or stability of the compounds according to the invention in pharmaceutical compositions. Depending on the mode of administration, the pharmaceutical composition preferably comprises from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of formula (I), and To a 9.99% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of the pharmaceutically acceptable carrier, all percentages are based on the total weight of the composition. The following examples illustrate the invention. EXAMPLES Hereinafter, the term "DCM" means dioxane; "MeOH" means methanol; "LCMS" means liquid chromatography/mass spectrometry; "HPLC" means high liquid chromatography; "sol. "Aq." means an aqueous solution; "rt" means room temperature; "mp" means a bright point; "RP" means a reverse phase; "min" means a minute; "h" means an hour; " EtOAc" means ethyl acetate; "eq" means equivalent; "rm" means reaction mixture 46 201245162; "DIPE" means diisopropyl ether; "THF" means tetrahydrofuran; "DMSO" means Dimethylene sulfoxide; "DMF" means dimercaptomethylamine; "X-phos" means dicyclohexyl [2,,4,6,-paran (1-mercaptoethyl)[1,Γ -Biphenyl]_2-yl]phosphine; "Pd(dppf)Cl2" means [1, bis-bis(diphenylphosphino) ferrocene] dichloropalladium (II); "DIPEA" means two Isopropylethylamine; "9-BBN" means 9-borabicyclo[3.3.1]nonane; "i-PrOH" means 2-propanol; and "Pd2(dba)3" means -[(1,2_ η : 4,5-η)-(1Ε,4Ε)-1,5-diphenyl-1,4-pentadien-3-one]]dipalladium. A. Intermediate production method Example A1 Intermediate 1 production method

Add a solution of diphenyl cyanoimin diphenyl phthalate (5.3 g, 21.56 mmol) in DCM (50 mL) to 1-(4-methoxyphenyl)-2,2-dimethylpiperidine (5 g, 21.56 mmol) in DCM (190 mL). The reaction mixture was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with DCM. The separated organic layer was dehydrated (MgS04), filtered and evaporated. The residue was suspended in DIPE and filtered off and dried in an oven. Yield: 6.12 g of intermediate 1 (77%). 47 201245162 Example A2 a) Intermediate 2 method

ό Add a third butanol (5.87 g, 52.28 mmol) to a 1-kid-4-based base. Set (5 g, 26.14 mmol) in DMS (12 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, hydrazine-gas hydrazine 11 hydrochloride (4.31 g, 28.75 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours (microexotherm) and water was added, and the mixture was extracted with EtOAc. The separated organic layer was subjected to dehydration (MgS. 4), after hydrazine, and evaporation of the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. g intermediate 2 (60%) 〇b) intermediate 3 preparation method

Intermediate 2 was added to a suspension of MeOH (150 mL) containing Pd / C. The reaction mixture was stirred at 25 ° C under a hydrogen pressure. After absorbing H2 (1 eq), the catalyst was filtered through Shixia. The filtrate was evaporated. Yield: 2.6 g of intermediate 3 (94%). 48 201245162 c) Intermediate 4 method

DIPEA (2.51 mL, 14.59 mmol) and DCM (36 mL) (br.) (br. In DCM (126 mL) solution. The reaction mixture was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with DCM. The separated organic layer was subjected to dehydration (MgS04), filtered and evaporated. The residue was purified by flash column chromatography (solvent: DCM/Me〇H, from 100/0 to 95/5). The product was collected and concentrated in vacuo. Yield: 2.84 g of intermediate 4 (60%). Example A3 a) Intermediate 5 preparation method

Add 60% NaH in mineral oil suspension (6 g, 150 mmol) to 〇C of 4-hydroxy-piperidine q·decanoic acid tert-butyl ester (14 g, 7〇mm〇1) in anhydrous THF ( 120 mL) in solution. The reaction mixture was stirred under 〇〇c. An anhydrous solution containing 4-chloro-6-methyl-pyrimidine (9 g, 7 〇 mm 〇 1) was added. 49 201245162 THF (30 mL) solution The reaction mixture was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with DCM. The separated organic layer was subjected to dehydration (MgSO.sub.sub.sub.sub.sub.sub.sub. And concentrated in vacuo. Yield: 13 g intermediate 5 (63%) b) Intermediate 6 preparation

A mixture of 4 M HCl in MeOH (200 mL) EtOAc (EtOAc) Evaporate the solvent. The residue was suspended in DIPE (200 mL), stirred at room temperature for 30 min, filtered and dried in oven. Yield: 9.5 g intermediate 6 (93%) c) Intermediate 7 method

A solution of DIPEA (3 mL, 17.41 mmol) and diphenyl cyanoimide diphenyl phthalate (2.14 g, 8.71 mmol) in DCM (21 mL) In DCM (77 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with DCM. The separated organic layer was dehydrated (MgS04), filtered, and evaporated. The residue was purified by flash column chromatography (solvent: DCM/MeOH, 50 201245162 from 100/0 to 97.5/2.5). The product fractions were collected and concentrated in vacuo. Yield: 2.09 g Intermediate 7 (71%). Example A4 Intermediate 8 method

Add a solution of diphenyl cyanoimidoate (2·62 g, 10.68 mmol) in DCM (26 mL) to a solution containing 1-(4-decyloxyphenyl) · 68 mmol) in DCM (94 mL) solution. The reaction mixture was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with DCM. The separated organic layer was subjected to dehydration (MgS04), filtered, and evaporated. Yield: 3.45 g of intermediate 8 (96%). Example A5 Intermediate 9 method

Add a solution of diphenyl cyanoimide diphenyl phthalate (3·〇1 g, 12.25 mmol) in DCM (15 mL) to DCM containing 1-(pyridinyl)piped (2 g, 12.25 mmol) (32 mL) in solution. The reaction mixture was stirred at room temperature for 1 hour. Steam 51 201245162 Solvent. The residue was purified by flash column chromatography (solvent DCM / MeOH ' from 100 / 0 to 9 〇 / 1 〇). The product was collected and concentrated. The residue was suspended in DIPE, filtered off and dried in an oven. Production of two 3.7 g intermediates 9 (98%). Example A6 a) Intermediate 10 method

2.5 Μ 丁基 butyl lithium hexane solution (3 〇 mL, anhydrous to the -78 ° C containing methyl triphenyl squamous desert (2 〇 g, 56 〇 m Fu)

A solution of mm 〇 1) in anhydrous THF (40 mL) was added to the mixture. A white (four) float is formed during the addition. The reaction mixture was aged for 16 hours at room temperature. Water (1 mL) was added dropwise at 0 °C, and the solvent was evaporated and water (7 mL) was evaporated. The separated organic layer was dehydrated (MgS〇4), filtered, and spread with 9 shots. Purification by residual column chromatography (dissolved solution: petroleum ether / EtOAc 15/1). The product was taken up in vacuo and concentrated in vacuo. Yield: 5.3 g Intermediate 1 〇 (32%, purity 60 ο/.). b) Intermediate 11 method

To a degassed intermediate 10 (11.3 g, 57.36 mmol), EtOAc (EtOAc m. After cooling to room temperature, the reaction mixture was added to 4-bromo-2-indolyl-σ-pyridinidine (10.8 g, 63.09 mmol), Pd(dppf)Cl2 (1.259 g, 1.721 mmol) and K2C03 (23.7 g, The mixture was heated at 60 ° C for 4 hours in a mixture of 172.1 mmol of DMF / water 10/1 (250 mL). The reaction mixture was cooled to room temperature and poured into water. A 10% aqueous NaOH solution was added to adjust to pH 11 and extracted with EtOAc. The separated organic layer was dehydrated (MgS04), filtered, and evaporated. The residue was purified by flash column chromatography (solvent: petroleum ether /EtOAc 20/1). The product was collected and concentrated in vacuo. Yield: 7.6 g of intermediate 11 (46%). c) Intermediate 12 method

A mixture of 4]^11 (:1^^〇11 solution (30 mL) containing intermediate 11 (7.6 liter, 20.27 111111 〇1) was stirred at room temperature for 4 hours. The solvent was evaporated. The residue was suspended in DIPE. (200 mL), stirred at room temperature for 3 minutes, filtered off and dried in an oven. Yield: 5.65 g Intermediate 12 (96%; .HC1) d) Intermediate 13 Method

A solution of DIPEA (1.52 mL, 8.82 mmol) and diphenyl cyanoimidocarboxylate (1.08 g, 4.41 mmol) in DCM (11 mL) ) in DCM (39 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. Evaporate the solvent. Yield: 〇·5 g of intermediate 13 (34%). Example A7 Intermediate 14 Method

Add a solution of diphenyl cyanoimidoate (2.77 g, 11·28 mmol) in DCM (15 mL) to 1-(4-pyridinyl)-piped (2 g, 11.28 mmol) In DCM (16 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was suspended in DIPE, filtered off and dried in an oven. Yield: 3.5 g Intermediate 14 (96%) Example A8 a) Intermediate 15 preparation method

54 201245162 Add a third butanol (8.8 g, 78.4 mmol) to a solution containing 4-hydroxy-buckling small carboxylic acid tert-butyl ester (7.89 g, 39.2 mmol) in DMSO (39 mL); The reaction mixture was stirred at room temperature for 1 hour. Then 4-chloro·, picoline (5 g, 39.2 mmol) was added and the reaction mixture was stirred at 50 ° C for 48 hours. The reaction mixture was then allowed to cool to room temperature. Add water to

The mixture was extracted with Et〇Ac. The separated organic layer was passed through a NaHC03 solution and a salt: under-washed, dehydrated (MgS04), filtered, and evaporated. The residue was purified by flash chromatography (separation: DCM/MeOH, from 100/0 to 98/2). The product was taken up in vacuo and concentrated in vacuo. Yield: 8.8 g Intermediate (77 b) Intermediate 16

A solution of 6 N HCl in 2·propanol (8.62 mL, 51.7 mmol) was added to a solution of intermediate 15 (2.5 g, 8.55 mmol) in 2-propanol (52 mL) and stirred at room temperature for 30 min. Evaporate the solvent. The residue is suspended in ch3CN. The product was filtered off and dissolved in water. The base was released using aqueous K2C03 solution and the mixture was extracted with DCM. The organic phase was separated, dehydrated (MgS04), passed over, and evaporated. The product was used in the next step without further purification. Yield: 1.52 g Intermediate 16 (93%). 55 201245162 C) Intermediate 17 method

A solution of diphenyl cyanoimide diphenyl phthalate (1.28 g, 5.2 mmol) in DCM (5 mL) EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 1 hour. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was collected and concentrated in vacuo. Yield: 1.75 g of intermediate 17 (100%). Example A9 a) Intermediate 18 method

Add 2-Methyl-5-decyloxy 0 to bite (2 g, 10.64 mmol), Cs2C03 (10.4 g, 31.91 mmol), X-Phos (l.12 g, 2.34 mmol) and

Pd2(dba)3 (974 mg, 1,06 mmol) to 2-mercapto-2-propanol (3.96 g, 21.27 mmol) containing piperidinic carboxylic acid tert-butyl ester under nitrogen pressure (120 56 201245162) mL) in solution. The reaction mixture was heated at i ° ° C for 48 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo. <RTI ID=0.0></RTI> The product was taken up in vacuo and concentrated in vacuo. The residue was then purified by Rp preparative HPLC [RP Vydac Denali C18 - ΙΟμπι, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC03 aqueous solution) / MeOH / CH3CN). The product was taken up in vacuo and concentrated in vacuo. Yield: 100 mg intermediate 18 (3.2%). b) Intermediate 19 method

A solution of 6 N HCl in 2-propanol (2 mL, 12 mmol) was added to EtOAc (EtOAc) Evaporate the solvent. The residue was dissolved in DCM and washed with 1 n NaOH solution. The separated organic layer was washed with brine (NaHC.sub.3) and brine and dried (MgSO.sub.sub. 20 methods

Add DCM (15 mL) solution containing cyanoimidocarboxylic acid diphenyl vinegar (65 mg, 〇η匪〇1) to DCM (38 mL) containing intermediate 19 (53, 〇27 〇1) In solution. The reaction mixture was stirred at room temperature for 5 hours. Evaporate the solvent. It was used in the next step without further purification. Yield: 12 mg mg intermediate 20 (full yield). Example A10 Preparation of Intermediate 21 and Intermediate 22 (Positive Isomers)

Intermediate 21 Intermediate 22 Methylhydrazine (0.14 mL, 2.68 mmol) was added to a solution of Intermediate 1 ( s. The reaction mixture was stirred at room temperature for 16 hours. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 97/3). The product was taken up in vacuo and concentrated in vacuo. Yield: 270 mg intermediate 21 (32%) and 157 mg intermediate 22 (18%). 58 201245162 Example All Intermediate 23 and Intermediate 24 (Positive Isomers)

Intermediate 24 was added hydrazinium (0.47 mL, 8.69 mmol) to a solution of intermediate 4 (2.8 g, 8.69 mmol) in 2-propanol (5 〇 mL). The reaction mixture was heated under reflux for 6 hours. Evaporate the solvent. The residue was suspended in CH3CN, filtered and dried in an oven. Yield: 1.67 g 'containing 59% of intermediate 23 and 34% of intermediate 24 . Example A12 Preparation of Intermediate 25 and Intermediate 26 (Positive Isomers)

Mercaptopurine (0.34 mL, 6.19 mmol) was added to a solution of intermediate 7 (2.09 g, 6.19 mmol) in 2-propanol (35 mL). The reaction mixture was heated under reflux for 6 hours. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in a portion and concentrated in vacuo. The residue was suspended in DIPE, filtered off and dried in an oven. Yield: 179 mg intermediate 25 (10%) and 159 mg intermediate 26 (9 %). 59 201245162 Example A13 Intermediate 2 7 and Intermediate 2 8 (Positive Isomers)

Intermediate 27

Intermediate 28 was added hydrazinium (0.55 mL, 10.17 mmol) to a solution of intermediate 8 (3.42 g, 10.17 mm 〇i) in 2-propanol (58 mL). The reaction mixture was heated under reflux for 6 hours. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was suspended in DIPE, filtered off and dried in an oven. Yield: 510 mg intermediate 27 (17%) and 720 mg intermediate 28 (24%). Example A14 Intermediate 29 and intermediate 3〇 (position isomer) preparation method

Intermediate 29 Intermediate 30 曱 肼 0.7 (0.71 mL, 13.01 mmol) was added to a solution of Intermediate 9 (4 g, 13.01 mmol) in 2-propanol (75 mL). The reaction mixture was heated under reflux for 16 hours. Additional methyl hydrazine (〇 % mL, 6.50 60 201245162 mmol) was added and the reaction mixture was heated at reflux for 16 h. Evaporate the solvent. The residue was crystallized from CHsCN, filtered off and dried in an oven. Yield: 2.9 g, containing a mixture of intermediate 29 and intermediate 30, which was used directly in the next reaction step. Example A15 Method for preparing intermediate 31 and intermediate 32 (position isomer)

Mercaptopurine (0.081 mL, 1.5 mmol) was added to a solution of intermediate 13 (500 mg, 1.5 mmol) in 2-propanol (8 m:L). The reaction mixture was heated under reflux for 6 hours. The solvent was evaporated and the product was used in the next step without further purification. Yield: 510 mg, containing 56 〇/0 of intermediate 31 and 32 〇/0 of intermediate 32. , ° Example A16 Intermediate 33 and Intermediate 34 (Positive Isomers)

Intermediate 33 Intermediate 34 61 201245162 Add methyl hydrazine (0.59 mL, 1 〇·89 mmol) to a solution of intermediate 14 (3.5 g, 10.89 mmol) in 2-propanol (62 mL). The reaction mixture was heated under reflux for 16 hours. Additional methyl hydrazine (0.59 mL, 10.89 mmol) was taken and the mixture was heated at reflux for 16 h. Evaporate the solvent. The residue was crystallized from CHAN, filtered off and dried in an oven. Yield: 1·1 g of intermediate 33 (37%). The positional isomer (intermediate 34) of the intermediate 33 was also formed during this reaction, but was not isolated. Example A17 Intermediate 35 and Intermediate 36 (Positive Isomers)

Intermediate 35 Intermediate 36 was added hydrazinium (0.28 mL, 5.2 mmol) to a solution of Intermediate 17 (1.75 g, 5.2 mmol) in 2-propanol (30 mL). The reaction mixture was heated under reflux for 16 hours. Evaporate the solvent. The residue was crystallized from Ch3CN, poured out and dried in an oven. Yield · 361 mg of intermediate 35 (24 ° / 〇) ° also formed a positional isomer of intermediate 35 (intermediate 36) during this reaction, but not isolated. 62 201245162 Example A18 Intermediate 37 and Intermediate 38 (Positive Isomers)

Intermediate 37 Intermediate 38 was added hydrazinium hydrazide (0.019 mL, 0.36 mmol) to EtOAc (2 mL). The reaction mixture was heated at room temperature for 16 hours. Evaporate the solvent. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 97/3). The product was taken up in vacuo and concentrated in vacuo. Yield: 25 mg intermediate 37 (24%). The positional isomer (intermediate 38) of intermediate 37 was also formed during this reaction, but was not isolated. Example A19 Intermediate 39 Method

A mixture of 4-fluorophenylhydrazine (5 g, 31.53 mmol) was added to a mixture of sulfur (1. Then 1-(4-methoxyphenyl)-n bottom η well (5 76 g 29.96 mmol) was added and the mixture was stirred at room temperature for 1 hour. Reaction mix 63 201245162 compound poured into ice water. Filter out the sinking hall and dry it. Yield: 5.68 g of intermediate 39 (48%). Example A20 Intermediate 40 Method

K2CO3 (0.74 g, 5.35 mmol) was added to a mixture of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was spoiled at room temperature for 30 minutes. Add dish tortoise (0.84 g, 5.89 mmol). The reaction mixture was stirred at room temperature for 1 hour. Evaporate the solvent. Water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo. Yield: 2.07 g of intermediate 40 (full yield). B. Compound preparation method Example B1 Compound 1 preparation method

64 201245162 Add 2-bromoindole (0.076 mL, 0.63 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2(dba)3 (58 mg, 0.063 mmol) to nitrogen Intermediate (21 mg, 0.63 mmol) in 2-methyl-2-propanol (14 mL). The reaction mixture was heated at 10 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was ground with DIPE, filtered, and dried. Yield: 120 mg of compound 1 (47%). Example B2 Compound 2 Preparation

Add 2-&gt; stinky-tri-I-nonylbenzene (0.086 mL, 0.63 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2(dba)3 (58 mg, 0.063) Methyl) to a solution of intermediate 21 (200 mg, 0.63 mmol) in EtOAc (EtOAc) The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature and water was added to extract the mixture. The combined organic layers were dehydrated (MgS 〇 4) filtered and concentrated in vacuo. The residue was purified by Rp preparative HPLC 65 201245162 [RP Vydac Denali C18 - ΙΟμπι, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC〇3 in water) / MeOH)]. The product was collected and concentrated in vacuo. The residue was purified by RP preparative HPLC [RP Vydac Denali C18 - ΙΟμηι, 250 g, 5 cm); mobile phase: gradient (〇·15% aqueous formic acid, MeOH/CK^CN). The product was collected and concentrated in vacuo. Yield: 44 mg of compound 2 (15%). Example B3 Preparation of Compound 3

Add 1-oxa-3-gas-2-trifluoromethyl-benzene (0.095 mL, 0.95 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Ph〇s (73 mg, 0.13 mmol) and Pd2 (dba) 3 (58 mg, 0.063 mmol) to a solution of intermediate 21 (200 mg, 0.63 mmol) in 2-methyl-2-propanol ( η mL). The reaction mixture was at 100. (The mixture is heated for 16 hours. The reaction mixture is then cooled to room temperature, water is added, and the mixture is extracted with DCM. The combined organic layer is dried (MgSO4), filtered, and concentrated in vacuo. (Solution: DCM/MeOH, from 100/0 to 95/5). The product was dissolved in vacuo and concentrated in vacuo. The residue was suspended in DIPE and filtered. The residue was purified by RP preparative HPLC [R^ Vydac Denali C18 - ΙΟμπι, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HCO3 in water/MeOH). The product fractions were collected and concentrated in a vacuum at 66 201245162. The residue was purified by RP preparative HPLC [RP Vydac Denali C18 - ΙΟμηι, 250 g, 5 cm); mobile phase: gradient (〇 15% aqueous formic acid, MeOH/CHfN). The product fractions were collected and concentrated in vacuo. 30 mg of compound 3 (10%). Example B4 Compound 4 method

Add 1-bromo-3-trisethoxycarbonyl-benzene (0.093 mL, 0.95 mmol), Cs2C03 (618 mg, 1.9 mmol), x_ph〇s (73 mg, 0.13 mmol) and Pd2(dba)3 (58 mg) , 0.063 mmol) to a solution of intermediate 21 (200 mg, &lt;RTI ID=0.0&gt;&gt; The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO.sub.sub.sub.sub. The residue was suspended in DIPE and filtered off. The residue was suspended in 2-propanol and treated with 6 N HCl in 2-propanol solution. The obtained material was collected and dried. Yield: 13 0 mg Compound 4 (41 %) of the HCl salt. Example B5 67 201245162 Compound 5 preparation

Add 1-&gt;Smelly-3-Ga-5-tris-decyl-benzene (2 30 mg, 0.95 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2 ( To a solution of intermediate 21 (200 mg, 0.63 mmol) in EtOAc (EtOAc) (EtOAc) The reaction mixture was at 1 Torr. Heat under the arm for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was suspended in DIPE and treated with 6 N HCl in 2-propanol. The resulting precipitate was collected by filtration and dried. Yield: 121 mg of compound 5 (38%) of HCl salt (.0.8 HCl). Example B6 Compound 6 Preparation

Add 1-bromo-4-fluoro-2-indolyl-benzene (0.12 mL, 0.95 mmol), Cs2C〇3 (618 mg, 1. 9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2 (dba) 3 (58 mg, 〇 〇 mmol 63 mmol) to a solution of intermediate 68 in a solution of EtOAc EtOAc EtOAc (EtOAc) The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (solvent: DCM/MeOH) from 100/0 to 95/5. The product was taken up in vacuo and concentrated in vacuo. The residue was suspended in DIPE and treated with 6 N HCl in 2-propanol. The resulting precipitate was collected by filtration and dried. Yield: 115 mg of compound 6 (37%) of HCl salt (.1.2 HCl, 1.5H20). Example B7 Preparation of Compound 7 and Compound 7a

Add 3-Deve-4-fluoro-trifluoromethylbenzene (0.39 mL, 2.73 mmol), Cs2C03 (1.78 g, 5.47 mmol) 'X-Phos (211 mg, 0.36 mmol) and Pd2(dba)3 (167 mg , 0_18 mmol) to a mixture of intermediates 69 201245162 23 and intermediate 24 (500 mg, 1 82 mmol) in 2-methyl-2-propanol (41 mL). The reaction mixture was heated at 1 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dehydrated (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. Yield: 69 mg of compound 7 (9 %) and 1 〇 8 mg of compound 7a (14%; positional isomer of compound 7). Example B8 Compound 8 Method

Add 3-bromo-4-fluoro-trifluorodecylbenzene (0.086 mL, 0.63 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2(dba)3 ( 58 mg, 0.063 mmol) to a solution of intermediate 25 (200 mg, 0.63 mmol) in 2-methyl-2-propanol (14 mL). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 70 201245162 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was ground using DIPE, filtered off, and dried. Yield: 79 mg of compound 8 (28%). Example B9 Compound 9 Method

Add 3-bromo-4-fluoro-trifluorodecylbenzene (0.22 mL, 1.56 mmol), Cs2C03 (1.02 g, 3.12 mmol), X-Phos (120 mg, 0.21 mmol) and Pd2(dba)3 ( 95 mg, 0.1 mmol) to a solution of intermediate 27 (300 mg, 1.04 mmol) in 2-methyl-2-propanol (23 mL). The reaction mixture was heated at 10 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was ground using DIPE, filtered off, and dried. Yield: 120 mg of compound 9 (25 %). Example B10 71 201245162 Compound 10 and compound l〇a method

Add 3-bromo-4-fluoro-trifluoromethylbenzene (0.21 mL, 1.45 mmol), Cs2C〇3 (943 mg, 2.89 mmol), X_Phos (92 mg, 0.19 mmol) and Pd2(dba)3 (88 mg) , 0.096 mmol) to a mixture of intermediate 29 and intermediate 30 (250 mg, 0.96 mmol) in 2-mercapto-2-propanol (20 mL). The reaction mixture was heated at i〇〇〇c for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dehydrated (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was purified by RP preparative HPLC [1^&gt;¥丫(13〇〇61131丨(:18-ΙΟμιη, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC03 in water/CH3CN)). Dissolved and concentrated in vacuo. The residue was crystallized from DIPE, filtered and dried. Yield: 112 mg Compound 72 201245162 10 (28 %) and 8 mg of compound 10a (20%; positional isomer of compound 10) Example B11 Preparation of Compound 11 and Compound 11a

Add 3-&gt; Omega-4-fluoro-trifluorodecylbenzene (0.38 mL, 2.67 mmol),

Cs2C03 (l.74 g, 5.34 mmol), x_ph〇s (207 mg, 0.036 mmol) and Pd2(dba)3 (164 mg, 0.18 mmol) to a mixture of intermediate 31 and intermediate 32 under nitrogen pressure ( 51 mg, 1.78 mmol) in 2-mercapto-2-propanol (40 mL). The reaction mixture was heated at i〇〇〇c for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (solvent: 73 201245162 DCM/MeOH, from 100/0 to 95/5). The product was collected and concentrated in vacuo. Both residues were suspended in DIPE and treated with 6 N HCl in 2-propanol. The resulting precipitate was collected by filtration. The first impure compound was purified by RP preparative HPLC [RP Vydac Denali C18 - ΙΟμιη, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC03 aqueous solution / CHsCN). The product was taken up in vacuo and concentrated in vacuo. Both residues were crystallized from DIPE and dried. Yield: U8 mg compound 11 (13%) of HCl salt (.HC1 · Η20) and 97 mg of compound lla (12%; positional isomer of compound 11). Example B12 Compound 12 Method

Add 3-bromo-4-It-trifluoromethylbenzene (0.20 mL, 1.37 mmol), Cs2CO3 (0.89 g, 2.74 mmol), X-Phos (87 mg, 0.18 mmol) and Pd2(dba)3 (94 mg , 0.091 mmol) to a solution of intermediate 33 (250 mg, 0.91 mmol) in 2-methyl-2-propanol (20 mL). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature and water was added to extract the reaction mixture with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Residues were purified by flash tube 74 201245162 column chromatography (dissolved solution: DCM/MeOH, from 100/0 to 95/5). The product was taken up in vacuo and concentrated in vacuo. The residue was ground using DIPE, filtered off, and dried. Yield: 210 mg of compound 12 (53%). Example B13 Compound 13 Method

Add 1-bromo-2-indolyl-benzene (0.016 mL, 0.13 mmol), Cs2C03 (0.084 g, 0.26 mmol) 'X-Phos (10 mg, 0.017 mmol) and Pd2(dba)3 (8 mg, 0.0086 mmol) An intermediate 37 (25 mg, 0.086 mmol) in 2-mercapto-2-propanol (2 mL). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by RP preparative HPLC [RP Vydac Denali C18 - ΙΟμπι, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC〇3 aqueous solution / CHfN)]. The product was taken up in vacuo and concentrated in vacuo. Yield: 7 mg of compound 13 (21%). Example B14 75 201245162 Compound 14 Method

Add Cul (150 mg, 0.79 mmol) and 7 V, A^-dimethylethylenediamine (0. Π mL, 1.58 mmol) to 3-bromo-4- gas-trifluorodecylbenzene (768 mg, 3 · 16 mmol), intermediate 21 (250 mg, 0.79 mmol), and a mixture of Cs2C03 (644 mg, 1.98 mmol) in DMF (3 mL). The reaction mixture was heated at 170 ° C for 2 minutes for 2 minutes. The reaction mixture was cooled and EtOAc was added, and the mixture was washed with 1M aqueous NH4OH, water and brine. The organic layer was dried (MgSO.sub.4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 97/3). The product was taken up in vacuo and concentrated in vacuo. The residue was purified by RP preparative HPLC [RP Vydac Denali C18 - ΙΟμπι, 250 g, 5 cm); mobile phase: gradient (0.25% NH4HC03 aqueous solution VCH/N)]. The product was taken up in vacuo and concentrated in vacuo. Yield: 75 mg of compound 14 (20%). Example B15 76 201245162 Compound 15 preparation method

Add Cul (186 mg, 0.98 mmol) and A^V1-dimercaptoethylenediamine (0.17 mL, 1.58 mmol) to 3-bromo-4-fluoro-trifluoromethyl stupid (58 mg, 3.91 mmol) Intermediate 35 (282 mg, 0.98 mmol), and

Cs2C03 (796 mg, 2.44 mmol) in DMF (3 mL) mixture. The reaction mixture was heated at 170 ° C for 90 minutes. The reaction mixture was cooled, and EtOAc was added and washed with 1M aqueous NH?? The organic layer was dried (M.g.sub.4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography (solvent: DCM/MeOH, from 100/0 to 98/2). The product was taken up in vacuo and concentrated in vacuo. The residue was crystallized from CHAN, filtered off and dried. Yield: 92 mg of compound 15 (21 %) 实例 Example B16 Compound 16 method

Mercaptopurine (713 mg, 15.5 mmol) was added to a solution of intermediate 40 (2 g, 5.16 mmol) in toluol (5 mL). The reaction mixture was heated under a stream of 77 201245162 for 2 hours. The product crystallized from the reaction mixture. The reaction mixture was cooled to room temperature. The crystals were filtered off, washed with i-PrOH and DIPE, and dried. Yield: 663 mg of compound 16 (35 %). Table 1 lists the compounds prepared in analogy to the above examples. 'Pr.' means the example number of the process used to synthesize the compound. 'Co. No.' means the compound number. 'cb' means a covalent bond. Co. No. 1-3, 7-10 and 12-16 are prepared as free base. Co. No. 4-6 and 11 are obtained as hydrochloride (determined by elemental analysis): Co. No. 4 (.HC1); Co. No. 5 (.0.8 HC1); Co. No. 6 (.1.2 HC1 .1.5 H20) ; Co. No. 11 (.HC1 ·Η20). Table 1

Co, No. Pr. R1 R2 L1 R4a R4b X L2 Y1 Y2 R5 1 B1 2-CH3 H NH ch3 ch3 N cb CH COCH3 H 2 B2 2-CF3 H NH ch3 ch3 N cb CH COCH3 H 3 B3 2-CFj 3 -F NH CH3 ch3 N cb CH COCH3 H 78 201245162

Co. No. Pr. R1 R2 L1 R4a R4b X L2 Y1 Y2 R5 4 B4 3- ocf3 H NH ch3 ch3 N cb CH COCH3 H 5 B5 3-F 5-CFj NH ch3 ch3 N cb CH COCH3 H 6 B6 2- CHj 4-F NH ch3 ch3 N cb CH COCH3 H 7 B7 2-F 5-CF3 NH HH CH 〇CH NH 8 B8 2-F 5-CF3 NH HH CH 〇NN ch3 9 B9 2-F 5-CF3 NH HHN Cb CH COCH3 H 10 BIO 2-F 5-CF3 NH HHN cb CH NH 11 Bll 2-F 5-CF3 NH HH CH ch2 CH N ch3 12 B12 2-F 5-CF3 NH HHN ch2 CH NH 13 B13 2-CH3 H NH HHN cb N COCH3 H 14 B14 2-F 5-CF3 NH CH3 CH3 N cb CH COCH3 H 15 B15 2-F 5-CFj NH HH CH 0 CH N ch3 16 B16 4-FH cb HHN cb CH COCH3 H Analysis Partial LCMS (liquid chromatography / mass spectrometry)

The general process A LC method uses the Acquity UPLC (Ultra Performance Liquid Chromatography) (Waters) system, which includes a binary pump, a sampler, a column heater (setting 55.0), and a two-pole array detector (; DAD) The column specified separately from each of the following methods. After the pipe is discharged, 79 201245162 is diverted to the MS mass spectrometer. The structure of the MS detection ii includes an electrospray ionization source. Mass spectra were acquired from 1 Torr to 1000 Å in 0.18 seconds using an interval of 〇.〇2 sec. The capillary needle voltage is 3·5 kv, and the power supply temperature is maintained at 140 °C. Nitrogen was used as the atomizing gas. Data was obtained using the Trader ~ Micromass MassLynx-Openlynx data processing system.

General Process B HPLC assays were performed using the Alliance HT 2790 (Waters) system, which included a binary pump with an additional degasser, an autosampler, and a column oven (set 40. (: unless otherwise stated) The two-pole array detector (DAD) is specified separately from the following methods. After flowing out of the column, it is shunted to the MS mass spectrometer. The structure of the MS detector includes the electrospray ionization source. The interval is used (U seconds, in The mass spectrum is obtained from 1 broom to 1000 ' in 1 second. Capillary needle voltage &amp; 3 kv, the power supply temperature is maintained at 140 ° C. Nitrogen is used as the atomizing gas.

The Micromass MassLynx-Openlynx data processing system captures data. LCMS Method 1 In addition to the general procedure A: further bridged ethyl oxane / vermiculite hybrid (BEH) C18 column (1.7 (four), 21 χ 5 〇 _; edit (10)

Reverse phase UPLC (Super Liquid Chromatography) was performed on Acquity) with a flow rate of 8 ml/min. Two mobile phases (25 mM ammonium acetate in 〇2〇/acetonitrile 95/5 solution; mobile phase Β: acetonitrile) were operated according to the gradient conditions: from 95 % Α and 5% Β to 5% in 13 minutes (min) Α and 95 0 / 〇Β, Bao 80 201245162 only temple 〇 3 ·, .mm. The injection volume is 0.5 μΐ. The cone voltage is 3 〇 V in positive ionization mode and 30 V in negative ionization mode. LCMS Method 2 except for the general procedure A: followed by a bridged ethyloxane/verine hybrid (EH) Cl8 column (17 2·1 X 50 mm; reverse phase UPLC on Waters, flow rate 0.8 ml/ Min. Use two mobile phases (mobile phase A: Ο.1% citric acid H20/sterol 95/5 solution; shift

^ Phase. Β • sterols are operated according to the gradient conditions: from 95 % A 0 B to 5 /〇 a and 95 % B in 1.3 min, for 0.2 min. The injection volume is 0·5 μΐ. The cone voltage is 1 〇 v in the positive ionization mode and 20 V in the negative mode. , L CMS Method 3 In addition to the general process B: a reverse phase HpLC 'flow rate 丄 6 腕 n on the xterra MS C18 column (3.5 m 4.6 X 1 〇〇 mm). Three mobile phases were used (mobile phase A: 95% 25 mM ammonium acetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase c: f alcohol), operating according to the gradient: from 1% to % within 6 5 min A, 49% 6 and 5〇% c, Mi within 1 A and 99% B, maintain these conditions 1 mjn, re-equilibrate 1.5 min using 1〇〇% a. The injection volume is 10 μιη. The cone voltage is 2 V for the positive ionization mode and 2 〇 V for the negative ionization mode. , LCMS Method 4 In addition to the general process A: reverse phase UPLC, flow rate on the bridged ethyl oxirane / vermiculite hybrid (BEH) C18 column (1.7 μηι, 2.1 X 50 mm; Waters Acquity) 0.8 ml/min. Two mobile phases were used (shifting 81 201245162 phase A: 10 mM ammonium acetate in H20/acetonitrile 95/5 solution; mobile phase B: acetonitrile), operating according to gradient conditions: 95% A and 5% ugly in 1_3 minutes Up to 5% A and 95% B for 0.2 min. The injection volume is 0.5 μΐ. The cone voltage is 10 V in positive ionization mode and 20 V in negative ionization mode. Melting point Some compounds were tested for melting point (m.p.) using DSC823e (Mettler-Toledo). The melting point was measured using a temperature gradient of 30 ° C / min. The highest temperature is 400 °C. The value is the peak value. The analytical measurement results are shown in Table 2a. Table 2a: residence time (Rt) in minutes, [M+H] + peak (protonated molecule), LCMS method and m.p. (melting point, .C). (n.d. means not measured)

Co. No. Rt [M+H] + LCMS Method mp (°C) 1 1.15 407 1 156.8 2 1.24 461 1 nd 3 1.23 479 1 nd 4 1.29 477 1 nd 5 1.33 479 1 nd 6 1.15 425 1 nd 7 1.02 437 1 nd

Co· No· Rt [M+H] + LCMS method mp(°C) 8 1.08 452 1 158.0 9 1.18 451 1 145.4 10 0.86 422 1 261.8 11 1.13 449 1 nd 12 0.97 436 1 161.4 13 0.98 380 4 nd 14 1.28 479 1 nd 82 201245162

Co. No. Rt [M+H] + LCMS Method m.p.(°C) 15 5.95 451 3 177.4

Co. No. 16 Rt [M+H] + LCMS Method m.p.(°C) 1.29 368 2 191.6

The 1H NMR spectra of various compounds of NMR were synthesized on a Bruker DPX-360 or Bruker DPX-400 mass spectrometer using standard pulse procedures at 360 and 400 MHz, respectively, using chloroform-¢/(氘化气仿, CDC13 Or DMSO-t/6 (gasified DMSO 'dimercapto-d6 sub-* wind) was carried out as a solvent. The chemical shift (δ) is reported in parts per million (ppm) relative to tetramethyl oxalate (TMS) as an internal standard. Table 2b: 1H NMR results

Co. No. h NMR Results 1 (360 MHz, DMSO-i/6) 669 ppm 0.96 (s, 6 H), 2.23 (s, 3 H), 3.00 - 3.06 (m, 2 H), 3.08 (s, 2 H), 3.21 - 3.31(m, 2 H), 3.51(s, 3 H), 3.72(s, 3 H), 6.83(111, /=8.6 Hz, 2 H), 6.92(t, /=7.3 Hz, 1 H), 7.〇6(m, /=8.7 Hz, 2 H), 7.12(t, /=7.5 Hz, 1 H), 7.16(d,/=7.4 Hz, 1 H), 7.27( d, /=8.0 Hz, 1 H), 7.79(s, 1 H) 6 (400 MHz, DMSO-i/6, 125 °C) δ ppm 1.14(s, 6 H), 2.24(s, 3 H) , 3.38(br. s., 2 H), 3.42(br. s., 2 H), 3.50(s, 3 H), 3.58(br. s., 2 H), 3.77(s, 3 H), 6.83 -6.99(m, 4 H), 7.29(dd, 7=8.9, 5.7 Hz, 1 H), 7.40(br. s., 2 H) 8 (360 MHz, DMSO-i/6) δ ppm 1.61 - 1.76(m, 2 H), 2.02(d, 7=12.7 Hz, 2 H), 2.36(s, 3 H), 3.1 l(ddd, /=12.6,9.7,2.6 Hz, 2H), 3.60(s, 3 H), 3.67 (dt, /=12.8, 4.2 Hz, 2 H), 5.24 (tt, 7=8.6, 4.2 Hz, 1 H), 6.79(s, 1 H), 7.27 -7.36(m, 1 H ), 7.47 (dd, /=11.1, 8.5 Hz, 1 H), 8.25 (dd, J~lj^ 2.4 Hz, 1 H), 8.64(s, 1 H), 8.90(s, 1 H) 83 201245162

Co. No. 1HNMR Results 14 (360 MHz, CHLOROFORM-fiT) δ ppm 1.08(s, 6 H), 3.16 - 3.24(m, 2 H)^ 3.30(s, 2 H), 3.50 - 3.57(m, 2 H), 3.64(s, 3 H), 3.80(s, 3 H), 6.22(br. s., 1 H), 6.82(d, 7=8.6 Hz, 2 H), 7.09(d, 7=8.6 Hz, 2 H), 7.13 - 7.24(m, 2 H), 8.41(d,7=7.7Hz, 1H) ' 16 (400 MHz, DMSO-c/6) δ ppm 3.02 - 3.15(m, 4 H) , 3.40 - 3.49(m, 4 H), 3.69(s, 3 H), 3.79(s, 3 H), 6.84(d, &gt;9.1 Hz, 2 H), 6.95(d, 7=9.2 Hz, 2 H), 7.37 (t, 7 = 8.9 Hz, 2 H), 7.78 (dd, 7 = 8.8, 5.4 Hz, 2 H) Pharmacology A) Screening method for the compounds of the invention for regulating γ-secretase activity Α 1 Method 1 Screening was performed using SKNBE2 cells with ΑΡΡ695-wild type, which was grown in Invitrogen (catalog number 10371-029) and contained 5% serum/Fe, supplemented with 1% non-essential amino acid, i-bran Plumonium 2 mM, Hepes 15 mM, penicillin 50 U/ml (unit/ml), streptomycin 50 pg/ml of pulbecco's Modified Eagle's Medium/nutrient mixture F_i2 (DMEM/NUT-mix F-12) (HAM). Let the cells grow to almost full. This screening method was performed by modifying the assay described by Citron et al. (1997) Nature Medicine 3:67. Briefly, cells (104 cells/ml) were plated in 384-well plates in Ultraculture medium (Lonza, BE12-725F) containing test compounds at different test concentrations (supplement of 1% branamine (Invitrogen, 25030) -024), 1% non-essential amino acid 84 201245162 (NEAA), penicillin 50 U / m streptomycin 50 pg / ml). The cells/compound mixture was incubated overnight at 37 ° C with 5% C 〇 2 . On the next day, two sandwich immunoassays were performed to analyze the medium Αβ 42 and total Αβ. The total Αβ and Αβ42 concentrations in the cell supernatant were quantified using Aphalisa technology (Perkin Elmer). Alphalisa is a sandwich assay that utilizes a biotinylated antibody attached to a streptavidin-coated donor bead that is then coupled to the acceptor bead. In the presence of the antigen, the beads are in close proximity. The energized donor beads can excite the release of singlet oxygen molecules, initiating a series of energy transfers in the acceptor beads, resulting in light emission. In order to quantify Αβ42 in the cell supernatant, a monoclonal antibody (JRF/cAfl42/26) directed against the C-terminus of Αβ42 was conjugated to the acceptor beads, and a biotinylated antibody directed against the Α-terminal Αβ was used ( JRF/A|3N/25) reacts with the donor beads. In order to quantify the total Αβ content in the cell supernatant, the 抗体-terminal monoclonal antibody pRF/AJ3N/25 for Αβ was coupled to the acceptor beads and the biotinylated antibody against the middle region of Αβ was used. The elementylated 4G8) reacts with the donor beads. In order to obtain the values shown in Table 3, the percentage was calculated from the data with respect to the highest amount of the powdery protein β42 measured without the test compound. The S-type dose-response curve was analyzed by nonlinear regression analysis, and the percentage of the control group was plotted against the logarithmic degree of the compound. The four-parameter formula determines IC5Q. Table 3: 85 201245162 IC50 IC50 Co. AB42 Total Αβ No. (_ (μΜ) 1 0.05 &gt;10 2 0.09 &gt;10 3 0.05 &gt;10 4 0.07 &gt;10 5 0.14 &gt;10 6 0.05 &gt;

Co. No. IC50 AB42 (μΜ) IC50 Total Αβ (μΜ) 7 0.72 &gt;10 8 0.95 &gt;10 9 0.56 &gt;10 10 4.90 &gt;10 11 6.92 &gt;10 12 &gt;10 &gt;10

Co. No. IC50 A/342 _ IC50 Total Αβ (μΜ) 13 ndnd 14 0.11 &gt; 10 15 0.25 &gt; 10 4.07 &gt; 10 B) Confirmation of in vivo efficacy The medicament for reducing Αβ42 of the present invention is used to treat mammals (eg: The AD of humans is demonstrated in potency in animal models such as, but not limited to, petty, rat or guinea pigs. The mammal is not diagnosed with AD or a tendency to AD, but can be over-produced by genetically transgenic methods similar to human AD patients and eventually deposited with Αβ. The reduction of ΑΡ42 can be administered in any standard manner using any standard method. For example, but not limited to, the reduction of Αβ42 may be in the form of an oral or injectable form such as a liquid, a key or a capsule. The agent that lowers Α 42 42 can be administered at any dose sufficient to significantly reduce blood, plasma, sputum, brain fluid (CSF) or Αβ42 in the brain. Non-genetically transfected old teeth (e.g., mice or rats) can be used to determine whether acute administration of an agent that reduces Αβ42 can reduce Αβ42 concentration in vivo. k Check the article to reduce the Αβ42 drug treatment of animals, compared with the untreated group or vehicle treatment group, using standard techniques, for example: using eusa 86 201245162 to quantify the soluble Αβ42 and total Αβ content in the brain. The treatment period ranges from a few hours to several days. Once the time course for the onset of efficacy is established, the treatment period is adjusted based on the Αβ42 decline. The typical procedure presented to determine the extent of Αβ42 decline in vivo is only one of many different methods that are most suitable for determining the detectable Αβ concentration. For example, a compound that reduces Αβ42 can be formulated in an aqueous solution of 2% of Captisol® (sulfobutyl ether of p-cyclodextrin) or 20% hydroxypropyl β-cyclodextrin. The Αβ42-reducing agent is administered to a single oral dose or to any animal that has been fasted for one night according to any acceptable route of administration. After 4 hours, the animals were sacrificed and analyzed for Αβ42 concentration. Blood was collected by decapitation and bloodletting into an EDTA-treated collection tube. The blood was centrifuged at 1900 g for 1 minute at 4 ° C, and the plasma was recovered and rapidly frozen for later analysis. Take care of the brain and take the brain out of the back. Remove the cerebellum and separate the left and right hemispheres. The left hemisphere is kept at _18.匸, for quantitative analysis of test compound concentrations. The right hemisphere was washed with saline buffered saline (PBS) and immediately frozen on dry ice and stored at _80 °C until homogenization was required for biochemical analysis. The brain of the non-transgenic animal was resuspended in 0.4% DEA (diethylamine) / 50 mM NaC per gram of tissue containing protease inhibitor (Roche-11873580001 or 04693159001) using § times volume, for example: 0_158 g added 1.264 ml 0.4% DEA to the brain. All samples were homogenized in a FastPrep-24 system (MP Biomedicals) using lysis medium D (MPBio #6913-100)' at 6 m/s for 20 seconds. The homogenate was centrifuged at 221.300 X g for 50 min. The resulting high-speed supernatant was transferred to a fresh centrifuge tube at 87 201245162. 9 parts of the supernatant were neutralized using 1 part of 0.5 M Tris-HCl pH 6.8 for quantification of total Αβ and Αβ42. In order to quantify the total Αβ and Αβ42 content in the soluble fraction of the brain homogenate, Enzyme_Linked-Immunosorbent-Assays was used. In short, the standard (synthetic Αβ1-40 and Αβ1·) was taken. 42 dilutions, Bachem) added to 1.5 ml

In the Ultraculture in Eppendorf centrifuge tubes, the final concentration range is 10,000 to 0.3 pg/ml. Samples and standards were co-cultured with antibodies to the N-terminally labeled HRPO for detection of Αβ42, and biotinylated mid-domain functional antibody 4G8 was used for detection of total Αβ. Then add 50 μΐ of the vehicle/sample or the mixture/standard mixture to the coated assay disc (the capture antibody that selectively recognizes the C-terminus of Αβ42 is the antibody JRF/cAB42/26 for detection of Αβ42, And the capture antibody that selectively recognizes the Ν-end of Αβ is the antibody JRF/rAfl/2 for detection of total Αβ). Let the analysis be at 4. (: culture overnight for the formation of antibody-amyloid complex. Following the incubation and washing steps, the Quanta Blu-producing peroxidase substrate was added according to the manufacturer's instructions (Pierce Corp., Rockford, II). The ELISA for quantification of Αβ42 was completed. The value was read after 10 to 15 min (excitation light 320 nm / emission light 420 nm). When total Αβ was detected, anti-streptomycin-peroxidase-complex was added, after 60 minutes. Quanta Blu produces a fluorescent peroxidase substrate according to the manufacturer's instructions (Pierce Corp., Rockford, II). The value is read after 10 to 15 minutes (excitation light 320 / emission light 420). 88 201245162 This mode Among them, it should be at least 20% lower than the control animals. Αβ42 is favorable. The results are shown in Table 4 (oral dose 30 mg/kg) (the value of untreated animals (Ctrl) as a control group is 1〇〇):

Co. Αβ42 (% relative to the control group total Αβ (% relative to the control group) _ average %) _ average 14 78 111 6 45 109 1 50 107 Composition examples These examples use "active ingredients" (ai) is a compound of the formula (I), including any stereochemically isomeric form thereof, a pharmaceutically acceptable salt thereof, or an octa-valley compound, any of the exemplified compounds. Examples of typical formulations of the formulations of the present invention are as follows: Ingredients 5 to 50 mg of linolenic acid 2 J 丐 20 mg Lactose 30 mg Talc 10 mg Magnesium stearate 5 mg Ma Ling Shan Dian powder added to 200 mg 201245162 2. Preparation of suspension An aqueous suspension for oral administration comprising 1 to 5 mg of active ingredient per ml, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and 1 ml of water. 3. Injection The parenteral composition was prepared by stirring 1.5% (w/v) of the active ingredient in 0.9% NaCl solution or 10% by volume in an aqueous solution of propylene glycol. 4. Oil taste active ingredient 5 to 1000 mg Stearyl alcohol 3g Lanolin 5g White petrolatum 15 g Water added to 100 g In this example, the active ingredient may be replaced with an equivalent amount of any one of the compounds according to the present invention, specifically modified Replace with an equivalent amount of any of the exemplified compounds. Reasonable variations are not to be regarded as a departure from the scope of the invention. It is understood that the person skilled in the art can change the described invention in many ways.

Claims (1)

201245162 VII. Patent application scope: 1. A compound of formula (I), R1 R4a or a stereoisomeric form thereof, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halo, (^-4 alkyl, Cm alkoxy, substituted with one or more substituents) (^_4 alkyl, Cm alkoxy substituted with one or more halo substituents; L1 is NR6, anthracene, carbonyl or a covalent bond; wherein R6 is hydrogen or Cm alkyl; R3 represents Q_4 alkyl; Ruler 43 and R4b are each independently selected from the group consisting of hydrogen and Cm; Z is N or CH; L2 is Ο, CH2 or a covalent bond; however, the restriction is that when L2 is Ο, X is CH; R5 is hydrogen or Cm alkyl; Y1 is CH or N; Y2 is CR7 or N; wherein R7 represents hydrazine or Cm alkoxy; or a pharmaceutically acceptable addition salt thereof, or a combination thereof 201245162 2. A compound according to claim 1 wherein R4a is the same as R4b and represents a nitrogen or C1 _4 alkyl group. 3. A compound according to claim 1 wherein R1 and R2 are each independently selected from the group consisting of In the group consisting of: hydrogen, a halogen, a Cm alkyl group, a Cm alkyl group substituted with one or more halo substituents, and substituted with one or more halo substituents Cm alkoxy; L1 is NH or a covalent bond; R3 represents a Cm alkyl group; R4a is the same as R4b and both represents hydrogen or Cm alkyl; X is N or CH; L2 is hydrazine, CH2 or a covalent bond; The restriction is that when L2 is Ο, then X is CH; R1 2 3 is hydrogen or Cm alkyl; Y1 is CH or N; and Y2 is CR4 or N; wherein R4 represents Cm alkoxy. The compound of the above item 1, wherein 2 R1 and R2 are each independently selected from the group consisting of hydrogen, fluorine, sulfhydryl, trifluoromethyl, and trifluoromethoxy; L1 is NH or a covalent bond R3 represents a fluorenyl group; 3 R4a is the same as R4b and both represent hydrogen or a fluorenyl group; 4 X is N or CH; 201245162 L2 is Ο, CH2 or a covalent bond; however, the constraint is that when L2 is 0, then X Is CH; R5 is hydrogen or hydrazine; Υ1 is CH or hydrazine; Υ2 is CR1 2 or hydrazine; wherein R2 represents a decyloxy group. 5. A compound according to claim 1 wherein R1 is at the 2-position and a group selected from the group consisting of halo, Cm alkyl, (^-4 alkoxy, Cm alkyl substituted with one or more i-substituents, and substituted with one or more substituents Alkane oxygen And the R2 thereof is selected from the group consisting of hydrogen, halo, alkyl, Cm alkoxy, Cm alkyl substituted with one or more i-substituents, and one or more A CV4 alkoxy group substituted by a halo substituent. 93 1 A compound according to claim 1, wherein R1 represents a fluorenyl group and is at the 2-position, and R2 represents hydrogen or fluorine and is at the 4-position; 2 L1 is NH R3 represents a methyl group; Ruler 43 is the same as 11415 and both represent a thiol group; X is N; L2 is a covalent bond; R5 is hydrogen; 201245162 Y1 is CH; Y2 is CR7; wherein R7 represents a methoxy group. 7. A compound according to claim 1 wherein L1 is NR6 or a covalent bond. 8. A compound according to item 7 of the patent application, wherein L1 is NH. 9. A compound according to claim 1 wherein X is a covalent bond between N and L2. 10. The compound according to claim 1, wherein the compound is selected from the group consisting of: 3-[4-(4-decyloxyphenyl)-3,3-diindenyl-1 -旅0井基]-1-mercapto-N-(2_nonylphenyl)-1Η-1,2,4-triazole-5-amine, N-(4-fluoro-2-methylphenyl )-3-[4-(4-methoxyphenyl)-3,3-diindenyl-1-pipedyl]-1-indolyl-1H-1,2,4-triazole_5- Amine, and N-(4-fluoro-2-indolylphenyl)-3-[4-(4-decyloxyphenyl)-3,3-dimethyl-1 _piperidinyl-1- Mercapto-1H-1,2,4-triazole-5-amine.1.2 HC1.1.5 H20, its stereoisomeric form, and its pharmaceutically acceptable addition salts and solvates. 94 201245162 A medical compound containing the root of the therapeutically effective f. Please supplement (4) to 4 and use the compound as an active ingredient. According to any of the patent applications, it is used as a medicine according to the patent application scope. Defining as defined in any one of items 1 to 10. 13. According to any one of items 1 to 10 of the scope of application of the patent, it is determined that the group consists of the following groups: two V, C ? · Alzheimer's disease, traumatic brain injury, mild cognitive makeup, dementia, dementia associated with Lewy body, brain starch lesions, multiple infarction, dementia, boxer dementia, Tang = Deaf group, dementia associated with Parkinson's disease and related dementia. 2 = the patent scope of 13 compounds of 'the disease is 95 201245162 IV. Designated representative map: (1) The representative representative of the case is: No (2) The symbol of the representative figure is a simple description: No five, if the case has In the chemical formula, please reveal the chemical formula that best shows the characteristics of the invention: None 3