TW555694B - Tetrahydroisoquinolinyl amides, their preparation and pharmaceutical composition containing the same - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof: where Q is a monocychc or bicyclic aryl or heteroaryl ring, R1 is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl. C1-6alkynyl, C1-6alkylCO-, formyl, CF3CO- or C1-6alkylSO2-, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkl-C1-4alkyl-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS-, C1-6alkylS02-, (C1-4alkyl)2NSO2-, (C1-4alkyl)NHSO2-, (C1-4alkyl)2NCO-, (C1-4alkyl)NHCO- or CONH2; or -NR3R4 where R3 is hydrogen or C1-4alkyl, and R4 is hydrogen, C1-4alkyl. formyl, -CO2C1-4alkyl or -COC1-4alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and X is hydrogen, halogen, C1-6alkoxy, C1-6alkyl, amino or trifluoroacetylamino; but when X is hydrogen excluding compounds in which R2 is 2-alkoxy and when X is halogen excluding the compounds N-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide,N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirnylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazirinyl benzamide and N-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide, are useful inter alia in the treatment and prophylaxis of epilepsy.

Description

555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (/) This invention relates to novel compounds, their preparation methods, and their use as therapeutic agents. In WO 97/48683 (SmithKlune Beec ^ am), which was not published at the time of the application, it is disclosed that tetrahydroisofluorinyl benzamidine, wherein the benzamidine moiety contains an oxy substituent, and the compounds include: iodine 1 methyl-1 , 2,3,4-tetraazaisoisoline-5-yl) -5-benzylfluorenyl-2-methoxybenzylamine, hydrazone (7_iodo-I, 2,3, fluorenetetrahydroisoquine Phenyl-5-yl) -5-benzylfluorenyl-2-methoxybenzylamine, ^^ (5-11,2,3,4-tetrahydroisofluorinyl) > 5 tellurium fluorenyldongmethoxy Benzamidine, N- (5-Qi-1, 2, 3, 4, hydrogen isoquinoline winteryl) winter methoxy ice trifluoromethyl dimethyl benzylamine, N_ (5-iodine_1 , 2,3,4, tetrahydroisofluorin-7-yl) -2-methoxy-5-trifluoromethyldimorphyl benzamidine, N_ (7-iodosine ^, 'tetrahydroisoquine Pyridin-5-yl) -2-methoxy-5-trifluoromethyldipyridylbenzylamine and N- (8-fluoro-2_methyl-1,2,3,4-tetrahydroisophosphonium _5_yl) -4-tert-butyl-2_methoxybenzylamine. It has been surprisingly discovered that the following amine compounds of formula (I) have anticonvulsant, active, and therefore salty use For the treatment and / or prevention of anxiety, mania, depression, fear disorders and / or aggression, diseases related to subarachnoid hemorrhage or neuroshock , Stop the abuse of substance-related effects such as cocaine, nicotine, alcohol and benzodiazepines, diseases that can be treated and / or prevented with anticonvulsants such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, prevalence Headaches, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Haddington's disease, schizophrenia, obsessive-compulsive thinking and compulsive behavior disease (OCD), AIDS-related neurological deficits, sleep disorders (Including circadian disorder, insomnia & sleep), convulsions (such as this paper size applies Chinese National Standard (CNS) A4 size (210'X 297)) (Please read the precautions on the back before filling this page)

1T work 694 A7

() ^ (16 curtin 011_6 syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, cancer pain, such as diabetes, multiple sclerosis (MS) and exercise In neurogenic diseases, improper neural activity caused by neurological disorders, ataxia, muscle stiffness (spasm), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). Accordingly, the present invention provides the formula: Compounds or pharmaceutically acceptable salts thereof:

Ο) (Please read the notes on the back before filling in this page}

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R1 is hydrogen, fluorenyl (substituted by hydroxyl or Cm alkoxy if necessary), Cl_6 alkenyl, Ci -6decyl, C1-6 alkylCO-, formamyl, cf3co- or Cu alkyl so2-, R2 is hydrogen, hydroxyl or up to three selected from halogen, N02, CN, N3, 'CF3CK CF3S-, CF3CCK trifluoromethyl diphenyl, CV6 alkyl, CK6 fluorenyl, (6 fluorenyl, C16 all 1 alkyl, c > 6 cycloalkyl, c3-6 cycloalkyl (Ci, alkyl, Ci6 alkyl, 0, C16 alkynyl CCK C> 6 cycloalkyl group 0, C% cycloalkyl group c, c36 cycloalkyl group (^ 4 alkyl group 0-, C3.6 cycloalkane scM alkyl group co, phenyl, benzyloxy, benzyl Medium CNS for oxygen paper ruler) Λ4 specification (, 11 555694

V. Description of the invention (fluorenyl), benzamidine, phenyl CM alkyl, cl6 alkyl s_, Ci6 alkyl Sor, (CM alkyl) 2NS02-, (CM alkyl) NHSOr, (CM alkyl) ) 2NCO-, (CM alkyl) NHCO- or 〇〇 2 substituents; or -NR3R4 where R3 is argon or [14 fluorenyl, and R4 is chlorine, alkyl, methyl, _C02CM alkyl or- COCM alkyl group; or two R2 groups together to form a carbocyclic ring, which is saturated or unsaturated and unsubstituted or substituted with _OH or == 〇; and X is hydrogen, halogen, alkoxy, cK6 alkyl , Amine or trifluoroacetamido; but does not include compounds when X is hydrogen where fluorene is alkoxy, and does not include compound N- (7-iodo-2-methyl-1 when χ is halogen , 2,3,4-tetrahydroisoquinolin-5-yl) -5-chrysyl-2-methoxybenzylamine, N- (7), 2,3,4-tetrahydroisofluorene Lin-5-yl) -5-Excerpt-2-Methoxybenzylamine, Uro-Cyclo-4Hydroxyisoamidine-7-yl) -5, Benzyl-1methoxylamine, n_ (5_ ^], 2,3,4-tetrahydroiso + Lin-7 · yl) _2_methoxy + trifluoromethyl dibenzylbenzyl, n_ (5,1,2,3,4-tetrahydroiso + Lin-7_yl) -2 • methoxytrifluoromethyldiphthyl? Fermented amines, N- (7-prepared 1,2,3, ^ tetrahydroisobutyrene, 2-methoxy, difluoromethyldimorphylbenzylamine, and N_ (bufluoro-2_methyl 4, 2,3,4_tetrahydroisoquinolin-5-yl) -4-tert-butyl-2-methoxybenzylamine. Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs (please read the back first) Please note this page, please fill in this page.) The compounds of the present invention are typically (tetrahydroisoquinone; base) amines, especially hydrazone (tetrahydroisoquinolin-7-yl) benzamidine. When the substituent χ is not When it is hydrogen, it can be at the 5, 6, or 8 position of the dihydroiso + forest moiety, especially at the position;:,,, ^ decay system Qit is often a substituted silk or a substituted <heteroaryl group as needed , Usually age-based or 3_ 异, recorded, #two 觚 2 bases form ~ 5 'scales applicable to Chinese National Standards (CNS) Λ4 specifications (210x297 mm) 555694 A7 _______ 137 V. Description of the invention (?) A In the case of a carbocyclic ring, this is usually a 5-7 member ring, and Q may be a naphthalene or indene or indenone ring system or a bicyclic heteroaryl such as 5-dihydrobenzofuranyl or 3- (4-third butyl) Isofluorenyl). Alkyl in formula (I) includes other moieties such as alkoxy or fluorene A part of the alkyl group may be linear or branched. The phenyl group includes a part of the phenyl group of the other part of R2, and may be independently selected from one or more halogens or ^ 1-6 alkyl groups, Ck oxygen, as required. Substituted by a substituent of a radical or a radical. Suitable c3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and suitable halogen substituents include fluorine, gas, iodine and bromine. A suitable group The compound of the present invention is a compound of formula (IA) (please read the precautions on the back before filling this page)

, TT and another suitable group of compounds of the invention are compounds of formula (IB)

Suitable compounds of formula (I) have R1 as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, methyltolyl, ethylfluorenyl, trifluoroethylsulfonyl or methylsulfonyl Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ~ 6 ~ This paper ruler is printed with towels (CNS) (297 public trips) 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 ) R2 is hydrogen or one or more methyl, ethyl, n-butyl, isopropyl, isobutyl, third butyl, benzene leather, methoxy, ethoxy, isopropoxy, n-butyl Oxy, cyclopropylmethoxy, phenoxy, benzyloxy, cyclopropylmethoxy, amine, acetate amino, nitro, azide, cyano, bromine, chlorine, fluorine, iodine , Ethylamyl, pentamyl, isobutylamyl, benzamidine, iodobenzyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetamyl, trifluoromethyldiphthyl , Methylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylaminesulfonyl; or two R2 groups to form a benzene, cyclopentane or cyclopentanone ring; X is hydrogen , Chlorine, bromine, iodine Fluoro, amino, trifluoromethyl acetylglucosamine. Preferred compounds of formula (I) have R1 is hydrogen, methyl, methoxyethyl, R2 is hydrogen or one or more methyl, n-butyl, third butyl, isopropyl, phenyl, and methyl Ethoxy, ethoxy, isopropoxy, phenoxy, acetamyl, nitro, nitro, cyano, bromo, chloro, fluoro, moth, amyl Methoxy, X is hydrogen, hydrogen, hydrogen, bromine or trifluoroethylamine. An example of a compound of formula (I) is: N- (l, 2,3,4-tetramurino-7-yl) -5-phenanthin-2-S, amidamine N- (2-methyl-1, 2,3,4-tetrahydroisoquinoline-7-yl) -5-chlorothiophene-2-amidamine N- (2-methyl-1,2,3,4-tetrahydroisoquinoline-7- Group) benzamidine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) benzamidine N- (2-methyl-1,2,3, 4-tetrahydroisofluorolin-7-yl) -4-tert-butylbenzylamine ~ 7 ~ This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 g t) (Please read the note on the back first (Fill in this page again)

555694 A7 137 V. Description of the invention (i) N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-isopropoxybenzylamine N- (2 -Methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-phenoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroiso Quinolin-7-yl) -4-nitrobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylbenzylamine N -(2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-methylbenzylamine N_ (2-methyl-1,2,3,4-tetrahydro Isocyanolin-7-yl) -3-fluorobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) each cyanobenzylamine N- ( 2-methyl-1,2,3,4-tetrahydroisoxanthroline; yl) -3,4-dichlorobenzylamine N- (2-methyl-1,2,3,4-tetramuridine Mouth Chalin-7-yl) -4-kasperamide N_ (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-bromobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methylbenzylamine N- (2-methyl-1,2,3,4-tetrahydro Isofluorin-7-yl) each nitrobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxybenzylamine N -(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-butylbenzylamine N- (2-methyl-1,2,3,4- Tetrahydroisoquinolin-7-yl) -2-ethoxybenzyl Amidoamine, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) trifluoromethylbenzylamine N- (2-methyl-1,2,3 , 4-tetrahydroisoquinolin-7-yl) -2,4-difluorobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) &gt; 3,4-dimethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) &gt; 2-fluoro-4-trifluoromethyl benzyl acid Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Amine Economy (please read the precautions on the back before filling this page) N- (2-methyl-1,2,3,4-Tetrasorcin-7-based) 4-Mutan-3-nitropyridinamine N_ (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3,5-di-trifluoromethylchlorobenzyl Ammonium N- (2-methyl_1,2,3,4_tetrakis-isocyanine-7-yl) -2,4-dimur-5--5-ammonium amine ~ 8 ~ This paper is applicable to China National Standards (CNS) Λ4 specifications (210X297) 尨 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (7) N- (2-methyl-1, 2, 3, 4-quad Hydroisoquinolin-7-yl) -3-fluoro-5-trifluoromethylbenzylamine, N- (2-methyl · 1,2,3,4-tetraazaisopropane-7-yl ) -3-Ao-4-methyllactylcarbohydrazone N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4,5 Trimethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethoxybenzylamine N- (2-methyl -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-pentamylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-yl) -3-bromo-4-isopropoxybenzylamine hydrazone (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethenyloxy Benzamidine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-cyclopentyloxybenzamide N- (2-methyl-1,2 , 3,4-tetrahydroisoquinoline-7-yl) -4-cyclopropylmethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinoline-7 -Yl) each cyano-4-methoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-naphthylamine, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methylbenzylamine N- (2-methyl-1,2,3, 4-Four mice. Kuilin-7-yl) -Peptan-1-donylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-methoxy Benzamidine N- (2-methyl-1,2,3,4-tetraargonisoquinolin-7-yl) _4-tert-butoxybenzamide N- (2-methyl-1,2 , 3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxybenzylamine N- (2-methyl-1,2,3,4-tetramurine.Chalin-7- ) Benzodiol-5- @ 备 月 安 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-6-fluorenamine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -2,3-dihydrobenzofuran-5-fluorenamine, 9 ~ This paper size applies to Chinese national standards ( CNS) Λ4 specification (210X 297 male) (Please read the precautions on the back before filling this page)

555694 A7 V. Description of the invention (p) N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -2-methylbenzimidazole-5-amidamine, N -(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-isopropoxybenzylamine ^^-(2-methyl-1, 2,3,4-tetramustriol-7-yl) -3- &gt; odorant 4-ethyllactylamidine 6-stilbylamine N- (2-methyl-1,2,3,4-tetraargon Isoquinoline-7-yl &gt; 3-chloroethoxybenzylamine N- (2-methyl-1,2,3,4-tetraarginoisopyridin-7-yl) -4-methoxy N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-digas-4-methoxy Benzamidine N- (2-methyl-1,2,3,4-tetrakisone-7-yl) -3,5-dirat-4-ethyllactamidine N- (2- Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-isopropoxybenzylamine N- (2-methyl-1,2 , 3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl benzamidine, N- (2-methyl-1,2,3,4-tetrahydroisoquinoline-7 -Yl) bromo-4-tert-butylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-bromo-5-methoxy N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methoxybenzylamine hydrochloride Central Standard of the Ministry of Economy Bureau staff Printed by Fei Cooperative (please read the precautions on the back before filling out this page) N- (2-methyl · 1,2,3,4-tetrahydroisoquinolin-7-yl) small methylpyrazole-4 -Amidoamine N- (2-methyl-1,2,3,4-tetraazaisolone-7-yl) -4-trismethylmethyl 0bitulol-3-methylamine N- (2-methyl 1,2,3,4-tetrahydroisoquinoline-7-yl) -2-methylthiazole-4-fluorenamine ~ 10 ~ This paper size applies to China National Standard (CNS) A4 (210X297) Chu) 555694

V. Description of the invention (f) N- (2-methyl-1,2,3,4-tetrahydroisoquinoline tolyl) _5_methylisogaszol printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Amine N- (2-methyl-1,2,3,4-tetrahydrodecaquinoline-7-yl) -5-third butylisosalyl-3_amidoamine N- (2-methyl- 1,2,3,4-Tetrakis iso-isochaline-7-yl) -3-methoxyisokisamine amine hydrochloride N- (2-methyl-1,2,3,4-tetrakis Hydrogen isoquinone-7-yl) Badodol-2-g panamine N- (2-methyl-1,2,3,4-tetrawind co-lyn-7-yl) -3- &gt; Benzene-4-isopropylidene g amine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoquinone-7-yl) -3-cyano-4-isopropyl Benzylamine amine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoamyl-7-yl) -3_fluoro-4-methoxybenzylamine N- (2 -Methyl-1,2,3,4-tetrahydroisoamyl-7-yl) -3-cyano-ice-n-propyl benzylamine N- (2-methyl-1,2,3,4- Tetrahydroiso + Lin-7-yl) -3-cyano-4-ethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoprene-7-yl ) -3-bromo-4-n-propoxybenzylamine N- (2-methyl-1,2,3,4-tetramethoxin-7-yl) -3- &gt; odor- 4-ethylbenzylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoamyl-7-yl) -3-debran-4-methoxybenzylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoamyl-7-yl) -4-isopropyl-3-trifluoromethyl benzylamine N- (2-methyl- 1,2,3,4-tetrahydroisoprene-7-yl) -4-chloro-3-methoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroiso Bite-7-yl) -4-n-propoxy-3-trifluoromethylbenzylamine ~ 11 This paper is sized for China National Standard (CNS) Λ4 (210X 297 mm) (Please read the back (Please fill in this page again)

, 11 555694 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, K1 137 5. Description of the invention (π) N- (2-methyl_1,2,3,4_tetrahydroisoquinoline-7-yl) -3 -Chloro-4-tert-butylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxybenzylamine Hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methylbenzylamine hydrochloride N- (2-methyl 1,2,3,4-tetraarginoisofluorin-7-yl) -3-chloro-4-isopropylbenzylamine N- (2-methyl-1,2,3,4-tetrakis Hydroisoquinolin-7-yl) each cyano-4-ethylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 4-isopropyl-3-trifluoromethylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-ethyl- 3-trifluoromethylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) each cyano-4-isopropoxybenzidine Amine hydrochloride, N- (l, 2,3,4-tetrahydroisoquinolin-7-yl) _4-methoxy-3-trifluoromethylbenzylazine I N- (2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methyl-3-methylsulfonyl benzylamine N- (2-methyl-1,2,3,4- Tetrahydroisoquinoline-7-yl) -4-ethyl-3-methylsulfosulfanyl donkey amine N -(2-methyl-1,2,3,4-tetraazaisosigmaquine-7-yl) -3-methylpyridyl-4-isopropylbenzylamine N- (2-methyl 1,2,3,4-tetrahydroisoquinoline-7-yl) -3-methylsulfonylmethylmethoxybenzylamine ~ 12 'This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X297mm) (Please read the notes on the back before filling this page)

Order 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (M) &gt; ^-(2-methyl-1,2,3,4-tetrahydroiso-jun-7-yl)- 3-trifluoroethylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-methoxy-3-pentafluoro Ethyl benzamidine hydrochloride N- (2-n-propyl-1,2,3,4-tetrahydroisoprene-7-yl) -3-bromo-4-ethoxybenzylamine N -(2-n-propyl-1,2,3,4-tetrahydroisoamyl-7-yl) -4-methoxy-3-trifluoromethylbenzylamine N- (2-n-propyl 1,2,3,4-tetrahydroisofluorin-7-yl) -3-chloro-4-isopropoxybenzylamine. N- (2-methyl-1,2,3,4- Tetrazine sigmaquine-7-yl) -3-amino-4-isobutyl arthylamine hydrochloride N- (2-methyl-1,2,3,4-tetraargonium 7-yl) _4_isobutyl_3_trifluoromethylbenzylamine hydrochloride N- (2-ethyl-1,2,3,4-tetrakisene sigma-7-yl)- 3- &gt; odor-4_ethoxybenzylamine, N- (2-ethyl-1,2,3,4-tetrahydroiso + lin-7-yl) -4-methoxy-3- Trifluoromethyl behenate amine N_ (2-isopropyl-1,2,3,4-tetrahydroisoamyl-7-yl) -3-bromo-4-ethoxybenzylamine N- (2 -Isopropyl-1,2,3,4-tetrahydroisoalpha-chaline-7-yl) 4-methoxy-3- Trimethylbenzylamine is called 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxy-3-methylsulfonylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisoachaline-7-yl) -4-oxochroman-6-fermented amine salt ~ 13 This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297) (Please read the precautions on the back before filling this page)

555694 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (A &gt;) N- (2-methylamino-1,2,3,4-tetrahydroisofluorin-7-yl ) -4-methoxy-3-trifluoromethylbenzylamine N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4 -Ethoxybenzylamine N- (2-hydroxyethyl-1,2,3,4-tetraargonisoquinolin-7-yl) -3-bromoethylbenzylamine N- (2-methyl -1,2,3,4-tetrahydroisofluorin-7-yl) -4-phenylmethoxy-3-trifluoromethylbenzylamine N- (2-methyl-1,2, 3,4-tetrahydroisoquinolin-7-yl) -4-hydroxy-3-trifluoromethylbenzylamine. N- (2-methoxyethyl-1,2,3,4-tetrahydro Isoquinolin-7-yl) -3-bromoisopropoxybenzylamine N- (2-methoxyethyl-1,2,3,4-tetrahydroisofluoren-7-yl)- 3-Chloro-isopropoxyl-S-amine N- (2-methoxyethyl-1,2,3,4-tetrahydroisofluorin-7-yl) pipe-methoxy-3-tri, Fluoromethylbenzylamine N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-azidobenzylamine trifluoroacetate N- (2-methyl Methyl-5-trifluoroacetamidino-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzylamine N- (2-methyl- 5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo- 4-ethoxybenzylamine N- (2-methyl-5-chloro-1,2,3,4-tetraazaisolone-7-yl) -3- &gt;酉 Amine ~ 14 'This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297). (Please read the precautions on the back before filling this page)

555694 B7 V. Description of the invention (printed by the Central Ministry of Economic Affairs and the Consumers' Cooperative) When synthesized, these compounds are usually in the form of salts, such as hydrochloride or difluoroacetate, and such salts also form the present invention In part, these salts can be used to prepare pharmaceutically acceptable salts, and compounds and their salts can be obtained as solvates, such as hydrates, and also form part of the present invention. Furthermore, the above compounds and their pharmaceutically acceptable Accepted salts, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form the preferred aspect of the present invention. When these compounds are administered to mammals, they can be taken orally, without administration. Intestinal crest, sublingual, nasal, rectal, topical or transdermal administration. The amount that can effectively treat the above diseases depends on general factors, such as the nature and severity of the disease to be treated and the mammal's weight but one unit Dosage usually contains 1 to 1 mg of riding compound, suitably from 500 mg, for example in the range of 2 to 400 mg, for example 2, 5, 10, 20. 30, 40, 50, 100, 2000, 3,000, and 4,000 mg, usually daily with Le- or multiple unit doses, for example, daily medication, 2, 3, 4 times, and more Frequently, it is administered once every day, so the total daily dose for% kg adulterates is usually in the range of 1 to _mg, for example, α500mg beans are in the range of about _ to 15mg / kg / day, more often 01 to 6 Mg / kg / day, for example, 1 to 6 mg / kg / day. The compound of formula (I) is more preferably administered orally at a dosage of the unit dose composition, including the sublingual and rectal tablets which are intravenous in the early stage). , Intuition, local children are not parenteral (especially these components are prepared by storage and mixing, and suitable for oral administration or -15 ~ (Please read the precautions on the back before filling in this page)

、 Explanation of the invention (^ The granules printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs = Le ', for example, tablets, capsules, or oral liquid preparations, powders, suspensions, re-weiguanguan, injectable and perfusion solutions Or suspension, because j, '. Oral medicinal composition is more suitable for oral administration in a specific shape, which is more convenient for general use. Tablets and capsules containing customary medicines usually exist in units of 継, and 5 lubricants such as Adhesives, fillers, diluents, tableting agents, two tablets of medium cooked 1, tablet 3, flavors and wetting agents can be coated with tablets according to this technology. Suitable fillers include Cellulose powder, sugar, and other similar agents, suitable decomposing agents include: fine, trimethyl, tripyrrolidone, and starch derivatives such as starch glycolic acid, and lubricants such as magnesium stearate, suitable pharmaceuticals The above-mentioned moisturizing agents include sodium sulfate, and the conventional composition can be dispersed through mixing, filling, tableting, etc. to the use of turbine blending operation in order to separate the active agent into the skill Idiomatic operations. Therefore, the liquid preparation can be in the form of, for example, an aqueous or oily suspension solution, glycocalyx or guanine, or it can be reconstituted with water or other suitable vehicle before use as a dry product. For example, suspending agents, such as sorbitol, sugar paddles, 'methyl ethyl cellulose, carboxymethyl cellulose, aluminum stearate, or lice can be used &lt;fat; emulsifiers such as grease, sorbitan monooleate I., or Gum Arabic; non-aqueous vehicle (may include edible oils. Such as kernel oil, surplus coconut oil, oily vinegars such as glycerol vinegar, etc. Crimson paper hate common Chinese national standards (CNS ) Λ4 specifications ^ (Please read the precautions on the back before filling this page}

1T 555694 A7 B7 V. Description of the invention (/.Γ) II, or ethanol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid, and if necessary, can be prepared orally with conventional spices or dyes The substance may also contain conventional long-acting preparations, such as tablets containing an enteric coating. For parenteral administration, the preparation of a fluid unit dosage form containing this compound and a sterile vehicle depends on the vehicle and concentration. The compound can be suspended or decomposed. The preparation of parenteral solutions usually dissolves the compound. In the vehicle, aseptically filter and seal before filling into a suitable vial or vial. It is suitable to dissolve auxiliary agents such as local anesthetics, preservatives and buffers in the vehicle. In order to enhance stability, fill in small The glass bottle can be used to freeze the composition and remove the water under vacuum. Essentially the same method is used to prepare parenteral suspensions, but the compounds are suspended rather than transferred to the vehicle, and exposed to ethylene oxide before being sterilized by riding in a sterile vehicle, and the surface of the composition is suitable. The active agent or moisturizing agent promotes uniform dispersion of the compound of the present invention. In general practice, this composition is usually accompanied by a hand socket or printed for medical treatment. 0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and based on this, the present invention also provides a pharmaceutical composition for the treatment and / or prevention of anxiety, mania, depression, fear disorder and / or aggression, and subarachnoid space Bleeding or neuroshock-related diseases, stopping abuse related to substances such as cocaine, nicotine, alcohol and benzodiazepines, diseases that can be treated and / or prevented with k-spasm agents such as epilepsy including post-traumatic epilepsy , Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Haddington's disease, schizophrenia, obsessive-compulsive ideas and compulsive behavior diseases (0CD) 、 And AIDS = 关 刀 ~ 17 '------

Γ Jing first read the notes on the back before filling in this hundred C. This paper size is applicable to China National Standards (CNS) Λ4 Rule 21GX 297 Public Office 555694 A7 B7 V. Description of Invention (M) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy Systemic neurological deficits, sleep disorders (including circadian disorders, insomnia &amp; sleep), convulsions (e.g., 1 to 1 &D; 01 ^ Ru's syndrome), traumatic brain injury, tinnitus, miscellaneous pain, especially It is a trigeminal axis, neuropathic pain, toothache, cancer pain, improper nerve activity from neurological disorders in diseases such as diabetes, multiple sclerosis (MS), and motor neuropathy, ataxia, muscle stiffness (spasm) Gu Gu joint dysfunction and amyotrophic lateral sclerosis (ALS), which contains a compound of formula VII or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The present invention also provides a method for the treatment and / or prevention of anxiety, mania, depression, fear disorders and / or aggression, diseases related to subarachnoid hemorrhage or neuroshock, stopping; supervision such as coca test, Nicotine, alcohol and benzodiazepine-related effects, diseases that can be treated and / or prevented with anticonvulsants such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's Zheimer's disease and other degenerative diseases such as Haddington's disease, schizophrenia, obsessive-compulsive thinking and compulsive behavior disease (OCD), neurological deficits related to AIDS, sleep disorders (including circadian disorders, insomnia & amp (Paroxysmal sleep), convulsions (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, cancer pain, in e.g. diabetes, multiple sclerosis (MS ) And motor neuropathy, improper nerve activity caused by neurological disorders, ataxia, muscle stiffness (spasm), temporomandibular joint dysfunction Amyotrophic lateral sclerosis (ALS), which comprises administering an effective or prophylactic dose of the formula (!) Patients may be a compound or a pharmaceutically acceptable salt or solvate of the drug to the desired. ～ 18 ～ This paper size applies the Chinese National Standard (CNS) Λ4 Regulations (2 丨 〇 X 297) (Please read the precautions on the back before filling this page)

1T ceremony 555694 A7 B7 V. Description of the invention (Q) Printed by the Consumers' Cooperative Bureau of the Ministry of Health, Central Government, Procurement Bureau, and another aspect of the present invention is to provide compounds of formula ① or their pharmaceutically acceptable salts Or solvate but manufacture pharmaceuticals for the treatment and / or prevention of anxiety, mania, depression, fear disorders and / or aggression, diseases related to subarachnoid hemorrhage or neuroshock, stop abuse such as cocaine, , Nicotine, alcohol and benzodiazepine-related effects, antispasmodic treatment and / or lion diseases such as post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia , Alzheimer's disease and other degenerative diseases such as Haddington's disease, schizophrenia, obsessive-compulsive ideas and obsessive-compulsive behavior diseases (OCD), neurological defects related to sleep, sleep disorders ( Including circadian disorders, insomnia & hairy sleep), convulsions (e.g. Giles de la Tourette's syndrome), extrinsic knowledge, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, Pain, cancer pain, ataxia of inappropriate neuroactivity from neurological disorders in diseases such as diabetes, multiple sclerosis (Ms), and motor neuropathy, muscle stiffness (spasm), temporomandibular joint dysfunction, and muscular atrophy Lateral spinal cord sclerosis (ALS). Another aspect of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament for the treatment and / or prevention of anxiety, mania, anxiety, fear disorder and / or aggression. Diseases related to subarachnoid hemorrhage or neuroshock, effects of stopping the abuse of substances such as coca test, nicotine, alcohol and benzodiazepine, diseases that can be treated and / or prevented with anticonvulsants such as epilepsy Including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease, and other degenerative diseases such as Haddington's chorea, mental score Λ9-, long-standing Chinese national standard (CNS ) A4 size (210X297) (Please read the precautions on the back before filling this page)

Order 555694 A7 I5 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs — _______ Invention Description (W) — Schizophrenia, obsessive-compulsive concepts and obsessive-compulsive behavior diseases (〇CD), AIDS-related neurological defects, sleep disturbance (Including circadian disorder, insomnia & narcolepsy), convulsions (e.g. GilesdelaTourette's syndrome), phenotypic injuries, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, cancer pain Improper neuroactivity from neurological disorders in diseases such as diabetes, multiple sclerosis (MS), and motor neuropathy, ataxia, muscle stiffness (spasm), temporomandibular joint dysfunction, and amyotrophic spinal cord Hardening (ALS). Another aspect of the present invention is a method for preparing a compound of formula (I), which comprises

Where R1% is the same as R1 as defined in formula (I) or a group that can be converted to ri and X is the same as defined in item 1 of the scope of patent application, and reacts with compounds of formula (III) COY ♦ &gt; • Q, « I \ ·% · r2A where Q is the same as defined in formula (I), Y is Cl or 0H, and 112 ~ Pi are independently the same as R2 defined by formula 或 or a group that can be converted into R2, and where R1A4R2 / ^ is converted to R1 or R2 group, one R1 or R2 group is converted to another R1 or R2 group, the salt product is converted to a free state base or another pharmaceutical sail, (ill)% (Please read the back (Please fill in this page again)

'1T 20 This paper size is applicable to China National Standards (CNS) Λ4 specification (210X 297 public form) 555694 A7 B7 5. The invention description (β) can be accepted ^: the test, or the free test can be transferred to money pharmacologically Salt. The postal reaction of YC1 will directly lead to the hydrochloride salt. A suitable solvent includes ethyl acetate or dichloromethane, and if necessary, it is performed in the presence of triethylamine. (111) When the compound is an aromatic acid (Y = 0H), the conventional case of condensing this acid and amine can be used, for example, the component is (dimethylaminopropyl) -ethylcarbodiimide / mer The benzotriazole mixture is reacted in a suitable solvent such as dimethylformamide. The conversion of R1A4R2A * to R1 or R2 group usually occurs during the above coupling reaction or the preparation of reactants by the following steps. When a protecting group is needed, one R1 or R2 group is internally converted into another R1 or R2 group, which usually occurs at When one compound of formula (I) is used as an intermediate precursor to another compound of formula VII, or when it is easier to introduce more complex or reactive substituents after the end of the synthetic sequence. Compounds of formula (II) where X is hydrogen can be prepared from nitrotetrahydroisoquinoline of formula (IV),

-NO,-, (IV) Printed by the Consumer Cooperatives of the Central Associated Bureau of the Ministry of Economic Affairs through reaction with the compound RjAZ, where Z is a releasing group such as a prime, especially iodine or tosylate, to obtain the middle of formula (V) Thing

/ Meal Ten, (V)

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Standard (CNS) Λ4 specification (210X297) You 555694 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (&gt; /) When nitro-isoquinoline is substituted, the nitro group is replaced in the hydrogenation step Conversion to amine. When the desired R1 is hydrogen, it is more preferable to protect the N of tetrahydroisoxoline or isoquinoline by conventional methods, for example, using a second butoxy group or two Fluoroacetate, compounds can be removed under standard conditions, such as using trifluoroacetic acid / dichloromethane. The amine / nitro-isojunline of formula (VI) and the reagents used can be obtained from commercial supplies, or can be prepared from commercially supplied raw materials by conventional methods disclosed in the literature. When the substituent X is not argon, it may be introduced in any of the above steps, for example, via a conventional aromatic ring substitution reaction of a compound of the formula (IV), (V), or (VII), or may exist in the above steps in advance Commercially available starting materials are most suitable for introducing the substituent X into a compound of formula (II) where X is hydrogen. For example, when X is hydrogen, the Sandmeyer chemistry described in the following description can be used to introduce it via an amine group. The compound of formula (II) can be prepared by conventional methods to further replace the commercially available benzoic acid or oxaphene acid derivative, or the corresponding substituted benzyl alcohols through oxidation. The benzoic acids can be replaced from the corresponding substituted Phenols are prepared, for example, via acetate formation, conversion to acetophenone and subsequent conversion to the desired acid. When the aforementioned intermediate is a novel compound, it may form part of the present invention. The preparation of the compound of the present invention is further illustrated by the following description and examples. The use of the compound of the present invention is shown by the pharmacological data after the examples. This paper size applies to Chinese National Standards (CNs) A4 (210X 297 cm) (Please read the precautions on the back before filling this page)

555694 A7 B7 V. Description of the invention (narration 1 Ν_2- (4 · nitrophenyl) ethyltrifluoroethylamine) The solution of cellulose difluoroacetate (10.6 ml) in digas formamidine (100 ml) was dropped dropwise Add to a stirred solution of 2,6-lutidine (17.4 ml) and 4-nitrophenethylamine hydrochloride (15.2 g, 75 mmol) at 0 ° C, so that the mixture = 25 ° C and Stir overnight under argon pressure, then wash with dilute citric acid (χ2), brine, and dry over NajO4. The material in the organic layer gives the title ^ ^^^ as a pale yellow solid (19.04 g). Description 2 7-Nitro- 1,2,3,4-Tetraargon-2_trifluoroacetamidinoisophosphine According to the procedures of GE Stokker., Tet Lett "1996, 37, 5453, acetic acid (10 ml) and concentrated H2S04 ( 15 ml),

Dl (2.26 g, 9.15 mmol) and Polycarbam (0.45 g, 14.4 mmol) were removed at 25 C for 20 hours. After treatment, the title compound was obtained as a white solid (2.17 g). ^ -NMR (CDC13): δ 3.1〇 (2H5 m) 5 3.92 (2H, m) 5 4.85 + 4.92 (2H, 2xs), 7.38 (1H, t), 8.10 (2H, m); m / z (EI): 274 (M +) Description 3 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 7 · Nitro-1,2,3,4_tetrahydroisocyanate A solution of potassium carbonate (46.6 g) in 10% aqueous methanol (660 ml) was used to hydrolyze trifluoroacetamide D2 (17.22 g, 63 mmol) at room temperature. The title compound was obtained after treatment with dichloromethane. (11 grams). -24- 555694 Economy, that printed by A7 Consumer Cooperatives of the Central Bureau of quasi-government Bureau ------------ ______________ V. Description of the invention (〇) Narrative 4 2-methyl-7-nitro-1, 2,3,4-Tetraazaisopropylquinine According to the procedures of GM Carrera and DS · Garvey, J. Het · Chem ·, 1992, 29,847, amine 03 (2.08 g, 11.7 mmol) was used with 88% formic acid (3.45 ml) and 37% aqueous formaldehyde (5.88 ml) were treated at 80 ° C for 2 hours, tested with 10% hydroxide # 3, and then treated with ethyl glycerate to obtain orange gum (2.3 g), Chromatography on silica gel 60 with 0-3% methanol-ethyl acetate gave the title compound as an orange solid (1.7 g). m / z (CI): 193 (MH +) Description 5 7-Amino-2-methyl-1,2,3,4-tetrahydroisoxoline at 10% Pd / C (l0) at atmospheric pressure 0 mg) of 7-nitro compound D4 (0.25 g, 1.3 mmol) in methanol (40 ml), filtered through celite to remove the catalyst, and evaporated in vacuo to give the title compound as a white solid ( 213 mg). m / z (CI): 163 (MH +) Narrative 6 7-amino group: (third butoxycarbonyl) -i, 2,3,4-tetrahydroisophosphonium The title compound is prepared from the compound of D3, A catalyst hydrogenation reaction was carried out using di-tert-butyl dicarbonate in 10% aqueous mouse oxide under No. 2 tiger and 2Yc according to the procedure described in the preparation of D5. ～ 25 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 male)

1T 4P! 555694 A7 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (w) Description 7 N- (2-Second-butoxycarbonyl-1,2,3,4-tetrahydroisobutene -7-yl) -5-chlorophenphen-2-ylamine Carbodichloride 5-chloropyrimidine-2-carboxylic acid (214 mg, 1.3 mmol), ethyldimethylaminopropyl Amine (250 mg, 1.3 mmol) and hydroxybenzotriazole (176 mg, 1.3 mmol) were stirred at room temperature in anhydrous DMF (25 ml) for 30 minutes, and N-boc amine D6 (300 (Mg, 1.21 mmol) in methylene chloride (5 ml) and the mixture was kept at room temperature overnight. After treatment, a pink gum was obtained. 30% ethyl acetate-hexane was used on silica gel 60. Metachromatography, combined with appropriate fractions, gave the title compound as a gray solid (0.5 g). lH-NMR (400MHz, CDC13): 5 1.51 (9¾ s) 5 2.82 (2¾ t) 5 3.65 (2H, t), 4.56 (2H, s), 6.95 and 7.37 (2H, ABq), 7.12 (1H, d ), 7.28 (lH, s), 7.46 (lH, br). , Describe 8 7-Nitro-2-n-propyl-1,2,3,4-tetrahydroisocyanine nitro compound D3 (1.55 g, 8.7 mmol) and propionaldehyde (2.52 g, 43.5 mmol) Ear) To 2-Dichloroethane (50 ml), add sodium triethoxyhoxyhydropeptide (0.28 g, 13.1 mmol) and glacial acetic acid (0.6 ml, 9.0 mmol) The mixture was stirred at 25 ° C over the weekend, then diluted with methane (50 ml), the mixture was washed with saturated NaHC03, dried and evaporated under vacuum, and chromatographed on a silica gel 60 with ethyl acetate. The title compound was obtained afterwards. ~ 26 'This paper ruler (210χ 297 male waste) (Please read the precautions on the back before filling this page)

555694 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (meaning) ~ — Narrative 9 7-Amino-2-n-propyl-1,2,3,4-tetraazaisoquineline will The nitro compound D8 (0.73 g, 3.32 mmol) in ethanol (100 ml) was heated to 50 ° C and tin (II) chloride (2.52 g, 13.27 mmol) was added in concentrated HC1 (10 Ml) solution, stirred for 3 hours, the mixture was basified with 40% NaOH and the product was extracted into dichloromethane, treated and chromatographed on silica gel 60 with 10% methanol: dichloromethane to obtain the title compound Yellow oil (0.26 g, 41%). ιη / ζ (ΑΡΓ): 191 (MH +, 80%) Description 10 7-Amino-2-isopropyl-1,2,3,4-tetrahydroisophospholine Use a method similar to that disclosed in descriptions 8 and 9 The title compound was prepared from D3 and acetone in a total yield of 10%. Narrative 11 7-Aminoethyl-1,2,3,4-tetrahydroisoquinoline The title compound was prepared from D3 and acetaldehyde in a total yield of 14% using a method similar to that disclosed in Narrations 5 and 8. Narrative 12 2-Methylmethyl-Initro-i, 2,3,4-tetrahydroisoxoline. A mixture of liver acetate (1.4 ml) and formic acid (0.7 ml) was stirred at 50 ° C for 15 minutes and cooled. After 0 ° c, add D3 (1.78g) and 4-dimethyl ~ 27 ~ &amp; Applicable to China National Standard (CNS) Λ4 regulation; (21GX 297 public place) (Please read the precautions on the back before filling (This page)

、 1T 555694 A7 B7 V. Description of the invention 7) Dimethylsilicon (1Z0ml, 56.0mmol) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and stirred at 80 ° C overnight to cool the mixture to room temperature. The solvent was removed gently and under vacuum, and the residue was purified by column chromatography and eluted with 50% ether / petroleum ether to obtain the title compound (4.2 g, 44%). ! H.NMR (250MHz, CDC13): δ 0.00 (6Η5 s)? 0.83 (9Η5 s) 5 2.66 (2Η, t, J = 6Hz), 2.79 (2Η, t, J = 6Hz), 2.90 (2Η , T, J = 6Hz), 3.71 (2H, s), 3.77 (2H, t, J = 6Hz), 7.16 (1H, d, J = 9Hz), 7.82 (1H, d, J = 2Hz ), 7.89 (1H, dd, J = 9, 2Hz). '' Description 15 Amino-2_ (2-third butyl dimethylsilyloxyethyl y, 2,3,4 · tetrahydroiso is similar to the method described in 5. Dimethyl dimethyl ethoxylate) compound DM (2.88 g, 8.57 mmol) and 10% Pd / C (05 g, 60% paste in water) in methanol (100 ml) Hydrogenation to give the title compound (2.62 g). W W-NMR (250 MHz, CDC13): 5 00 (6H, s), 0.83 (9H, s), 2.61 (2H, t, J = 6Hz) , 2.71 (4H, s, signal overlap), 3.55 (2H, s), 3 · 7'7 (2H t, J = 6Hz), 6.27 (1H, d, J = 2Hz), 6.43 (1H , D, J = 8Hz), 6.80 (in d5 J = 8Hz) 〇 'Narrative 16 2- (2-Di-dibutylmonomethyllithium ethynylethyl) -1,2,3,4-tetrazole Yijun Linyi? Iso-3-bromoethoxybenzylamine '^ ~ 29 ~ (Please read the precautions on the back before filling this page}

II

I This paper size applies to Chinese National Standards (CNS) Λ4 specifications 555694 Λ7 5. Description of the invention Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, triethylamine (0.112 ml, 0.81 mol) and bromoethoxylate Methenyl chloride (193 mg, 0.73 mol) was dissolved in dichloromethane, (100 ml) with stirring, and to this mixture was added compound D15 (204 mg, &quot; 67 mol). ), The mixture was stirred overnight, and the resulting residue was evaporated under vacuum and purified by chromatography on silica gel with 10% methanol: digasmethane to give the title compound (123 mg, 35%). ^ -NMR (250MHz, CDC13): (500.0 (6H, s), 0.82 (9H, s), 1.42 (3Η, t, J = 7Hz), 2.80 (2Η, t , J = 5Hz), 2.91 (2Η, t, J =: 5Hz), 2.95 (2H, t, J = 4Hz), 3.81 (2H, s), 3.87 (2H, t, J = 6Hz), 4.08 (2H , Q J = 7Hz), 6.84 (1H, d, J = 9Hz), 7.00 (1H, d, J = 8Hz), 7.29 (2H, d J = 8Hz), 7.33 (1H, s), 7.77 (1H, dd, J = 9, 2Hz), 8.00 (1H, d, 'J = 2Hz) 〇 17 17-amino-2- (2-methoxyethyl) -1, 2, 3, 4-tetraargon isoquinoline ^ -NMR (250MHz, CDC13): 5 2 · 74 (6H, m), 3.38 (3H, s), 3.60 (4H, m), 3.20-3.70 (2H, br), 6 37 (1H, s), 6.50 (1H, dd, J = 8, 2Hz), 6.88 (1H, d, J = 8Hz). Description 18 5-iodo-7-nitro-1, 2, 3, 4 -Tetrahydroiso + Lin Add the nitro compound of description 3 (750 mg, 3.9 mmol) and succinimide (U3 g) to trifluoromethanesulfonic acid (5 ml) at 25 ° C Flip overnight and carefully pour the mixture into the saturated 1 ^^^ 03, then '30 ~ (Please read the notes on the back first ^ then fill out this page}

The paper size of the edition is applicable to the national standard of China (Ministry of Economic Affairs of the People's Republic of China, Zhuanxun Subcontractor Consumer Cooperative Press 555694 A7 V. Description of the invention (θ) After extraction to ether (2 times), the combined organic extracts are thiolated The residue was washed with an aqueous solution of sodium sulfate, dried (MgS04) and evaporated under vacuum. The residue was obtained by chromatography on silica gel 60 with 2% methanol-dichloromethane to give the title compound (650 mg). Description 19 7-Amino-5 -A solution of Ki-1,2,3,4-tetrahydroisojunline nitro compound D18 (650 mg, 2.14 mmol) in ethanol (20 ml) at 50 C was added tin (Π) ( (1.42 g) in concentrated HC1 (3 ml), the resulting yellow solution was basified with 10% aqueous sodium hydroxide solution, the product was extracted into dichloromethane, and flash chromatography (5% methanol on silica gel 60) -Dichloromethane) to give the title compound (428 mg, 73%). Narrative 20 7-Aminopoort (third butoxycarbonyl group) 丨, 2,3,4, hydroisoxoline DMF (30 ml) of iodoamine D19 (580 mg, 2.12 mmol) was added with DMAP (20 mg) and di-tert-butyl dicarbonate (466 mg, 2.13 mmol). After stirring overnight at room temperature, the reaction mixture was dried under vacuum and chromatographed on silica gel 60 (2% methanol-digasmethane) to give the title compound (745 mg, 94%). Description 21 5,7-mononitro -1,2,3,4-Tetrahydroisopirin will be in 5_nitro_ 丨, 2,3,4_tetrahydroisoquinoline in sulphuric acid (3 φ liter) ~ 31 ~ Chinese National Standard (CNS) Μ specifications ((Please read the notes on the back before filling this page)

Order 555694 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, printed A7 V. Description of the invention (1.0 grams, 5.6 * moles) Add concentrated nitric acid (1 ml), and stir the mixture at room temperature for 1 hour, so that It was cooled, basified with a 40% aqueous NaOH solution, and treated with dichloromethane to give the title compound (114 g). Statement 22 5,7-mononitro-2-methyl-i, 2,3,4-tetrahydroisoquinoline is similar to the method described in statement 2 so that the amine D21 (1.8 g) in formic acid (5 ml) Reaction with polyoxymethylene (7 ml) to give the title compound (174 g, 91%). Oc iH-NMR (CDC13): δ 2.51 (3H, s), 2.75 (2H, t), 3.27 (2H, t ), 3.75 (2H, s), 8.16 (1H, d, J = 2Hz), 8.66 (1H, d, J = 2Hz), m / z (Cl): 238.1 (MH +, 1000 / o ) ○ State 23 5-amino-7-nitro-2-methyl-i, 2,3,4_tetrahydroisoquinine, similar to the method described in State 19, reducing tin nitrate with tin (II) chloride Compound D22 (1.7 g) to give the title compound (0.6 g). Description 24 Amine Dr (〇 ·) 5-trifluoroacetamido-7-nitro-2-methyl-1,2,3,4-tetrahydroisobate in dichloromethane (10 ml) 5 g) and triethylamine (15 equivalents), trifluoroacetic anhydride (u equivalent) was added, and the mixture was stirred at 25 t for 3 hours. After treatment with digas methane, 3% methanol: dichloromethane was burned on silicone 60. Chromatography gave the title compound (0.7 g, 96%). ～ 32 ～ This paper size applies to the Chinese national standard of “((CNS) M” (&quot; &quot; ^ ° x 297)) f Please read the notes on the back ¾ before filling out this page "Order the staff of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the cooperative 555694 A7 V. Description of the invention (w) m / z (Cl): 304 (MH +, 80%) Description 25 * 7-aminotrifluoroethylamidoamino-2-methyl-1, 2, 3,4-tetrahydroisoquinoline. Nitro compound in ethanol (20 ml)] 2) 24 (0.7 g, 2.28 mmol) was hydrogenated with 10% Pd / C (70 mg) via silica The catalyst was removed by filtration through celite and passed to a milky white solid (0.6 g, 93%) of the title compound after being developed under vacuum. · Narration 26 5-Chloro-7-nitromethyl-fluorene, 2,3, φ · Tetrahydroisoxoline will be 5-amino compound D23 (1 · 6 in 5 mol concentration HC1 (25 ml) G, 7.7 mmol), add nitrous acid to 55 g at 80 ° C, a solution of 80 mmol in water (3 ml) for 5 minutes, then slowly add the cooled solution to the gas A solution of copper (I) (1.0 g, 10 mmol) in 5 mol fertilizer (25, * liters), the mixture was stirred at 25 ° C for 30 minutes, and then 40 / 〇NaOH Assay, treated with digas formamidine (300 ml), and then purified by flash chromatography (5% methanol: dichloroformamidine) on stone gum 60 to give the title compound (1.1 g, 62%) Yellow solid. H-NMR (CDC13): (5 2.32 (3H, s), 2.61 (2H, t), 2.79 (2H, t), 3.57 (2H, s), 7.96 (1H, d, h2HZ ), 8.G8 (1H, cU = 2Hz). Description 27 7-Aminochloro-2-methyl—1,2,3,4-tetrahydroisocyanine ~ 33 ~: Paper size applies to China 6 votes准 （CNS) A4 ^^ 2l〇x ^^ y (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 555694 A7 B7 r— ~ &quot; V. Description of the invention (&gt;) The nitro compound D26 (0.80 g, 3.5 mmol) was dissolved in ethanol (70 ml) and concentrated HC1 (7 ml) was heated to 50 t; and vaporized tin (π) (2 66 g, 14¾ mol) was added, and the mixture was heated for 15 minutes and then cooled, the same treatment as disclosed in description 19 to obtain the title compound Yellow oil (0.48 g). iH-NMR (CDC13) ... (5 2 · 42 (3H, s), 2.64 (2H, m), 2.77 (2H, m), 3.45 (2H, d), 6.27 (1H, d, J = 2Hz), 6.59 (1H, d, J = 2Hz). Preparation of 1 3-bromobenzyl TBMS ether in 3-bromobenzyl alcohol (5.00 g, 0.027 mole) in dichloromethane (30 ml) and To a solution of EhN (4.2 ml, 0.03 mol) was added a 1 mol concentration solution of tert-butyldimethylsilyl chloride in dichloromethane (30 ml), and the organic layer was washed with brine and dried. (Na2S04) and evaporated to give a red oil, which was purified by flash chromatography on silica gel with 20% diethyl ether in hexane to give a colorless oil (8.0 g). Preparation of 2,3-tetrabenzylbenzyl alcohol TBDMS Ether N-butyllithium (2.80 ml, 7.0 mmol, 2.5 mole in hexane) was slowly added to TBDMS ether (1.80 g, 6.0 mmol) at Preparation -78 ° C. Mol) in anhydrous THF (10 ml) solution for 5 minutes, the reaction mixture was maintained at argon pressure and -78 ° C for 1 hour, and then added dropwise in THF (2 ml) under stirring and -78 ° C. ), Ν, α-dimethylhydroxytetram- 34- This paper is in accordance with Chinese National Standards (CNs) A4 (210X 297) ((Please read the notes on the back before filling this page)

555694 Μ B7 V. Description of the invention (B) Amidoamine (0.86 g, 6.60 mmol), the resulting mixture was stirred at -78 ° C for 2.5 hours, and the reaction was stopped by dissolving the taste with NH4C1 and warmed to room temperature. The mixture was extracted with diethyl ether (2x50 mL), and the combined organic layers were dried (Na2SO4) and concentrated under vacuum to give a colorless oil (1.75 g). m / z (APr): 307 (MH +, 8%) Preparation of 3-t-amylpyrrolyl alcohol The ether of Preparation 2 (1.47 g, 4.80 mmol) was dissolved in methanol (25 ml), and concentrated HC1 ( (20 drops) and the whole reaction was stirred at room temperature for 4 hours, saturated NaHC03 solution was added and the mixture was extracted with ether (2 x 50 ml). The organic layer was dried over sodium sulfate and concentrated under vacuum to give a colorless oil (0.80 g ). m / z (API +): 193 (MH +, 17%) (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Preparation of 4 sharp 3-terobenzoic acid. 3-Tentamylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in Erhu Tiger (20 ml) and added sequentially. A solution of K〇Η (0.35 g, 6.30 mmol) in water (5 ml) and KOM0 (1.45 g, 9.17 mmol), the mixture was stirred at room temperature over the weekend, The solution was filtered through diatomaceous earth and extracted with ethyl acetate. The aqueous layer was acidified with dilute HC1 and extracted with acetic acid (3 × 50 ml). The organic layer was dried over magnesium sulphate: and concentrated under real chilli to give the title compound (0.80 g ). This paper size is applicable to China National Standards (CNS) Λ4 specification (210X 297 cm) Φ 555694 A7 B7 V. Description of the invention (w) Preparation of 8 3-bromo-4-ethoxybenzoic acid is similar to the method of step 1, The title compound (4.3 g) was prepared from 4-ethoxybenzoic acid. iH-NMR (DMSO-d6): 5 1.45 (3Η, t, J = 7Hz), 4.26 (2Η, q, J = 7Hz), 7.26 (1H, d, J = 9Hz), 7.98 (1H , Dd, J = 2, 9Hz), 8.12 (lH, d, J = 2Hz). '9' Preparation of 9 3-bromo-4-ethylbenzoic acid The title compound was prepared from 4-ethylbenzoic acid. ^ -NMR (DMSO-d6): δ 1.20 (3Η, t? J = 7Hz) 5 2.78 (2H, q, J = 7Hz), 7.50 (1H, d, J = 8Hz), 7.90 (1H, dd , J = 2, 8Hz), 8.07 (1H, d, J = 8Hz). Preparation of 10 3-Amino-4-Isopropylbenzoic Acid The title compound was prepared from 4-isopropylbenzoic acid in a similar manner to step 5. iH-NMR (DMSO-d6): 51 · 07 (6H, d, J = 7Hz), 3.13 (1H, m, overlap), 7.48 (1H, d, J = 7Hz), 7.96 (1H, dd , J = 2, 8Hz), 8.00 (1H, d Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs J = 2Hz) 〇 ~ 37' This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 555694 Kl printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs —————— ______ V. Description of the invention (from) Preparation of 11 4-methoxy-3-trifluoromethylbenzoic acid is similar to step 3 And method 4, the title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate. ^ -NMR (DMSO-d6): 5 3.78 (3H? S) 5 7.18 (1H, d? J-9Hz), 7.90 (1H, d, J = 2Hz), 8.〇〇 (ih, dd, J = 2, 9Hz), 12.70-13.10 (1H, br, interchangeable). Preparation of 12 4-methoxy-3-trifluoromethylbenzyl chloride. From 4-methoxy-3-trifluoromethylbenzoic acid and grass St base gas with DMF in chloroform at room temperature. Reaction [D. Levin, Chem. Br., 1977, 20] followed by evaporation under vacuum to prepare the title compound. Preparation of 13, 3-bromo-4-isopropoxybenzoic acid methyl ester 3-Bromo-4- # to dimethylbenzoate in DMF (35 ml) (25 g, 10-8 mmol) Ear) Potassium carbonate (3.0 g, 21.6 mmol), alkane (2.76 g, 2 L 6 mmol) were added and stirred at 25 ° C for 48 hours. The title compound (3.0 g) was obtained after treatment with ethyl acetate. . iH-NMR (250MHz, CDC13): (5 1.41 (6H, d, J = 7Hz), 3.89 (3H s), 4.66 (1H, m), 6.90 (1H, d, J = 8Hz), 7 · 93 (1H, dd, J = 8, 8.22 (lH, d, J = 2Hz). Z '3 8 ~ This paper size and photo towel (CNS) A4 size (210 X 297 mm) (please first Read the notes on the back and fill out this page}

Order # · Gong 694 A7 B7 V. Description of the invention (37) Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs ¾ Preparation of 14 3-cyano-4-isopropoxy benzyl carpentine will be in N-methyl 3-Bromo- winter isopropoxybenzylformate (2.0 g, 7.3 mmol) and copper cyanide in late pyrrolidone (50 ml) ① heated under intense reflux for 4 hours and treated with ethyl acetate The title compound (10 g) was then obtained. H-NMR (250MHz9 CDC13): δ 1.56 (6H? D, J = 7Hz), 4.05 (3H, s), 4.88 (1H, m), 7.13 (1H, d, J = 8Hz), 8.31 (1H, dd, 2Hz), &amp; 38 (1H, d, J = 2Hz). 'Preparation of 15 3,5-dichloro-'ethoxybenzoic acid methyl ester is similar to the method of preparation 6 from 3,5-dichloro-4-hydroxybenzoic acid and ethane iodide in 69% yield Title compound. H-NMR (250MHz, CDC13): 51 · 47 (3H, t, J = 7Hz), 3.91 (3H, s), 4.16 (2H, q, J = 7Hz), 7.96 (2H, s). Preparation of 16 3-methylsulfonyl-4-isopropylbenzoic acid. Chloromethyl-4-isopropylbenzoic acid (2.62 g, 10 mmol) was similar to that disclosed in steps 7 and 8. Method, prepared from 4-isopropylbenzoic acid] Slowly add NaHC03 (2.52 g, 30 mmol) and Na2CO3 (1.26 g, 10 mmol) in water (9 ml) at 75 ° C In the thick slurry, the mixture was stirred for 1 hour, then bromoacetic acid (2.08 g, 15 mmol) and NaOH (0.60 g, 15 mmol) were added, and the temperature was raised to 105 ° C. and the mixture was refluxed ( Please read the notes on the back before filling in this page j

(CNS) A4 specification (2 丨 0X 297 gong) 137__555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (β) Heating for 24 hours, cooling the mixture, acidifying it to pH 1 and collecting the resulting precipitate, The title compound (1.43 g, 59%) was obtained after washing and drying. iH-NMR (250MHz, acetone-d6): 51.24 (6H, d, J = 7Hz), 3.13 (3H, s), 3.88 (1H, m), 7.72 (1H, d, J = 7Hz) , 8.15 (1H, dd, J = 7Hz), 8.52 (1H, d, J = 2Hz). Preparation 17 4-methyl-3-methylsulfonylbenzoic acid The title compound was prepared in a yield of 30% in a similar manner to that of Preparation 16. W-NMR (250MHz, acetone-d6): 5 2.57 (3H, s), 2.99 (3H, s), 7.39 (1H, d, J = 7Hz), 7.97 (1H, dd, J = 7, 2Hz ), 8.39 (1H, d, J = 2 Hz). Preparation of 18.4-ethyl-3-methylsulfonamidobenzoic acid was performed in a similar manner to that of Preparation 16 to prepare the title compound in 44% yield. iH-NMR (250MHz, isopropyl-d6): 5 1 · 22 (3H, t, J = 7Hz), (3H, s), 3.05 (2H, q, J = 7Hz), 3.12 (3H, s) , 7.57 (1H, d, Jwhz), 8.13 (1H, dd, J = 7, 2Hz), 8.51 (1H, d, J = 2Hz). Preparation 19 3-Methylbenzyl-4-methoxybenzoic acid 40 ~ This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 cm) (Please read the precautions on the back before filling this page)

Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 555694 V. Description of the Invention (outside) Similar to the method of Preparation 16, the title compound was prepared at 20% yield. iH-NMR (250MHZ, acetone-d6): 5 3.00 (3H, s), 3.89 (3H, s) 7.17 (1H, d, J = 7Hz), 8.06 (1H, dd, J = 7, 2Hz), 8.31 (1H d J = 2Hz) 〇5 Preparation of 20 4-ethoxy-3-methylsulfonylbenzoic acid Similar to the method of Preparation 16, the title compound was prepared at 20% yield. . ^ -NMR (250MHz, acetone-d6): (Π · 44 (3H, t, 7Hz), (3H, s), 4.35 (2H, q, &gt; 7Ηζ), 7.40 (1H, d, J = 7Hz), 8.20 (lH, dd, J '= 7,' 2Hz), 8.37 (lH, d, J = 2Hz). '' 'Preparation of 21,3-chloro-4-ethoxybenzoic acid H-NMR (DMSO-d6): δ 1.39 (3H? T, J = 7Hz)? 4.20 (2H, q? J = 7Hz), 7.22 (1H, d, J = 7Hz), 7.87 (2H, m). ' '' Preparation 22 4-Isopropoxy-3-trifluoromethylbenzoic acid will be 3-bromo-4-isopropoxybenzoic acid methyl ester in DMF (25ct: liter) g (mg g, 3.03¾ Mo Ear) potassium trifluoroacetate (922 mg, 6.06 mmol), copper (1) (1.15 g, 6.06 mmol) and toluene (50 ml) were added, so ~ 41 ~ This paper size is applicable to China National Standard (CNS) A4 Regulation (210X 297) (Please read the precautions on the back before filling this page)

555694 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (The resulting mixture is heated under reflux for 1.5 hours (removing about 50 ml of distillate with Dean and Stark). After refluxing for 18 hours, cool down. The mixture was poured into Etp (100 ml) and water (100 ml). The two-phase mixture was stirred at room temperature for 0.5 hours, then filtered through celite, the two phases were separated, and Et20 (50 ml) was used. The aqueous phase was extracted, the organic layers were combined and washed with saturated Na2S203, ·% 0, saturated brine, dried (MgS04) and evaporated in vacuo to a colored oil, which was decomposed in MeOH (approximately 20 ml) And 2 mol NaOH (2 ml, 4 mmol) was added, the resulting solution was heated under reflux for 3 hours, the volatiles were removed under vacuum, and the residue was distributed in EtOAc and 0 ° C. The layers were separated. The aqueous layer was acidified to pH 1 with 2 molar HC1 in the presence of EtOAc and the layers were separated. The aqueous layers were extracted with EtoAc, the extracts were combined, washed with H2O, saturated brine, and dried. (MgS04) and evaporated to dryness under vacuum to give the title compound as a white solid (671 Mg, 89%). ^ H-NMR (250MHz, (CD3) 2CO): δ 1.02 (6Η? D? J = 6Hz)? 4.53-, 4.63 (1Η? M) 5 7.01 (1Η, d5 J = 9Hz) 5 7.85-7.88 (2H5 m)? M / z (ΑΡΙ): 205_0 [Μ_Ρή. '' Preparation 23 4-ethyl-3-trifluoromethylbenzoic acid According to the method disclosed in the preparation of U, from 4-ethyl Xi benzoic acid methyl alcohol (1 · 10 g, 4.52 * mol) was prepared and separated into a white solid (923 mg, 93%) ° ~ 42 ~ 家家 料 (CNS) λ7 ^ Ύ21 () χ297 male (please read first (Notes on the back then fill out this page)

、 \ 口 555694 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (¥ /) ^ -NMR (250MHz, (CD3) 2CO): δ 0.98 (3Η? T5 J-7Hz)? 2.60 ( 2Η, q, J = 7Hz), 7.36 (1Η, d, J = 8Hz), 7.89 and 7.93 (1Η, m), 7.96 (1Η, br s), m / z (API): 217.1 [Μ-Η]. Preparation 24 4-n-propoxy-3-trifluoromethylbenzoic acid According to the method described in Preparation 22, from 3- &gt; methyl-4-n-propoxybenzoic acid methyl ester (1.43 g, 5.23 mmol) ) Was prepared and isolated as a white solid (118 g, 91%). 'H-NMR (250MHz, (CD3) 2SO): 5 1.09 (3H515 J-7Hz)? 1.79- 1.93 (2H, m), 4.26 (2H, t, J = 6Hz), 7.45 (1H, d, J = 9Hz), 8.19 (1H, d, J = 2Hz), 8.25 and 8.28 (1H, dd, J = 9, 2Hz), m / z (API): 203.1 [M-C02H] 〇 Preparation 25. 4-Third-butyl-3-trifluoromethylbenzoic acid was prepared from methyl 3-bromo-4-butylbenzoate (2.46 g, 9.1 mmol) according to the method disclosed in Preparation 22 and isolated as a white solid (I.% g, 69%). Y-NMR (250MHz, (CD3) 2SO): 5 1.42 (9H, s), 7.86-7.90 (1H, m), 8.09-8.13 (1H, m), 8.23 (1H, d, J = 2Hz) , M / z (API): 245.1 [MH] 〇 (Please read the notes on the back before filling this page)

## This paper size applies the Chinese National Standard (CNS) A4 regulations (210x 297) 555694 A7 ___________ ^ V. Description of the invention (W) ~ — The solid compound is filtered, washed with cold water and dried to obtain the title compound (1.66 g , 73%). Step 1 5-Bromo-2,4-dimethoxybenzoic acid in a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mole) in chloroform (1 ml) Bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) was added, and after stirring at room temperature overnight, the precipitate was filtered and dried to give the title compound as a white solid (2.87 g). Step 2 5-bromo-4-isopropyl-2-methoxybenzoic acid in 2-methoxy-4-isopropylbenzoic acid (7.0 g, 36.0 mmol) in chloroform (100 ml) Bromine (1.86 ml) in chloroform (20 ml) was added dropwise, and the reaction was stirred at room temperature overnight. After evaporation under vacuum, the title compound was obtained as an oil (9.27 g). m / z (CI): 275, 273 (ΜΗ +, 70%) Step 3 5-Bromo-4-isopropyl-2-methoxybenzoic acid -&gt; Odor-4-isopropyl-2-methoxybenzoic acid (9.268 g, 34.0 mmol) was dissolved in methanol (250 ml) and concentrated 112804 (2 ml) was added, and the mixture was refluxed for 5 hours And concentrated under vacuum, dissolved the remaining material in ethyl acid and water, dried the organic layer (MgS04), concentrated under vacuum to obtain 45 ~ This paper size applies Chinese National Standard (CNS) Λ4 regulations (2丨 0x297) 1i 555694 Μ B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (5.5 grams). Step 4 2.4- Dimethoxy-5-trifluoromethylbenzoic acid In argon, place 2.4-dimethoxy-5-bromobenzoic acid in DMF (25 mL) and toluene (8 mL). g (1-5 grams, 5.4 millimoles) was added potassium trifluoroacetate (1.53 grams, 10.1 millimoles) and copper iodide (1) (2.1 grams, 10.9 millimoles), so that the mixture Heat and remove water (C) ean / Stark at C, then heat at 155 ° C overnight, allow the mixture to cool, pour into ether and water and filter through celite, dry the organic layer (Na2S04) and Finely concentrated in vacuo to obtain a brown solid, which was chromatographed on silica gel 60 with 1: 1 ether / petroleum ether to obtain a solid (1.03 g), which was hydrolyzed with 1 methanol: NaOH aqueous solution (50 ml) at 50 ° C. After treatment, the title compound was obtained as a white solid (1 g). Step 5a Methyl 2-methoxy-5-cyano-4-isopropylbenzoate Add copper (I) cyanide (550 mg, 6 mmol) to 2-methoxy-5-bromo- A solution of methyl 4-isopropylbenzoate (86 mg) in N-methylpyrrolidone (30 ml). The mixture was stirred under argon pressure and boiled under reflux for 4 hours. Cool, pour into excess ice / water and ethyl acetate and filter. Separate the organic layer, wash with water, brine, and dry (MgS04). Evaporate to obtain a crude brown solid. Ethyl acetate 46 'on silicone. This paper size applies to China National Standard (CNS) A4 (210X 297 cm) (Please read the precautions on the back before filling this page)

555694 A7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention Ur) ester / n-hexane (1: 4) was purified by chromatography to obtain the product (523 mg) as a white solid. ^ -NMR (250MHz, CDC13): 5 1.33 (6H? D, J = 7Hz), 3.38 (1H, sep, J = 7Hz), 3.89 (3H, s), 3.98 (3H, s), 6.91 (1H, s), 8.08 (1H, s); m / z (ΑΡΓ): 234 (MH +, 30%). Step 5b 2-Methoxy-5-yl-4-isopropylbenzoic acid Add 2 equivalents of NaOH (1.25 ml) to a solution of methyl g P5a (490 mg) in methanol (10 ml) so that The solution was stirred overnight at room temperature, then the solution was diluted with water, concentrated under vacuum and washed with ethyl acetate, then the aqueous layer was acidified with 2 equivalents of HC1 and extracted with ethyl acetate, and the extract was washed with brine and dried (MgS04) After evaporation and drying, the product was obtained as a white solid (418 mg). lH-NMR (250MHz? CDC13): (5 1.35 (6H, d, J = 7Hz), 3.43 (1¾, seP, J = 7Hz), 4.14 (3H, s), 7.00 (1H, s), 8 41 (1H, s); m / z (ΑΡΓ): 220 (MH +, 100〇 / 〇). Step 6a 2-ethoxy-4-isopropyl-5-chlorobenzoic acid ethyl ester according to step 5 It was revealed that 2-ethoxy-4-isopropyl-5-bromobenzoic acid ethyl acetate (1.2 g, 3.8 mmol) was used in N-methyl-2-pyrrolidone (40 ml) The copper cyanide (1) (682 mg, 7.6 millimoles) was treated to obtain the oil of the title compound (400 mg). ~ 4 7 ~ This paper size is applicable to China National Standards (CNS) Λ4 (210X 297) Mm) (Please read the notes on the back before filling out this page)

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Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 555694 A7 _ B7 V. Description of invention uw W-NMR (250MHz, CDC13): 5 U2 (6H, d, J = 7Hz), 1.30 (3H, t, J = 7Hz), 1.84 (3H, U = 7Hz), 3.17 (1H, sep, J = 7Hz), 3.99 (2H, q, J = 9Hz), 4.16 (2H, q, J == 7Hz), 6_69 (1H, s), 7.86 (1H, s); m / z (ΑΡΓ): 262 (MH +, 100%). Step 6b 2-Ethoxy-2-isopropyl-5-cyanobenzoic acid Dissolve the ester P6a (370 mg, 1.41 mmol) in methanol (5 ml) and add 1 equivalent of NaOH (2.1 ml , 2.1 millimolar) for 24 hours, the solution was concentrated under vacuum, diluted with water and washed with ethyl acetate, then the aqueous layer was acidified with 2 equivalents of HC1 and extracted with ethyl acetate, the extract was washed with brine, and dried (MgS04 ) And evaporated to dryness to give the title compound as an acid (306 mg). ^ -NMR (250MHz? CDC13): δ 1.39 (3Η? D, J = 7Hz) 5 1.66 (3Η, t, J = 7Hz), 3.47 (1Η, sep, J = 7Hz), 4.46 (2Η, q, J = 7Hz), 7.03, (1H, s) 5 8.47 (1H, s); m / z (ΑΡΓ): 234 (MH +, 100%) 〇Step 7 4-ethoxy-2-methoxy- 5-Methylsulfonylbenzoic acid was prepared by using MW Harrold et al "J · Med · Chem" 1989, 32 874 in 49% yield of 4_ethoxy_2-methoxy_5_chloro Sulfobenzoic acid was prepared according to the method of RW Brown, J. Org. Chem., 1991, 56, 4974, in 19% yield. (H-NMR ^ DMSO-cy: (5 1.3〇 (3H, t), 3.10 (3H, s), 3.83 (3H, s), (Please read the precautions on the back before filling in this page)

i 'Invention description U; 7) 4 · 24 (2H, q), 6.73 (1H, s), 8.07 (1H, s). Step 8 4-Isopropyl-2-methoxy-5-methylsulfonylbenzoic acid is similar to C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall, J. Org. Chem., 1956, The step 21,265 gave the intermediate 5-plysulfomethyl-4-isopropyl-2-methoxybenzoic acid, which was converted to the title compound using the method of step 7. ^ -NMR (DMSO-d6): 5 1.30 (6H, d) 5 3.21 (3H, s), 3.80 (1H, m), 3.94 (3H, s), 7.26 (1H, s), 8.19 (1H, s). Example 1 Ν- (1,2,3,4 · tetrahydroisochachaline-7-yl) _5-chloroacephene-2-vinylamine monotrifluoroacetate N-boc amine D7 (0.48 g , 1.22 mmol) in dichloromethane (25 ml) containing trifluoroacetic acid (2, ml) at 25 ° C for 18 hours. After evaporation under vacuum, the residue was removed from ethyl acetate-acetic acid Recrystallize to obtain gray crystals (0.46 g, 92%) of Muqian compound, melting point i53-5 ° C. 々-NMR (400MHz, DMSO-d6): ά 2.96 (2H, t), 3.38 (2H, t) 4.29 (2H, s), 7.23 (1H, d), 7.28 (1H, d , ABq), 7.51 (1H, dd) '7.63 (1H, d), 7.90 (1H, d, ABq), 9.01 (2H, br, s), 10.33 (1H, Consumer Consumption Cooperative of the Central Standards Bureau, Ministry of Economic Affairs Printed (Please read the notes on the back before filling this page) s); m / z (Cl): 293 100%). '~ 49, This paper hate scale applies Chinese National Standard (CNS) Λ4 specification (210X297 public place) 555694 M--V. Description of the invention (#) Example 2 N_ (2-methyl), 2, 3, 4- Hydroxantholin-7-yl) -5-chlorothiophene-2-g amine. The compound of Example 1 (200 mg, ο 'millimolar), 98% formic acid (0.4 ml), and Aqueous formic acid solution (0.6 ml) was chromatographed on Shixijiao 60 with methanol-ethyl acetate, and then recrystallized from ethyl acetate-ethyl ether to obtain the title compound as a gray powder with a melting point of 138-40 ° G. W-NMR (250MHz, CDC13): 5 2.46 (3H, s), 2.69 (2H, t), 2.89 (2H, t), 3.54 (2H, s), 6.93 and 7.37 (2H, ABq) , 7.07 (1H, d), 7.25 (1H, dd), 7.34 (1H, d), 7.63 (1H, br, s); m / z (Cl): 307 +, 100%). Example 3 N- (2-methyl-i, 2,3,4-tetrahydroisoxanthen-7-yl) chrylamine N-methylamine D5 in dichloroamine containing triethylamine (0.5 ml) To methane (25 ml) was added benzamidine chloride and the mixture was kept at 25 ° C. It was maintained at 0 ° C for 18 hours. After normal treatment, the product was obtained. The silica gel 60 was subjected to ethyl acetate-hexane gradient A separation chromatography. The appropriate fractions were combined to obtain the title compound. ^ -NMR (250MHz, CDC13): ά 2.46 (3Η? S)? 2.69 (2Η, t)? 2.91 (2Η, t), 3.58 (2Η, s), 7.10 (1Η, d), 7 30 (1Η, dd), 7.40-7.60 (4H, overlapping m), 7 75 (1H, br s), 7.87 (2H, m). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 0 ^ -5 Applicable 3 I Records Mandatory One copy One standard One country One country

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555694 kl B7 87104135 V. Description of the invention (#) The following examples were prepared using a method similar to that described above. Example 4, (Please read the precautions on the back before filling this page) N- (2-methyl-1,2,3,4-tetrahydroisoquinoline_7_yl) -3-chlorobenzylamine ^ -NMR (250MHz, CDC13): 5 2.46 (3H, s)? 2.68 (2H, t) 5 2.90 (2H, t), 3.57 (2H, s), 7.10 (1H, d), 7.29 (1H, dd, Overlapping with CHC13), 7.39 (1H, s), 7.42 (1H, d), 7.52 (1H, m), 7.73 (1H, m), 7.83 (2H, m). Example 5 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-tert-butylbenzylamine 1H-NMR (250MHz, CDC13): (5 1.34 (9¾ s)? 2.44 (3¾ s) 5 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7.07 (1H, d), 7.29 (1H, dd, and CHC13 signals Overlapping), 7.38-7.53 (3H, m, overlapping signals), 7.75-7.90 (3H, m, overlapping signals). Example 6 Printing N- (2-methyl- 1,2,3,4-tetraazaiso-isochaline-7-yl) -4-isopropyl card § blueamine! H-NMR (250MHz5 CDC13): 5 1.38 (6H5 d)? 2.46 (3H? S )? 2.69 (2¾ t), 2.90 (2H, t), 3.58 (2¾ s), 4.64 (1H, seven heavy peaks), 6.94 (2H, m), 7.09 (1H, d), 7.23-7.34 (1H, m, overlapping with CHC13 signal), 7.42 (1H, s), 7.70 (1H, br s), 7.81 (2H, m); m / z (Cl): 325 (MH +, 100%). 51 This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297). 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (夂.) Example 7 N- (2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenoxybenzylamine iH-NMR (250MH z, CDC13): 5 2.46 (3H, s), 2.69 (2H, t), 2.91 (2H, t), 3.59 (2H, s), 7.00-7.50 (10H, overlap m), 7.72 ( 1H, br s), 7.83 (2H, m). Example 8 N- (2-methyl-1,2,3,4-tetrahydroisoprene-7-yl) -4-nitrobenzidine Amine'H-NMR (CDC13): 5 2.45 (3H? S)? 2.70 (2H? M) 5 2.90 (2H, m)? 3.60 (2H, s), 7.10 (2H, dd), 7.25 (1H , Dd), 7.40 (1H, d), 8.00 (2H, dd), 8.35 (2H, dd), 7.80 (1H, s); m / z (Cl): 312 (MH +, 70%). Example 9 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-phenylbenzamide, 'H-NMR (CDCI3): 5 2.45 (3H? S )? 2.70 (2H? M) 5 2.90 (2H? M)? 3.60 (2H, s), 6.30 (1H, d), 6.50 (1H, dd), 6.90 (1H, dd), 7.10 (1H, d) , 7.40 (2H, m), 7.60 (1H, dd), 7.70 (1H, dd), 7.80 (1H, s), 7.90 (1H, d), 8.05 (1H, s); m / z (Cl): 343 (MH +, 90%). Example 10 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylbenzylamine W-NMR (CDC13): (5 2.43 (3H, s ), 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.60 (2H, s), 7.05 (1H, dd), 7.30 (1H, m), 7.35 '52' This paper size applies to China National Standard (CNS) A4 specification (210X 297 public trend) (Please read the precautions on the back before filling this page)

555694 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention U /) (2H, m), 7.45 (1H, s), 7.65 (3H, m); m / z (CI): 281 (MH + , 90%). Example 11 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-fluorobenzylamine &quot; H-NMR (CDC13): δ 2.50 (3H, s ), 2.75 (2H, t), 2.90 (2H, t), 3.65 (2H, s), 7.10 (1H, dd), 7.28 (2H, m), 7.40 (2H, m), 7.60 (2H, m), 7.75 (1H, s); m / z (Cl): 285 (MH +, 100%). Example 12 N- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyanobenzylamine ^ -NMR (CDC13): 5 2.47 (3H? S) ? 2.70 (2H? T) 5 2.90 (2H? T)? 3.60 (2H, s), 7.12 (1H, dd), 7.30 (1H, m), 7.40 (1H, s), 7.65 (1H, dt), 7.80 (2H, m), 8.10 (1H, d), 8.15 (1H, s); m / z (Cl): 292 (MH +). Example 13 N- (2-methyl-1, 2, 3 , 4-tetrahydroisoquinolin-7-yl) -3,4-dichlorobenzylamine W-NMR (CDC13): δ 2.50 (3H, s), 2.80 (2H, t), 2.90 (2H , T), 3.70 (2H, s), 7.10 (1H, d), 7.30 (1H, dd), 7.40 (1H, s), 7.55 (1H, d), 7.70 (1H, dd), 8.00 (2H, m); m / z (Cl): 335 (MH +). Example 14 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-iodobenzylamine ~ 53. This paper size applies to China National Standard (CNS) Α4 specifications (210X 297) (Please read the notes on the back before filling this page)

1T 555694 A7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (θ) 'H-NMR (CDC13): 5 2.47 (3H5 s) 5 2.71 (2H51), 2.89 (2H51)? 3.58 (2H s), 7.10 (1H, d), 7.30 (1H, m), 7.43 (1H, s), 7.60 and 7.85 (4H, ABq), 7_82 (1H, s); m / z (Cl): 393 (MH +, 100%). Example 15 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-bromobenzylamine ^ -NMR (CDCI3): 5 2.47 (3H5 s) 5 2.71 (2H? T)? 2.89 (2H? T)? 3.60 (2H, s), 7.10 (1H, d), 7.30 (1H, m), 7.43 (1H, s), 7.64 and 7.74 (4H? ABq )? 7.70 (1H? S); m / z (Cl): 347, 345 (MH +, 100%). Example 16 N- (2-methyl · 1,2,3,4-tetrahydroisovalin-7-yl) -4-methylbenzylamine iH-NMR (CDC13): 5 2 · 44 (3H, s), 2.48 (3H, s), 2.75 (2H, t), 2.90 (2H, t), 3.63 (2H, s), 7.10 (1H, d), 7.28 And 7.78 (4H, ABq), 7.30 (1Η, m), 7_44 (1Η, s), 7.74 (1Η, m); m / z (CI): 281.2 (MH +, 100%). Example 17 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-nitrobenzylamine 1H-NMR (CDCI3): δ 2.48 (3Η, s)? 2.71 (2H? T), 2.92 (2H, t), 3.61 (2H, s), 7.13 (1H, d), 7.34 (1H, dd), 7.42 (1H, s), 7.71 (1H , T), 8.00 (1H, d), 8.26 (1H, d), 8.40 (1H, d), 8.70 (1H, t); ~ 54 'This paper size applies to the Chinese National Standard (CNS) Λ4 Specifications (210X 297 hours) (Please read the precautions on the back before filling in this page)

1T 555694 A7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (B) m / z (Cl): 312.1 (MH +, 100%). Example 18 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-ethoxybenzylamine 1H-NMR (CDC13): 5 1.46 (3H, m \ 2.47 (3H, s) 9 2.71 (2H, t)? 2.90 (2H, t), 3.61 (2H, s), 4 · 11 (2H, m), 7.14 (1H, d), 7.30 (1H , M), 7.49 (1H, s), 7.68 (1H, s), 7.82 (2H, d), 8.10 (3H, m); m / z (CI): 311.2 (MH +, 100 %). Example 19 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-n-butylbenzylamine ^ -NMR (CDCI3): (5 0.93 (3H? T), 1.25-1.48 (2H? M), 1.52-% L70 (2H, m), 2.51 (3H, s), 2.66 (2H, m), 2.80 (2H, t), 2.95 ( 2H, t), 3.69 (2H, s), 7.12 (1H, d), 7.20 (1H, d), 7.29 (2H, d), 7.32 (1H, m), 7.47 (1H, s) , 7.78 (2H, d), 7.93 (1H, d); m / z, (Cl): 323.2 (MH +, 100%) 〇 Example 20 N- (2-methyl-1, 2, 3, 4 -Tetrahydroisoquinolin-7-yl) -2-ethoxybenzylhydrazone amine 1H-NMR (CDCI3): 5 2.33 (3H? S)? 2.48 (3H, s) 3 2.71 (2H? T)? 2.91 (2H, t), 3.61 (2H, s), 7.10 (1H, d), 7.16 (1H, d), 7.23 (1H, m), 7.32-7.45 (2H, m), 7.52 (1H, t), 7.83 (1H, d), 7.94 (1H, s); m / z (Cl): 325.2 (MH +, 100%). ~ 55 ‘This paper size applies the Chinese National Standard (CNS) Α4 specification (210X 297 common trend) (Please read the precautions on the back before filling this page)

1T 555694 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (eg) Example 21 N- (2_methyl-1,2,3,4_tetrazyl yijunlin-7-based) 3-Hydroxymethylcarbamidine'H-NMR (CDCI3): 5 2.48 (3¾ s)? 2.73 (2H? T) 5 2.92 (2H? T)? 3.62 (2H, s), 7.11 (1H , D), 7.32 (1H, d), 7.42 (1H, s), 7.63 (1H, t), 7.75-7.91 (2H, m), 8.07 (1H, t), 8.12 (1H, s); m / z (Cl): 335.1 (MH +, 100%). Example 22 N- (2-methyl-1,2,3,4-tetrachloroisoquinone_7-yl) -2,4-dipyridinamine W-NMR (CDC13): 5 2 · 47 (3H, s), 2.71 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 6.95 (1H, m), 7.00-7.18 (2H, m), 7.32 (1H, dd ), 7.44 (1H, s), 8.14-8.36 (2H, m); m / z (Cl): 303.1 (MH +, 100%). Example 23, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dimethoxybenzylamine m / z (Cl): 327.2 ( MH +, 100%). Example 24 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-fluoro-4-trifluoromethylbenzylamine iH-NMR (CDC13): 5 2.47 (3H, s), 2.70 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 7.11 (1H, d), 7.35 (1H, dd), 7. · 45 (2H, s), 7.50 (lH, s), 7.59 (lH, d), 8.20-8.40 (2H, brm); m / z (Cl): 353.1 ~ 56 'This paper size applies to Chinese national standards (CNS) Λ4 specification (210X297 male f) (Please read the precautions on the back before filling out this page), 11 555694 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Invention Description (Lamp) (MH +, 100% ). Example 25 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4 · chloro-3-nitrobenzylamine iH-NMR (CDC13): δ 2 · 48 (3H, s), 2.72 (2H, t), 2.94 (2H, t), 3.60 (2Η, s), 7.10 (1Η, d), 7.32 (1Η, d), 7.38 (1Η, s), 7.67 (1Η, d), 7.95-8.13 (2H, br m), 8.38 (1H, d); m / z (Cl): 348 (MH +, 33% ), 346.1 (MH +, 100%). Example 26 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-di-trifluoromethylbenzylamine ^ -NMR (CDC13): δ 2.52 (3H? S \ 2.78 (2H? T)? 2.94 (2H, t)? 3.66 (2H, s), 7.14 (1H, d), 7.36 (1H, d), 7.42 (1H, s), 7.94 (1H, m), 8.04 (1H, s), 8.32 (2H, s); m / z (Cl): 403.1 (MH +,, 100%). Example 27 N- (2-methyl-1 , 2,3,4-tetrahydroisoquinolin-7-yl) -2,4-digas-5-fluorobenzylamine 1H-NMR (CDCI3): (5 2.47 (3H? S)? 2.70 (2H t)? 2.91 (2H51), 3.60 (2H, s), 7.11 (1H, d), 7.25 (1H, d), 7.38 (1H, s), 7.52 (1H, dd), 7.62 (1H, dd), 7.90 (1H, brs); m / z (Cl): 353.0 (MH +, 100%). ~ 57 ~ This paper size applies to China National Standard (CNS) A4 gauge (210X 297 mm) (please first Read the notes on the back and fill in this page),-555694 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 5. Description of Invention (jU), Example 28 N- (2-methyl-1, 2, 3, 4-tetrahydroquinolin-7-yl) -3-fluoro-5-trifluoromethylbenzylamine W-NMR (CDC13): 5 2.49 (3H, s), 2.73 (2H, t), 2.91 (2H, t), 3.62 (2H, s), 7.1 3 (1H, d), 7.32 (1H, dd), 7.40 (1H, s), 7.50 (1H, d), 7.80 (1H, m), 7.90 (1H, s), 8.02 (1H, s) m / z (Cl): 353.1 (MH +, 100%). Example 29 N- (2-methyl-1,2,3,4-tetramethyrine-7-yl) -3- &gt; -4-methoxy card S &amp; Yuean W-NMR (CDC13): 5 2 · 47 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.60 (2H, s), 3.97 (3H, s), 6.96 (1H, d), 7.10 (1H, d), 7.29 (1H, m), 7.40 (1H, s), 7.67 (1H, s) , 7.84 (1H, dd), 8.02 (1H, s), 8.05 (1H, d); m / z (Cl): 377, 375 (MH +, 30%). , Example 30 N- (2-Methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3,4,5-trimethoxybenzylamine iH-NMR (CDC13): 5 2 · 42 (3H, s), 2.66 (2H, t), 2.88 (2H, t), 3.55 (2H, s), 3.83 (3H, s), 3.86 (6H, s), 7 · 00 (1H, s), 7.05 (1H, d), 7.19 (1H, s), 7.26 (1H, d), 7.34 (1H, s), 7.68 (1H, s), 7.94 (1H, s); m / z (Cl): 357.2 (MH +, 100%). Example 31 · N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethoxybenzylamine 5 8 ~ This paper size applies to Chinese national standards ([Chemical] 8 rules (210 '/: 297 mm) (Please read the precautions on the back before filling in this page)

Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 555694 ΚΊ _______ Β7 _____ V. Description of the Invention (X7) · W-NMR (CDC13): 5 2 · 47 (3Η, s), 2.70 (2Η, t), 2.91 (2Η, t), 3.60 (2H, s), 7.10 (1H, d), 7.25 (1H, m), 7.32 (2H, d), 7.40 (1H, s), 7.74 (1H, s), 7.90 (2H, d); m / z (Cl): 351.1 (MH +, 100%). Example 32 N- (2-methyl-1,2,3,4-tetrahydroisopropane-7- Base) -3-tetramethylene chloride 1000 g amine hydrochloride will prepare 5 acids (200, mg 1.0 mmol) and chlorpyrrolyl chloride (140 mg, U mmol) in DMF (5 drops ) Of dichloromethane (10 ml) and stirred at 25 ° C. for 1 hour, then evaporated to dryness under vacuum. The residue in dichloromethane was treated with amine D5 (162 mg, 1.0 mmol) and kept After treatment at 25 ° C overnight, treatment similar to Example 2 gave the title compound (110 mg), m.p. 197-201 ° C (from methanol: ether). W-NMR (free state test, 250MHz, CDC13): 51.38 (9H, s), 2.45, (3H, s), 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7 08 (1H, d), 7.30 (1H, d), 7.40 (1H, s), 7.49 (1H, t), 7.83 (1H, d) 5 7.95 (1H, d), 8.08 (1H, s) ), 8.14 (1H, s); m / z (Cl): 351.2 (MH +, 100%). Example 33 N- (2-methyl-1, 2, 3, 4-tetrahydroisoxoline-7- Group) -3-bromo-4-isopropoxybenzylamine iH-NMR (CDC1J 5 1.4 · 6 (6H, d, J = 6Hz), 2.47 (3H, s), 2.71 ~ 59 'This paper size is applicable Chinese National Standard (CNS) A4 Regulation (210X 297 total) (Please read the precautions on the back before filling this page)

555694 Five_I_______ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Invention description (π) (2Η, t, J = 6Hz), 2.91 (2Η, t, J = 6Hz), 3.60 (2Η, s) , 4.67 (1Η, dt, J = 6Hz), 6.96 (1H, d, J = 9Hz), 7.10 (1H, d, J = 8Hz), 7.30 (1H, m), 7.40 (1H, d, J = 2Hz), 7.71 (1H, s), 7.80 (1H, dd, J = 2 and 9Hz), 8.05 (1H, d, J = 2Hz). Example 34 N- (2-methyl-1,2,3,4-tetrahydroisophosphorin · 7-yl) -4-ethoxybenzylamine W-NMR (CDC13): δ 2.34 (3H, s), 2.48 (3H, s), 2.73 (2H, t, J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.62 (2H, s), 7.11 (1H , D, J = 8Hz), 7.21 (2H, m), 7.31 (1H, m), 7.43 (1H, s), 7.75 (1H, s), 7.88 (2H, m); m / z (Cl): 325 (MH +, 100%). Example 35 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopentyloxybenzylamine &quot; H-NMR (CDC13): δ 1.56- 1.68 (2H, bm), 1.74-1.97 (6H, bm),, 2.61 (3H, s), 2.95 (4H, m), 3.79 (2H, s), 4.81 (1H, m), 6.38 (1H, s), 6.54 (1H, dd, J = 2 and 8Hz), 6.85 (2H, m), 6.93 (2H, d, J = 8Hz), 7.95 (2H, d, J = 8Hz ); m / z (Cl): 349 (MH +, 20%). Example 36 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopentylmethoxybenzylamine! H-NMR (CDC13): (5 0.36 (2H, m) 5 0.66 (2H? M)? 1.28 (1H, m)? 2.44 (3H, s), 2.81 (2H, t, J = 6Hz), 2.89 (2H, t, J = 6Hz ), 3.51 60 'This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297g t) (Please read the precautions on the back before filling this page)

, 11 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ((2H, s), 3.86 (2H, m), 6.34 (1H, d, J = 2Hz), 6.50 (1H, dd, J = 2 and 8Hz), 6.92 (2H, m), 7.06 (1H, d, J = 8Hz), 7.31 (1H, dd, J = 2 and 8Hz), 7.82 (1H, m) , 8.00 (1H, m); m / z (Cl): 337 (MH +, 100%). Example 37 N- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl ) -3-cyano-4-methoxybenzylamine ^ -NMR (CDC13): 5 2.47 (3H? S)? 2.70 (2H? T? J = 6Hz)? 2.91 (2H, t, J = 6Hz ), 3.59 (2H, s), 4.02 (3H, s), 7.09 (2H, t, J = 8Hz), 7.29 (1H, dd, J = 2 and 8Hz), 7.39 (1H, d, J = 2Hz) , 7.80 (1H, s), 8.10 (2H, m); m / z (Cl): 322 (MH +, 100%). Example 38 N- (2-methyl-1, 2, 3, 4-tetrahydro Isoquinoline-7-yl) -2-naphthylamine, iH-NMR (CDC13): δ 2.50 (3H, s), 2.75 (2H, t, J = 6Hz), 2.94 (2H, t, J = 6Hz), 3.65 (2H, s), 7.13 (1H, d, J = 8Hz), 7.38 (1H, dd, J = 2 &amp; 8Hz), 7.50 (lH, d, J = 2Hz) , 7.56-7.22 (3H, bm), 7.88-8.07 (4H, bm), 8.38 (1H, s); m / z (Cl): 317 (MH +, 100%). Example 39 N -(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methylbenzylamine 1H-NMR (CDCI3): (5 2.47 (6H5 bs ), 2.71 (2H? T? J = 6Hz)? 2.91 (2H, t, J = 6Hz), 3.60 (2H, s), 7.10 (1H, d, J = 8Hz), 7.23-7.39 61 ~ This paper size Applicable Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

Order 555694 A7 B7 V. Description of the invention (") (2H, bm), 7.42 (lH, s), 7.70 (2H, dd, J = 2 and 8Ηζ), 8.02 (1H, d, J = 2Hz ); m / z (Cl): 359, 361 (MH +, 100%). Example 40 N- (2-methyl-1,2,3,4-tetraazaisoquinolin-7-yl) -Cai 1-¾amine'H-NMR (CDC13): (5 2.50 (3H5 s)? 2.75 (2H? T5 J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.66 (2H, s), 7.12 (1H, d, J = 8Hz), 7.35 (1H, d, J = 8Hz), 7.45-7.70 (5H, m), 7.75 (1H, d, J = 8Hz), 7.90 (1H, m), 7.96 (1H, d, J = 7Hz), 8.36 (1H, d, J = 8Hz); m / z (ΑΡΓ): 317.2 (MH +, 100%). Example 41 N- (2-methyl-1, 2 , 3,4-tetrahydroisofluorin-7-yl) -3-chloro-4-methoxybenzylamine NMR (CDC13): 5 2 · 47 (3H, s), 2.70 (2H, t, J = 6Hz), 2.91 (2H, t, J = 6Hz), 3.59 (2H, s), 3.97 (3H, s), 6.99 (1H, d, J = 9Hz),, 7.09 (1H, d, J = 8Hz), 7.32 (1H, dd, J = 2 and 8Hz), 7.40 (1H, s), 7.79 (2H, m), 7.90 (1H, d, J = 2Hz). Example 42 Employees of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling this page) N- (2-methyl-1,2,3,4-tetrahydro Quinolin-7-yl) -4-tert-butoxybenzylamine ^ -NMR (CDCI3): (5 1.41 (9H? S), 2.47 (3H, s), 2.71 (2H? T5 J = 6Hz) , 2.91 (2H, t, J = 6Hz), 3.61 (2H, s), 7.03-7.12 (3H, bm), 7.30 (1H, dd, J = 2 and 8Hz), 7.43 (1H, d, J = 2Hz), 7.68 (1H, s), 7.79 (2H, d, J = 9Hz); m / z (Cl): 339 (MH +, 100%). 62 'This paper size applies to the Chinese National Standard (CNS ) Λ4 gauge (210 X 297) 555694 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (έ /) Example 43 Ν- (2-methyl-1, 2, 3, 4- Tetrahydromaquinolin-7-yl) -4-n-propoxybenzylamine'H-NMR (CDCI3): (5 1.01 (3¾ t, J = 7Hz)? 1.83 (2H? M) 5 2.87 (3H , S), 3.19 (2H, m), 3.44 (2H, t, JN7Hz), 3.61 (2H, s), 3.87 (2H, m), 4.40 (2H, s), 6.93 (2H, d ), 7.09 (1H, d), 7.51 (1H, dd, J = 8, 2Hz), 7.61 (1H, d), 7.92 (2H, d), 8.39 (1H, s). Example 44 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -benzotriazole-5-fluorenamine m / z (CI): 308 (MH +, 65 %). Example 45 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -benzotriazole-6-amidamine ^ -NMR (CDC13): 5 2.48 (3H, s), 2.72 (2H, t, J = 6Hz), 2.93 (2H, t, J = 6Hz), 3.62 (2H, s), 7.13 (1H, d, J = 8Hz) ,. 7.34 (1H, dd, J = 2 and 8Hz), 7.45 (1H, d, J = 2Hz), 7.88 (1H, s), 7.97 (1H, dd, J = 2 and 8Hz), 8.22 (1H , D, J = 2Hz), 8.56 (1H, d, J = 2Hz), 9.15 (1H, s); m / z (Cl): 322 (MH_, 100%). Example 46 N- (2-methyl-1,2,3,4-tetraazaisolone-7-yl) _2,3-diazepine-5_ hydrazine ^ -NMR (CDCI3): 5 2.48 (3H, s)? 2.73 (2H51, J = 6Hz), 2.91 (2H, t, J = 6Hz), 3.27 (2H, t, J = 9Hz), 3.62 (2H, s), 4.66 (2H , T, 63 This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

1T% 555694 V. Description of the invention (β) J = 9Hz), 6.83 (1Η, d, J = 8Hz), 7.08 (1Η, d, J = 8Hz), 7.28 (1Η, 'dd, J = 2 And 8Hz), 7.42 (1H, s), 7.64 (1H, d, J = 8Hz), 7.76 (2H, m); m / z (Cl): 309 (MH +, 100%). Example 47 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylbenzimidazole-5-amidamine ^ -NMR (drMeOH): 5 2.51 (3H, s), 2.61 (3H, s), 2.92 (2H, t, J = 6Hz), 2.96 (2H, t, J = 6Hz), 3.69 (2H, s), 7.14 ( 1H, d, J = 9Hz), 7.47 (3H, m), 7.56 (1H, d, J = 8Hz), 7:80 (2H, dd, J = 2 and 8Hz), 8 · 10 (1H, s); m / z (CI): 321 (MH +, 100%). 48 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-gas-4-isopropoxybenzylamine, 'H-NMR (CDC13 ): 5 1.42 (6H? D5 J = 6Hz)? 2.49 (3H? S)? 2.74 (2H, t, J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.63 (2H, s), 4 · 67 (1H, quintet, J = 6Hz), 6.98 (1H, d, J = 9Hz), 7.09 (1H, d, J = 8Hz), 7.28 (1H, dd, J = 2 and 8Hz) , 7.40 (1H, d, J = 2Hz), 7.67-7.81 (2H, bm), 7.88 (1H, d, J = 2Hz); m / z (Cl): 359 (MH +, 100%). Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 49 N- (2-methyl-1,2,3,4-tetraargon isoquinoline-7- Group) -3-bromo-4-ethoxybenzylamine ^ -NMR (CDCI3): 5 1.51 (3H? T? J = 7Hz) 5 2.49 (3H, s) 5 2.74 ~ 64 'This paper size applies to China National Standard (CNS) Λ4 specification (210 X 297 Gongchu) 555694 A7 B7___ V. Description of the invention (θ) (2Η, t, J = 6Hz), 2.92 (2Η, t, J = 6Hz), 3.62 (2Η, s), 4.17 (2Η, q, J = 7Hz), 6.93 (1H, d, J = 9Hz), 7.09 (1H, d, J = 8Hz), 7.28 (1H, dd, J = 2 and 8Hz), 7.39 (1H, d, J = 2Hz), 7.71 (1H, s), 7.80 (1H, dd, J = 2 and 9Hz), 8.05 (1H, d, J = 2Hz); m / z (Cl): 389, 391 (MH +, 100%) 〇 Example 50 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) &gt; 3-chloro- 4-ethoxybenzylamine W-NMR (CDC13): 5 1.51 (3H, t, J = 7Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6Hz), 2 92 (2H, t, J = 6Hz), 3.62 (2H, s), 4.18 (2H, q, J = 7Hz), 6.96 (1H, d, J = 9Hz), 7.09 (1H, d, J = 8Hz), 7.31 (1H, dd, J = 2 and 8Hz), 7.39 (1H, d, J = 2H z), 7.76 (2H, m), 7.89 (1H, d, J = 2Hz); m / z (Cl): 345 (MH +, 100%). Example 51 • N- (2-methyl-1 , 2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine ^ -NMR (CDC13): (5 2.48 (3H? S)? 2.72 (2H, t5 J = 6Hz)? 2.92 (2H, t, J = 6Hz), 3.60 (2H, s), 3.98 (3H, s), 7.09 (2H, m), 7.32 (1H, dd , J = 2 and 8Hz), 7.41 (1H, d, J = 2Hz), 7.83 (1H, s), 8.07 (2H, m); m / z (Cl): 365 (MH +, 100%). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 52 N_ (2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl) -3,5-Digas-4-methoxybenzylamine 65 This paper is in accordance with Chinese National Standard (CNS) Λ4 specification (210X297) while 555694 A7 V. Description of the invention Uc) ^ -NMR (CDC13): 5 2.46 (3H? S)? 2.69 (2H? T, J = 6Hz)? 2.90 (2H, t, JN6Hz), 3.57 (2H, s), 3.96 (3H, s), 7.09 (1H, d, J = 8Hz), 7.30 (1H, dd, J = 2 and 8Hz), 7.34 (1H, d, J = 2Hz), 7.81 (2H, s), 7.89 (1H, s); m / z (Cl) : 365 (MH +, 100%). Example 53 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-digas-4-ethoxybenzylamine ^ -NMR (CDCI3) : (5 1.49 (3H? T? J = 7Hz) 5 2.46 (3H? S) 5 2.69 (2H, t, J = 7Hz), 2.90 (2H, t, J = 6Hz), 3.56 (2H, s ), 4 · 17 (2H, q, J = 7Hz), 7.09 (1H, d, J = 8Hz), 7.29 (1H, dd, J = 2 and 8Hz), 7.32 (1H, s), 7 · 80 (2H, s), 7.86 (1H, s); m / z (Cl): 379 (MH +, 100%). Example 54, hydrazone (2-methyl-1, 2, 3, 4-tetrahydrofuran) Hydroisoquinolin-7-yl) -3,5-dichloro-4-isopropoxybenzylamine ^ -NMR (CDCI3): ά 1.39 (6H? D? J = 6Hz)? 2.47 (3H, s ) 5 2.70 (2H, t, J = 6Hz), 2.91 (2H, t, J = 6Hz), 3.59 (2H, s), 4.72 (1H, quintet, J = 6Hz), 7.10 ( 1H, d, J = 8Hz), 7.30 (1H, dd, J = 2 and 8Hz), 7.36 (1H, s), 7.76 (1H, d, J = 2Hz), 7.80 (2H, s) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 55 N- (2-methyl-1,2,3,4-tetraaza-iso-junlin-7- Base) -3-methyl continued donkey base donkey month donkey 66 'This paper size applies to Chinese National Standard (CNS) Λ4 gauge Taiwan (210X29 * 7) 4 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (") NMR (CDCI3): 5 2.48 (3¾ s)? 2.71 (2H, t5 J = 6Hz) 5 2.92 (2H, t, J = 6Hz), 3_12 (3H, s), 3.60 (2H, s), 7 · 12 (1H, d, J = 8Hz), 7.35 (1H, dd, J = 2 and 8Hz), 7.42 (1H , S), 7.73 (1H, t, J = 8Hz), 8.05 (1H, s), 8.11 (1H, d, J = 8Hz), 8.22 (1H, d, J = 8Hz), 8.40 (1H, s); m / z (Cl): 345 (MH +, 100%) 〇 Example 56 N- (2-methyl-1,2,3,4-tetrahydroisoammon-7-yl) -3-bromo -4_ Tertiary butyl benzylamine Amine D5 (162 mg, 1.0 mmol) and 3-bromo-4-tert-butylbenzoic acid (25 7 g, 1.0 mmol) To a solution of anhydrous n, N-dimethylformamide (7 ml), add 1-hydroxybenzotriazole (135 mg, 1.0¾ mole) and 1- (3-monomethylamine at 25 ° C. Propyl) -3-ethylcarbodiimide (192 mg, 1.0¾ mole). After shaking the mixture for 48 hours, the product was extracted to a formazan, and the solution was decanted with 10% NaHC03 water, Washed with brine, organic. The layer was dried over MSSO and evaporated in vacuo to give 373 mg of the title compound, It was 93%. Ή-NMR (CDC13) ·· 5 1.54 (9H, s), 2.47 (3H, s), 2.71 (2H, t, J = 6Hz), 2.91 (2H, t, J = 6Hz), 3.60 (2H , S), 7.10 (1H, d, J = 8Hz), 7.31 (1H, dd, J = 2 and 8Hz), 7.41 (1H, d, J = 2Hz), 7.54 (1H, d, 'J 8Hz), 7.72 (2H, m), 8.06 (1H, d, J = 2Hz). Example 57 N- (2-methyl-1,2,3,4-tetraargon isoquinolin-7-yl) -2-bromo-5-methoxybenzylamine ~ 67 ~ National standard 隼 (CNS ) M size (210x297), (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 555694 V. Description of Invention (“) lH-NMR (CDCI3): ά 2.47 (3H5 s), 2.70 (2H, t, J = 6Hz), 2.91 (2H, t, J = 6Hz), 3.61 (2H, s), 3.83 (3H, s), 6.88 (1H, dd), 7.11 (1H, d, J = 8Hz), 7.21 (1H, d), 7.31 (1H , Dd, J = 2 and 8 Hz), 7.44 (1H, d), 7.50 (1H, d), 7.71 (1H, s); m / z (ΑΡΓ): 375.0 +, 100%). Example 58 N_ (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-fluoro-3-methoxybenzylamine hydrochloride ^ -NMR (free state base CDC13): 5 2.53 (3H, s), 2.76 (2H, t, J = 6Hz), 2.97 (2H, t, J = 6Hz), 3.63 (2H, s), 4.01 (3H, s), 7.16 (1H, dd, J = 6, 2Hz), 7.21 (1H, d), 7.32-7.50 (3H, m), 7.64 (1H, dd, J = 6, 2Hz), 8.00 (1H, brs ); m / z (ΑΡΓ "315.1 (MH +, 100%) 〇. Example 59 N- (2-methyl-1,2,3,4-tetrachloroisolone-7-yl) -1-methyl Command * also -4-§ Styramine 1H-NMR (250MHz5 CDC13): (5 2.30 (3H, s) 3 2.53 (2H, m) 5 3.40 (2H, s), 3.78 (3H, s), 6.91 (1H, d, J = 8Hz), 7.11 (1H, m), 7.21 (1H, d), 7.20 (1H, brs), 7.46 (1H, b r), 7.68 (1H, s), 7.76 (1H, s); m / z (ΑΡΓ): 271 (MH +, 100%). Example 60 N- (2-methyl-1, 2, 3, 4- Siqi iso-p-quine-7-yl) -4-digas methyl p-p-ton-3-donylamine '68 ~ This paper size applies to Chinese National Standard (CNS) Λ4 gauge (210X 297) (Read the notes on the back before filling out this page)

555694 A7 B7 V. Description of the invention ('7) ^ -NMR (250MHz? D6-DMSO): 5 2.41 (3H5 s), 2.81-2.85 (4H? M), 7.13 (1H, d, J = 8Hz) , 7.46 (2H, m), 8.64 (1H, s); m / z (ΑΡΓ): 325 (ΜΗ +, 100%). Example 61 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylthiazole-4-amidamine ^ -NMR (250MHz? CDC13): 5 2.47 (3¾ s)? 2.67-2.76 (5¾ m)? 2_89 (2H, m), 3.60 (2H, s), 7.10 (1H, d, J = 8Hz), 7.40 (1H, dd, J = 8, 2 Hz), 7.49 (1H, brs), 8.02 (1H, br), 9.12 (1H, br); m / z (ΑΡΓ): 288 (ΜΗ +, 100%). Example 62 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -5-methylisoxazol-3-amidamine ^ -NMR (250MHz, CDC13): δ 2.46 (3H, s), 2.51 (3H, m), 2.68 (2Η, m), 2.90 (2Η, m), 3.58 (2Η, s), 6.51 (1Η, s), 7.10 • (1H, d, J = 8Hz), 7.33 (1H, dd, J = 8, 2Hz), 7.41 (1H, brs), 8.47 (1H, brs); m / z (API +): 272 (MH + , 100%). Example 63 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-tert-butylisoxazole-3-amidamine Employees' consumption at the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling this page) ^ -NMR (250MHz? CDC13): 5 1.38 (9H5 s) 5 2.46 (3H? S)? 2.66-2.71 (2H, m), 2 · 89 (2H, m), 3.59 (2H, s), 6.48 (1H, s), 7.10 (1H, d, J = 8Hz), 7.30 (2H, brd, J = 8Hz), 7.41 (1H, brs ), 8.43 '69' This paper size is applicable to Chinese National Standard (CNS) A4 (210X297). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 555694 A7 B7 V. Description of the invention (in) (1H, brs); m / z (ΑΡΓ): 314 (MH +, 100%). Example 64 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methoxyisoxazole-5-amidine hydrochloride iH-NMR (250 MHz , DMS〇-d6): (5 especially 2.81 (3H, brs), 3.88 (3H, s), 7.00 (1H, s), 7.16 (2H, d, J = 8Hz), 7.52 (2H M / z (ΑΡΓ): 288 (ΜΗ +, 100%). Example 65 N- (2-methyl-1,2,3,4-tetrahydroisoprene-7-yl) indole The -2-S amine is similar to the procedure in narration 7, and D5 is converted to the title compound by reaction with indole-2-carboxylic acid. ^ -NMR (d6-DMSO): 5 2.84 (3H? S) 5 3.07 ( 2H? T? J = 6Hz), 3.29 (2H, t, J = 6Hz), 3.97 (2H, s), 5.01 (1H, m), 7.53 (2H, m), 7.70 '(2H, m) , 8.08 (4H, m), 9.90 (1H, brs); m / z (ΑΡΓ): 306 (MH +, 100%). Example 66 N- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -3-bromo-4-isopropylbenzylamine hydrochloride iH-NMR (free state base, CDC13): 51.26 (6H, d, J = 7Hz), 2.48 (3H, s), 2.75 (2H, m), 2.90 (2H, m), 3.41 (1H, sep, J = 7Hz), 3.62 (2H, s), 7.09 (1H, d, J = 8Hz ), 7.31 (2H, dd, J = 8, 2Hz), 70 'This paper size applies to China National Standard (CNS) A4 specifications ( 210X 297 office) (Please read the notes on the back before filling this page)

555694 A7 B7 Economy, the consumer cooperation of the Central Bureau of quasi-government, printing 5. Inventory (6?) 7.37 (2H, m), 7.76 (1H, dd, J = 8, 2Hz), 7.90 (1H, br * s), 8.02 (1H, d, J = 2Hz); m / z (ΑΡΓ) · 387, 389 (MH +, 100%). Example 67 N- (2-methyl-1,2,3,4-tetrahydroiso + lin-7-yl) -3-cyano-4-isopropylanoic acid amine hydrochloride W-NMR (free Base, CDC13): 51.25 (6H, d, J = 7Hz), 2.37 (3H, s), 2.60 (2H, m), 2.80 (2H, m), 3.45 (1H, sep, J = 7Hz) , 3.62 (2H, s), 7.00 (1H, d, J = 8Hz), 7.25 (2H, m), 7.41 (1H, d), 7.97 (1H, dd, J = 8, 2Hz), 8.03 (1H, d, · J = 2Hz), 8.10 (1H, brs); m / z (API) 334 (MH +, 100%). Example 68 Ν- (2.methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoromethoxymethoxybenzylamine W-NMR (250MHz, CDC13): (5 2.48 (3H, s), 2.73 (2H, t, J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.61 (2H, s), 3.96 (3H, s) 5 7 · 〇 5 (2H, m), 7.30 (1H, dd, J = 6, 2Hz), 7.40 (1H, s), 7.63 (2H, d), 7.80 (1H, d); m / z (ΑΡΓ): 315.2 (MH +, 100%). Example 69 N- (2_methyl-1,2,3,4_tetramurisoisoquinolin-7-yl) -3-propanyl_4_ N-propoxybenzylamine! H-NMR (250MHz, CDC13): 51.10 (3H, t? J = 8Hz) 5 i .92 (2h m)? 2.47 (3H, s), 2.70 (2¾ t5 J = 6Hz ), 2.90 (2¾ t5 J-6Hz), 3 5g -lb (Please read the precautions on the back before filling this page)

Λ Zhang scale phase H National Standard (CNS) Λ4 gauge (210X 297) 555694 555694 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs kl B7 V. Description of the invention (π) (2H, s), 4.10 (2H, t, J = 8Hz), 7.02 (1H, d), 7.09 (1H, d), 7.33 (1H, dd, J = 6, 2Hz), 7.38 (1H, s), 8.02 ( 1H, s), 8.08 (2H, m); m / z (API +): 350.2 (MH +, 100%). Example 70 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-cyano-4-ethoxybenzylamine iH-NMR (250 MHz, CDC13) : 5 1.53 (3H, t, J = 8Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.62 ( 2H, s), 4.23 (2H, q, J = 8Hz), 7.04 (1H, d), 7.10 (1H, d), 7.32 (1H, dd, J = 6, 2Hz), 7.40 (1H, d ), 7.92 (1H, s), 8.09 (2H, m); m / z (ΑΓ): 336.2 (MH +, 100%). Example 71 N- (2-methyl-1,2,3,4-tetrakis-iso-junline-7-yl) -3- &gt; odor-4-n-propoxystilbene blue • amine iH-NMR (250 MHz, CDC13): 51.10 (3H, t, J = 8Hz), 1.90 (2H, m), 2.46 (3H, s), 2.69 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz), 3.58 (2H, s), 4.05 (2H, t, J = 8Hz), 6.93 (1H, d), 7.09 (1H, d), 7.30 (1H, dd, J = 6, 2Hz) , 7.39 (1H, d), 7.72 (1H, s), 7.80 (1H, dd, J = 6, 2Hz), 8.05 (1H, d); m / z (ΑΡΓ): 403.1 (MH +, 100% ). Example 72 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-bromo-4-ethylbenzylamine ~ 72 ~ (Please read the note on the back first (Fill in this page again)

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 public dredging) 555694 Α7 Β7 V. Description of invention (77) 'H-NMR (250MHz, CDC13): 5 1.26 (3H515 J = 8Hz), 2.46 (3H5 s), 2.69 (2H, t, J = 6Hz), 2.82 (2H, q, J = 8Hz), 2.90 (2H, t, J = 6Hz), 3.59 (2H, s), 7 · 10 (1H, d), 7.28 (1H, dd, J = 6, 2Hz), 7.34 (1H, d), 7.41 (1H, d), 7.74 (2H, dd), 8.03 ( 1H, s); m / z (ΑΡΓ): 373.1 (MH +, 100%) Example 73 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3 -Iodo-4-methoxybenzylamine ^ -NMR (250MHz, CDC13): 5 2.50 (3H? S)? 2.79 (2H, t5 J = 6Hz), 2.93 (2H, t, J = 6Hz) , 3.64 (2H, s), 3.94 (3H, s), 6.85 (1H, d), 7.21 (1H, d), 7.08 (1H, d), 7.34 (1H, dd, J = 6, 2Hz) , 7.38 (1H, d), 7.89 (1H, dd), 8.12 (1H, s), 8.29 (1H, d); m / z (API) 423.0 (MH +, 100%). Example 74 'N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-isopropoxy-3-trifluoromethylbenzylamine W-NMR (250MHz, CDC13) : (5 1 · 39 (6H, d, J = 8Hz), 2.48 (3H, s), 2.70 (2H, t, J = 6Hz), 2.87 (2H, t, J = 6Hz), 3.54 (2H, s), 4.72 (1H, m), 7.06 (2H, t), 7.30 (1H, dd, J = 6, 2Hz), 7.37 (1H, s ), 8.03 (3H, m); m / z (ΑΡΓ): 393.2 (MH +, 100%). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 75 N -(2-methyl-1,2,3,4-tetrakis-iso-alpha-charin-7-yl) -4-chloro-3-methoxyfluorenamine ~ 73 ~ This paper is sized to Chinese National Standard (CNS ) Α4 specification (210X 297 public trend) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 555694 A7 B7 V. Description of the invention (] H-NMR (250MHz, CDC13): 5 2.47 (3H? S) 5 2.70 (2H, t ? J = 6Hz), 2.88 (2H, t, J = 6Hz), 3.59 (2H, s), 3.98 (3H, s), 7.11 (1H, d), 7.21 (1H, d), 7.30 (2H M), 7.40 (1H, d), 7.45 (1H, d), 7.75 (1H, s); m / z (API +): 33U (MH +, 100%). Example 76 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxy-3-trifluoromethylbenzylamine [H-NMR ( 250MHz, CDC13): 51.08 (3H, t, J = 8Hz), 1.86 (2H, m), 2.46 (3H, s), 2.70 (2H, t, J = 6Hz), 2.90 (2H, t , J = 6Hz), 3.58 (2H, s), 4.08 (2H, t, J = 8Hz), 7.07 (2H, m), 7.29 (1H, dd, J = 6, 2Hz), 7.41 (1H, d) , 7.97 (1H, s), 8.03 (1H, d), 8.07 (1H, s); m / z (ΑΓ) · 393.2 (MH +, 100%). Example 77'N- (2-Methyl-1,2,3,4-tetrahydroisofluorin-7-yl) trichlorobenzyl benzylamine hydrochloride ^ -NMR (250MHz, DMS. -d6): 5 especially 1.68 (9H, s), 7.36 (1H, d, J = 8Hz), 7.77 (3H, m), 8.00 (1H, dd, J = 8, 2Ηζ), 8 · 11 (1H , D, J = 2Hz); m / z (API) · 357 (MH +, 100%). Example 78 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxybenzylamine hydrochloride '74' This paper size applies to Chinese national standards (CNS) Λ4 specification (210X 297 male Chu ·) (Please read the precautions on the back before filling this page)

555694 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (a) Similar to Example 3, D5 was converted at 95% yield by reaction with 4-methoxybenzyl chloride. Into the title compound. 'H-NMR (d2〇): 5 3.13 (3H, s) 3 3.25 (2H? Brs), 3.68 (2H? Brs), 3.69 (3H, s), 4.48 (2H, brs), 7.15 (2H, d, J = 9Hz), 7.35-7.50 (3H, m), 7.90 (2H, d, J = 9Hz). Example 79 N- (2-methyl-; i, 2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methylbenzylamine hydrochloride W-NMR (free state Base, CDC13): 5 2.34 (3H, s), 2.46 (3H, s), 2.69 (2H, t, J = 6Hz), 2.90 (2H, t, &gt; 6Ηζ), 3.58 ( 2H, s), 7.08 (2H, m), 7.30 (1H, dd), 7.40 (1H, d), 7.60-7.80 (2H, m), 7.74 (1H, s); m / z ( ΑΡΓ): 299.2 (MH +, 100%) 〇 Example 80 N- (2-methyl-1,2,3,4_tetraazepine-7-yl) -3 • chloro-4-isopropyl segment g Amine W-NMR (free state base, 250 MHz, CDC13): (Π · 40 (6H, d, J = 7Hz), 2.59 (3H, s), 2.82 (2H, m), 3.03 ( 2H, m), 3.58 (1H, sep, J = 7Hz), 3.71 (2H, s), 7.23 (1H, d, J = 8Hz), 7.42 (1H, dd, J = 8, 2Hz) , 7.53 (2H, m), 7.82 (2H, m), 7.96 (1H, d5 J = 2Hz); m / z (API) · 343, 345 (MH +, 100, 50%). Example 81 N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-cyano-4-ethylbenzylamine hydrochloride ~ 75, This paper is applicable to China National Standard (CNS) Α4 Specification (210X 297) (Please read the precautions on the back before filling this page)

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555694 V. Description of the invention (汴) iH-NMR (free state base, 250 MHz, CDC13): 5 1.31 (3H, t, J = 8Hz), 2.43 (3H, s), 2.66, (2Η, m ), 2.90 (4H, m), 3.55 (2H, s), 7.09 (1H, d, J = 8Hz), 7.28 (2H, dd, &gt; 8, 2Hz), 7.36 (1H, brs), 7.44 (1H, d, J = 8Hz), 7.86 (1H, brs), 8.00 (1H, dd, J = 8, 2Hz), 8.09 (1H, d, J = 2Hz); m / z (ΑΡΓ): 320 ( MH +, 100%). Example 82 N- (2-Methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-isopropyl-3-trifluoromethylbenzylamine hydrochloride ^ -NMR (Free state base, 250MHz, CDC13): (5 especially 1.38 (6H, d, J = 6Hz), 2.32 (3H, s), 2.57 (2H, m), 2.76 (2H, m), 3.25 ( 1H, m), 3.45 (2H, s), 6.95 (1H, d, J = 8Hz), 7.16 (1H, brd, J = 8Hz), 7.26 (1H, brs), 7.43 (1H, d, J = 8Hz ), 7.72 (1H, bfs), 7.84 (1H, d, J = 8Hz), 7.93 (1H, brs); m / z (ΑΡΓ): 377 (MH +, 100%). Instance 83 N -(2-Methyl-1,2,3,4-Tetrasorcin-7-yl) -4-Ethyl-3-digas methylcarboxamide hydrochloride Employees' consumption of Central Standards Bureau of Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling in this page) W-NMR (free state base, 250MHz, CDC13): 5 especially 1.25 (3H, t, J = 8Hz), 2.46 (3H , S), 2.68 (2H, m), 2.90 (2H, m), 3.58 (2H, brs), 7.10 (1Η, d, J = 8Hz), 7.30 (1Η, dd, J = 8, 2Ηζ), 7.47 (1Η, d, J = 8Hz), 7.40 (1H, brs), 7.78 (1H, brs), 7.97 (1H, dd), 8.08 (1H, brs); m / z ( API ·): 361 (ΜΗ '100%).' 76 'paper Applicable to China National Standard (CNS) A4 specification (210X297 mm) 555694 A7 B7 V. Description of the invention (γ) Example 84 Ν- (2-methyl-1,2,3,4-tetrahydroisophosphorin-7 -Yl) -3-cyano-4-isopropoxybenzylamine hydrochloride ^ -NMR (250MHz? CDC13): ά 1.45 (6Η? D? J = 8Hz)? 2.47 (3Η? S), 2.70 (2Η, t, J = 6Hz), 2.91 (2Η, t, J = 6Hz), 3.59 (2Η, s), 4.75 (1H, m), 7.04 (1H, d), 7.10 ( 1H, d), 7.29 (1H, dd, J = 6, 2Hz), 7.37 (1H, d), 7.71 (1H, s), 8.05 (2H, m); m / z (ΑΡΓ): 350.2 (MH +, 100%). Example 85 N- (l, 2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine ^ -NMR (250MHz, CDC13 ): 5 2.65 (2H, t5 J = 6Hz)? 3.00 (2H, J = 6Hz), 3.85 (3H, s), 3.89 (2H, s), 6.95 (2H, d), 7.17 (1H, dd , J = 6, 2Hz), 7.25 (1H, s), 7.57 (1H, s), 7.93 (2H, m); m / z (API) 351.1 (MH +, 100%). Example 86 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methyl-3-methylsulfonyl benzamidine Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a consumer cooperative (please read the notes on the back before filling this page) lH-NMR (CDC13): 5 2.48 (3H5 s)? 2.71 (2H? T? J = 7Hz), 2.80 (3H, s), 2.92 (2H, t, J = 7Hz), 3.15 (3H, s), 3.61 (2H, s), 7.13 (2H, d), 7.35 (1H, dd), 7.43 (1H, s), 7.52 (1H, d), 7.93 (1H, s), 8.14 (1H? Dd)? 8.45 (1H5 d); m / z (ΑΡΓ): 359.2 (MH +, 100%) 〇'77 'This paper size is applicable China National Standard (CNS) A4 gauge (210X297 mm) 555694 kl B7 V. Description of the invention) Example 87 N- (2-methyl-1, 2, 3, 4-tetrahydroisofluorene-7-yl) Ethyl-3-methylsulfonyl benzamidine 1H-NMR (CDC13): 5 1.49 (3¾ t? J-8Hz) 5 2.59 (3H? S) 5 2.81 (2H, t, J = 7Hz), 3.03 (2H, t, J = 7Hz), 3.27 (5H, m), 3.71 (2H, s), 7.23 (2H, d), 7.46 (1H, dd), 7.54 (1H, d), 7.69 (1H, d), 8.04 (1H? S)? 8.29 (1¾ dd) 5 8.55 (1H, d); m / z (ΑΡΓ): 373.2 (MH +, 100%). Example 88 N- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-isopropylseneamine ^ -NMR (CDCI3 ): (5 1.27 (6¾ d5 J = 8Hz)? 2.37 (3H? S)? 2.60 (2H, t, J = 7Hz), 2.81 (2H, t, J = 7Hz), 3.06 (3H, s), 3 46 (2H, s), 3.85 (1H, m), 7.00 (2H, d), 7.26 (1H, dd), 7.31 (1H, d), 7.57, (1H, d), 8.10 (1H, dd), 8.21 (1H, s), 8.37 (1H, d); m / z (ΑΓ): 387.2 (MH +, 100%). Example 89 N- (2-methyl-1, 2 , 3,4-tetrahydroisoquinoline-7-yl) 3-methylsulfonyl-4-methoxybenzylamine Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) Fill out this page again) ^ -NMR (CDCI3): ά 2.31 (3H? S) 5 2.54 (2H, t? J = 7Hz), 2.75 (2H, t, J = 7Hz), 3.09 (3H, s), 3.42 (2H, s), 3.87 (3H, s), 6.95 (2H, m), 7.12 (1H, s), 7.21 (1H, d), 8.08 (2H, m), 8.23 (1H, ~ 7 8 ~ This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 555694 V. Description of the invention (77) dd); m / z (ΑΡΓ): 375.2 (MH +, 100%). Example 90 N -(2-methyl-1,2 , 3,4-tetrahydroisoquinolin-7-yl) -3-trifluoroacetamidinyl benzamidine hydrochloride W-NMR (free state test, CDC13): 52.47 (3H, s), 2.46 (3H , S), 2.77 (2H, t, J = 6Hz), 2.94 (2H, t, J = 6Hz), 3.63 (2H, s), 7.13 (1H, d, J = 6Hz), 7.45 (1H, d, J = 6Hz), 7.54 (1H, t, J = 6Hz), 7.81 (1H, d, J = 6Hz), 7.97 (1H, d, J = 6Hz), 8.20 (1H, m / z (ΑΡΓ): 363.2 (MH +, 60%). Example 91 N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-formaldehyde Oxy-3-pentafluoroethyl benzate hydrochloride iH-NMR (free state base, 250 MHz, CDC13): 5 2.46 (3H, s), 2.70 '(2H, m), 2.90 (2H, m) , 3.59 (2H, s), 3.94 (3H, s), 7.10 (2H, m), 7.30 (1H, dd, J = 8, 2Hz), 7.39 (1H, brs), 7.73 ( 1H, brs), 8.01 (1H, d, J = 2Hz), 8.06 (1H, dd, J = 9, 2Hz); m / z (ΑΡΓ): 415 (MH +, 100%). Example 92 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N- (2-n-propyl-1,2,3,4-Siqi Yijunlin-7- Base) -3-'/ Ask-4-ethyllactylamine! H-NMR (CDC13): ά 0.95 (3H515 J = 7Hz), 1.51 (3H51, J = 7Hz)? ~ 79' This paper is for China National Standard (CNS) A4 gauge (210X 297mm) 555694 A7 B7 V. Description of the invention (7 &lt; P) 1.62 (2H, m), 2.47 (2H, t, J = 8Hz), 2.72 ( 2H, t, J = 6Hz), 2.88 (2H, t, J = 6Hz), 3.61 (2H, s), 4.17 (2H, q, J = 7Hz), 6.92 (1H, d, J = 9Hz) , 7.07 (1H, d, J = 8Hz), 7.26 (1H, d, J = 8, 2Hz), 7.39 (1H, d, J = 2Hz), 7.72 (1H, brs), 7.79 (1H, dd , J = 9, 2Hz), 8.04 (1H, d, J = 2Hz); m / z (ΑΡΓ): 417, 419 (MH +, 95%). Example 93 N- (2-n-propyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine'H-NMR ( CDC13): 5 0.96 (3H? T? J = 7Hz)? 1.61 (2H, m) 5 2.47 (2H, t, J = 8Hz), 2.73 (2H, t, J = 6Hz), 2.88 (2H, t, J = 6Hz), 3.62 (2H, s), 3.98 (3H, s), 7.08 (2H, m), 7.30 (1H, m), 7.41 (1H, d, J = 2Hz), 7 · 76 (1H, brs), 8.05 (2H, m); m / z (ΑΡΓ): 393 (MH +, 100%). '' Example 94 N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-isopropoxybenzylamine Central Bureau of Economic Affairs Printed by the employee consumer cooperative (please read the precautions on the back before filling this page) iH-NMR (CDC13): 5 0 · 95 (3H, t, J = 7Hz), 1.42 (6H, d, J = 6Hz), 1.62 (2H, m), 2.48 (2H, t, J = 8Hz), 2.73 (2H, t, J = 6Hz), 2.88 (2H, t, J = 6Hz), 3.63 (2H, s) , 4.66 (1H, sep, J = 6Hz), 6.98 (1H, d, J = 9Hz), 7.08 (1H, d, J = 8Hz), 7.26 (1H, m), 7.41 (1H , D, J = 2Hz), 7_65 (1H, brs), 7.73 (1H, dd, J = 9, 2Hz), 7.87 (1H, d, J = 2Hz); m / z (ΑΡΓ): 387 (MH +, 100%). 80, This paper size applies Chinese National Standard (CNS) A4 specification (210X 297) while 555694 A7 B7 V. Description of the invention (7?) Example 95 N- (2-methyl_1, 2, 3, 4_4 Hydroisoquinoline-7-yl) -3 · cyano-isobutylbenzylamine hydrochloride iH-NMR (250MHz, DMSO-d6): 5 especially 0.95 (6H, d, J = 7Hz), 1.99 (1H, sep, J = 7Hz), 2.77 (2H, brs), 7.26 (1H, d, J = 8Hz), 7.65 (3H, m), 8.21 (1H, dd, J = 8, 2Hz), 8.41 ( 1H, d, J = 8Hz); m / z (API +): 348 (MH +, 100%). Example 96 N- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) pipeisobutyl-3-trifluoromethyl behenate hydrochloride ^ -NMR (250MHz , DMSO-d6): 5 especially 1.01 (6H, d, J = 6.5Hz), 2.09 (1H, sep, J = 6.5Hz), 7.35 (1H, d, J = 8Hz), 7.75 (3H, m), 8.32 (1H, d, J = 8Hz); m / z (ΑΡΓ): 391 (MH +, 100%). Example 97 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N- (2-ethyl-1,2,3,4-tetraargon isoquinoline-7-based ) -3-bromo-4-ethoxybenzylamine W-NMR (CDC13): δ 1.20 (3H, t, J = 7Hz), 1.51 (3H, t, J = 7Hz), 2.61 (2H, q, J = 7Hz), 2.76 (2H, m), 2.90 (2H, m), 3.64 (2H, s), 4.16 (2H, q, J = 7Hz), 6.91 (1H, d, J = 9Hz ), 7.07 (1H, d, J = 8Hz), 7.26 (1H, m), 7.40 (1H, d, J = 2Hz), 7.79 (2H, m), 8.05 (1H, d, J = 2Hz) m / z (ΑΡΓ): 403, 405 (MH +, 65%). 81 This paper size applies to China National Standard (CNS) A4 (210X 297 public office) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 555694 V. Description of the invention (π) Example 98 N- (2-ethyl-1, 2 , 3,4-tetrahydroisoamyl-7-yl) -4-methoxy-3-difluoromethylbenzylamine 1H-NMR (CDC13): (5 1.21 (3H? T, J = 7Hz) , 2.65 (2H? Q5 J = 7Hz)? 2.80 (2H, d, J = 6Hz), 2.92 (2H, t, J = 6Hz), 3.67 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7.30 (1H, m), 7.41 (1H, d, J = 2Hz), 7.89 (1H, brs), 8.06 (2H, m); m / z (ΑΡΓ): 379 (MH +, 100 %). Example 99 N- (2-Isopropyl-1,2,3,4-tetraazaisolone-7-yl) -3- &gt; odor-4-ethoxy hypodonylamine 'H- NMR (CDCI3): ά 1.13 (6H? D? J = 7Hz) 5 1.51 (3H, t, J = 7Hz)? 2.84 (5H, m), 3.71 (2H, s), 4.16 (2H, q, J = 7Hz), 6.91 (1H, d, J = 9Hz), 7.06 (1H, d, J = 8Hz), 7.25 (1H, m), 7.42 (1H, d, J = 2Hz), 7.78 (2H, m ), 8.04 (1H, d, J = 2Hz); m / z (ΑΡΓ): 419, (MH +, 100%). Example 100 N- (2-isopropyl-1, 2, 3, 4-tetrahydro Isofluorolin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine WN MR (CDC13): 51.13 (6H, d, J = 7Hz), 2.84 (5H, m), 3.72 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7 · 26 (1H, m), 7.43 (1H, d, J = 2Hz) 5 7.83 (1H? Brs)? 8.04 (2H5 m); m / z (ΑΡΓ): 393 (MH +, 100%). ~ 82 sheets Standards apply Chinese National Standards (CNS) Α4 gauge (210X 297 public trend) ------ ^-(Please read the precautions on the back before filling this page)

、 1T 555694 Employees' Cooperative Bureau of the China Economic and Technological Bureau of the Ministry of Economic Affairs, printed by the company A7 B7 V. Description of the invention (? /) Example 101 N- (2-methyl-1, 2, 3, 4-tetrahydroisocyanine -7-yl) -4-ethoxymethyl methylcontinyl benzamidine 1H-NMR (CDCI3): δ 1.52 (3 (, t5 J = 8Hz)? 2.46 (3H5 s \ 2.69 (2H, t, J = 7Hz), 2.90 (2H, t, J = 7Hz), 3.26 (3H, s), 3.57 (2H, s), 4.27 (2H, q, J = 7Hz), 7.09 (2H, dd), 7.36 (1H, dd), 7.42 (1H, s), 7.83 (1H, brs), 8.12 (1H, s), 8.20 (1H, dd), 8.37 (1H, d); m / z (ΑΠ ,: 389.2 (MH +, 100%). Example 102 N- (2-methyl-1,2,3,4-tetrakisiso-sigmaquine-7-yl) -4- Oxychroman-6-3¾amine hydrochloride lH-NMR (d6-DMSO): δ 2.63 (3¾ fd)? 3.02 (2H? T? J = 7Hz)? 3.14 (2H, brm), 3.60 (2H, brm ), 4.54 (2H, brs), 4.77 (2H, d, J = 7Hz), 7.25 (1H, m), 7.31 (1H, d, J = 8Hz), 7.44 (2H, d, J = 6Hz), 8.20 (1H, dd, J = 8, 2Hz), 8.59 (1H, d, J = 2Hz), 10.31 (1H, s), 10.95 (1H, brs); m / z (ΑΡΓ): 337.4 (MH +, 100%). Example 103 N_ (2-methylfluorenyl-1,2,3,4-tetrahydroisoquinoline_7-yl) beetle Based on the procedure of Example 3, each trifluoromethylcarbazide contains 7-amino group 2-methyl · methyl hydrogen by reaction with 4-methoxytrifluorofluorenylbenzoyl and chloro. Iso + Lin 76) was converted to the title compound and the product was isolated as a white solid (35 g). ~ 83

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Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 555694 Α? Β7 f. Description of the invention (p) e-NMR (d6-DMSO) ·· δ 2 · 80 (2H, m), 3.65 (2H, width t ), 4.00 (3H, s), 4.59 (2H, d), 7.17. (1Η, d, J = 8Hz), 7.45 (1H, d, J = 8Hz), 7.60 (2H, m), 8 · 26 (3H, m), 10.30 (1H, s); m / z (ΑΡΓ): 379 (MH +) 〇 Example 104 N- (2- # emptyethyl-1, 2, 3, 4, tetrahydroiso α-Quillin "7-yl" _3_Acetoethoxybenzylamine Dissolve compound D16 (115 mg, 0.22 mmol) in Τρρ with stirring and add tetrabutylammonium fluoride (1 mole concentration at Butan HF, 0.216 mmol), the reaction was allowed to stand overnight and the mixture was purified by column chromatography using SiO to dissolve it in 10% methanol: dimethyl ether, and was triturated with petroleum ether to give the title compound (48 mg , 49%). θ ^ -NMR (250MHz? CDC13): 5 1.51 (3H? t, J = 7Hz) 5 2.77 (2H t J = 5Hz), 2.90 (4H, m, weighted signal), 3.74 (4H, m, overlap (,. Number), 4.17 (2H, q, J = 7Hz), 6.93 (1H, d, J = 10Hz), 7.10 (1H, d J = 8Hz), 7.36 (1H, dd, J = 8, 2 Hz), 7.48 (1H, d, J = 2Hz), 7 87 (1H, dd, J = 9, 2Hz), 7.97 (1H, s), 8_08 (1H, d, J = 2Hz). Example 105 N- (2-J ^ ylethyl-1,2,3,4-tetrahydroisoalpha-charin-7-yl) -3-mo-4_ethylbenzidine 16 and the method of Example 106 to prepare the title compound at 40% total τα D15. ~ 84 ~ This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 cm) (Please read the precautions on the back before filling this page)

J—I Jm, 555694 A7 B7 V. Description of the invention u &gt;) W-NMR (250MHz, CDC13): 52.77 (10H, m, overlapping signals), 3.68 (5H, m, overlapping signals), 7.08 ( 1H, d, J = 8Hz), 7.30 (2H, m, overlapping signals), 7.48 (1H, d, J = 2Hz), 7.75 (1H, dd, J = 8, 2 Hz), 8.02 (1H, d, J = 2Hz), 8.17 (1H, s). Example 106 N- (2-Methyl-1,2,3,4-tetraargonisofluorin-7-yl) -4-phenylmethoxy-3-trifluoromethylbenzylamine'H-NMR (CDC13): ά 2.50 (3H? S)? 2.75 (2¾ t, J = 6Hz)? 2.94 (2H, t, J = 6Hz), 3.64 (2H, s), 7.10 (2H, d, J = 8Hz) , 7.30-7.60 (7H, m, overlapping signals), 7.70 (1H, brs), 8.04 (1H, dd, J = 8, 2Hz), 8.10 (1H, d, J = 2Hz); m / z (Cl ): 441.2 (MH +, 100%). Example 107 N- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-hydroxy-3-trifluoromethylbenzyl'midine m / z (CI): 351 · 1 (MH +, 100%) Example 108 N- (2-methoxyethyl-1,2,3,4-tetra-isoprene-7-yl) -3- &gt; Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Propoxylated S Blueamine (please read the notes on the back before filling this page) W-NMR (250MHz, CDC13): 5 1.41 (6H, d, J = 6Hz) , 2.75 (4H, t, overlap, J = 6Hz), 2.83 (2H, d, J = 5Hz), 3.39 (3H, s), 3.61 (4H, t, overlap, J = 6Hz), 4 · 64 (1H, m), 6.91 (1H, d, J = 9Hz), 7.01 (1H, ~ 85) This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210 X 297) while 555694 B7 V. Description of the invention (Suppressed) (Please read the notes on the back before filling this page) d, J = 8Hz), 7.20 (1H, dd, J = 8, 2Hz), 7.29 (1H, d, J = 2Hz), 7.80 (1H , Dd, J = 9, 2Hz), 8.07 (1H, d, J = 2Hz), 8.10 (1H, s); m / z (ΑΡΓ): 447, 449 (MH +, 90%). Example 109 N- (2-methoxyethyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-chloro-4-isopropoxybenzylamine iH-NMR (250 MHz , CDC13): (5 1.41 (6H, d, J = 6Hz), 2.75 (4H, t, overlap, J = 6Hz), 2.83 (2H, d, J = 5Hz), 3.39 (3H, s ), 3.61 (4H, t, overlap, J = 5Hz), 4.64 (1H, m), 6.94 (1H, d, J = 9Hz), 7.01 (1H, d, J = 8Hz), 7.20 (1H, d, J = 8Hz), 7.30 (1H, s), 7.75 (1H, dd, J = 9, 2Hz), 7.90 (1H, d, JN2Hz); m / z (ΑΡΓ): 403, 405 (MH +) 〇 Example 110'N- (2-methoxyethyl-1,2,3,4-tetrahydroisovalin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine W- NMR (250MHz, CDC13): δ 2.75 (4H, m), 2.85 (2H, d, J = 5Hz), 3.39 (3H, s), 3.61 (4H, t, overlap), 3.96 (3H, s) , 7.04 (2H, m), 7.25 (1H, d, J = 10Hz), 7.35 (1H, s), 8.07 (3H, m); m / z (API) · 409 (MH +, 100%). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297). 555694 A7 B7 V. Description of the invention (K) Example 111 Acids and amines at 81 Prepared at% Yield Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Chemical Industry (Ah (5 1,2,3,4_tetrahydroisoplane; radical) | Azide_Acetate Use a method similar to Example 1 The title compound was prepared in 91% yield. M / z (CI): 420 (MH +, 100%) Example 112 N-Phenyl-5-trifluoroethyldonylamino-1,2,3,4-tetramethyl Hydroisoquinolin-7-yl) -3-bromo-4-methoxybenzylamine using a method similar to that described in description 7 from D25 (0.50 g) and 3-bromo-4-methoxybenzene Formic acid (0.63 g) prepared the title compound (0.66 g). M / z (CI): 486,488 (MH +, 90/0) Example 113 N- (2-methyl-5-chloro-1,2,3 , 4_tetrahydroisoquinine; base) each bromo | ethoxybenzylamine m / Z (CI): 425 (MiT, expected isotope pattern) This paper size applies Chinese National Standard (CNS) A4 regulations ^ (Please read the notes on the back before filling this page)

555694 A7 B7 V. Description of the invention (printed example 114N_ (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinoline-7-yl) -3 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -Bromo-4-ethylbenzidine. The title compound (0.66 g) was prepared from D25 (0.50 g) and 3-bromo-4-methoxybenzoic acid (0.63 g) using a method similar to that described in description 7. 'H-NMR (CDC13): 5 L25 (3¾ t? J = 7Hz)? 2.48 (3H5 s)? 2.70 ^ 3.00 (6H, m, overlapping signals), 3.59 (2H, s), 7.29 (1H , D, J = 2Hz), 7.33 (1H, d, J = 7Hz), 7.51 (1H, d, J = 2Hz), 7.71 (1H, dd, J = 7, 2Hz), 7.83 (1H, brs ), 8.01 (1H, d, J = 2Hz); m / z (Cl): 409 (MH +, expected isotope pattern). Pharmacological data 1. Combined test method W92 / 2293 (SmithKline Beecham) revealed Compounds having anticonvulsant activity, including especially the compound trans-(+) 4-acetamido-4S- (4-fluorobenzylamino) -3,4-dihydro-2,2-dimethyl -2Η-1-benzopiperan-3R-alcohol (hereinafter referred to as compound A), it was discovered that the compound of WO 92/2293 binds to abnormal receptors that can be obtained from rat forebrain tissue, as disclosed at w. 96 / l865〇 (SmithKline B eecham), the affinity of the test compound for the abnormal receptor site is evaluated as follows. Methods The atmosphere was obtained from the ore brain, and the tissue was first homogenized in a buffer (usually 50¾ Molar concentration of trimethylolamine oxane), and the sample was homogenized. Paper size is applicable to China National Standard (CNS) A4 specification (21 〇X 297) (Please read the precautions on the back before filling in this page}

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 555694 A7 B7 丨 丨 丨 Drawing __ ~ — — ----------- _ ___ V. Description of the invention (&lt; 57) Wash and resuspend in the same buffer and store at -70 ° C until use. For the radioligand binding test, the tissue portion prepared above (usually at a concentration of 1-2 mg protein / ml) was mixed with [3H] -Compound A, dissolved in buffer, and [3H] -Compound The end of A in the mixture; Chendutong # was 20¾ micromolar concentration, the mixture was incubated at room temperature for 1 hour, and then filtered through Whatman GF / B glass fiber filter paper to make the [3H] -compound bound to the tissue A was separated from the unbound [3Η] -compound a. The filter paper was quickly washed with ice-cold buffer, and the liquid scintillation counter was added to the filter paper. Then, the amount of radioactivity bound to the tissue on the filter paper was counted in the liquid scintillation counter. In order to determine the binding amount of [3, compound A, and, specifically, parallel tests as described above in which [3H] -compound A and tissue were cultured together in the presence of unlabeled compound A (usually 3 micromolar concentration), In the presence of this unlabeled compound, the combined amount of [3H] -compound A is called, non-specific, combined, and this amount is summarized from [3H] -compound A and the amount (that is, in the absence of unlabeled The amount in the presence of the compound) is subtracted to obtain the "specific" binding amount of [3H] -compound a to the abnormal site. a It is estimated that the binding affinity of the test compound to the abnormal site can be cultured together with [3H] -Compound A and the tissue in the presence of the test compound in the concentration range, and the specific PH] -Compound A will be caused by increasing the concentration of the compound in the test Combined with a plot of the decline, a non-linear regression analysis using the resulting curve can provide a compound affinity estimate, pKi. 89 'This paper size applies to China National Standard (CNS) A4 (210X 297 cm), \ st »(Please read the precautions on the back before filling this page)

Printed by the Central Bureau of quasi-Ministry of Economic Affairs, Shellfish Consumer Cooperative 555694 A7 B7 __ V. Description of the invention (find) Results The compounds of the present invention were active in the test, such as the compounds of Examples 1, 4, 5, 6, 7, 10 and The resulting pKi value is greater than 7. 2. MEST test Maximum electric shock seizures (MEST) in dentitions The test is particularly sensitive to detecting the properties of potential anticonvulsants1. In this mode, the anticonvulsant Tinan electron-induced tumor seizures The forgiveness limit helps to reduce the forgiveness for seizures. The method of the mouse mode is to randomly designate 10 to 20 mice (pure male, Charles River, UK CD-I, 25-30 g) in each group, and orally or peritoneally at a dose volume of 10 ml / kg. Internally administered different doses of compound (⑽ ^ ⑽mg / kg) or vehicle, a single electric shock (0.1 second, 50Hz, positive sine wave type) via a corneal electrode 30 or 60 minutes after application, in a specific treatment group 5 (^ (CC%) The average current and standard deviation required to induce compulsive seizures in mice are determined by Dixon and Mood's (I948) 2 method. The statistical comparison of the vehicle and agent treatment groups is Use the Lichfielwwilc method (1949) 3. The% in control animals is usually M-18 milliamps, so the first animal in the control group is subjected to a current of 16 milliamps, which increases if it does not cause a mandatory seizure. For the next mouse, if the current is = mandatory seizures, reduce the current until it moves in the group ^ (read the precautions on the back before filling in this page)

~ 90 ~ 555694 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. The invention descriptions (cleverness) have been tested. The Hugo Sachs Ekctronik Constant Current Shock Generator was used for the study. The total change of the electric shock was controlled from 0 to 300 milliamps, and a change of 2 milliamps was usually used. Results * The compounds of the present invention, at a dose of 10 mg / kg, orally administered as a suspension in methylcellulose for 1 hour showed an increase in the forgiveness limit of seizures, for example the compounds of Examples 4, 5, 6, and 7 each Shows 24%, 36%, 90% and 23% increase. Method for rat mode The maximum (mandatory hindlimb draft) electric shock epileptic seizure limit in male rats (Sprague Dawley, 80-150 g, 6 weeks old) is determined by the * HugoSachs ElectiOnik simulator, which Can deliver a fixed current (duration of 0 ~ 3's, ranging from 1-300 milliamps, 5-20 milliamps), similar to the steps described in the above small white β; ~, and the detailed description is made by Upt〇n et al revealed 4. Calculate the percentage of C (: 5g increase or decrease) of each group compared with the control group. The agent is suspended in methyl cellulose at 1 ° /. The result is at a dose of 2 mg / kg, after 2 hours of oral administration, Example 48 The compounds of, 49, 51, and 67 each show Mg%, 325%, 545%, and 303%. ～ 91 This paper size is applicable to China National Standards (CNS) Λ4 specification (210X 297) while (please read first (Notes on the back then fill out this page)

-Ding'II: _ 555694 Μ B7 V. Description of the invention (References 1. Loscher, W. And Schmidt, D. (1988). Epilepsy Res., 2, 145-181 2. Dixon, WJ and Mood, AM · (1948). J. Amer. Stat. Assn "43, 109-126 3. Litchfield, JT and Wilcoxon, F. (1949). Pharmacol, exp. Ther., 96, 99-113 4. N. Upton, TP Blackburn, CA Campbell, D. Cooper, ML · Evans, HJ Herdon, PD King, ΑΜ Ray, TO Stean, WN Chan? JM Evans and M. Thompson. (1997). BJ · Pharmacol ·, 121, 1679 -1686 (Please read the notes on the back before filling out this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 92 This paper size is applicable to the Chinese National Standard (CNS) Λ4 regulations (210X 297 mm)

Claims (1)

2. Λ * 6. Scope of patent application A8 B8 C8 D8 Patent Application No. 87104135 ROC Patent Appln. No. 87104135 Application without amendment after the amendment. Amend Claims in Chinese-Encl.d ) (Submitted on August yV, 2003) (Submitted on August yV, 2003) L A compound of formula (I) or a pharmaceutically acceptable salt thereof 10 NHCO- (I) 15 20 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 25 where Q is a monocyclic or bicyclic aryl or heteroaryl ring selected from benzene, benzotriol, benzofuran, benzo Miso, σ than ϋ, 嗔 u, 异, 异, 1, 1 chroman, R1 is hydrogen, Cw alkyl (substituted by hydroxyl or Cm alkoxy if necessary), Cl-6 dilute group, Ci_6 Fastyl, Ci-6 alkyl, CO-, sulfonyl CF3C〇 ^ Cw alkyl so2-, R is hydrogen or up to three selected from halogen, No2, CN, n3, cf3〇, CF3S, CF3CCK trifluoro Methyldiphenyl, Ci-6 alkyl, Cl.6 alkenyl, Cw alkynyl, Cw perfluoroalkyl, C3-6 cycloalkyl, c3-6 cycloalkyl, Cw alkyl, Cw alkyl, 0-, Cw Alkyl CO-, (3-6 cycloalkyl 0, C3.6 cycloalkyl CO-, C3-6 cycloalkyl Cm alkyl 0-, C3-6 cycloalkyl Cm alkyl CO-, phenyl, benzene Oxy, benzyloxy, benzamidine, phenyl Cw alkyl, Cu alkyl S ·, Cw alkyl S02-, (CM alkyl) 2NS02-, (Cm alkyl) NHS02-, (Cw alkyl) 2NCO-, (CM alkyl) NHCO- or CONH2 substituents; -93------------------ This paper size is suitable for financial standards (CNS) A4 Specification (210x297 mm) 8 7091B-connected 1 Α8 Β8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 555694 Claiming the scope of patents or seven R3r4 where R3 is hydrogen or CM alkyl, and R4 is hydrogen, Cm-based, cyano-based, -CC ^ Cm alkyl or -coCm alkyl; or two R2 groups together to form a carbocyclic ring, which is saturated or unsaturated and unsubstituted or substituted with -OH or = 〇; and 5 X is hydrogen, halo, C 〖6 alkoxy, (: w alkyl, amine or trifluoroacetamido; 2 but s X is hydrogen, halogen or Cw alkyl does not include compounds where 2-alkoxy, and when X For halogens, compounds are not included ^^-Methyl-2M + 2,3,4-tetrahydroisofluoren-5-yl) -5-benzylfluorenyl-2-methoxybenzylfluorene 10 face μ… Ethylene, 2,3,4-tetrahydroisofluorenyl_5-yl) _5-pentanyl-2_methoxyxylamine, N- (5-iodo-1,2,3,4- Tetrahydroisofluoren-7-yl) _5_benzylfluorenyl_methoxybenzylamine, N- (5-iodo-1,2,3,4-tetrahydroisofluoren-7-yl) -2 -Methoxy-4-trifluoromethyldicrotylbenzylamine, ^ (^ iodo-^ 'tetrahydroiso15pyridinyl) _2-methoxy-5-trifluoromethyldicrotylbenzylamine Amine, bucket (7-iodine j, 2,3,4-tetrahydroisofluororphine_5_yl) _2_ Oxy-5_trifluoromethyldioxenylamine and N- (8-fluoro-2-methyl_1,2,3,4-tetrahydroisofluoren-5-yl) Dibutyl-2-methoxybenzylamine, and it has a prerequisite: N- (2-fluorenyl-mi tetrahydroisophosphorinyl hydrazyl group)> 2〇3'4'5-dimethoxy Except for benzamide. 2. The compound of formula (I) or a pharmaceutically acceptable bis-salt thereof according to item 1 of the scope of the patent application, wherein Q is thienyl or phenyl. 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1 of the scope of the patent application, which is selected from the group consisting of: Ν〆1,2,3,4 · tetrahydroisoxoline-7- Based) -5_ thiothiophene-2-amidine Specifications of this paper ⑽χ297 '- 555694 A8 B8 C8 D8 VI. Application scope of patent N- (2-fluorenyl-1,2,3,4-tetrahydroisofluorin-7-yl) -5-chlorothiophene-2-fluorenamine N- (2 -Fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) benzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) ) -3-Gabenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-tert-butylbenzylamine 5 N- (2- Fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-isopropoxybenzylamine N_ (2-fluorenyl-1,2,3,4-tetraazaiso Kuilin-7-yl) -4-phenoxyfluorenamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-nitrobenzyl Amine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-phenylbenzylamine N- (2-methyl-1,2,3,4 -Tetraazepine-7-yl) -3-methylfluorenamine 10 N- (2-methyl_1,2,3,4-tetrahydroisofluoren-7-yl) -3-fluoro Benzamidine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-cyanobenzamine N- (2-fluorenyl-1,2, 3,4-tetrahydroisofluoren-7-yl) -3,4-dichlorobenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) 4-Iodobenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-bromobenzylamine 15 N- (2-methyl-1 , 2,3,4-tetrahydroisofluoren-7-yl) -4-form N- (2-fluorenyl-1,2,3,4-tetrahydroiso-4 咁 -7-yl) -3-nitrobenzylamine N- ( 2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-ethoxybenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydro Isofluoren-7-yl) -4-n-butylbenzylfluorenamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -2-ethenyloxy Benzamidine 20 N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-trifluoromethyl benzamidine N- (2-fluorenyl-1, 2,3,4-tetrahydroisofluoren-7-yl) -2,4-difluorobenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl ) -3,4-dimethoxybenzylamidine 1 ^-(2-fluorenyl-1,2,3,4-tetraazaiso * 1quinol-7-yl) -2_fluoro_4- Tris-1 methylfluorene-95-This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) 555694 A8 B8 C8 D8 VI. Patent application scope Naminium N- (2-fluorenyl-1, 2, 3 , 4-tetrahydroisofluoren-7-yl) -4-gas-3 · nitrobenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl ) -3,5-di-trifluoromethylchlorobenzylamine 5 N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -2,4-dichloro -5-fluorobenzylamine N- (2-methyl-1,2,3,4-tetra Hydroisofluoren-7-yl) _3_fluoro-5-trifluoromethylbenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3 -Bromo-4-methoxybenzylamidine 10 amine N_ (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-trifluoromethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-pentamylbenzylamine N- (2-methyl-1,2,3,4-tetramethyl Hydroisoiso-7-yl) -3-bromo-4-isopropoxybenzyl 15 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Employee Consumer Cooperative 11 Ν- (2-fluorenyl-1, 2, 3, 4 -Tetrahydroisofluoren-7-yl) -4-ethoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4- Cyclopentyloxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-cyclopropylmethoxybenzylamine 20 N- (2 -Fluorenyl_1,2,3,4-tetraazaisobutyrol-7-yl) -3-cyano-4-methoxypentanoamine N- (2-fluorenyl-1, 2, 3, 4-tetrahydroisofluorin-7-yl) -2-naphthylamine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-bromo-4 -Methylbenzylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -naphthalene-1-fluorenamine-96-This paper size applies to Chinese national standards ( CNS) A4 size (210x297 mm) 555694 A8 B8 C8 D8 6 Application scope: N- (2-methyl-1,2,3,4-tetrahydrazinoisoline-7-yl) -3-gas-4-methoxybenzylamine N- (2-methyl- 1,2,3,4-tetramethylisofluoren-7-yl) -4-tert-butoxybenzylamine 5 N- (2-fluorenyl-1,2,3,4-tetrahydroisofluorenyl Porphyrin-7-yl) -4-n-propoxybenzylfluorenamine N · (2-fluorenyl_1,2,3,4-tetrahydroisofluoren-7-yl) benzotriazole-5-fluorene Amine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) benzotriazole-6-fluorenamine N_ (2-fluorenyl-1,2,3,4 -Tetrahydroisopyridin-7-yl) -2,3-dihydrobenzofuran · 5-amidamine 10 Ν_ (2-methyl-1,2,3,4-tetramidine (Methyl) -2-methylbenzophenone 〇-5_ amine 1 ^ _ (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -3-chloro-4 -Isopropoxybenzylamine N- (2-fluorenyl-1,2,3,4-tetramethylisoisoquinol-7-yl) -3- &gt; odor-4-ethoxy 15 Amine N- (2-methyl-1,2,3,4-tetramethylisocyanate) N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-methoxy-3-trifluorofluorenyloctylamine 20 N- (2-fluorene -1,2,3,4-tetrahydroisofluoren-7-yl) -3,5-digas-4-methoxy Benzamidine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3,5-digas-4-ethoxybenzylamine N- (2- Fluorenyl-1,2,3,4-tetrahydroisofluorin_7_yl) -3,5-digas-4-isopropoxy-97-This paper size applies to China National Standard (CNS) A4 ( (210 X 297 mm) 555694 A8 B8 C8 D8 6. Application scope of patents Octylamine N- (2-methyl-1,2,3,4-tetrahydroisophosphorin-7-yl) -3-form Sulfosulfenylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-bromo-4-tert-butylbenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -2-bromo-5-methoxybenzylamine N- (2-methyl-1,2,3 , 4-tetrahydroisofluoren-7-yl) -4 • fluoro-3-methoxybenzylamine hydrochloride 10 N- (2-methyl-1,2,3,4-tetraazaisoquine -7-yl) -1 -methyl 11 than hydrazine-4-vinylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4_tri Fluoromethylpyrazole-3-fluorenamine N_ (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) _2-fluorenylthiazole-4-fluorenamine N- (2- Fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -5-fluorenylisoxazole-3-fluorin 15 amine sense (2-methyl-1,2,3,4- Tetrahydroiso4line-7-yl) -5-Third-butylisoxazole 2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-methoxyisoxazol-5-amidamine hydrochloride 20 N_ (2-fluorenyl-1, 2,3,4-tetrahydroisofluoren-7-yl) indole-2-fluorenamine N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl)- 3-bromo_4-isopropylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetraazaiso-7-yl) -3amino-4-isopropyl Methylamine hydrochloride-98-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Planning and Economics 555694 A8 B8 C8 D8 Range N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-fluoro-4-methoxybenzylamine N- (2-fluorenyl-1, 2,3,4-tetraazaisoazepinequinolin-7-yl) -3-lactyl-4-n-propylamidamine 5 N- (2-methyl-1,2,3,4-tetrakis Nitroisoisoquinone-7-yl) -3 -nitro-4-ethoxyfluorenamine N- (2-fluorenyl-1,2,3,4 · tetrahydroisofluorin-7-yl> ; 3-Bromo-4-n-propoxybenzylamine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-bromo-4-ethylbenzyl Ammonium 10 N- (2-methyl-1,2,3,4-tetraazaisotope, lin-7-yl) · 3_ange-4_methoxymethoxyamine t Ν- (2-methyl Base-1 , 2,3,4 · tetrahydroisofluoren-7-yl) -4-isopropyl-3-trifluorofluorenylpentanamine N- (2-methyl-1,2,3,4-tetrakis Hydrazinoline-7-yl) -4-chloro-3-methoxybenzylhydrazone 15 amine N- (2-methyl-1,2,3,4-tetrahydroisofluorinoline-7-yl)- 4-n-propoxy-3-trifluoromethylbenzylamine N- (2-methyl-1,2,3,4-tetramethylisofluoren-7-yl) -3-gas Tributyl benzyl hydrochloride 20 N- (2-fluorenyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-methyl printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Oxybenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetramethylisophosphon-7-yl) -4-fluoro-3-methylbenzylamine hydrochloride N -(2-methyl_1,2,3,4-tetraazaiso-iso-s--7-yl) -3-qi-4-isopropylammonium-99-This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 555694 A8 B8 C8 D8 VI. Patent application scope Amine N- (2-fluorenyl-1, 2, 3, 4-tetrahydroisofluoren-7-yl) -3-cyanine N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-isopropyl-3-trifluorofluorenyl 5-Methylbenzylamine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-ethyl-3-trifluoromethylbenzidine Amine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisophosphorin-7-yl) _3_cyano-4-isopropoxybenzylamine hydrochloride 10 N- (l, 2,3,4-tetrahydroisofluorin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine N- (2-methyl-1,2,3,4 -Tetra-misoisoquinine-lin-7-yl) -4-methyl-3-methylpyridylamine N- (2-fluorenyl-1,2,3,4-tetrahydroisofluorene- 7-yl) -4-ethyl-3-methylsulfonyl 15-benzylamine N- (2-methyl-1,2,3,4-tetraisoisulin-7-yl) -3 -Methylmethyl-4-isopropylbenzylamine N- (2-fluorenyl-1,2,3,4 · tetramethylene 11--7-yl) -3 -methylmethyl-4 -Tj oxybenzylamine 20 N- (2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-trifluoro Ethyl benzamidine hydrochloride N- (2-methyl-1,2,3,4-tetrahydroisofluorin-7-yl) -4-methoxy-3-pentafluoroethyl benzamidine Amine hydrochloride N- (2-n-propyl_1,2,3,4_tetraazaisoisoquinone-7_yl) _3- &gt; odor_4_ethoxyfluorene-100-paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 555694 A8 B8 C8 D8 6. Application scope of patent Namine (N- (2-n-propyl-1), 2,3,4-tetrahydroisofluorolin-7-yl) -4-methoxy-3-trifluoromethylbenzylamine N- (2-n-propyl-1,2,3,4-tetrakis Hydroisofluorin-7-yl) -3-gas-4-isopropoxy 5 benzamidine N · (2-methyl-1,2,3,4-tetraazaiso-7-yl) -3 -Cyano_4_isobutylamidamine hydrochloride N- (2_amidino-1,2,3,4-tetraazaisoshaphin-7-yl) -4_isobutyl_ 3_tridunylbenzylamine hydrochloride 10 N- (2-ethyl-1,2,3,4-tetrahydroisofluorolin-7-yl) -3-bromo_4-ethoxybenzyl Ammonium 11 N- (2-ethyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-methoxy-3-trifluoromethylbenzylamine N- (2- Isopropyl-1,2,3,4-tetraazaisoisoquinone-13-lin-7-yl) -3- &gt; Smell-4-ethoxyfluorene 15 ammonium N- (2-isopropyl-1 , 2,3,4-tetrahydroisofluoren-7-yl) -4 · methoxy-3-trifluoromethylbenzylamine N- (2-methyl-1,2,3,4-tetra Hydroisoxoline-7-yl) -4-ethoxy-3-fluorenylsulfonate Printed fluorenylbenzylamine 20 N- (2methyl-1,2,3, 4_Four moxibustion -7-yl) -4-oxochromanyl-6-bromoamine hydrochloride N- (2-bramyl-1,2,3,4-tetrazolium 7-yl) -4-methoxy-3-difluoromethylbenzylamine N- (2-Ethyl 1,2,3,4-Four winds and different commands (7-based) -3_ &gt; Smelt-4-ethoxy noon-101-This paper size applies to China National Standard (CNS) A4 (210 X 297) Li) 555694 A8 B8 C8 D8 6. Application for Patent Range Amines N- (2-hydroxyethyl-1,2,3,4-tetrahydroisofluoren-7-yl) -3-bromo-4-ethyl Benzamidine N- (2-methyl-1,2,3,4-tetraazaisoquinolin-7-yl) -4-phenylmethoxy-3-di-5fluoroamylbenzylamine N -(2-fluorenyl-1,2,3,4-tetrahydroisofluoren-7-yl) -4-hydroxy-3-trifluoromethylbenzylamine N · (2-methoxyethyl- 1,2,3,4-tetraazaisoisopropyl-7-yl) -3- &gt; odor-4-isopropoxy + amidamine 10 N- (2-methoxyethyl-1,2, 3,4_tetraazaisoisoquinone-7-yl) -3-gas-4-isopropoxybenzylamine N- (2-methoxyethyl-1,2,3,4-tetrakis What's wrong. Lin-7-yl) -4-methoxy-3_trifluoromethylpentanylamine N- (5-iodo-1,2,3,4-tetrahydroisofluoren-7-yl) -4-azide Benzyl benzamidine trifluoro 15 acetate N- (2-fluorenyl-5-trifluoroacetamidinyl-1,2,3,4-tetrahydroisofluorinyl-7-yl) -3-bromo- 4-methoxybenzylamine N- (2-fluorenyl-5-gas-1,2,3,4-tetrahydroisofluorin-7-yl) _3_bromo-4-ethoxy Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau, benzamidine 20 N- (2-fluorenyl-5-gas-1,2,3,4-tetrahydroisofluoren-7-yl) -3-bromo-4- Ethyl benzyl 6-panamine. 4. A pharmaceutical composition for the treatment and / or prevention of diseases related to spasms, comprising a compound according to any one of the claims 1 to 3 of the scope of patent application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt Acceptable load -102-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 555694 A8 B8 C8 D8_ VI. Patent scope agent. 5. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, which is a medicine for treating and / or preventing diseases related to spasm. 5 6 · —A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 of the scope of patent application, which comprises making a compound of formula (II) Printed by the Intellectual Property Bureau's Consumer Cooperatives of the Ministry of Economic Affairs, where R1A is the same as R1 as defined in item 1 of the scope of patent application or a group that can be converted to R1 and X is the same as the definition in item 1 of the scope of patent application. (III) Compound reaction 15 COY • \ • Q ·, ·· 〆 (ιπ) r2A 20 where Q is the same as the definition in item 1 of the scope of patent application, Y is Cl or OH, and R2A is independently the same as the patent application R2 as defined in the first item of the scope may be a group that can be converted into R2, and R1A or R2a group needs to be converted into R1 or R2 group, one R1 or R2 group is converted into another R1 or R2 group, and the salt The product is converted into free state alkali or another -103-This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 555694 A8 B8 C8 D8 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Scope pharmaceutically acceptable salts, or conversion of free bases to pharmaceutically acceptable salts. -104-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)