CN115322208B - 2-aminothiazole derivative and preparation method and medical application thereof - Google Patents
2-aminothiazole derivative and preparation method and medical application thereof Download PDFInfo
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Abstract
The invention discloses a novel 2-aminothiazole derivative, a preparation method and medical application thereof, wherein the compound is shown as a formula I, and also discloses a medicinal composition containing the compound, and application of the compound or medicinal salt thereof or the composition containing the compound in preparing medicaments for treating Alzheimer disease and related dementia symptoms.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to 2-aminothiazole derivatives or pharmaceutically acceptable salts thereof with beta-amyloid precursor protein lyase 1 (BACE-1) inhibitory activity and anti-dementia activity, a preparation method and application thereof.
Background
Alzheimer's Disease (AD), the most common type of dementia in the elderly, is a chronic neurodegenerative disease that results in progressive loss of cognitive function and a decline in daily function. Among the hypotheses explaining the onset of AD, the a β cascade hypothesis has been dominant. Amyloid Precursor Protein (APP) is a transmembrane Protein found in neurons and glial cells of the brain. Under pathological conditions, APP is cleaved by beta-secretase to form APP-beta, and then by gamma-secretase to form Abeta 42 A monomeric fragment. Abeta (beta) 42 Is the earliest form of senile plaque formation, A β in the extracellular environment 42 Can cause the deposition of toxic β -amyloid plaques. While BACE-1 is the rate-limiting enzyme in the production of A.beta.. The invention discovers a 2-aminothiazole compound with BACE-1 inhibitory activity and has great application potential in the aspect of AD treatment.
Disclosure of Invention
The invention aims to provide a 2-aminothiazole compound shown in a general formula I or a pharmaceutically acceptable salt thereof.
The invention also aims to provide a preparation method of the 2-aminothiazole compound shown in the general formula I.
It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a 2-aminothiazole compound represented by the general formula I, or a pharmaceutically acceptable salt thereof.
It is still another object of the present invention to provide a BACE-1 inhibitor comprising a 2-aminothiazole compound represented by the general formula I, or a pharmaceutically acceptable salt thereof.
The invention also aims to provide the application of the 2-aminothiazole compound shown in the general formula I, the pharmaceutically acceptable salt thereof and the pharmaceutical composition containing the same in treating dementia symptoms. Wherein the dementia symptom belongs to but not limited to central nervous system degeneration diseases such as Alzheimer disease, fronto-temporal lobe dementia, creutzfeldt-Jakob disease, lewy body dementia, parkinson disease, huntington disease and the like.
The technical scheme is as follows:
in view of the above objects, the present invention provides a 2-aminothiazole compound represented by the general formula I:
wherein:
z is H or C 1 ～C 3 An alkyl group;
x is O or C or S;
y is O or C or S;
R 1 ,R 3 and R 4 Is H or halogen;
R 2 is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from C 6 ～C 10 Aryl or C 2 ～C 10 A heteroaryl group; the substituents are selected from H, halogen, -CN, -NO 2 、-OH，-COOH、-NH 2 、C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, C 1 ～C 6 Haloalkyl, -N (H) -C (O) -C 1 ～C 3 Alkyl or C 1 ～C 6 An alkylamino group.
In some embodiments, Z is H or methyl or ethyl.
In some embodiments, R 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine, thiophene, pyrazole, thiazole, pyrimidine, naphthalene, furan, pyrrole, indene, quinoline or indole; the substituents are selected from H, halogen, -CN, -NO 2 、-OH，-COOH、-NH 2 、C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Haloalkyl, -N (H) -C (O) -C 1 ～C 4 Alkyl or C 1 ～C 4 An alkylamino group; in some embodiments, the substituent is selected from H, halo, -CH 3 、-CN、-NO 2 、-CF 3 、-OCH 3 Ethyl, N-propyl, isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
In some embodiments, Z is H or methyl; x is O or C; y is O or C; r 1 ,R 3 And R 4 Is H; r 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine or naphthalene, said substituents being selected from: H. halogen, -CH 3 、-CN、，-NO 2 、-CF 3 、-OCH 3 Ethyl, N-propyl, isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
In some embodiments, Z is H or methyl; x is O or C; y is O or C; r 1 ,R 3 And R 4 Is H; r 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine or naphthalene, said substituents being selected from: H. halogen, -CH 3 、-CN、-OCH 3 Isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
In some specific embodiments, the present invention provides any one of the compounds described below, or an isomer or a pharmaceutically acceptable salt thereof:
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazole ] -6-yl) -5-methoxypyrazine-2-carboxamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4 bromobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide;
n- (4- (N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -5-methoxymethyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -5-methoxypyrazine-2-carboxamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-bromobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide;
n- (4- (N- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -5-methoxymethyl picolinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
(S) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
(S) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
(S) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide.
Further, the preparation method of the compound shown in the general formula I is characterized by comprising the following steps:
in some specific examples:
(1) Carrying out nitration reaction on chromanone 1 to obtain a nitro chromanone intermediate 2, carrying out Witting reaction to obtain an alkene intermediate 3, cyclizing the intermediate 3 under the action of silver thiocyanate and iodine simple substance, carrying out amination reaction to obtain a parent nucleus intermediate 4, carrying out Boc protection to obtain an intermediate 5, carrying out hydrogen reduction to obtain an intermediate 6, carrying out condensation reaction with different substituted acyl chlorides or sulfonyl chlorides to obtain intermediates 7 and 8, and finally carrying out Boc removal through trifluoroacetic acid to obtain the 2-aminothiazole final product disclosed in claim 1.
(2) Reducing an aldehyde compound 9 by sodium borohydride to obtain an alcohol intermediate 10, reacting with tert-butyl bromoacetate or tert-butyl 2-bromopropionate to generate an intermediate 11, acidifying to obtain an acid intermediate 12, reacting the intermediate 12 with N, O-dimethylhydroxylamine hydrochloride to generate an amide intermediate 13, reacting under the catalysis of tert-butyl lithium to obtain a parent nucleus intermediate 14, performing Witting reaction to obtain an alkene intermediate 15, cyclizing under the action of silver thiocyanate and iodine to obtain an intermediate 16, protecting by Boc to obtain an intermediate 17, reducing by hydrogen to obtain an intermediate 18, performing condensation reaction with different substituted acyl chlorides or sulfonyl chlorides to obtain intermediates 19 and 20, and finally removing Boc by trifluoroacetic acid to obtain the 2-aminothiazole final product of claim 1.
The use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a BACE-1 inhibitor is also within the scope of the present invention.
The application of the compound or the pharmaceutically acceptable salt thereof disclosed in the application in preparing the anti-dementia medicines is also within the protection scope of the invention. The dementia symptoms belong to, but are not limited to, central nervous system degenerative diseases such as Alzheimer's disease, fronto-temporal dementia, creutzfeldt-Jakob disease, lewy body dementia, parkinson's disease, or Huntington's disease.
The invention also discloses a pharmaceutical composition which comprises the compound I and pharmaceutically acceptable auxiliary materials.
The application of the medicine composition in preparing BACE-1 inhibitor medicine and in preparing dementia-resisting medicine is also within the protection scope of the present invention.
Has the advantages that: the 2-aminothiazole compounds are compounds with a brand new framework structure, and can effectively inhibit the activity of BACE-1. Pharmacological experiments show that the 2-aminothiazole compound has obvious inhibition effect on BACE-1 targets. It has potential prospect of drug development in the aspect of AD treatment.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
"alkyl" means a saturated aliphatic group of 1 to 20 carbon atoms, including straight and branched chain groups (a numerical range referred to in this application, e.g., "1 to 6", refers to the group, in this case alkyl, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms). For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl and the like. C 1 ～C 6 The alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, etc.
"haloalkyl" means a halogen-substituted alkyl group, as described herein, which is substituted with one or more halogen atoms, which may be the same or different, e.g., -CH 2 Cl、-CF 3 、-CH 2 CF 3 、-CH 2 CCl 3 And the like.
"alkoxy" means-O- (unsubstituted alkyl) or-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"alkylamino" means-N- (unsubstituted alkyl) or-N- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, and the like.
"aryl" means an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one, two or three, and still more preferably one or two.
"heteroaryl" means a stable monocyclic or bicyclic carbon ring of up to 3-10 atoms in the ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Non-limiting examples of unsubstituted heteroaryl groups are pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, indolyl, benzotriazolyl, benzothienyl, benzofuranyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, tetrazolyl, triazinyl, carbazolyl, and the like. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two.
"substituted or unsubstituted" means that it may be unsubstituted or optionally substituted with a substituent as described herein. When substituted, it is understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and may be synthesized by techniques and methods of the art from available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but it should not be construed that the scope of the above subject matter is limited to the following examples, and all the technologies that can be realized in the art based on the above contents of the present invention shall belong to the contents of the present invention.
Example 1
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide
(1) 2.0g (13.5 mmol) of chroman-4-one is added into a 100mL two-necked flask, 20mL of concentrated sulfuric acid is added, the mixture is dissolved by stirring for 10min under ice bath, and then 1.5g (14.85 mmol) of KNO is added 3 Slowly dropwise adding the sulfuric acid solution into the reaction solution of the chroman-4-one, continuously stirring for reacting for 2 hours, pouring the reaction mixture into 200mL of ice water, continuously stirring for 30 minutes, and filtering. The solid was washed with water 3 times, dried and recrystallized from methanol to give intermediate 2. Methyltriphenylphosphine bromide (20.71 mmol) was added to anhydrous THF under argon blanket at 0 ℃ and n-butyllithium (18.64 mmol) was added slowly followed by stirring for one hour, intermediate 2 (10.35 mmol) in anhydrous THF was added and allowed to warm to room temperature for about one hour before quenching the reaction with water, extraction with ethyl acetate, combined organic layers were concentrated and column chromatographed using PE/EA =8 to afford intermediate 3. Intermediate 3 (7.85 mmol) was added to a solution of iodine (15.69 mmol) and silver thiocyanate (31.38 mmol) in toluene at 0 deg.C, stirred overnight at room temperature, filtered, the filtrate washed with saturated sodium sulfite, extracted with ethyl acetate, the organic layers combined, the resulting organic layer was then spin dried, dissolved in THF and added to NH at 0 deg.C 3 Was stirred for one hour, followed by stirring at room temperature for 2.5 days. After concentration, washing with ethyl acetate and suction filtration, intermediate 4 was obtained, which was dissolved in THF, triethylamine (28.27 mmol) and di-tert-butyl dicarbonate (28.27 mmol) were added, reacted at room temperature for 2 days, the solvent was concentrated, and column chromatography was performed directly with PE/EA =8 to obtain intermediate 5. Intermediate 5 (3.39 mmol) was added to ethanol andto a solution of saturated ammonium chloride solution 1 (30 mL) followed by addition of iron powder (6.79 mmol), heating at 87 ℃ for half an hour, filtering with hot celite, extraction three times with ethyl acetate, combining the organic layers, concentrating the solvent to afford intermediate 6 for the next step. Commercially available pyridine-2-carboxylic acid (0.67 mmol) was dissolved in 20mL toluene, sulfoxide chloride (3.38 mmol) was added slowly, and 1 drop of DMF was added, reacted at 120 ℃ for 1 hour, cooled to room temperature, and the solvent was concentrated to give pyridine-2 carbonyl chloride for use. Pyridine-2 carbonyl chloride (0.67 mmol) was dissolved in 5mL THF, the solution added to intermediate 6 (0.59 mmol) in THF (5 mL) under ice bath, pyridine (30 μ L) was added, followed by warming to room temperature and stirring for 30min, followed by quenching with 10mL saturated sodium bicarbonate solution and extraction three times with ethyl acetate. The solvent was concentrated to give intermediate 7, and intermediate 7 (0.59 mmol) was dissolved in 10mL of anhydrous dichloromethane, 10mL of trifluoroacetic acid was added, and reacted at room temperature for 2 hours, followed by adjustment of PH =9 with a saturated sodium bicarbonate solution. Extracted three times with ethyl acetate, the organic phases are combined, concentrated and purified with DCM: meOH =20 column chromatography 1 afforded the 2-aminothiazole final product, example I.
White solid, total yield of this partial synthesis was 5.6%. 1 H NMR(300MHz,CDCl 3 )δ9.90(s,1H),8.61(d,J＝3.7Hz,1H),8.29(d,J＝7.7Hz,1H),7.91(t,J＝7.6Hz,1H),7.88(s,1H),7.54(d,J＝7.9Hz,1H),7.51–7.42(m,1H),6.83(d,J＝8.7Hz,1H),4.62(s,1H),4.35(d,J＝11.4Hz,1H),4.166(s,1H),3.67(d,J＝11.0Hz,1H),3.45(d,J＝11.2Hz,1H),2.18(s,2H)；HRMS(ESI)calcd for C 17 H 17 N 4 O 2 S[M+H] + 341.1067,found 341.1067.
Example 2
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide
The procedure of example 1 is repeated, giving a yellow solid in 4.2% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.68(s,1H),9.16(s,1H),8.55(s,1H),8.25(d,J＝7.8Hz,1H),7.94(s,1H),7.62(d,J＝7.7Hz,1H),6.74(d,J＝8.5Hz,3H),4.33–4.13(m,2H),3.56–3.39(m,2H),1.98(d,J＝38.7Hz,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ162.3,161.2,153.2,151.8,150.6,142.5,131.2,128.9,122.6,121.9,120.6,117.1,116.6,111.8,73.4,64.1,46.7,33.7；HRMS(ESI)calcd for C 18 H 16 N 5 O 2 S[M+H] + 366.1019,found 366.1023.
Example 3
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide
The procedure of example 1 was followed, and a white solid was obtained in 6.5% yield. 1 HNMR(300MHz,CDCl 3 )δ9.68(s,1H),8.43(s,1H),8.32(dd,J＝8.5,4.4Hz,1H),7.76(s,1H),7.57(dd,J＝15.4,8.6Hz,2H),6.84(d,J＝8.9Hz,1H),4.72(s,2H),4.39(d,J＝11.3Hz,1H),4.20(s,1H),3.69(d,J＝11.0Hz,1H),3.48(d,J＝11.4Hz,1H),2.20(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ160.7,150.7,136.6,130.8,124.1,121.4,119.1,117.4,73.9,64.1,47.8,33.0；HRMS(ESI)calcd for C 17 H 16 FN 4 O 2 S[M+H] + 359.0973,found 359.0979.
Example 4
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide
The procedure of example 1 was followed, white solid, 5.2% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.51(s,1H),8.76(s,1H),8.16(d,J＝16.1Hz,2H),7.93(s,1H),7.62(d,J＝6.8Hz,1H),6.77(s,2H),6.75(d,J＝8.1Hz,1H),4.24(d,J＝32.7Hz,2H),3.59–3.43(m,2H),2.01(d,J＝53.0Hz,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ161.6,150.4,149.2,147.4,138.2,134.5,131.5,124.2,121.7,120.4,116.6,64.1,46.6,33.7；HRMS(ESI)calcd for C 17 H 16 ClN 4 O 2 S[M+H] + 375.0677,found 375.0680.
Example 5
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide
The procedure of example 1 was followed, and a white solid was obtained in 6.3% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.31(s,1H),8.37(d,J＝2.2Hz,1H),8.10(d,J＝8.7Hz,1H),7.92(d,J＝1.6Hz,1H),7.61(dd,J＝9.5,4.2Hz,2H),7.23–6.74(m,2H),6.74(d,J＝8.8Hz,1H),4.33–4.17(m,2H),3.93(s,3H),3.49(dd,J＝37.5,9.6Hz,2H),2.13–1.88(m,2H)； 13 CNMR(75MHz,DMSO-d 6 )δ162.2,158.1,150.1,143.0,136.8,131.8,128.6,124.0,121.4,120.0,116.6,64.1,56.4,46.6,33.7；HRMS(ESI)calcd for C 18 H 19 N 4 O 3 S[M+H] + 371.1172,found 371.1177.
Example 6
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide
The procedure of example 1 was followed, white solid, 3.6% yield. 1 HNMR(400MHz,CDCl 3 )δ9.85(s,1H),8.40(s,1H),8.16(d,J＝7.9Hz,1H),7.79(s,1H),7.68(d,J＝7.9Hz,1H),7.54(dd,J＝8.8,2.0Hz,1H),6.83(d,J＝8.8Hz,1H),4.48(d,J＝59.2Hz,2H),4.38(dd,J＝7.2,4.3Hz,1H),4.23–4.15(m,1H),3.69(d,J＝11.2Hz,1H),3.46(d,J＝11.2Hz,1H),2.43(s,3H),2.21(d,J＝14.0Hz,2H)； 13 C NMR(75MHz,CDCl 3 )δ162.0,160.6,150.6,148.5,147.5,138.0,136.6,131.1,127.6,122.0,121.5,119.1,117.4,73.8,64.1,47.7,33.1,18.6；HRMS(ESI)calcd for C 18 H 19 N 4 O 2 S[M+H] + 355.1223,found 355.1228.
Example 7
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide
The procedure of example 1 was followed, white solid, 5.2% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),8.70(s,1H),8.42(s,1H),7.67(d,J＝1.4Hz,1H),7.52(d,J＝8.7Hz,1H),6.75(d,J＝8.8Hz,1H),6.63(s,2H),4.29(d,J＝11.3Hz,1H),4.20(t,J＝10.6Hz,1H),3.52(d,J＝11.2Hz,1H),3.36(d,J＝6.9Hz,1H),2.06(d,J＝13.7Hz,1H),1.92(t,J＝10.6Hz,1H)； 13 C NMR(101MHz,DMSO-d 6 )δ162.4,150.3,146.3,138.3,132.6,131.6,129.3,121.0,119.5,116.8,73.7,64.1,46.9,33.7；HRMS(ESI)calcd for C 17 H 15 Cl 2 N 4 O 2 S[M+H] + 409.0287,found 409.0297.
Example 8
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazole ] -6-yl) -5-methoxypyrazine-2-carboxamide
The procedure of example 1 was followed, to obtain a white solid with a yield of 4.5%. 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),8.88(t,J＝9.4Hz,1H),8.38(d,J＝1.2Hz,1H),7.92(d,J＝2.5Hz,1H),7.57(dd,J＝8.8,2.6Hz,1H),6.75(t,J＝8.0Hz,3H),4.31–4.26(m,1H),4.19(dd,J＝10.9,8.9Hz,1H),4.01(s,3H),3.52(d,J＝11.3Hz,1H),3.42(d,J＝7.0Hz,1H),2.08(dd,J＝12.6,2.9Hz,1H),1.98–1.89(m,1H)； 13 C NMR(101MHz,DMSO-d 6 )δ162.0,161.5,150.3,141.7,138.5,133.9,131.6,128.4,121.9,120.4,116.6,114.7,64.0,54.7,46.4,33.7；HRMS(ESI)calcd for C 17 H 18 N 5 O 3 S[M+H] + 372.1125,found 372.1131.
Example 9
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide
The procedure of example 1 was followed, to obtain a white solid with a yield of 4.5%. 1 HNMR(400MHz,CDCl 3 )δ9.90(s,1H),8.40(s,1H),7.66(d,J＝7.7Hz,2H),7.52(d,J＝8.1Hz,1H),6.84(d,J＝8.7Hz,1H),4.86(s,2H),4.40(d,J＝11.3Hz,1H),4.21(t,J＝10.3Hz,1H),3.67(d,J＝11.2Hz,1H),3.46(d,J＝11.2Hz,1H),2.83(s,3H),2.28–2.10(m,2H)； 13 C NMR(75MHz,CDCl 3 )δ162.7,160.8,150.8,145.1,144.2,140.5,137.6,134.1,130.9,127.7,121.8,119.4,117.4,73.8,64.1,47.7,32.7,20.8；HRMS(ESI)calcd for C 18 H 18 ClN 4 O 2 S[M+H] + 389.0834,found 389.0841.
Example 10
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzamide
The procedure of example 1 was followed, white solid was obtained, yield 5.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),7.95(s,2H),7.71(s,1H),7.54(d,J＝23.6Hz,4H),6.74(d,J＝7.2Hz,1H),6.56(s,2H),4.37–4.11(m,2H),3.60–3.47(m,2H),2.15–1.86(m,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ165.4,159.0,150.1,135.4,132.3,131.8,128.7,127.9,121.8,120.5,116.4,73.9,64.1,47.0,33.7；HRMS(ESI)calcd for C 18 H 18 N 3 O 2 S[M+H] + 340.1114,found 340.1116.
Example 11
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide
The procedure of example 1 was followed, white solid was obtained, yield 5.3%. 1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),8.04(s,2H),7.69(s,1H),7.58(s,1H),7.35(s,2H),6.75(s,1H),6.61(s,2H),4.24(d,J＝33.5Hz,2H),3.49(d,J＝24.3Hz,2H),1.99(d,J＝54.3Hz,2H)； 13 CNMR(101MHz,DMSO-d 6 )δ164.3,150.1,132.2,130.7,129.1,121.9,120.5,116.5,115.8,115.5,73.8,64.1,46.9,33.7；HRMS(ESI)calcd for C 18 H 17 FN 3 O 2 S[M+H] + 358.1020,found 358.1025.
Example 12
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzenesulfonamide
The procedure of example 1 was followed, and white solid was obtained in 4.5% yield. 1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝5.4Hz,2H),7.63–7.36(m,3H),6.95(s,1H),6.12(d,J＝7.2Hz,1H),5.77(s,1H),4.25(d,J＝8.9Hz,1H),4.01(t,J＝10.8Hz,1H),3.50(d,J＝10.5Hz,1H),3.32(d,J＝10.8Hz,1H),2.25(d,J＝13.4Hz,1H),1.88(d,J＝10.8Hz,1H)；HRMS(ESI)calcd for C 17 H 18 N 3 O 3 S 2 [M+H] + 376.0784,found 376.0792.
Example 13
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide
The procedure of example 1 was followed, and a white solid was obtained in 6.3% yield. 1 H NMR(300MHz,CDCl 3 )δ7.80–7.68(m,2H),7.15(t,J＝8.6Hz,2H),6.93(d,J＝2.5Hz,1H),6.17(d,J＝8.6Hz,1H),5.77(dd,J＝8.6,2.5Hz,1H),4.28(dd,J＝8.1,3.5Hz,1H),4.05(t,J＝11.4Hz,1H),3.53(d,J＝11.1Hz,1H),3.36(d,J＝11.3Hz,1H),2.27(d,J＝14.5Hz,1H),1.85(t,J＝11.3Hz,1H)；HRMS(ESI)calcd for C 17 H 17 FN 3 O 3 S 2 [M+H] + 394.0690,found 394.0692.
Example 14
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide
The procedure of example 1 was followed, white solid, yield 5.2%. 1 HNMR(300MHz,CDCl 3 )δ7.62(d,J＝7.6Hz,2H),7.41(d,J＝7.4Hz,2H),6.92(s,1H),6.17(d,J＝8.4Hz,1H),5.81(d,J＝8.7Hz,1H),4.27(d,J＝11.1Hz,1H),4.02(t,J＝12.0Hz,1H),3.49(d,J＝11.1Hz,1H),3.33(d,J＝11.3Hz,1H),2.25(d,J＝14.1Hz,1H),1.87(t,J＝13.1Hz,1H)；HRMS(ESI)calcd for C 17 H 17 ClN 3 O 3 S 2 [M+H] + 410.0394,found 410.0402.
Example 15
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-bromobenzenesulfonamide
The procedure of example 1 was followed, to obtain a white solid with a yield of 4.3%. 1 H NMR(400MHz,CDCl 3 )δ7.64–7.54(m,4H),7.28(s,1H),6.93(d,J＝2.4Hz,1H),6.20(dd,J＝8.5,4.3Hz,1H),5.88–5.78(m,1H),4.30(dd,J＝7.9,3.7Hz,1H),4.05(t,J＝11.8Hz,1H),3.56–3.48(m,1H),3.36(dd,J＝11.2,4.2Hz,1H),2.28(d,J＝12.9Hz,1H),1.89(t,J＝12.9Hz,1H)；HRMS(ESI)calcd for C 17 H 17 BrN 3 O 3 S 2 [M+H] + 453.9889,found 453.9892.
Example 16
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide
The procedure of example 1 was followed, white solid, yield 4.6%. 1 H NMR(300MHz,CDCl 3 )δ7.63–7.57(m,2H),7.46–7.39(m,2H),6.95(d,J＝2.5Hz,1H),6.19(d,J＝8.6Hz,1H),5.94(dd,J＝8.7,2.5Hz,1H),4.27(dt,J＝11.4,3.7Hz,1H),4.03(dd,J＝11.6,10.1Hz,1H),3.45(d,J＝11.3Hz,1H),3.30(d,J＝11.3Hz,1H),2.25(d,J＝15.4Hz,1H),1.93(t,J＝11.1Hz,1H),1.32(s,9H)；HRMS(ESI)calcd for C 21 H 26 N 3 O 3 S 2 [M+H] + 432.1410,found 432.1411.
Example 17
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide
The procedure of example 1 was followed, white solid, 3.8% yield. 1 HNMR(300MHz,DMSO-d 6 )δ7.60(d,J＝8.9Hz,2H),7.04(d,J＝8.9Hz,2H),7.00(d,J＝2.6Hz,1H),6.79(dd,J＝8.7,2.6Hz,1H),6.60(d,J＝8.7Hz,1H),6.59(s,1H),4.28–4.04(m,2H),3.79(s,3H),3.43(s,2H),3.39(s,1H),3.07(d,J＝11.2Hz,1H),1.90(ddd,J＝20.2,14.0,7.2Hz,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ162.7,150.8,131.5,130.4,129.4,123.1,121.6,117.1,114.6,73.7,64.1,56.0,46.8,33.8；HRMS(ESI)calcd for C 18 H 19 N 3 O 4 S 2 [M+H] + 406.0890,found 406.0897.
Example 18
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide
The procedure of example 1 was followed, to obtain a white solid with a yield of 4.5%. 1 H NMR(300MHz,CDCl 3 )δ7.57(d,J＝8.3Hz,2H),7.22(d,J＝8.0Hz,2H),6.94(d,J＝2.5Hz,1H),6.21(d,J＝8.7Hz,1H),5.99–5.92(m,1H),4.33–4.22(m,1H),4.04(t,J＝10.7Hz,1H),3.49(d,J＝10.8Hz,1H),3.32(d,J＝11.3Hz,1H),2.40(s,3H),2.24(d,J＝15.5Hz,2H)；HRMS(ESI)calcd for C 18 H 20 N 3 O 3 S 2 [M+H] + 390.0941,found 390.0947.
Example 19
N- (4- (N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide
The procedure of example 1 was followed, white solid, 3.6% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.31(s,1H),9.71(s,1H),7.69(d,J＝8.9Hz,2H),7.58(d,J＝8.8Hz,2H),7.03(d,J＝2.5Hz,1H),6.80(dd,J＝8.7,2.6Hz,1H),6.61(d,J＝8.7Hz,1H),4.28–4.07(m,2H),3.44(d,J＝11.3Hz,1H),3.11(d,J＝11.2Hz,1H),2.06(s,3H),2.00(d,J＝16.1Hz,1H),1.86(t,J＝10.3Hz,1H)；HRMS(ESI)calcd for C 19 H 21 N 4 O 4 S 2 [M+H] + 433.0999,found 433.1003.
Example 20
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide
The procedure of example 1 was followed, and a white solid was obtained in 6.8% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.20(s,1H),8.67(d,J＝8.2Hz,1H),8.20(d,J＝8.2Hz,1H),8.09(dd,J＝12.8,7.5Hz,2H),7.65(ddd,J＝21.9,15.4,6.7Hz,3H),6.95(d,J＝2.5Hz,1H),6.70(dd,J＝8.7,2.5Hz,1H),6.53(s,1H),6.50(s,1H),4.23–3.98(m,2H),3.29(s,1H),2.85(d,J＝11.3Hz,1H),1.97–1.71(m,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ150.5,134.9,134.6,134.1,130.4,130.0,129.4,128.4,128.0,127.3,124.9,122.2,120.7,117.0,64.1,46.7,33.9；HRMS(ESI)calcd for C 21 H 20 N 3 O 3 S 2 [M+H] + 426.0941,found426.0947.
Example 21
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide
The procedure of example 1 was followed, white solid, yield 6.2%. 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),8.30(s,1H),8.05(dd,J＝24.2,8.2Hz,3H),7.68(ddd,J＝23.2,11.3,4.2Hz,3H),7.04(d,J＝2.6Hz,1H),6.84(dd,J＝8.8,2.6Hz,1H),6.58(d,J＝8.7Hz,1H),6.57–6.36(m,1H),4.25–4.01(m,2H),3.31(d,J＝11.4Hz,1H),2.91(d,J＝11.0Hz,1H),2.02–1.74(m,2H)；HRMS(ESI)calcd for C 21 H 20 N 3 O 3 S 2 [M+H] + 426.0941,found 426.0946.
Example 22
N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide
The procedure of example 1 was followed, and a white solid was obtained in 4.6% yield. 1 H NMR(300MHz,CDCl 3 )δ10.40(s,1H),7.03(s,3H),6.21(d,J＝8.6Hz,1H),6.05(dd,J＝8.6,2.4Hz,1H),5.66(s,1H),4.29(dd,J＝8.1,3.4Hz,1H),4.05–3.93(m,1H),3.88(dt,J＝13.4,6.8Hz,2H),3.33–3.17(m,2H),2.84(dq,J＝13.7,6.8Hz,1H),2.24(d,J＝14.6Hz,1H),1.98(td,J＝13.5,3.6Hz,1H),1.22(d,J＝6.8Hz,6H),1.11(d,J＝6.7Hz,6H),1.02(d,J＝6.7Hz,6H)；HRMS(ESI)calcd for C 26 H 36 N 3 O 3 S 2 [M+H] + 502.2193,found 502.2197.
Example 23
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) picolinamide
(2) Dissolving 2-bromo-4-nitrobenzaldehyde (10g, 43.48mmol) in 100mL of methanol, cooling in an ice-water bath, and slowly adding NaBH in batches when the temperature of the solution is reduced 4 (822mg, 21.74mmol), stirring for reaction for 20 minutes, concentrating the solvent until the amount of methanol is only 1/10 of the original amount, adding 100mL of water, stirring for half an hour, filtering, and drying to obtain a white solid 10. Intermediate 10 (5g, 21.55mmol) was dissolved in toluene (80 mL), t-butyl bromoacetate (5.04g, 25.86mmol) was added thereto, and the mixture was stirred at room temperature, 40% KOH aqueous solution (80 mL) and 0.1% TBAB were added thereto, and the mixture was stirred at room temperature for 1 hour
Ethyl acetate is added, extraction is carried out for three times, organic layers are combined, dried by anhydrous sodium sulfate and concentrated to obtain an intermediate 11. Intermediate 11 (5g, 14.4 mmol) was dissolved in methanol (80 mL), sodium methoxide (1.95g, 36.11mmol) was added, the reaction was stirred at room temperature for 30min, 80mL of water was added thereto, the reaction was carried out at room temperature for 20min, the solvent was concentrated, ethyl acetate and water were added, the aqueous layers were combined, 10% hydrochloric acid was slowly added to make PH =2, ethyl acetate was added and extraction was carried out three times, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 12. Intermediate 12 (3g, 9.83mmol) was dissolved in dry DCM (30 mL), and 10mL of oxalyl chloride was added, followed by a drop of DMF and reaction for 2h at RT. During this process, N, O-dimethylhydroxylamine hydrochloride (1.05g, 10.82mmol) was separately weighed and K was added 2 CO 3 (3.4g, 24.58mmol), 20mL of anhydrous acetonitrile was added, and the reaction was stirred. After the acyl chloride is completely prepared, DCM is concentrated, the acyl chloride is slowly dripped into N, O-dimethylhydroxylamine solution to react for 2 hours at room temperature, the solvent is concentrated, and EA and H are added 2 Completely dissolving O, extracting EA for three times, combining organic layers, drying by anhydrous sodium sulfate, concentrating, and performing column chromatography by using PE (ethylene diamine tetraacetic acid) EA =1 to obtain an intermediate 13. A three-necked flask with an appropriate size was selected and the weinreb amide compound 13 (2g, 5.74mm) was weighedol), nitrogen blanketed, syringe injected redistilled anhydrous THF (20 mL), dissolved with stirring, -78 ℃ for 10 minutes, strictly anhydrous oxygen-free operation, multiple additions of t-BuLi solution with a disposable syringe (note: the tert-butyl lithium is added in batches when the amount is large), the reaction is stirred for 5 minutes at 78 ℃, the solution is yellow and clear, and saturated ammonium chloride solution (20 mL) is added to quench the reaction. Adding ethyl acetate and a proper amount of water, extracting for 3 times by using ethyl acetate, combining organic layers, drying by using anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography by using PE (ethylene-vinyl acetate) EA =4 to obtain an intermediate 14. Methyl triphenyl phosphonium bromide (20.71 mmol) is added to anhydrous THF at 0 ℃ under argon blanket, n-butyl lithium (18.64 mmol) is added slowly followed by stirring for one hour, intermediate 14 (10.35 mmol) in anhydrous THF is added, the reaction is allowed to warm to room temperature for about one hour, after which the reaction is quenched with water, extracted with ethyl acetate, the organic layers are combined, concentrated, and chromatographed with PE/EA =8 to afford intermediate 15. Intermediate 15 (7.85 mmol) was added to a solution of iodine (15.69 mmol) and silver thiocyanate (31.38 mmol) in toluene at 0 deg.C, stirred overnight at room temperature, filtered, the filtrate washed with saturated sodium sulfite, extracted with ethyl acetate, the organic layers combined, the resulting organic layer was then spin dried, dissolved in THF and added to NH at 0 deg.C 3 Was stirred for one hour, followed by stirring at room temperature for 2.5 days. After concentration, the intermediate 16 was washed with ethyl acetate and filtered by suction to give an intermediate 17, which was dissolved in THF, added with triethylamine (28.27 mmol) and di-tert-butyl dicarbonate (28.27 mmol), reacted at room temperature for 2 days, and the solvent was concentrated and directly subjected to column chromatography with PE/EA = 8. Intermediate 17 (3.39 mmol) was added to a solution of ethanol and saturated ammonium chloride solution 1 (30 mL), followed by iron powder (6.79 mmol), heated at 87 ℃ for half an hour, filtered through celite while hot, extracted three times with ethyl acetate, the organic layers were combined, and the solvent was concentrated to give intermediate 18 which was directly fed to the next step. Commercially obtained pyridine-2-carboxylic acid (0.67 mmol) was dissolved in 20mL toluene, sulfoxide chloride (3.38 mmol) was added slowly, 1 drop of DMF was added, the reaction was allowed to react at 120 ℃ for 1 hour, and after cooling to room temperature, the solvent was concentrated to give pyridine-2-carbonyl chloride for use. Pyridine-2-carbonyl chloride (0.67 mmol) was dissolved in 5mL THF and the solution was added to intermediate 18 (0.59 mmol) at 0 deg.CTo THF (5 mL), pyridine (30 μ L) was added, followed by warming to room temperature and stirring the reaction for 30 minutes, followed by quenching with 10mL of saturated sodium bicarbonate solution and extraction three times with ethyl acetate. The solvent was concentrated to give intermediate 19, and intermediate 19 (0.59 mmol) was dissolved in 10mL of anhydrous dichloromethane, 10mL of trifluoroacetic acid was added, and reacted at room temperature for 2 hours, followed by adjustment of PH =9 with a saturated sodium bicarbonate solution. Extracted three times with ethyl acetate, the organic phases are combined, concentrated and purified with DCM: column chromatography in MeOH = 20. White solid, yield 2.5%. 1 H NMR(500MHz,Chloroform-d)δ9.61(s,1H),8.73(dd,J＝5.1,1.3Hz,1H),7.93(td,J＝8.0,1.3Hz,1H),7.82(dd,J＝8.0,1.0Hz,1H),7.63(ddd,J＝7.9,5.0,1.0Hz,1H),7.42(dd,J＝7.5,2.0Hz,1H),7.36(dt,J＝7.4,1.0Hz,1H),7.13(d,J＝2.0Hz,1H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.68(d,J＝6.6Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ162.21,159.38,148.98,148.55,142.20,136.89,128.80,127.04,124.33,123.59,120.48,118.76,117.20,80.32,70.02,67.26,38.64.
Example 24
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide
The procedure of example 23 was repeated, giving a yellow solid in 2.2% yield. 1 H NMR(300MHz,Chloroform-d)δ9.82(s,1H),8.50(d,J＝1.1Hz,1H),7.77(d,J＝8.0Hz,1H),7.69(dd,J＝8.0,1.2Hz,1H),7.39(dd,J＝7.5,2.0Hz,1H),7.33–7.26(m,2H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ162.28,160.58,148.31,141.37,138.58,130.25,128.80,128.53,128.27,125.78,120.02,118.88,117.76,117.62,78.89,70.31,67.26,38.64.
Example 25
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide
The procedure of example 23 was followed, and white solid was obtained in 2.5% yield. 1 H NMR(300MHz,Chloroform-d)δ9.76(s,1H),8.52(d,J＝1.2Hz,1H),7.93(d,J＝8.0Hz,1H),7.43(dd,J＝7.5,2.0Hz,1H),7.36(dt,J＝7.6,1.1Hz,1H),7.28(d,J＝1.9Hz,1H),7.05(dd,J＝8.0,1.3Hz,1H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ162.21,160.58,156.58,147.44,141.37,138.88,128.53,128.36,125.31,121.95,118.76,117.94,117.03,78.89,69.85,67.26,38.64.
Example 26
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.2%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.47(d,J＝1.2Hz,1H),7.88(d,J＝8.0Hz,1H),7.44–7.34(m,3H),7.28(d,J＝1.9Hz,1H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.48(dd,J＝18.1,0.9Hz,2H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ162.21,160.58,147.44,141.95,141.37,130.50,129.47,128.80,128.53,125.31,120.28,118.88,117.94,78.89,69.85,67.26,38.64.
Example 27
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide
The procedure of example 23 was followed, and white solid was obtained in 1.3% yield. 1 H NMR(300MHz,Chloroform-d)δ9.98(s,1H),8.11(d,J＝1.3Hz,1H),7.88(d,J＝8.0Hz,1H),7.39(dd,J＝7.5,2.0Hz,1H),7.33–7.25(m,3H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.83(s,2H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ162.21,160.58,152.96,143.97,141.37,134.12,128.80,128.53,125.78,123.97,122.73,118.88,117.62,78.89,70.31,67.26,56.63,38.64.
Example 28
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.6%. 1 H NMR(300MHz,Chloroform-d)δ9.75(s,1H),8.21(d,J＝1.2Hz,1H),7.88(d,J＝8.0Hz,1H),7.47–7.32(m,2H),7.25(d,J＝1.9Hz,1H),7.18(dd,J＝8.0,1.3Hz,1H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.48(dd,J＝18.1,0.9Hz,2H),3.68(d,J＝6.6Hz,2H),2.31(s,3H). 13 CNMR(75MHz,Chloroform-d)δ162.17,160.58,148.31,143.97,141.37,134.90,128.96,128.36,127.83,125.31,124.26,118.76,117.94,78.89,69.85,67.26,37.36,17.80.
Example 29
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.2%. 1 H NMR(300MHz,Chloroform-d)δ9.48(s,1H),8.47(d,J＝1.3Hz,1H),7.54(d,J＝1.1Hz,1H),7.38(dd,J＝7.5,2.0Hz,1H),7.29(dt,J＝7.5,0.9Hz,1H),7.25(d,J＝2.0Hz,1H),6.25(s,2H),4.59(d,J＝0.9Hz,1H),4.52–4.47(m,2H),4.42(s,1H),3.69(d,J＝16.7Hz,2H). 13 CNMR(75MHz,Chloroform-d)δ162.32,159.91,141.14,140.72,135.77,131.93,131.16,129.48,129.24,129.01,125.78,118.88,117.94,81.33,70.31,67.26,38.64.
Example 30
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methoxypyrazine-2-carboxamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.5%. 1 H NMR(300MHz,Chloroform-d)δ9.76(s,1H),8.01(d,J＝33.7Hz,2H),7.49–7.26(m,2H),7.25(d,J＝2.0Hz,1H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.48(dd,J＝18.1,0.9Hz,2H),3.92(s,3H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ163.49,162.17,160.58,142.00,137.14,135.91,133.30,128.80,128.53,125.78,118.88,117.62,78.89,70.31,67.26,54.26,38.64.
Example 31
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.5%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.21(d,J＝1.3Hz,1H),7.45–7.27(m,2H),7.25(d,J＝1.5Hz,2H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.48(dd,J＝18.1,0.9Hz,2H),3.68(d,J＝6.6Hz,2H),2.40(s,3H). 13 C NMR(75MHz,Chloroform-d)δ162.32,160.58,143.97,142.00,137.34,135.77,131.54,129.76,128.66,128.53,125.95,118.88,117.62,78.89,70.31,67.26,38.64,17.77.
Example 32
N- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) benzamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.6%. 1 H NMR(300MHz,Chloroform-d)δ8.03–7.96(m,2H),7.59–7.52(m,1H),7.55–7.48(m,2H),7.42(dd,J＝7.5,2.0Hz,1H),7.33(dt,J＝7.5,1.1Hz,1H),7.25(d,J＝2.0Hz,1H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ167.47,159.38,142.20,134.34,131.51,128.80,128.76,128.54,127.04,123.59,118.76,117.20,80.32,70.02,67.26,38.64.
Example 33
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.3%. 1 H NMR(300MHz,Chloroform-d)δ8.05–7.99(m,2H),7.50(dd,J＝7.5,2.0Hz,1H),7.44(d,J＝2.0Hz,1H),7.33(dt,J＝7.6,1.1Hz,1H),7.26–7.20(m,2H),6.25(s,2H),4.56–4.48(m,3H),4.46(d,J＝0.9Hz,1H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ167.47,162.72,160.58,140.72,135.81,129.72,128.53,128.36,125.31,118.76,117.94,115.62,78.89,69.85,67.26,37.36.
Example 34
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzenesulfonamide
The procedure of example 23 was followed, and white solid was obtained in 1.5% yield. 1 H NMR(300MHz,Chloroform-d)δ7.84–7.73(m,2H),7.62–7.55(m,1H),7.52–7.43(m,3H),7.43–7.34(m,2H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.45(dd,J＝11.5,0.9Hz,2H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ160.58,138.44,137.04,133.08,130.61,128.81,128.53,128.12,125.13,116.97,115.89,78.89,69.85,67.26,38.64.
Example 35
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.3%. 1 H NMR(300MHz,Chloroform-d)δ7.88–7.80(m,2H),7.49–7.39(m,2H),7.32(dt,J＝7.4,1.0Hz,1H),7.27–7.16(m,2H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.45(dd,J＝11.5,0.9Hz,2H),3.68(d,J＝6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ162.87,160.58,138.44,136.18,130.61,128.53,128.13,125.54,117.60,116.88,116.71,78.89,70.31,67.26,38.64.
Example 36
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.2%. 1 H NMR(300MHz,Chloroform-d)δ9.93(s,1H),7.73–7.64(m,2H),7.58–7.50(m,2H),7.48–7.40(m,2H),7.30(dt,J＝7.4,1.0Hz,1H),6.25(s,2H),4.51–4.47(m,3H),4.46(d,J＝0.9Hz,1H),3.69(d,J＝16.7Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ159.91,138.44,136.89,136.21,129.76,129.19,127.97,125.54,117.94,117.60,81.33,70.31,67.26,38.64.
Example 37
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-bromobenzenesulfonamide
The procedure of example 23 was followed, and white solid was obtained in 1.3% yield. 1 H NMR(300MHz,Chloroform-d)δ9.79(s,1H),7.72–7.56(m,4H),7.39(dd,J＝7.5,2.0Hz,1H),7.36–7.23(m,2H),6.25(s,2H),4.54–4.41(m,4H),3.69(d,J＝16.7Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ159.91,138.31,136.31,130.76,129.76,129.18,127.65,125.54,123.97,118.07,117.94,81.33,70.31,67.26,37.36.
Example 38
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.6%. 1 H NMR(300MHz,Chloroform-d)δ9.66(s,1H),7.75–7.60(m,2H),7.48–7.36(m,4H),7.30(dt,J＝7.4,1.0Hz,1H),6.25(s,2H),4.56–4.40(m,4H),3.69(d,J＝16.7Hz,2H),1.30(s,9H). 13 C NMR(75MHz,Chloroform-d)δ159.35,148.64,138.98,136.82,129.76,128.53,127.82,126.41,125.21,118.15,117.94,84.63,69.98,67.05,38.64,34.79,31.19.
Example 39
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.8%. 1 H NMR(300MHz,Chloroform-d)δ9.83(s,1H),7.64–7.55(m,2H),7.43(d,J＝1.9Hz,1H),7.42–7.21(m,2H),7.09–6.89(m,2H),6.25(s,2H),4.54–4.42(m,4H),3.86(s,3H),3.69(d,J＝16.7Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ159.61,159.35,138.98,136.16,129.76,128.79,127.83,125.36,117.60,116.88,114.76,84.63,69.98,67.05,55.19,38.64.
Example 40
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.5%. 1 H NMR(300MHz,Chloroform-d)δ9.92(s,1H),7.63–7.52(m,2H),7.46–7.38(m,2H),7.38–7.29(m,1H),7.17(dq,J＝7.3,1.0Hz,2H),6.25(s,2H),4.53(d,J＝11.0Hz,2H),4.45(dd,J＝11.5,1.0Hz,2H),3.68(d,J＝6.6Hz,2H),2.37(t,J＝1.0Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ160.58,142.86,138.44,136.71,130.61,128.83,128.57,128.53,125.54,117.60,116.88,78.89,70.31,67.26,38.64,21.26.
EXAMPLE 41
N- (4- (N- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.6%. 1 H NMR(300MHz,Chloroform-d)δ9.76(s,1H),7.96–7.64(m,4H),7.51–7.21(m,3H),6.25(s,2H),4.62–4.35(m,4H),3.69(d,J＝16.7Hz,2H),2.07(s,3H). 13 C NMR(75MHz,Chloroform-d)δ169.05,159.35,141.01,138.98,136.38,129.76,128.62,128.53,125.21,119.78,118.15,117.94,84.63,69.98,67.05,38.64,24.27.
Example 42
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.8%. 1 H NMR(300MHz,Chloroform-d)δ10.00(s,1H),8.05(d,J＝8.8Hz,2H),7.99(s,1H),7.85(s,1H),7.63(s,1H),7.51(s,1H),7.45(s,1H),7.43–7.35(m,2H),7.30(dt,J＝7.4,1.0Hz,1H),6.25(s,2H),4.71–4.34(m,4H),3.69(d,J＝16.7Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ159.91,138.98,134.25,132.91,129.76,129.30,128.93,128.56,128.53,127.94,127.82,127.37,126.97,126.59,125.21,118.85,117.94,84.63,69.98,67.05,38.64.
Example 43
N- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.2%. 1 H NMR(300MHz,Chloroform-d)δ9.71(s,1H),8.39(s,1H),8.19–7.94(m,3H),7.85(s,1H),7.63(d,J＝4.3Hz,2H),7.53–7.20(m,3H),6.25(s,2H),4.68–4.30(m,4H),3.69(d,J＝16.7Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ159.91,138.98,135.83,133.51,132.91,129.76,129.32,129.30,128.53,127.82,127.37,126.97,125.21,122.37,118.85,117.94,84.63,69.98,67.05,38.64.
Example 44
N- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide
The procedure of example 23 was repeated to give a white solid in a yield of 1.6%. 1 HNMR(300MHz,Chloroform-d)δ7.43(d,J＝1.9Hz,1H),7.29(dt,J＝7.5,1.1Hz,1H),7.24(dd,J＝7.5,1.8Hz,1H),7.21(t,J＝0.8Hz,2H),6.25(s,2H),4.64(d,J＝0.9Hz,1H),4.54–4.43(m,3H),3.89(s,2H),3.69(d,J＝16.7Hz,2H),2.91(t,J＝1.0Hz,1H),1.26(d,J＝24.9Hz,6H),1.19(d,J＝24.9Hz,12H). 13 C NMR(75MHz,Chloroform-d)δ159.91,146.63,143.72,138.16,137.67,129.76,127.83,125.36,123.80,118.57,117.94,84.63,72.79,70.21,36.71,34.39,28.81,24.54,24.12.
Example 45
N- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) picolinamide
The procedure is as in example 23, tert-butyl bromoacetate being replaced by tert-butyl 2-bromopropionate. The product was a white solid in 1.5% yield.
1 H NMR(300MHz,Chloroform-d)δ9.75(s,1H),8.72(dd,J＝5.0,1.2Hz,1H),7.93(td,J＝8.0,1.3Hz,1H),7.82(dd,J＝8.0,1.1Hz,1H),7.64(ddd,J＝8.0,5.1,1.1Hz,1H),7.46–7.31(m,2H),7.25(d,J＝1.9Hz,1H),6.25(s,2H),4.67(d,J＝0.9Hz,1H),4.57–4.42(m,2H),3.62(d,J＝26.2Hz,2H),1.34(s,3H). 13 C NMR(75MHz,Chloroform-d)δ162.17,157.86,148.98,148.55,141.37,136.81,130.97,125.99,125.31,125.26,120.48,118.76,114.71,91.57,75.02,68.23,41.63,22.60.
Example 46
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide
The procedure is as in example 45, white solid, yield 1.4%. 1 H NMR(300MHz,Chloroform-d)δ9.79(s,1H),8.52(d,J＝1.3Hz,1H),7.92(d,J＝7.9Hz,1H),7.37(dd,J＝7.4,1.9Hz,1H),7.36–7.23(m,2H),7.06(dd,J＝8.0,1.2Hz,1H),6.25(s,2H),4.67(d,J＝1.1Hz,1H),4.60(s,1H),4.54(d,J＝1.1Hz,1H),3.62(d,J＝26.2Hz,2H),1.34(s,3H). 13 C NMR(75MHz,Chloroform-d))δ162.21,157.86,156.58,145.44,141.37,137.76,131.05,126.53,125.78,121.95,118.88,117.03,114.71,97.36,75.02,67.84,41.63,22.60.
Example 47
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide
The procedure is as in example 45, white solid, yield 1.1%. 1 H NMR(300MHz,Chloroform-d)δ9.82(s,1H),8.47(d,J＝1.2Hz,1H),7.87(d,J＝8.0Hz,1H),7.47–7.32(m,2H),7.30(dt,J＝7.4,1.0Hz,1H),7.25(d,J＝1.9Hz,1H),6.36(d,J＝42.5Hz,2H),4.67(d,J＝1.1Hz,1H),4.63–4.47(m,2H),3.62(d,J＝26.2Hz,2H),1.35(s,3H). 13 C NMR(75MHz,Chloroform-d)δ162.21,158.53,147.44,144.65,141.37,131.05,130.50,129.33,127.49,125.95,120.05,118.88,114.71,97.36,75.02,68.23,41.63,22.55.
Example 48
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide
The procedure is as in example 45, white solid, yield 1.3%. 1 H NMR(300MHz,Chloroform-d)δ8.11(d,J＝1.3Hz,1H),7.88(d,J＝8.0Hz,1H),7.36–7.21(m,4H),6.36(d,J＝42.5Hz,2H),4.67(d,J＝1.0Hz,1H),4.59(s,1H),4.54(d,J＝1.0Hz,1H),3.82(s,3H),3.62(d,J＝26.2Hz,2H),1.33(s,3H). 13 C NMR(75MHz,Chloroform-d)δ162.21,158.53,153.98,143.97,140.83,134.36,130.97,127.49,125.78,124.72,123.08,118.88,114.35,99.86,74.84,68.23,56.67,41.63,22.55.
Example 49
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide
The procedure is as in example 45, white solid, yield 1.6%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.21(d,J＝1.2Hz,1H),7.88(d,J＝8.0Hz,1H),7.39(dd,J＝7.5,2.0Hz,1H),7.31(dt,J＝7.5,1.1Hz,1H),7.25(d,J＝2.0Hz,1H),7.18(dd,J＝8.0,1.3Hz,1H),6.25(s,2H),4.67(d,J＝1.1Hz,1H),4.60(s,1H),4.54(d,J＝1.1Hz,1H),3.62(d,J＝26.2Hz,2H),2.31(s,3H),1.34(s,3H). 13 C NMR(75MHz,Chloroform-d)δ162.28,157.86,145.44,143.97,141.37,134.79,131.05,128.96,125.99,125.78,124.26,118.88,114.71,97.36,75.02,67.84,41.63,22.60,17.77.
Example 50
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzenesulfonamide
The procedure is as in example 45, white solid, 1.5% yield. 1 H NMR(300MHz,Chloroform-d)δ9.92(s,1H),7.84–7.74(m,2H),7.64–7.52(m,1H),7.49–7.41(m,2H),7.38(dd,J＝7.5,2.0Hz,1H),7.35–7.28(m,2H),6.36(d,J＝42.5Hz,2H),4.67(d,J＝1.1Hz,1H),4.59(s,1H),4.54(d,J＝1.1Hz,1H),3.62(d,J＝26.2Hz,2H),1.35(s,3H). 13 C NMR(75MHz,Chloroform-d)δ158.53,138.44,136.96,133.74,131.05,128.81,128.61,128.50,125.54,117.60,114.24,97.36,75.02,68.23,41.63,22.55.
Example 51
N- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide
The procedure is as in example 45, white solid, yield 1.3%. 1 H NMR(300MHz,Chloroform-d)δ9.83(s,1H),7.92–7.80(m,2H),7.38(dd,J＝7.5,2.0Hz,1H),7.34(d,J＝2.0Hz,1H),7.30(dt,J＝7.5,1.0Hz,1H),7.26–7.16(m,2H),6.36(d,J＝42.5Hz,2H),4.67(d,J＝1.1Hz,1H),4.60(s,1H),4.54(d,J＝1.1Hz,1H),3.62(d,J＝26.2Hz,2H),1.33(s,3H). 13 C NMR(75MHz,Chloroform-d)δ163.31,157.86,138.98,136.32,130.97,128.50,128.13,125.36,117.60,116.54,114.24,99.86,74.84,68.23,41.63,22.55.
Example 52
N- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide
The procedure is as in example 45, white solid, yield 1.2%. 1 H NMR(300MHz,Chloroform-d)δ9.83(s,1H),7.74–7.64(m,2H),7.63–7.49(m,2H),7.43–7.24(m,3H),6.36(d,J＝42.5Hz,2H),4.76–4.43(m,3H),3.61(d,J＝37.2Hz,2H),1.33(s,3H). 13 C NMR(75MHz,Chloroform-d)δ158.53,138.98,136.57,136.19,130.97,129.19,128.50,127.97,125.36,117.94,114.45,99.86,74.58,68.23,41.63,22.55.
Example 53
N- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide
The procedure is as in example 45, white solid, yield 1.8%. 1 H NMR(300MHz,Chloroform-d)δ9.94(s,1H),7.67–7.51(m,2H),7.43–7.21(m,3H),7.08–6.83(m,2H),6.36(d,J＝42.5Hz,2H),4.72–4.46(m,3H),3.85(s,3H),3.61(d,J＝37.2Hz,2H),1.33(s,3H). 13 C NMR(75MHz,Chloroform-d)δ159.61,158.53,138.98,136.21,130.97,128.79,128.50,125.13,117.94,117.24,114.45,99.86,74.35,68.23,55.20,41.63,22.55.
Example 54
(R) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide
Example 1 was resolved by preparative chiral column in 100% yield.
Example 55
(S) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide
Example 1 was resolved by preparative chiral column in 100% yield.
Example 56
(R) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide
Example 2 was resolved by preparative chiral column in 100% yield.
Example 57
(S) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide
Example 2 was resolved by preparative chiral column in 100% yield.
Example 58
(R) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide
Example 3 was resolved by preparative chiral column in 100% yield.
Example 59
(S) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide
Example 3 was resolved by preparative chiral column in 100% yield.
Example 60
Tablet formulation
The above formula is taken, and the tablets are prepared by a conventional method.
The following are the results of pharmacological experiments with some of the compounds of the present invention:
in vitro enzyme activity inhibition experiment of part of compounds on BACE-1
1. Experimental methods
Method for determining BACE-1 inhibitory activity of compounds:
the experimental principle is as follows: BACE-1 is placed in the optimal enzyme reaction condition and reaction system, a substrate is added on a reaction template, and the activity of the enzyme is detected by a colorimetric method through the reaction of the enzyme and the substrate.
Experimental materials: all compound samples were made up to 10 in dimethyl sulfoxide (DMSO) -2 Gradually diluting the mol/L solution to the required concentration by using a sodium acetate buffer solution with the pH = 4.5; BACE-1 is a human enzyme.
The test method comprises the following steps: the BACE-1 inhibitory activity assay is the FRET method. Test compounds and positive control MK-8931 were dissolved in DMSO and diluted with a BACE-1 buffer gradient to the desired concentration, ensuring that DMSO levels were below 1%. To a fully black 384 well plate were added in sequence: 10 μ L BACE-1 enzyme, 10 μ L LBACE-1 substrate and 10 μ L of different concentrations of compound. The incubation was carried out at room temperature for 15min, and the change in fluorescence intensity was subsequently measured at an excitation wavelength of 545nM and an emission wavelength of 585 nM. The formula for calculating the inhibition rate is as follows: [1- (Experimental group fluorescence intensity Change/blank group fluorescence intensity Change)]X 100%. Testing IC 50 The method comprises selecting eight concentrations of target compound, determining the inhibition rate (0.001-10 μ M) of BACE-1 enzyme, performing linear regression on the logarithm of the molar concentration and the inhibition rate, and determining the concentration of the enzyme when the inhibition rate reaches 50% as the IC of the compound 50 The value is obtained.
Each experiment was repeated three times and the results expressed as mean ± SEM.
1. The experimental results are as follows:
IC of the Compounds of Table 1 50 Value of
And (4) analyzing results: we have determined the inhibition activity of the compounds of the examples on BACE-1 by FRET assay, and used the clinical drug MK-8931 developed by Moshadong as positive control, and it can be seen from Table 1 that the inhibition activity of BACE-1 of all the compounds is in nanomolar level and superior to that of the positive control.
Toxicity of partial compounds to SH-SY5Y nerve cells
1. The experimental method comprises the following steps:
(1) And (3) SH-SY5Y cell subculture: discarding the old culture solution in a cell culture bottle, adding 4mL of D-Hanks, slightly shaking, washing FBS serum in the old culture solution, discarding a washing solution after the washing is finished, adding 2mL0.25% pancreatin to digest cells for 1min, adding 4mL of fresh culture solution to stop digestion, uniformly mixing, transferring to a 20mL centrifuge tube, centrifuging at 1000rpm for 10min, discarding the supernatant, adding 5mL of new culture solution, and carrying out subculture according to the proportion of 1;
(2) SH-SY5Y cell plating: mu.L of the cell suspension was seeded in a counting plate and counted by an inverted fluorescence microscope to 2X 10 5 Inoculating SH-SY5Y cells per mL into a 96-well culture plate at a ratio of 100. Mu.L/well, by 5% 2 Culturing in a constant-temperature incubator at 37 ℃;
(3) Liquid changing: after SH-SY5Y cells are cultured for 24h, the culture solution in a 96-well culture plate is replaced by MEM/F12 culture solution;
(4) Preparation and dilution of the compound: dissolving a compound to be tested by DMSO, and gradually diluting the compound to be tested by using fresh MEM/F12 culture solution to prepare the required test concentration;
(5) Administration: adding 10 μ L of test compound at corresponding concentration to each well of the administration group, adding the same volume of solvent to the control group, incubating for 2h, adding 10 μ L of MEM/F12 culture solution to each well, and adding to the total content of 5% CO 2 Culturing in a constant-temperature incubator at 37 ℃;
(6) Adding MTT: 24h after SH-SY5Y cell culture, 10. Mu.L of MTT was added to each well and the content of CO was reduced to 5% 2 Culturing in a constant-temperature incubator at 37 ℃;
(7) And (3) MTT measurement: continuing culturing SH-SY5Y cells for 3h, discarding old culture solution, adding 100 mu LDMSO into each well, shaking to dissolve for 20min, measuring absorbance value of each well at 490nM with FC microplate reader, and calculating cell survival rate and toxicity after administration.
2. The experimental results are as follows:
TABLE 2 toxicity of some Compounds to SH-SY5Y
And (4) analyzing results: as can be seen from Table 2, the SH-SY5Y cell viability of the Control group is 100%, and the cell viability of the tested compounds reaches over 90% at the concentrations of 1. Mu.M, 10. Mu.M and 50. Mu.M, which indicates that the part of the examples has no obvious toxicity to SH-SY5Y cells.
Part of compounds reduce A beta in rat brain 40 The level of (c):
1. the experimental method comprises the following steps:
male CD rats (weighing approximately 200 g) were grouped and acclimated to animal housing for 5-7 days prior to study use. The compound was dissolved with 20% hydroxypropyl-beta-cyclodextrin and administered orally at 10mg/kg. After three hours the rats were euthanized with excess carbon dioxide, the brains were removed and frozen on dry ice. All brain tissues were stored at-78 ℃ and subsequently assayed for A β by ELISA 40 And (4) horizontal.
2. The experimental results are as follows:
TABLE 3 rat cortical Ass 3 hours following oral administration of 10mg/kg compound 40 Variations in
And (4) analyzing results: as can be seen from Table 3, these compounds all reduced Abeta in rat brain well 40 And is superior to positive medicine MK-8931.
While the present invention has been described with reference to the particular embodiments set forth above, many alternatives, modifications, and other variations will be apparent to those skilled in the art. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the present invention.
Claims (12)
1. A2-aminothiazole compound represented by the general formula I-a or the general formula I-b, an isomer or a pharmaceutically acceptable salt thereof:
wherein:
z is H or C 1 ～C 3 An alkyl group;
R 1 、R 3 and R 4 Is H or halogen;
R 2 is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from C 6 ～C 10 Aryl or C 2 ～C 10 A heteroaryl group; the substituents are selected from H, halogen, -CN, -NO 2 、-OH，-COOH、-NH 2 、C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, C 1 ～C 6 Haloalkyl, -N (H) -C (O) -C 1 ～C 3 Alkyl or C 1 ～C 6 An alkylamino group.
2. 2-aminothiazole derivatives, isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein: z is H or methyl or ethyl.
3. 2-aminothiazole derivatives, isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein: r is 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine, thiophene, pyrazole, thiazole, pyrimidine, naphthalene, furan, pyrrole, indene, quinoline or indole; the substituents are selected from H, halogen, -CN, -NO 2 、-OH，-COOH、-NH 2 、C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Haloalkyl, -N (H) -C (O) -C 1 ～C 4 Alkyl or C 1 ～C 4 An alkylamino group.
4. 2-aminothiazole derivatives, isomers or pharmaceutically acceptable salts thereof according to claim 3, wherein: the substituent is selected from H, halogen and-CH 3 、-CN、-NO 2 、-CF 3 、-OCH 3 Ethyl, N-propyl, isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
5. 2-aminothiazole derivatives, isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein: z is H or methyl; r is 1 ,R 3 And R 4 Is H; r 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine or naphthalene, said substituents being selected from: H. halogen, -CH 3 、-CN、-NO 2 、-CF 3 、-OCH 3 Ethyl, N-propyl, isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
6. 2-aminothiazole derivatives, isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein: z is H or methyl; r 1 ,R 3 And R 4 Is H; r 2 Is substituted or unsubstituted-N (H) -C (O) -R 5 Or substituted or unsubstituted-N (H) -S (O) 2 )-R 6 ，R 5 Or R 6 Independently selected from benzene, pyridine, pyrazine or naphthalene, said substituents being selected from: H. halogen, -CH 3 、-CN、-OCH 3 Isopropyl, tert-butyl or-N (H) -C (O) -CH 3 。
7. Any one of the following compounds, or an isomer or a pharmaceutically acceptable salt thereof:
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-methoxypyrazine-2-carboxamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4 fluorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-bromobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide;
n- (4- (N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazole ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -3, 5-dichloropicolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-methoxypyrazine-2-carboxamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) -3-chloro-5-methyl picolinamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-bromobenzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4- (tert-butyl) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -4-methylbenzenesulfonamide;
n- (4- (N- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) sulfamoyl) phenyl) acetamide;
n- (2 ' -amino-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) naphthalene-1-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) naphthalene-2-sulfonamide;
n- (2 ' -amino-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -2,4, 6-triisopropylbenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ iso-chromane-4, 4' -thiazol ] -6-yl) picolinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-chloromethylpyridinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -5-methoxymethylpyridine amide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochromane-4, 4' -thiazol ] -6-yl) -5-methyl picolinamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) benzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-fluorobenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4-chlorobenzenesulfonamide;
n- (2 ' -amino-3-methyl-5 ' H-spiro [ isochroman-4, 4' -thiazol ] -6-yl) -4- (methoxy) benzenesulfonamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
(S) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) picolinamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridine amide;
(S) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-cyanomethylpyridinamide;
(R) -N- (2 ' -amino-5 ' h-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide;
(S) -N- (2 ' -amino-5 ' H-spiro [ chromane-4, 4' -thiazol ] -6-yl) -5-fluoromethylpyridinamide.
8. A process for producing the compound, isomer or pharmaceutically acceptable salt thereof according to claim 1,
9. a pharmaceutical composition comprising a compound, isomer, or a pharmaceutically acceptable salt thereof according to any of claims 1-7, and a pharmaceutically acceptable carrier.
10. The use of a compound, isomer, or a pharmaceutically acceptable salt thereof according to any of claims 1-7, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a BACE-1 inhibitor.
11. Use of a compound, isomer, or a pharmaceutically acceptable salt thereof according to any of claims 1-7, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment of dementia.
12. The use according to claim 11, wherein the dementia symptoms are selected from alzheimer's disease, fronto-temporal lobe dementia, creutzfeldt-jakob disease, dementia with lewy bodies, parkinson's disease or huntington's disease.
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| US20070281938A1 (en) * | 2004-05-24 | 2007-12-06 | Amgen Inc. | Inhibitors of 11-Beta-Hydroxy Steroid Dehydrogenase Type 1 |
| WO2011123674A1 (en) * | 2010-03-31 | 2011-10-06 | Array Biopharma Inc. | Compounds for treating neurodegenerative diseases |
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