WO2012013012A1 - Benzo-azacyclic hydroxyethylamine compound, preparation method and uses thereof - Google Patents

Abstract

Disclosed are a benzo-azacyclic hydroxyethylamine compound, a preparation method and uses thereof, where the compound is shown as formula (I). A composition containing such compound is also disclosed. The compound can markedly inhibit Betasecretase 1 (BACE 1), and would be used as drugs for preventing or treating diseases characterized by enhanced β-amyloid level or β-amyloid deposits, such as Alzheimer's disease, Parkinsonism's disease or Down's disease and so on.

Description

 Benzodiazepine heterohydroxyethylamine compound, preparation method and use thereof

 The invention belongs to the field of medicinal chemical industry and relates to a benzoazepine heterocyclic hydroxyethylamine compound, a preparation method thereof and use thereof. The invention also relates to a pharmaceutical composition comprising such a compound, a method of treating and/or preventing a disease characterized by elevated P-amyloid levels or P-amyloid deposits, in particular Alzheimer's disease And a method of modulating BACE1 activity or modulating P-amyloid levels in vivo or in vitro. Background technique

 Alzheimer's disease is a common senile neurodegenerative disease that has become the fourth leading killer of cardiovascular disease, malignant tumors and post-stroke health threats in the elderly. The key pathological feature of Alzheimer's disease is the formation of senile plaques (Seni le Plaque, SP) outside the nerve cells, and the main component of senile plaques is β-amyloid (A β ), which is neurotoxic and can cause inflammatory reactions. Nerve cell death. According to the pathological hypothesis of the P-amyloid (Aβ) cascade proposed by Hardy et al. in 1992, Αβ is a β-amyloid precursor protein (ΑΡΡ) followed by Ρ-secretase (BACE1), γ-secretase Obtained by cleavage.

BACE1 (also known as Asp2, Memaps in2) belongs to the aspartic acid acid-drug family and has the characteristics of P-secretase. It is the rate-limiting enzyme catalyzed AP generated (Hardy J., Higgins GA Science, 1992, 256 (5054): 184-185) ₀ BACE1 catalytic hydrolysis principle is: the catalytic center of a two aspartic acid residue activated water Molecule, nucleophilic attack on substrate peptide bonds causes hydrolysis to break (31111^211 11., 61 & 1., Mol. Cellar Biol., 2008, 28 (11): 3663-3671). Therefore, ACE ACE 1 is considered to be a valid ί& standard for the treatment of Alzheimer's disease (Ghosh AK, et al., Neuro thera peu tics, 2008, 5: 399 - 408). Strategies to alleviate or treat Alzheimer's disease by inhibiting BACE1 activity to reduce AP levels in the brain have been widely accepted. BACE1 inhibitors are not only highly effective as a therapeutic agent for Alzheimer's disease, but their selectivity for BACE1 should be stronger than for other members of the aspartic protease family (eg BACE2, cathepsin D, etc.) Sex (Saunders AJ, et al., Science, 1999, 286 (5443): 1255-1255).

 Since the first generation of the BACE1 inhibitor OM99-2, a large number of literatures have reported different types of BACE1 inhibitors. Most of these inhibitors are BACE1 catalyzed transition state mimics, that is, two days through the catalytic center. The amino acid residues interact to exert an inhibitory activity of 'I (Ghosh AK, Gemma S., Tang J. Neuro therapeutics, 2008, 5: 399-408). The core structures according to their action can be roughly divided into several categories, such as s tat ine, nors tat ine, hydroxye thy 1 amine inhibitors.

 However, there is still a need to discover new BACE1 inhibitors with good pharmaceutical properties. Summary of the invention

 The inventors have obtained a class of benzodiazepine heterohydroxyethylamine compounds through creative labor and intensive research, and surprisingly found that these compounds can significantly inhibit BACE1, in which TruPointTMP-secretase is used. The assay kit was evaluated at the molecular level, and some of the compounds even reached micromolar levels. The compounds of the invention have the effect of preventing diseases characterized by elevated P-amyloid levels or P-amyloid deposits (eg, Alzheimer's disease, Parkinson's disease, or Down's syndrome, etc.) The prospect of drugs. The following invention is thus provided:

One aspect of the invention relates to a compound of formula U), a pharmaceutically acceptable salt thereof, or a solvate thereof:

 (I)

 among them,

-AB- selected from -CH=CH -, -(CH ₂ ) ₂ -, - CH=N -, CH ₂ -NH -, - N=CH -, -NH-CH ₂ -, -(CH ₂ ) ₃ -, -CH=CH-CH ₂ -, -CH wide CH-CH -, -N=CH-CH ₂ -, -NH-CH=CH-, -NH-CH ₂ -CH ₂ - , -CH=N -CH ₂ - , -CH ₂ -N=CH-, -CH-wide NH-CH ₂ -, -CH ₂ -CH=N -, -CH=CH-NH -, and -CH ₂ -CH ₂ -NH- ;

R ^{1 is} selected from the group consisting of hydrogen, -S0 ₂ -R ⁵ , and -CO-R ⁵ ;

R ² is selected from d- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl group, (^ cycloalkyl, -d-6-alkyl -. C3-I O pit ring group, - Co- 6 pit-aryl, -Co-6-heteroaryl, and -Co-6 alkyl-heterocyclic;

R ^{3 is} selected from the group consisting of hydrogen and Cw. Alkyl, CH. Alkenyl group, C ₃ - ₁₀ alkynyl, d. Cycloalkyl, -Cw. Cycloalkenyl, -C. — ₆ alkyl-aryl, —C. - ₆ alkyl-heteroaryl, -C _{0 -6} alkyl-heterocyclyl, -Cl-6 alkyl-C3-0 cycloalkyl, -C ₃ -10 cycloalkyl-aryl, -C ₃ -] 0 ring-alkyl-heteroaryl, - Cw. Cycloalkyl-heterocyclyl, -C ₃ - i. Cycloalkyl - d- ₆ alkyl - aryl, - heterocyclyl - aryl, - d- ₆ alkyl - aryl group - ^{heteroaryl, -C (R 8 R 9)} -CONH-d-6 alkyl Base, -CO^lO -CONH-Cw. Cycloalkyl, -C _{2 -6} alkyl-S-d- ₆ alkyl, -C ₂ - ₆ alkyl-NR^R ¹¹ , -C (R ⁸ R ⁹ ) - alkyl, -C (R ⁸ R ⁹ ) -C. - ₆ alkyl-aryl, -C (R ⁸ R ⁹ ) -C. - ₆ alkyl-heteroaryl, -C (R ⁸ R ⁹ ) -C. - ₆ alkyl-heterocyclyl, -C ₂ - ₆ alkyl-0-C. - ₆ alkyl-aryl, -C ₂ - ₆ alkyl-0-C. - ₆ alkyl-heteroaryl, and -C ₂ - ₆ alkyl-0-C. a _6- alkyl-heterocyclic group, wherein R ⁸ and R ⁹ are each independently selected from hydrogen, d- ₆ alkyl or R ⁸ and R ⁹ together with the carbon atom to which they are attached. a cycloalkyl or heterocyclic group; R ^ie and R ¹¹ may independently represent hydrogen, d- ₆ alkyl. a cycloalkyl group, and a nitrogen atom to which 1 and R ¹¹ are attached Forming a nitrogen-containing heterocyclic group together;

R ^{4 is} selected from the group consisting of hydrogen, d- ₆ alkyl, halogen, halogenated d- ₆ alkyl, _-6 alkenyl, C ₂ - ₆ block, cyano, nitro, hydroxy, -C. - ₆ alkyl-0R ⁶ , -C. - _6- alkyl-NR ⁶ R ⁷ , -Co-6 alkyl-SR ⁶ , -C. - ₆ alkyl - 0C0R -C. - ₆ alkyl - C00R ⁶ , -C. - _6- alkyl-NR ⁶ C0R', -C. - ₆ alkyl-C0NR ⁶ R ⁷ , -C. - ₆ alkyl-S0 ₂ NR ⁶ R ⁷ , -C. - ₆ alkyl-NHC0NHR ⁶ , or -C. ₆ alkyl-C0R ⁶ , wherein R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, d- ₆ alkyl, haloalkyl, C _{3 -1Q} cyclodecyl, and substituted. Cycloalkyl, -C. - ₆ alkyl-aryl, -C. - ₆ alkyl-heteroaryl, and -C. — ₆ alkyl-heterocyclic groups;

 m represents an integer from 0 - 3 (eg 0, 1, 2 or 3);

R ^{5 is} selected from the group consisting of hydroxyl groups, -C. - ₆ alkyl-0R ⁶ , - C. - ₆ alkyl-NR ⁶ R ⁷ , C, - ₆ fluorenyl, C _{3 -6} alkenyl, C ₃ - ₆ block, C ₃ -,. Cycloalkyl, -C. - ₆ alkyl-aryl, -C. — ₆ alkyl-heteroaryl, —C. - ₆ alkyl-heterocyclic group, - Cw. Cycloalkyl-aryl, -. a cycloalkyl-heteroaryl group, and a -C _{3 -1Q} cycloalkyl-heterocyclyl group; wherein, optionally, an aryl group, a heteroaryl group or a heterocyclic group in R ⁵ is taken at a different substitution position or more of the following radicals substituted with: d- ₆ alkyl, ¾ element, ¾ substituting d_ ₆ alkyl, (: ₂ - ₆ alkenyl, C _2--6 alkynyl, cyano, nitro, oxo, - Co-6 alkyl-0R ^fi , -C _{0 -6} alkyl-SR ⁶ , -Co-6 alkyl-0C0R ⁶ , -C._ ₆ alkyl-C00R ⁶ , -C.- ₆ alkyl-NR ⁶ C0R ⁷ , -C.- _6- alkyl-C0NR ⁶ R ⁷ , -C.— ₆ -yl-S0 ₂ NR ⁶ R ⁷ , -C.— _6- alkyl-NHC0NHR ^fi , -C.- ₆ alkyl -NR ^fi R ⁷ , or -C _Q - ₆ -alkyl ⁶ ; wherein, and R ⁷ are each independently selected from the group consisting of hydrogen, d- ₆ alkyl, halo d- ₆ alkyl, cycloalkyl, halo a cycloalkyl group, a C-- ₆ alkyl-aryl group, a C-- ₆ alkyl-heteroaryl group, and a -C-- ₆ alkyl-heterocyclic group;

 among them,

The aryl group is a C ₆ - ₁₂ monocyclic or bicyclic hydrocarbon ring, wherein at least one ring is an aromatic ring; the heteroaryl group is 5 - 6 yuan containing 1 - 4 hetero atoms selected from oxygen, nitrogen and sulfur a monocyclic aromatic ring or a fused 8- to 12-membered bicyclic aromatic ring;

The heterocyclic group is 4 to 7 members containing 1 to 4 hetero atoms selected from oxygen, nitrogen and sulfur. Monocyclic or fused 8- 12-membered bicyclic rings which are saturated or partially unsaturated. Examples of the aryl group include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and the like. Examples of heteroaryl groups, wherein examples of monocyclic aromatic rings include, but are not limited to, hayl, thiol, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, Oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl, tris Examples of fused aromatic ring groups include, but are not limited to, quinolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, acridinyl, porphyrinyl, 2, 3- Naphthyridinyl, naphthyridinyl, fluorenyl, isodecyl, azaindole, mesoindolyl, carbazolyl, fluorenyl, pyrrolopyridinyl, furopyridinium Base, benzofuranyl, isobenzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxazole A oxazolyl group, a benzothiadiazolyl group, and the like.

Examples of the heterocyclic group, wherein, examples of the monocyclic ring include, but are not limited to, pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl , thiomorphol inyl, thiazolyl group, hydantoinyl, valerolactamyl, oxiranyl, azetidinyl, dioxolane, Dioxolyl, oxathiolanyl, oxathianyl, di thianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyridyl Meryl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepyl, azepanyl, and the like. Examples of bicyclic rings include, but are not limited to, dihydroindenyl, isoindoline, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1 3-benzonitrile Weed (benzazepine), tetrahydrogen Isoquinolyl and the like.

 The compound of the formula (I) contains at least one amino group which can form various salts with an acid as a form of pharmaceutical application. It should be understood that when used in medicine, the salt of the compound of formula (I) should be pharmaceutically acceptable, including

Salts as described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates , acetate, benzoate, citrate, nitrate, succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palm An acid salt, a methanesulfonate, a p-toluenesulfonate, a naphthalenesulfonate, a decanoate, or a trifluoroacetate.

 The compound of formula (I) can be prepared in crystalline or amorphous form, the crystalline form of which may contain solvent molecules, and if crystalline, may optionally be solvated, such as a hydrate. The present invention includes stoichiometric solvates (e.g., hydrates) and compounds containing variable solvents (e.g., water) within its scope.

 The compound of formula (I) contains a plurality of chiral centers, and some of the compounds of formula (I) can exist in stereoisomeric forms (such as diastereomers and enantiomers), and the invention extends to these stereo Each of the isomeric forms and mixtures thereof, including racemates. The different stereoisomeric forms can be separated from other forms by conventional methods, or any of the formulated isomers can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric form and mixtures thereof. Specifically, the compound of formula (I) is a single enantiomer or diastereomeric form of the compound of formula (I a):

Wherein -AB -, R ¹ , R ² , R ³ , R ⁴ , m are as defined above, respectively.

 In one embodiment of the invention,

-AB- selected from -CH=CH-, -(CH ₂ ) ₂ -, -CH=N -, CH ₂ -NH -, -N=CH -, and -NH-CH ₂ -;

R ¹ is -S0 ₂ -R ⁵ or -C0-R ⁵ ;

R ² is d- ₆ alkyl or -C. — ₆ alkyl-aryl ί

R ³ is -C ₃ -iocycloalkyl or -C. - ₆ alkyl-aryl;

R ^{4 is} selected from the group consisting of hydrogen, d- ₆ alkyl, halogen, NR ⁶ R\ and -OR ⁶ ;

 m means 2;

R ^{5 is} selected from -C. - ₆ alkyl-0R ⁶ , - C. - _6- alkyl-NR ⁶ R ⁷ , d- ₆ alkyl, - C. - ₆ alkyl-aryl, and -C. a ₆ alkyl-heteroaryl group; wherein the aryl, heteroaryl or heterocyclic group in R ⁵ may be substituted at a different substitution position by one of the following groups: halogen, -C. - ₆ alkyl-0R ⁶ , -C. - ₆ alkyl-NR ⁶ R ⁷ , or -C. - ₆ alkyl-C0NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are each independently selected from hydrogen, d- ₆ alkyl. Cycloalkyl, -C. - ₆ alkyl-aryl, -C. - _6- mercapto-heteroaryl, and -C. - ₆ alkyl-heterocyclic group ^

 Wherein the heteroaryl group is selected from the group consisting of: thienyl, furyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, pyranyl, pyrazolyl, pyrimidinyl , pyridazinyl, pyrazinyl, pyridyl, fused aromatic ring group, etc., wherein the fused aromatic ring group includes quinolyl, isoquinolyl, fluorenyl, isodecyl, nitrogen a heterocyclic group, a carbazolyl group, a fluorenyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, and a benzisothiazolyl group; The group is selected from the following structures: pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, limazinyl, morpholinyl, oxiranyl, azetidin Base, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydropyridyl.

 In one embodiment of the invention,

-AB- is -CH=CH-; R ¹ is - SO wide R ⁵ ;

R ² is a benzyl group;

R ^{3 is} selected from the group consisting of benzyl, methoxybenzyl, and cyclopropyl;

R ⁴ is hydrogen;

 m means 2;

R ^{5 is} selected from the group consisting of phenyl, decyloxyphenyl, propyl, thienyl, benzylamino-phenyl, ethyl-phenyl, and phenyl substituted by one fluorine or chlorine.

 In one embodiment of the invention,

 The compound of formula (I) is selected from the group consisting of:

 N-[(IS, 2R)-3-cyclopropylamino-2-hydroxy-1-benzyl]-1-methylsulfonyl 4- 4-carboxamide;

 N-[(IS, 2R)-3-cyclopropylamino-2-hydroxy-1-yl]-1-phenylsulfonyl-4-phthalamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-benzenesulfonyl-4-carboxamide;

 N-[(1S, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(4-methoxy-benzenesulfonyl)-4-carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(4-fluoro-benzenesulfonyl)-4-carboxamide;

N-[(1S, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(3-chloro-benzenesulfonyl) ^-4 -carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(1-propanesulfonyl)-4-carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(2-thienyl-sulfonyl)-4-carboxamide;

N-[ (IS, 2R) -3-cyclopropylamino-2-hydroxy-1-benzyl]-1-(4-methoxy- Benzenesulfonyl)-4-carboxamide;

 N-[(1S, 2R)-3-cyclopropylamino-2-hydroxy-1-benzyl]-1-(2-thienyl-sulfonyl)-4-indolamide;

 N-[(1S, 2R)-3-(3-methoxy-benzyl)amino-2-hydroxy-1-benzylbenzenesulfonyl-4-carboxamide;

 N-[(1S, 2R)-3-(3-decyloxy-benzyl)amino-2-hydroxy-1-benzyl]-1-(4-methoxy-benzenesulfonyl)-4-methyl Amide

 N-[(1S, 2R)-3-(3-decyloxy-benzyl)amino-2-hydroxy-1-benzyl

 (3-chloro-benzenesulfonyl)-4-carboxamide;

 N-[(1S, 2R)-3-(3-decyloxy-benzyl)amino-2-hydroxy-1-benzyl

 (1-propanesulfonyl)-4-carboxamide;

 N-[(IS, 2R)-3-Benzylamino-2-hydroxy-1-benzyl]-1-[3-(benzylamino-)-benzenesulfonyl)-4-carboxamide. Another aspect of the invention relates to a process for the preparation of a compound of formula (I) above, which comprises the steps of: using dimethylformamide and/or dichloromethane as solvent, carbodiimide and/or HOBt as condensing agent, The reaction temperature of the compound of the formula (Π) with the compound of the formula (m) in the presence of triethylamine is between ox: and room temperature,

Wherein -AB -, R ¹ , R ² , R ³ , R\ m are as defined above, respectively.

Compounds of the above formula ((R) or formula (III) can be prepared according to the prior art to those skilled in the art. For example, when R ¹ represents S0 ₂ -R ⁵ , the compound of the formula (Π) can be prepared as follows:

(IV) (V) (Ha) Step (i) is typically included at a suitable temperature, such as 0-60·€, in the presence of a suitable base such as NaH, potassium carbonate, with a compound of the formula R ⁵ S0 ₂ C1 A solvent such as disulfoxide (DMS0) and tetrahydrofuran (THF) are reacted.

Step (ii) typically involves the formation of hydrazine in a suitable solvent such as dioxane or methanol (MeOH) at a suitable temperature, such as room temperature, under conditions of 1.5 N LiOH/H ₂ 0. The reaction of the base protection removal.

Wherein R ³ and R ⁴ are as defined above, and P ¹ represents a suitable amino protecting group such as t-butoxycarbonyl.

Step (iii) typically comprises reacting a compound of formula (VI) with an amine (NH ₂ -R ³⁾ a suitable temperature in a suitable solvent such as ethanol in the presence of, as at the reflux temperature of the reaction.

Step (iv) typically includes, as when P ¹ represents a tert-butoxycarbonyl group, the deprotection reaction typically uses trifluoroacetic acid in a suitable solvent such as dichloromethane at a suitable temperature, such as between 0 and room temperature. Carry out the reaction.

Compounds of formula (IV) and formula (VI) are either commercially available or can be prepared from commercially available compounds using standard test procedures. A further aspect of the invention relates to a pharmaceutical composition comprising a compound of the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier or adjuvant.

 In one embodiment of the invention, the pharmaceutical composition further comprises at least one of the following: an acetylcholinesterase inhibitor, an inhibitor against amyloid aggregation, a Y-secretase inhibitor, an a-secretase agonist Agents, anti-inflammatory agents, and antioxidants. A further aspect of the invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof thereof as a BACE1 inhibitor. In one embodiment of the invention, the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof thereof as a secretase inhibitor is contemplated.

 A further aspect of the invention relates to the preparation of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof thereof, for reducing P-amyloid in a mammal, particularly a human, particularly in the brain Use in medicine.

 Still another aspect of the present invention relates to the use of the above compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof for the preparation of a medicament for treating Alzheimer's disease, Parkinson's disease, or Down's syndrome . A further aspect of the invention relates to a method of treating and/or preventing a disease characterized by elevated amyloid levels or P-amyloid deposits in a human or animal, the method comprising administering to a human or An animal effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The diseases characterized by elevated P-amyloid levels or P-amyloid deposits include, but are not limited to, Alzheimer's disease, Parkinson's disease, Down's syndrome, and the like.

According to the invention, the compound of formula (I) can be formulated in any conventional manner For administration, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, is formulated with one or more physiologically acceptable diluents or carriers.

When used in the above treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of a compound of the invention may be applied in pure form or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of such forms) . Alternatively, the compound can be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients. The phrase "prophylactically and/or therapeutically effective amount" of a compound of the invention refers to a sufficient amount of a compound to treat the disorder in a reasonable effect/risk ratio suitable for any medical prophylaxis and/or treatment. It will be appreciated, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained. 001-1000 mg/kg重量/天, for example, between 0. 01-100 mg/kg body weight/day, for example, in the case of a mammal, especially a human. 01-10 mg / kg body weight / day. A further aspect of the invention relates to a method of modulating BACE1 activity or modulating P-amyloid levels in vivo or in vitro, comprising using an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof A step of. In the present invention, the alkyl, alkenyl, alkynyl and cycloalkyl groups not specifically mentioned above may be optionally substituted by one or more (for example, 1 to 6) of the following groups: halogen, D- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, halo d- ₆ alkyl, d- ₆ alkoxy, amino, cyano, hydroxy, -C00R ¹² , -Sd- 6 alkyl or -d- ₆ alkyl-NR ¹² R ¹³ . Wherein R ¹² and R ^{1 3} independently represent hydrogen, d- ₆ alkyl or. Cycloalkyl.

The aryl, heteroaryl or heterocyclic group not specifically indicated as described above may be optionally substituted by one or more (e.g., 1-6) of the following groups at different substitution positions: d- ₆ alkyl, Prime, ^ ₆ alkyl, halogenated d- ₆ alkoxy, hydroxy, d-6 alkoxy,

C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, amino, cyano, nitro, -C00R ¹⁴ , -NR ¹⁴ COR ¹⁵ , -CONR ¹⁴ R] ⁵ , -S0 ₂ NR"R ¹⁵ , -NR ¹⁴ R ¹⁵ , -C alkyl-NR ¹⁴ R ¹⁵ , -d- ₆ alkyl-0-CH alkyl, -d- ₆ alkyl- 0C0R ¹⁵ , wherein R" and R ¹⁵ independently represent hydrogen, D- ₆ alkyl or. Ring base.

The "C alkyl group" (e.g., dC ₆ alkyl) means a term as a group or part of a group used herein containing X to y carbon atoms, straight-chain or branched saturated hydrocarbon chain. Examples of such groups include mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl Wait.

The term "C _X - _Y chain dilute" as used herein refers to one or more carbons

a linear or branched hydrocarbon group having a carbon double bond and having x-y carbon atoms. Examples of such a group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group or a hexenyl group.

The term "C _{X -Y} alkynyl" as used herein refers to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds and having xy carbon atoms. Examples of such a group include an ethynyl group, a propynyl group, a butyl group, a pentynyl group or a hexynyl group and the like.

As used herein, the term "d- _y-alkoxy" refers to -0-C _x - _y alkyl, wherein C _X - _Y group as defined herein. Examples of such groups include decyloxy, ethoxy, Propyloxy, butoxy, pentyloxy, hexyloxy and the like.

The term " _Cx - _ycycloalkyl " as used herein refers to a saturated monocyclic hydrocarbon group containing from X to y carbon atoms. Examples of such a group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.

 The term "(^cycloalkenyl) as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon group of from X to y carbon atoms of one or more carbon-carbon double bonds. Examples of such groups include Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.

In the above "C _x - _y ", X and Y respectively indicate that the number of carbon atoms of the group is from X to Y, and when the number of carbon atoms is zero, it means that there is no such group, for example, C. Alkyl-aryl represents the absence of an alkyl group, i.e., only an aryl group.

The term "halogen" as used herein refers to a fluorine, chlorine, bromine or iodine atom. The term "substituted C alkyl" as used herein refers to a _Cx - _y alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halogen. Examples of such a group include a fluoroethyl group, a trifluoromethyl group.

The term "3⁄4 _Cx - _y alkoxy" as used herein refers to a C alkoxy group, as defined herein, wherein at least one hydrogen atom is replaced by a halogen. detailed description

 The embodiments of the present invention are described in detail below with reference to the accompanying drawings. Those who do not specify the conditions in the examples are subject to the usual conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that are commercially available.

 The abbreviations used in the present invention have the following meanings:

DMF dimercaptoamide DCM dichloromethane

 DMSO dimethyl hydrazine

 THF tetrahydrofuran

 EDC N-ethyl-N,-3-diammonium carbodiimide hydrochloride

 Diox dioxane

 HOBt 1-Hydroxybenzotriazole The following Examples 1 - 8 relate to the preparation of the acid A1 - A8.

Example 1: Preparation of 1-(methylsulfonyl)-indole-4-carboxylic acid (No. A1) NaH (0.55 g, 16 mmol) was placed in a one-neck round bottom flask, and DMSO (6 ml) was added. , I 吲哚-4-carboxylic acid oxime ester (2 g, 11. 4 mmol) was dissolved in THF, the solution in which the ruthenium substrate was dissolved was slowly added dropwise to the DMS0 solution, and the reaction was carried out for 3 hours or more. . Further, mercaptosulfonyl chloride (1.32 ml, 24 mmol) was added to the reaction mixture, and the reaction was carried out for 2 h or more. The reaction solution was poured into H ₂ 0, extracted with DCM, and the organic layer was combined, washed with saturated NaCl, and dried over anhydrous Na ₂ SO _{4 for} 6 h or more. 8克。 The drying agent was filtered, and the solvent was evaporated under reduced pressure. The solid was placed in a single-necked round bottom flask, Diox was added, 1.5 N LiOH/H ₂ 0 solution (15 ml) was added dropwise, and the reaction was carried out for 1 h or more, and H ₂ 0 (30 ml) was added thereto, and pH 2 was adjusted by IN HC1 to precipitate. The title compound (Al) was obtained as a white solid. Example 2: Preparation of 1-(phenylsulfonyl)-indole-4-carboxylic acid (No. A2) according to the similar procedure described for the synthesis of (A1), but using phenylsulfonyl chloride instead of mercaptosulfonate The acid chloride is prepared to give 1-(phenylsulfonyl)-indole-4-carboxylic acid (A2). Example 3: Preparation of 1-(4-methoxyphenylsulfonyl)-indole-4-carboxylic acid (No. A3) NaH (0. 235 g, 6. 9 mmol) was placed in a succinient round bottom flask, EtOAc (10 mL) The solution in which the ruthenium substrate was dissolved was slowly added dropwise to the DMSO solution for 3 hours or more. Further, a THF solution in which (1. 53 g, 7.4 mmol) of 4-methoxyphenylsulfonyl chloride solid was dissolved was added to the reaction mixture, and the mixture was reacted for 2 hours or more. The reaction solution was poured into H ₂ 0, extracted with DCM, and the organic layer was combined, washed with saturated NaCI solution and dried over anhydrous Na ₂ SO _{4 for} 6 h or more. The lyophilic acid was filtered off, and the solvent was evaporated under reduced pressure. The solid was placed in a single-necked round bottom flask, Diox was added, 1.5 N LiOH/H ₂ 0 solution (30 ml) was added dropwise, and the reaction was carried out for 2 h or more, and H ₂ 0 (30 ml) was added thereto, and pH 2 was adjusted by IN HC1 to precipitate. The title compound (A3) was obtained as a white solid. Example 4: Preparation of 1-(4-fluorophenylsulfonyl)-indole-4-carboxylic acid (No. 4)

 According to the similar method for the synthesis of (A3), but using 4-fluorophenylsulfonyl chloride instead of 4-methoxyphenylsulfonyl chloride, 1-(4-fluorophenylsulfonyl)-indole was obtained. 4-carboxylic acid (Α4). Example 5: Preparation of 1-(3-chlorophenylsulfonyl)-indole-4-carboxylic acid (No. Α5)

According to the similar method described for the synthesis of (A3), but using 3-chlorophenylsulfonyl chloride instead of 4-decyloxyphenylsulfonyl chloride, 1-(3-chlorophenylsulfonyl)-indole was obtained. 4-carboxylic acid (Α5). Example 6: Preparation of 1-(thiophenesulfonyl)-indole-4-carboxylic acid (No. 6) was carried out in a similar manner as described for the synthesis of (A3), but using thiohethanesulfonyl chloride instead. 4-methoxyphenylsulfonyl chloride, 1-(thienylsulfonyl)-indole-4-carboxylic acid (A6) was obtained. Example 7: Preparation of 1-(propylsulfonyl)-indole-4-carboxylic acid (No. A7) according to the similar procedure described for the synthesis of (A1), but using propylsulfonyl chloride instead of methylsulfonate The acid chloride was prepared to give 1-(propylsulfonyl)-indole-4-carboxylic acid (A7). Example 8: Preparation of 1-(3-(benzylcarbamoyl)-benzenesulfonyl)-indole-4-carboxylic acid (No. A8)

NaH (0. 69 g, 19. 8 ol) was placed in a single-neck round bottom flask, EtOAc (10 mL) This solution in which the ruthenium substrate was dissolved was added to the DMSO solution and reacted for 3 hours or more. A THF solution in which m-carboxybenzenesulfonyl chloride solid (2.4 g, 10.8 mmol) was dissolved was added to the reaction solution, and the reaction was carried out for 4 hours or more. The reaction solution was poured into cold H ₂ 0, extracted with DCM, and the organic layer was combined, washed with a saturated NaCI solution and dried over anhydrous Na ₂ SO _{4 for} 6 h or more. The desiccant was filtered off, the solvent was evaporated under reduced pressure, and purified by column chromatography, and then purified to afford white crystals of 1-(3-carboxybenzenesulfonyl)-indole-4-carboxylate as a white solid. Methyl 1-(3-carboxybenzenesulfonyl)-indole-4-carboxylate (1 g, 2. 8 mmol), EDC'HCl (0. 56 g, 2. 94 mmo l) The round bottom flask was dissolved in DCM, and the mixture was stirred at room temperature for a while, and benzylamine (0. 31 g, 2.94 mmol) was added thereto, and the mixture was reacted at room temperature for 2 h or more. Supplemented with DCM, washed with saturated NaCl solution, the organic layer was dried over anhydrous Na ₂ S0 ₄ was dried over 6h, the drying agent was filtered off, the solvent was distilled off under reduced pressure, product was directly purified by silica gel column chromatography to give a colorless solid 0. 78 g. The product was placed in a single-necked round bottom flask, dissolved in Diox, and added with a solution of 1. 5N LiOH/H ₂ 0 (24 ml), reacted for 3 h, supplemented with H ₂ 0 (30 ml), and adjusted to pH 2 with IN HC1. A large amount of the title compound (A8) was obtained as a white solid. The following Examples 9-11 relate to the preparation of the amines B1-B3.

 Example 9: Preparation of (2R, 3S)-3-amino-1-(cyclopropylamino)-4-phenyl-butyl-2-alcohol Di-trifluoroacetate (No. B1)

 ((S) - (S)-1-Ethylene oxide-2-phenyl-ethyl)-tert-butyl carbamate (5 g, 19 mmol) was placed in a one-neck round bottom flask and dissolved in ethanol. To this was added cyclopropylamine (21.7 g, 380 leg ol), heated to about 82 TC, and reflux was started, and the reaction was carried out for 4 h at this temperature. The solvent and most of the cyclopropylamine were evaporated under reduced pressure to give a pale yellow oil which was used directly for the next reaction. To the oil was added 50% TFA / DCM (150 ml), and the mixture was evaporated. Example 10: Preparation of (2R, 3S)-3-amino- 1-(benzylamino)-4-phenyl-butan-2-difluoroacetate (No. B2)

 (2R, 3S) -3-amino-1-(benzylamino)-4-phenyl-but-2 was prepared according to the similar method used for the synthesis of (B1), but using benzylamine instead of cyclopropylamine. - alcohol di-trifluoroacetate (B2). Example 11: (2R, 3S)-3-amino-1-(3-methoxy-benzylamino)-4-phenyl-butan-2-ol-trifluoroacetate (No. B3) Preparation

(2R, 3S)-3-Amino-1-(3-decyloxy-benzyl) was prepared according to the similar method used for the synthesis of (B1), but using 3-methoxy-benzylamine instead of cyclopropylamine. Base amino)-4-phenyl-butan-2-ol trifluoroacetate (B3). The following Examples 12-26 relate to the preparation of compounds 1-15 of the present invention. Example 12: N-[(lS,2R)-3-cyclopropylamino-2-yl-1-yl]-1- Preparation of sulfonyl-4-carboxamide (this 1)

Compound 1

A1 (0.224 g, 0.94 mmol), 1-hydroxybenzotriazole (HOBt) (0.127 g, 0.94 mmol), N-ethyl-N,-3-dimethylaminocarbodiimide hydrochloride ( EDO HC1) (0.18 g, 0.94 mmol) was placed in a one-neck round bottom flask, dissolved in dichloromethane, and stirred for 2 or more. A solution containing B1 (0.4 g, 0.89 leg 01) and 81^ (0,64 ml, 4.46 mmol) in dichloromethane was placed in a single-necked round bottom flask, and the reaction solution of the above A1 was added dropwise thereto in portions. 4 or more. Washed with saturated NaCl solution, the organic layer was dried over anhydrous Na ₂ above S0 ₄ 6 h, the drying agent was filtered off, the solvent was distilled off under reduced pressure, product was directly purified by silica gel column chromatography to give the title compound as a colorless solid 1 (52 mg), MS: ( [M+H] ) = 442.7 (as shown in Table 1). Examples 13-26: Preparation of Compounds 2-15 of the Invention

 The acid selected from A1-A8 and the amine selected from B1-B3 were subjected to a condensation reaction in the same manner as described in Example 12 to give Compound 2-15. As shown in Table 1 below.

 Table 1: Partial specific compounds with the formula ( I )

Example 27: BACE1 Inhibitory Activity Test of Compounds 1 - 15 of the Invention in Vitro

The activity was evaluated using the TruPointTM Secretase Assay Kit (PerkinElmer), and the final concentrations of the test compounds were 10 - ⁴ , 10 - ⁵ , and 10 - ⁶ mol / L , respectively. The specific operations are as follows:

Add 2 μM of DMS0 in which the test drug was dissolved to 15 buffer solution containing human recombinant BACE1 (Tr i s-HCl, pH 7.5), incubate for 30 min at room temperature, and add 15 μL of TruPoint BACE1 substrate. (Eu-CEVNLDAEKK-QSY7), incubate for 6 h at room temperature, add 10 stop solution to stop the reaction. The Victor 3 multi-function microplate reader (PerkinElmer) was used to measure at 340 nm excitation wavelength and 615 nm emission wavelength. Determine the fluorescence intensity.

 The results are as follows:

The screening system selected catechol EGCG as a positive control (EGCG is a natural BACE1 inhibitor), and its final concentration is reported according to its literature IC ₅ . (1.6 μ Μ), to ^{10- 7, 5 x 10- 7,} 10 6, 5 10 "6 10 5, 10- 4 mol / L, the dose-dependent inhibition of BACE1, percent inhibition at six concentrations 2.2, 14.4, 28.1, 62.0, 81.5, 92.6, measured BACE1-IC ₅ is 0.76 μ M, which is consistent with 1.6 μΜ reported in the literature, and the activity test method is stable and reliable. At the level of 10 - ⁴ mol/L, the BACE1 inhibition rate of compound 1 - 15 was between 80% and 100% (Table 2). The IC _{5 of} compound 11, 12, 13, 14, 15 was 173 nM, respectively. , 158 nM, 130 nM, 813 nM, and 116 nM.

 Table 2: Inhibition rates of compounds 1-15 at three concentrations

Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and substitutions may be made to those details in light of the teachings of the invention, which are within the scope of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

Rights request

A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof:

-AB- selected from -CH=CH -, -(CH ₂ ) ₂ -, - CH=N -, CH ₂ - NH -, -N=CH -, -NH-CH ₂ -, - (CH ₂ ) ₃ -, -CH=CH-CH ₂ -, -CH ₂ -CH=CH -, -N=CH-CH ₂ -, -NH-CH=CH-, -NH-CH ₂ -CH ₂ - , -CH= N-CH ₂ - , -CH -N=CH- , -CH ₂ -NH- CH ₂ -, -CH ₂ -CH=N -, -CH=CH-NH -, and -CH ₂ -CH ₂ -NH -;

R ^{1 is} selected from the group consisting of hydrogen, S0 ₂ -R ⁵ , and CO-R ⁵ ;

R ^{2 is} selected from the group consisting of d- ₆ alkyl, (: ₂ - ₆ alkenyl, C ₂ - ₆ alkyl, cycloalkyl, -Cw alkyl - C ₃ - cycloalkyl, - C. - ₆ alkane Alkyl-aryl, -C.- ₆ alkyl-heteroaryl, and -C.- ₆ alkyl-heterocyclyl;

R ^{3 is} selected from the group consisting of hydrogen. Alkyl, CH. Alkenyl, Cw. Alkynyl, -C ₃ —. Cycloalkyl, -Cw. Cycloalkenyl, -C. - _6- mercapto-aryl, -C. — ₆ alkyl-heteroaryl, —C. - ₆ alkyl-heterocycle

- C Bu 6 C3-I O ring pit ^^, -. 3-10 ring-aryl ^ *, -. 3-10 ring pit ^ ^-heteroaryl, -Cw. Cycloalkyl-heterocyclyl, -Cw. Cycloalkyl-d- ₆ alkyl-aryl, -heterocyclyl-aryl, -d- ₆ alkyl-aryl-heteroaryl, -C(R ⁸ R ⁹ ) -C0NH-C ₁ - ₆ Alkyl, -CO^lO -CONH-Cw. Cycloalkyl, -C _{2 -6} alkyl-S-CH alkyl, -C ₂ - ₆ alkyl-NR ¹⁰ R ^N , -C IO -CH decyl, -C (R ⁸ R ⁹ ) -C. - ₆ alkyl-aryl, -C (R ⁸ R ⁹ ) -C. — ₆ alkyl-heteroaryl, —C (R ⁸ R ⁹ )—C0-6 alkyl-heterocyclyl, —C ₂ - ₆ alkyl- 0-C. — ₆ alkyl- Aryl, -c ₂ - ₆ alkyl - 0-C. - ₆ alkyl-heteroaryl, and -C ₂ - ₆ alkyl-0-C. a _6- alkyl-heterocyclic group, wherein R ⁸ and R ⁹ are each independently selected from hydrogen, d- ₆ alkyl or R ⁸ and R ⁹ together with the carbon atom to which they are attached. a cycloalkyl or heterocyclic group; R ^lfl and R ¹¹ may independently represent hydrogen, d- ₆ alkyl. a cycloalkyl group, and R ^lfl and R ¹¹ together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclic group;

R ⁴ is selected from hydrogen, d- ₆ alkyl, halo, haloalkyl d- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, cyano, nitro, hydroxy, -C. - ₆ alkyl-0R ⁶ , -C. - _6- alkyl-NR ⁶ R ⁷ , -Co-6 alkyl-SR ⁶ , -C. - ₆ alkyl-0C0R ⁶ , -C. - ₆ alkyl - C00R ⁶ , - C. - _6- alkyl-NR ⁶ COR ⁷ , -C. — _6- alkyl-C0NR ⁶ R ⁷ , -C. — ₆ alkyl-S0 ₂ NR ^fi R ⁷ , -C. - ₆ alkyl-NHC0NHR ^fi , or -C. ₆ alkyl-C0R ^fi , wherein R ⁶ and R ⁷ are each independently selected from hydrogen, d- ₆ alkyl, haloalkyl. a cycloalkyl group, a cycloalkyl group, a -C.- ₆ alkyl-aryl group, a -C.- ₆ alkyl-heteroaryl group, and a -C.- ₆ alkyl-heterocyclic group;

 m represents an integer of 0 - 3;

R ^{5 is} selected from the group consisting of hydroxyl groups, -C. - ₆ alkyl-0R ⁶ , - C. - _6- alkyl-NR ⁶ R ⁷ , d- ₆ alkyl, C ₃ - ₆ alkenyl, C ₃ - ₆ alkynyl, . Cycloalkyl, -C. - ₆ alkyl-aryl, -C. - ₆ alkyl-heteroaryl, -(.- _6- alkyl-heterocyclyl, -Cw.cycloalkyl-aryl, -Cw.cycloalkyl-heteroaryl, and -Cw.cycloalkyl- a heterocyclic group; wherein, optionally, the aryl, heteroaryl or heterocyclic group in R ⁵ is substituted at one or more of the following groups at different positions: d- ₆ alkyl, aryl, halo D- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ block, cyano, nitro, oxo, -C.- ₆ alkyl-OR ⁶ , -Co-6 alkyl-SR ⁶ , -Co-6 alkyl-0C0R ⁶ , -C.- ₆ alkyl-C00R ⁶ , -C.- ₆ alkyl-NR ⁶ COR ⁷ , -C _Q - ₆ alkyl-C0NR ⁶ R ⁷ , -C - ₆ alkyl-S0 ₂ NR ⁶ R ⁷ , -C.- ₆ alkyl-NHC0NHR ⁶ , -C.- ₆ alkyl-NR ⁶ R ⁷ , or -C.- ₆ alkyl-COR ⁶ ; , R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, d- ₆ alkyl, halo d- ₆ alkyl, cycloalkyl, halo. cycloalkyl, -C.- ₆ alkyl-aryl, -C.- ₆ alkyl-heteroaryl, and -C.- ₆ alkyl-heterocyclic group;

among them, The aryl group is a C ₆ - ₁₂ monocyclic or bicyclic hydrocarbon ring, wherein at least one ring is an aromatic ring; the heteroaryl group is 5 - 6 yuan containing 1 - 4 hetero atoms selected from oxygen, nitrogen and sulfur a monocyclic aromatic ring or a fused 8-12 membered bicyclic aromatic ring;

 The heterocyclic group is a 4 - 7 membered monocyclic or fused 8 - 12 membered bicyclic ring containing 1-4 selected from the group consisting of oxygen, nitrogen and sulfur hetero atoms, the monocyclic or bicyclic ring being saturated or partially not Saturated.

 The compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 1, wherein

 The aryl group is selected from the group consisting of phenyl, naphthyl, and tetrahydronaphthyl;

 The heteroaryl group is selected from the group consisting of thienyl, furyl, furyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazole , oxadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridyl, pyridyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxaline Alkyl, acridinyl, porphyrinyl, 2,3-diazanaphthyl, diaza naphthyl, anthracenyl, isodecyl, azaindolyl, carbazinyl, carbazolyl, Mercapto, pyrrolopyridyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothianyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzo Thiazolyl, benzisothiazolyl, benzooxadiazolyl, and benzothiadiazolyl;

The heterocyclic group is selected from pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, ethyl Endoylureido, valerolactam, oxiranyl, azetidinyl, dioxolanyl, dioxanyl, oxathiolan, oxathiolanyl, dithiane , dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothio, tetrahydrothiopyranyl, diazepane , azepanyl, indanyl, isoindoline, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydrobenzoaza, and Hydrogen isoquinolyl.

The compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 1, wherein

- AB- is selected from the group consisting of -CH-CH-, _(CH ₂ ) ₂ -, -CH=N -, CH -NH-, -N-CH -, and -NH-CH;

R ¹ is S0 ₂ - R ⁵ or C0-R ⁵ ;

R ² is a Ci-6 pit group or a -C-6 alkyl group-aryl group;

R ³ is -C _{3 -iecycloalkyl} or -C ₆ alkyl-aryl;

R ^{4 is} selected from the group consisting of hydrogen, d- ₆ alkyl, halogen, NR ⁶ R ⁷ , and -OR ⁶ ;

 m means 2;

R ^{5 is} selected from -C. - ₆ alkyl-0R ⁶ , - C. - ₆ alkyl-NR ⁶ R ⁷ , d- ₆ alkyl, -C. — 6 alkyl-aryl, and —( _6- alkyl-heteroaryl; wherein, optionally, the aryl, heteroaryl or heterocyclic group in R ⁵ may be substituted by one or less at different positions group substituted by: halo, -c.- ₆ alkyl -0R _^6, - C.- ⁶ alkyl group -NR ⁶ R ^7, -C.- ₆ alkyl or - CONR ⁶ R ^7;

R ⁶ and R ⁷ are each independently selected from hydrogen, d- ₆ alkyl. Cycloalkyl, -C. - ₆ alkyl-aryl, -C. - ₆ alkyl-heteroaryl, and -C. - ₆ alkyl-heterocyclic group;

 among them,

 The heteroaryl group is selected from the group consisting of: thienyl, furyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, pyranyl, pyrazolyl, pyrimidinyl, indole a pyridyl group, a pyrazinyl group, a pyridyl group, a fused aromatic ring group, etc., wherein the fused aromatic ring group includes a quinolyl group, an isoquinolyl group, an anthracenyl group, an isodecyl group, an azaindole Anthracenyl, carbazolyl, fluorenyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and benzisothiazolyl;

 The heterocyclic group is selected from the group consisting of pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, Azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydropyridyl.

4. A compound of formula (I) according to claim 1 which is pharmaceutically acceptable a salt, or a solvate thereof, wherein

 - A-B- is -CH=CH- ;

R ¹ is S0 ₂ -R ⁵ ;

R ² is a benzyl group;

R ^{3 is} selected from the group consisting of benzyl, decyloxybenzyl, and cyclopropyl;

R ⁴ is hydrogen;

 m means 2;

R ^{5 is} selected from the group consisting of phenyl, methoxyphenyl, propyl, thienyl, benzylamino-phenyl, ethyl-phenyl, and phenyl substituted by one fluorine or chlorine.

The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of the formula (I) is selected from the group consisting of:

 N-[(IS, 2R)-3-cyclopropylamino-2-hydroxy-1-benzyl]-1-methylsulfonyl-4-phthalamide;

 N-[(IS, 2R)-3-cyclopropylamino-2-hydroxy-1-benzyl]-1-benzenesulfonyl-4-carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-benzenesulfonyl-4-carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(4-methoxy-benzenesulfonyl)-4-carboxamide;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(4-fluoro-benzenesulfonyl)-4-carboxamide;

 N-[(1S, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(3-chloro-benzenesulfonyl)-4-decylamine;

 N-[(IS, 2R)-3-benzylamino-2-hydroxy-1-phenyl]-1-(1-propanesulfonyl)-4-indolamide;

N-[ (IS, 2R)-3-benzylamino-2-hydroxy-1-benzyl]-1-(2-thienyl-sulfonate) Acyl)-4-carboxamide;

 N-[ (1S, 2R)-3-cyclopropylamino-2-hydroxy-l-benzyl]-1-(4-methoxy-benzenesulfonyl)-4-carboxamide;

 N-[(IS, 2R)-3-Cyclopropylamino-2-hydroxy-1-phenyl]-1-(2-thienyl-sulfonyl)-4-carboxamide;

 N-[(1S, 2R)-3-(3-methoxy-benzyl)amino-2-hydroxy-1-yl]- 1-benzenesulfonyl-4-indoleamide;

 N-[(1S, 2R)-3-(3-decyloxy-benzyl)amino-2-hydroxy-1-benzyl]-1-(4-methoxy-benzenesulfonyl)-4-methyl Amide

 N-[(1S, 2R)-3-(3-methoxy-benzyl)amino-2-hydroxy-1-benzyl]-1-(3-chloro-benzenesulfonyl)-4-indolamide;

 N-[(1S, 2R)-3-(3-methoxy-benzyl)amino-2-hydroxy-1-benzyl]-1-(1-propanesulfonyl)-4-indolamide;

 N-[(IS, 2R)-3-Benzylamino-2-hydroxy-1-benzyl]-1-[3-(benzylamino-)-benzenesulfonyl)-4-indoleamide.

 6. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, comprising the steps of:

 The compound of the formula (m) is reacted with the compound of the formula (m) in the presence of triethylamine using a dimercaptoamide and/or methylene chloride as a solvent and a carbodiimide and/or HOBt as a condensing agent. "Between C and room temperature,

Wherein -AB -, R ¹ , R ² , R ³ , R ⁴ , m are as defined in claims 1-5, respectively.

A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier or adjuvant Optionally, the pharmaceutical composition further comprises at least one of the following:

 An acetylcholinesterase inhibitor, an inhibitor against P-amyloid aggregation, a γ-secretase inhibitor, an o-secretase agonist, an anti-inflammatory agent, and an antioxidant.

 The use of a compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 1 to 5 as a BACE1 inhibitor.

 9. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of claims 1 to 5, for the manufacture of a medicament for reducing P-amyloid in the brain of a mammal .

 The compound of the formula (I) according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a treatment for Alzheimer's disease, Parkinson's disease, or Down's syndrome Use of the drug.

 11. A method of treating and/or preventing a disease characterized by elevated amyloid levels or P-amyloid deposits in a human or animal, the method comprising administering an effective amount to a human or animal (I) a step of a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

 12. The method of claim 11, wherein the disease characterized by elevated amyloid levels or P-amyloid deposits is Alzheimer's disease, Parkinson's disease, or Down's syndrome .

 13. A method of modulating BACE1 activity or modulating amyloid levels in vivo or in vitro, comprising the step of using an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.