TWI298999B - Acylated 6,7,8,9-tetrahydro-5h-benzocycloheptenyl amines and their use as pharmaceutical - Google Patents

Description

1298999 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (The present invention relates to a 6,7,8,9-tetrahydro-5Η-p-cycloheptenylamine, R1 to R5 and Α to D of the formula (I) The definitions are listed below, any of its isomeric forms or mixtures thereof in any ratio or pharmaceutically acceptable salts thereof, and their use as pharmaceuticals.

10 15 20 The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed endothelial NO synthase (eNOS, NOS-III), which is one of three isozymes, which can produce nitric oxide (N〇), endothelium via oxidized arginine. Sexually released NO is important in a variety of key cardiovascular mechanisms, including blood & dilation effects and inhibition of platelet aggregation, adhesion of leukocytes to the endothelium, and replication of intimal smooth muscle cells. Endothelial NO synthase can also be physiologically and pathologically regulated at the transcriptional and post-transcriptional levels. Enzymes already present in the endothelium can undergo calcium-related and calcium-independent activation via phosphorylation of specific amino acids, but Through direct interaction with specific proteins, this stimulator, usually a transient NO release, is extracellular arginine, 17/^ estrogen and acts on the surface of the endothelial lumen via blood flow (shear stress) Mechanical stimulation, which also results in the regulation of eNOS at the transcriptional level, so for example, Sessa et al. (Circ. Research 74 (1994) 349_353) can significantly increase ecN〇s via exercise training and increased shear stress associated with it. Whether the adjustment of the post-transcriptional level is related to the living body has not been clearly confirmed. I -· · - - - ― - -1 - - I I I (Please read the notes on the back and fill out this page)

, 1T ~ 3 - This paper is read for China 2H) X297 mm 1298999

Therefore, for example, after administration of a high arginine dose, the endothelium-associated vasodilation is transiently improved only in patients with coronary heart disease. Conversely, the importance of the up-regulation of eNOS patients is scientifically linked. Therefore, it has been found that the reductase inhibitor, shnvastatin, can increase eNOS expression in vivo in addition to lipids. Protective properties (Endres et al., pr〇c·deleted Acad

Sd. USA 95 (1998) 8880-8885), also known in the Japanese population, a single point mutation in the 5'-flanking region of the eNOS gene ("eN〇s promoter,") and a decrease in its associated eNOS gene Transcription rate is associated with an increase in risk of coronary sputum (Nakayama et al., Circulation 99 (I"9) 2864_287〇) 〇 Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, so the current hypothesis is the transcription of eNOS regulation And post-transcriptional mechanisms are severely distributed in a variety of diseases, especially in cardiovascular diseases, even in the very early stages of a variety of cardiovascular diseases, can also have such dysfunction in the vascular endothelium leading to the lack of biologically active NO, It shows up to 15 measurable pathological and morphological changes in disease development, therefore, an important stage in early atherogenesis is accelerated reduction of endothelial NO release, such as low-density lipoprotein lipid oxidation, in endothelium mononuclear cells The recruitment and deposition, and the proliferation of endothelium cells, the formation of atheroma is the formation of patches in the blood vessels, which can reduce shear stress A further 20 steps to reduce endothelial NO release and further worsen pathology, because endothelium is also a dilating agent, and its reduction often leads to hypertension, which can become an independent risk factor and cause further organ damage. The medical goal of the disease is to terminate this chain of events by increasing the release of endothelial NO. In the in vitro test of gene transfer, the paper scale is applicable to China National Standard (CNS) A4 (210X297 mm) 1298999 A7 B7 V. DESCRIPTION OF THE INVENTION (5) 15 Excessive release of NO synthetase in previously injured blood vessels is in fact resistant to the above development and is therefore a proof of the correctness of this trend (Varenne et Hum. Gene Ther 11 (2000) 1329). It is revealed in the literature that some low molecular weight compounds can cause direct effects on the transcription and expression of eNOS in cell culture fluids, but the statins that have been mentioned are currently the only side effects in vivo to increase this eNOS. Substance, but from the known range of side effects of such substances, do not understand the dose that does not cause problems in toxicology Liao et al., WO 99/47153 and WO 00/03746 disclose that rhoGTPase inhibitors and agents that affect the tissue action of the actin cytoskeleton are used to increase eNOS in endothelial cells and to treat a variety of diseases. For example, the use of stroke or pulmonary hypertension, but does not indicate a particular way of achieving this use. Therefore, there is a strong need for agents that modulate eNOS expression in endothelial cells, and it is an object of the present invention to provide compounds exhibiting this ability. For this purpose, via the general formula (I), 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine in any of its stereoisomeric forms or in any proportion of mixed cation or A pharmaceutically acceptable salt is achieved. ίPlease read the notes on the back and fill out this page.} Order 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed R1

This paper is suitable for 1~5- 1298999

V. In the above formula, R1 and R4 are each independently selected from the group consisting of the following radicals; unsubstituted and at least monosubstituted CrC1 (r-alkyl, CVCur alkenyl and CrC1 (r alkynyl) a substituent selected from the group consisting of F, hydrazine H, CKV alkoxy, (crC8-alkyl) fluorenyl, 5 CN, COOR6, CONR7R8, and unsubstituted and at least monosubstituted phenyl and heteroaryl groups, The substituent is selected from the group consisting of a fluorenyl group, a pseudohalo group, a cvcv alkyl group, a CrCr system group, and a CF3 group; an unsubstituted group and at least a monosubstituted group and a heteroaryl group, the substituents being selected from the group consisting of Halogen, C1_C3_alkyl, CrCr alkoxy and CF3; R9CO; CONKER11; COCWR^10; CF3; halo; pseudohalyl; NR13R14; 〇R15; S(〇)mR16; S02NR17R18; and n〇2; And R3 are each independently selected from the group consisting of: H; halo; pseudo-yl; unsubstituted and at least monosubstituted crc1 (ralkyl, the substituent of which is selected from the group consisting of hydrazine H, phenyl and heteroaryl ;〇H ; CrC1 (r alkoxy; phenoxy; 15 S(0)mR19 ; Cf3 ; CN ; N〇2 ; (CrCi〇)alkyl;

Alkyl, (crC6-alkyl)_CONH-; unsubstituted and at least monosubstituted phenyl-CONH- and phenyl-SOrO-, the substituents of which are selected from the group consisting of halo, pseudohalo, CH3 and methoxy; (Cr(V alkyl)SCV〇_; unsubstituted and at least monosubstituted alkyl)CO, the substituent of which is selected from the group consisting of F, di(CVCr alkyl)amine groups, Pyrrolidinyl and hexahydropyridinyl; and phenyl-CO, the phenyl moiety of which may be substituted with one or more substituents selected from the group consisting of alkyl, halo and methoxy; A is selected from the group consisting of CH2 CHOH and CH-(CrC3_alkyl); B is selected from the group consisting of CH2 and CH-(CrCr alkyl); (Please read the back of the note first and then fill out this page) - Order · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298999 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Β7 Β7 V. Invention Description (r) C independently has the same definition of B; D independently has the same definition of b; R5 is At base or Hetar base, Both may be unsubstituted or carry one or more substituents selected from the group consisting of: a functional group; a pseudo il group; NH2; an unsubstituted and less than 5 early substituted Ci-Ci 〇-alkyl group, C2-C10- dilute a group, a C2_Ci〇- fast radical, a Ci_Cl〇-alkoxy group, a (Cl-ClQ-alkyl) amine group, a bis(Cl-ClQ-alkyl) amine group, the substituents being selected from the group consisting of F, OH, CrC8-alkoxy, aryloxy, (Cr Q-alkyl) fluorenyl, NH2, (CrC8-alkyl)amino group and bis((^-(:8-alkyl)amino group; CrCV dialkyl; Phenyl; heteroaryl: aryl- or heteroaryl-substituted 10-Ci_C4-alkyl; CF3; N02; 0H; phenoxy; oxy group; (Cl-c1(r-alkyl)COO; S( 0) mR2G; SH; phenylamino group; benzylamino group; (Crc1 (r-alkyl) CONH-; (CrC1 (r-alkyl)_CON(CrC4-alkyl)-; phenyl-CONH-; phenyl -CON(CrC4-alkyl)-;heteroaryl_c〇NH_ ;heteroaryl-CON(CrC4-alkyl)-;(CrC1(ralkyl)-C0;phenyl-CO 15 ;heteroaryl <0;0?3<:0;-0(:1120-;-€〇^0-;- och2ch2o- ; .ch2ch2o- ; COOR21 ; conr22r23 ; cnh_2) ·,so2nr24r2,r26so__ ; R27S〇2N(Ca And a saturated or at least monounsaturated aliphatic mononuclear 5- to 7-membered heterocyclic group selected from hetero atoms including N, 0 and s, which may be One or more selected from the group consisting of _ group, Crcr alkyl group, crC3-alkoxy group, 0H, hydrazine and CF3 a base substitution wherein the heterocyclic group can be condensed to the Ar group or the Hetar group as desired; wherein all of the aryl group, heteroaryl phenyl aryl group, heteroaryl group, and phenyl group-containing group are optionally present In the substituent of the "based" or the Hetar group, one or more of the substituents may be selected from the national standard (CN-S_) A Na (210χ297$ (please read the back of the note first) Page). "ml clothing · order 1298999 A7

Substituted by a base group, a fluorenyl group, a CrCr group, an OH group, a hydroxy group, an OH group, a hydroxy group, and a cf3 group; and R is selected from the group consisting of: H; crc1 (r alkyl group, which may be selected from one or more selected from the group consisting of F and CrCr Substituted with alkoxy and di(Ci-Cralkyl)amino groups; 5 aryl-(CrCV alkyl) and heteroaryl-(CrCr alkyl), which may be selected from one or more selected from the group consisting of halo groups, Substituted by a substituent of a CVQ-alkoxy group and a di(CrC6-alkyl)amino group; R7 is selected from the group consisting of: hydrazine; CrC1 (ralkyl group, which may be selected from one or more selected from the group consisting of F, CrCr alkoxy groups) a bis(Cl_Cr alkyl)amino group and a substituent of a phenyl group; a phenyl group; a hydroquinone group and a heteroaryl group; and wherein each of the above aromatic groups may be unsubstituted or have one or more selected from the group consisting of a halo, a pyridyl, a crc3-alkyl, a Q-CV alkoxy group and a substituent of cf3; R8 is an anthracene or a CpCur alkyl group; and R9 is selected from the group consisting of: CrC1 (ralkyl, which may be unsubstituted or With one or more substituents selected from the group consisting of F, CrC4-alkoxy, bis(CrC3-alkyl)amine; and unsubstituted and at least monosubstituted phenyl and heteroaryl, substituted The base is selected from the group consisting of CrCr alkyl, CrCr alkoxy, halo, and pseudo Quito CFa/, 'R10 independently has the same definition as R7; 20 R11 independently has the same definition as R8; R12 independently has the same definition as R6; R13 is selected from: Η; CrC6-alkyl; Unsubstituted and substituted phenyl, benzyl, heteroaryl, (CrC6-alkyl)-CO, phenyl-CO and heteroaryl-CO, the substituents of which are selected from the group consisting of halo, pseudohalo ,CrCr alkyl, ~8~ This paper scale is applicable to China National Standard (CNS > A4 specification (210X297 mm) 1· i I LI III n II (please read the back note before filling this page), 11 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed • mn 1298999 A7

=-cr oxime and cf3, and the scent thereof can be bribed in _ 这些. These substituents R independently have the same definition as R13; R15 is selected from the group consisting of: Η; Cl-Cl0-hospital; (CpCr alkoxy a Ci_Cr 5 alkyl group; and a substituted or unsubstituted indolyl group, a phenyl group and a heteroaryl group, the substituents being selected from the group consisting of a halogen group, a pseudo-, an oxy group and a CF3, and one or more of which may be present And a substituent selected from the group consisting of: CrC10-alkyl, which may be selected from one or more selected from the group consisting of F, OH, CrC8. alkoxy, aryloxy, (QQ-alkyl) fluorenyl, Substituted by a substituent of a Cr 10 alkyl)amino group and a bis(CrCr alkyl)amine group; CF^; and a substituted or unsubstituted phenyl group and a heteroaryl group, the substituent of which is selected from the group consisting of a halogen group and a dummy Halo, CrCr alkyl, CrCy alkoxy and CF3, and wherein one or more of these substituents may be present; R17 independently has the same definition as R7; 15 R18 independently has the same definition as R8; The ground has the same definition as R16; R2G independently has the same definition as R16; R21 independently has the same definition as R6; · R22 independently has the same R7 Definitions; 20 R23 independently have the same definition as R8; Ministry of Economic Intelligence Intellectual Property Officer R24 independently has the same definition as R7; R25 independently has the same definition as R8; R26 independently has the same definition as R16; R27 is independent The ground has the same definition as R16; 1298999

a heteroaryl group is a 5- to 10-membered aromatic- or bicyclic ring containing one or more heterocyclic groups selected from hetero atoms including n, 0 and 8;

Hetar-based 疋5_ to 1G_membered aromatic mono- or bicyclic-containing or a plurality of heterocyclic groups selected from hetero atoms including n, fluorene and 8; 5 aryl fluorenyl, naphthalen-1-yl or Naphthalene_2-based;

The Ar group is phenyl, naphthalen-1-yl or naphthyl; m is 0, 1 or 2. In (I) a compound towel, if a group or a substituent such as a silk, a heteroaryl group or a burnt group is present exclusively for several times, all of them have the above-mentioned definitions independently of each other and thus, in each independent case, each other The same or different, one example is a di(Crc1(r alkyl)amine group wherein the alkyl substituents may be the same or different. The alkyl, alkenyl and alkynyl groups may be straight or branched, acyclic or cyclic This can also be applied when it is part of another group, such as in an alkoxy group, a pyridyl group or an amine group, or when it is substituted. Examples of 15 alkyl groups are methyl, ethyl, Propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl and the normal isomers of these groups, isopropyl, isobutyl, isopentyl, second butyl, third Butyl, neopentyl, 3,3-dimethylhydrazine butyl, 'noun alkyl group also includes cycloalkyl and cycloalkyl-alkyl group containing at least three carbon atoms (alkyl group substituted by cycloalkyl group) Example 20 of the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, all of which may be the same or different via one or more Alkyl substituted, especially methyl substituted, examples of substituted cycloalkyl are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl, and Unless otherwise stated, the term "burning base" also includes unsubstituted base and the Chinese National Standard (CNS) A4 specification (210X297 mm) is applied to the paper size of 〜10~ (please read the notes on the back and fill in the form) This page)

, 1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999

, invention description (days) A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives print a number of substituents such as -, two, three or quaternary or different groups such as square group substitution, in the substituted base, such as aromatic An alkyl group, a lightly alkyl group such as <C1:C3)-alkyl group-OH or an alkoxyalkyl group such as _(CrC3>alkyl group_(Ci CI4··alkyl), the substituent may be present in any The desired position. 5 Examples of dilute and alkynyl groups are ethyl, 1-propenyl, 2-propenyl (dilyl), 2-butyryl, 2-methyl-2-propenyl , 3-methyl-pyridinyl ethynyl, 2-propynyl (flash), 2-butanyl or alkynyl, and the alkenyl group also includes a cycloolefin having at least three carbon atoms. And a cycloalkenyl-alkyl group, a ring of a ring, a cyclohexyl group, a cycloheptenyl group and a cyclooctenyl group, all of which may be one or more The same or different (CVCV alkyl) substitutions, especially by methyl substitution, and unless otherwise stated, the noun alkenyl and alkynyl groups here also include unsubstituted alkenyl and alkynyl groups and one or more Substituents such as one, two, three or four phases Or a different group such as an aryl substituted group, an alkynyl group, a substituted alkenyl group and an alkynyl group, for example, an aralkenyl group, a hydroxyalkenyl group such as _(C2_C3)-alkenyl group 0H or an alkoxylated alkene group. The substituent may be present at any desired position, for example. An example of a Crcr alkanediyl group is seven h2CH2CH2'_CH2CH ((:HJ_, _ch2ch2ch2ch2_a_ch2ch2ch2oi2ch2_yl. '20) Unless otherwise stated, the above phenyl, naphthyl and hydroquinone groups and heterocyclic groups (including heteroaryl groups) may be Unsubstituted or having one or more substituents such as one, one, two or four, as defined above, at any desired position, if the nitro group may be present as a substituent in the compound of formula (I), a total of at most two The nitro group is preferably present in the molecule. In the monosubstituted phenyl group, the substituent is ~11~. The paper size is universal. The national standard (CNS) A4 specification (210x297 cm) (please read the back note first) Fill in the book 贳) 1298999, invention description (/6 10 15 20 can be in the 2-position, 3-position or 4-position, in the disubstituted phenyl, the substituent can be in the 2,3-position, 2 , 4-position, 2,5-position, 2,6-position, 3,4_ position or 3,5-position, in a trisubstituted phenyl group, the substituent may be in the 2;4_ position, 2,3,5 - position, 2, 3, 6-position, 2, 4, 5-position, 2, 4, 6-position or 3, 4, 5-position, in a tetra-substituted phenyl group, the substituent may be 2,3,4,5_position, 2,3,4,6-position or 2,3,5,6-position, tolyl (=methylphenyl) may be 2-tolyl, 3·tolyl Or 4-tolyl, naphthyl may be 丨-tea or anthranyl, in the monosubstituted 1-naphthyl, the substituent may be in the oxime position, the 3 _ position, the 4 _ position, the 5-position, the 6-position , 7-position or position, in the monosubstituted 2-naphthyl group, the substituent may be in the μ position, the 3_ position, the 4_ position, the 5-position, the 6-position, the 7-position or the 8-position, In the high-substituted scent, such as 1-naphthyl or 2-naphthyl, it may have two or three substitutions. Substituents may also be used in all possible assays, including hydrogen nodal groups and hydrogen. a private group which may be unsubstituted or substituted with one or more of the substituents described, and where a hydroquinone is substituted, the substituent or group of substituents may be at any possible position. And the following definitions apply equally to divalent phenyl, base and heteroaryl groups which may be attached to the phase group via any ring carbon atom, in the case of phenyl groups, which may be in the I, 2 position (o-phenyl), position ( - the position of the phenyl group (p-phenylene), in the case of a naphthyl group, the free bond may be at (=1, 2-naphthyl or naphthyl) or at position, 14_ position η =, (d) set, position, (four) set, called stand, ice position or, 7-position, in a 5-a-membered ring aryl group containing a hetero atom such as singular or 吱-12- (CNS) (21〇X297^jft) (Please read the notes on the back and fill out this page) Order - 1298999 A7 ~~ ---~ -- B7 _ V. Invention Description (") ;~ -

In the case of whispering, the two free keys can be in the 2, 3_ position, 2, 4_ position, A position or 3, 4- position, and the divalent group derived from the bite can be 2, 3, 2, 4_, 2>, 2,6' 3,4_ or 3,5-acridinediyl, in the case of asymmetric divalent groups

In the present invention, the present invention includes all positions of isomers, that is, for example, in H 5 , which includes a compound in which one adjacent group is present at the 2_ position and the other phase (4) is present at 3_. The position, as well as one of the adjacent groups of the compound, is present at the 3_ position and the other adjacent groups are present at the 2_ position. a ring formed by a non-additional group, a sulfhydryl group, an anomer, a heterocyclic group, and a two group bonded to the nitrogen via a bond 10, preferably derived from a heterocyclic ring having the same or different one, two, three or four a hetero atom; more preferably derived from a heterocyclic ring containing one, two or three, especially one or two identical or different heteroatoms, unless otherwise stated, the heterocyclic ring may be monocyclic or polycyclic, for example, monocyclic, a ring or a tricyclic ring, which is a parent or a monocyclic ring or a bicyclic ring, and the ring is preferably a 5-membered ring, a 6-membered ring or a 15-membered ring, and can be derived from a single ring of a group present in the compound of the formula (I). And the bicyclic heterocyclic system is a batch of 11 each, 吱 喧, 喧 、, 味 吼, 吼 sal, 1 1 1 ϋ sitting, 1,2,4- 嗤, 1,3-dioxolane , ι, 3_ υ 嗤 (= 11 〇 sitting), 1 崎 唾 (= isoxazole), 1,3-thiazole (= thiazole), a thiazole isothiazole), tetrazole, pyridine, sorghum, pyrimidine, Pyridin, pyran, thiopyran, hydrazine, 4_dioxo 20 芑, 12-mouth ploughing, 1,3-mouth ploughing, 1, 'slogan ploughing, 1,2 _ ti, ι, 3- Thiol, 1,4-σ plug well, 1, 2, 3-two wells, 1, 2, 4_ three wells, 1, 3, 5 - three π wells, 1 2,4,5-four spray, aggonine, 1,2-dioxine, 1,3-dioxine, dioxin, 1,3: aglyin, I, 3-嗔吖Geng, 吲哚, stupid and thiophene, stupid and furan, benzothiazole, benzimidazole, benzodioxolane, oxime, isoindole~13~ This paper scale is applicable to China National Standard (CNS) Α4 Specifications (210Χ297 mm) (Please read the notes on the back and fill out this page) 4 Port Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298999

The Intellectual Property Office of the Intellectual Property Department of the Ministry of Economic Affairs prints 4 materials, 4 ah, materials, 并 并 、, 18_笑 bite and other private, narration or quotation, its form 5, each form is known and compared, In this context, the formula = "heteroaryl", including the bicyclic group, wherein both rings are known and the two ring groups are only - the ring is aromatic, independently, the same applies to nouns respectively. Ar-based, or the noun "Hetar-based,", suitable heterocyclic groups include 7 such as saturated heterocyclic sulfhydryl, hexammine, hexahydropurine, oxime and "Ifu" The degree is expressed in its respective definition, and the unsaturated heterocyclic ring may contain, for example, one, two or three double bonds in the ring system, and the 5_ and & member rings may especially be aromatic, and may be derived from these heterocyclic rings. The substituent may be bonded via any suitable carbon atom, and the group derived from the nitrogen heterocycle may have a hydrogen atom or a substituent on the ring nitrogen atom, and the examples include abbreviations, saliva, pyridinium, or Fushun, hexaerythritol, etc., these nitrogen heterocyclic groups may also be attached via a ring nitrogen atom, especially if each heterocyclic group Is bonded to a carbon atom, for example, a thienyl group may be a 2-thienyl group or a 3-thienyl group, a furyl group may be a furyl group or a 3-furyl group, and a pyridyl group may be 2, a pyridyl group, a 3-pyridyl group or 4 Pyridyl, hexahydropyridyl can be 1-hexahydropyridyl (=hexahydropyridyl), indole hexahydropyridinyl, 3-hexahydropyridinyl or 4-hexahydropyridyl, (thio)offos The base may be 2_(bowl) of ruthenyl, 3-(thio)fosfoyl or 4_(thio)fosfosyl (=thiofamidyl), which is derived from 1>thiazole or imidazole via a carbon atom linkage The group may be linked via a 2_ position, a 4_ position or a 5-position. If the heterocyclic group is substituted, it may carry one or more, for example, one or two 15 20

This paper scale applies to China National Standard (CNS > M specification (210 >< 297 mm)

1298999

Description of Invention (/)) 5 10 15 20 Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed, three or four identical or different substituents, substituents in the heterocyclic group may exist in any desired position, for example 2 -Thienyl or 2-furanyl at the 3-position and/or 4-position and/or 5-position, 3-nonyl or 3-meryl at 2-position and/or 4-position and/or 5 - Location, 2-吼. The base is at the 3-position and/or the winter position and/or the 5-position and/or the 6-position, 3-. The pyridine group is at the 23_ position and/or the 4-position and/or the 5-position and/or the 6-position, and the 4_σ ratio is fixed at the 2_ position and/or the 34_ position and/or the 5-position and/or At the 6-position, a suitable I heterocyclic ring may also be present as a quaternary salt of a group oxide or a counter ion containing a chemically acceptable acid. For example, a pyridyl group may be present as a pyridine oxide. The halogen group is fluorine, chlorine, bromine and iodine, and is preferably fluorine or gas. Examples of pseudohalo groups are CN and oxime 3, and preferred pseudohalo groups are cn. The present invention includes all stereoisomeric forms of the compounds of formula (I), the asymmetric centers present in the compounds of formula (I) all having an 8 configuration or an R configuration independently of each other, the invention including all possible pairs of palms a mixture of a construct and a non-palphaliomer and a mixture of two or more stereoisomers, for example, a mixture of palmo isomers and/or non-palphaliomers in all ratios, according to which The compound according to the present invention may exist in a pure form for palmar isomerism, including the left-handed and right-handed enantiomers, the racemic isomer form, and a mixture of two palmier isomers in all ratios. In the case of cis/trans isomers, the invention includes both cis and inverse forms, as well as mixtures of these forms in all ratios, all of which are the subject of the invention; the preparation of each stereoisomer can be carried out via The mixture is isolated by conventional methods, for example via chromatography or crystallization, via the use of stereochemically compatible starting materials for synthesis or via stereoselective synthesis, optionally derivatization (please read the note on the back) Matters then fill out this page) set 45-

1298999, the invention description (/d ^ can be carried out before the separation of the lions, the separation of the domain frequency mixture can be carried out in the stage of the compound of the formula (I) or in the synthesis of the intermediate phase, the invention also includes the formula (I The total interconversion of the compound (4) is, for example, = (s> 2-methyl-3H-benzoxanthic acid (6,7,8,9_tetragas but benzocylidene-6-yl) - guanamine, the present invention also includes its tautomeric form (8) · 2-mercapto-1H-benzo-salicylic acid (6,7,8,9-tetrahydro-benzophene-glycine-6- 10) 20 15 20 20 Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperative Printed If the compound according to formula (I) contains - or more than one acidic or experimental group, Ben, Ming also includes its corresponding pharmaceutical or toxicology The above-mentioned acceptable salts are especially the pharmaceutically usable salts thereof, whereby the compound of the formula 1 containing an acidic group may be present in these groups and may be used as an alkali metal salt, an alkaline earth metal salt or ammonium according to the present invention. For salt use, more specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, diethanolamine or amino acids. A compound of the formula (I) which is a plurality of basic groups, that is, protonatable groups, may be present and may be used in accordance with the invention in its addition to an inorganic or organic acid. Examples of suitable acids include hydrochloric acid. , hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methyl acid, p-toluene, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactase, salicylic acid, benzoic acid, citric acid, propionic acid, Pivalic acid, diethyl acetate, malonic acid, succinic acid, azelaic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotine Acid, citric acid, adipic acid and other acids known to those skilled in the art. If the compound of formula 1 contains both acidic and basic groups in the molecule, the present invention includes, in addition to the above salt forms, internal salts or betaine. (Zwitterionic), each salt according to formula 1 can be obtained from the work of ~16~ This paper scale applies Chinese National Standard (CNS) M specification (2丨〇><297 mm [298999 A7 B7 invention description (/ f) 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print this skill Known conventional methods, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange for other salts, the present invention also includes all salts of the compound of formula (1) due to Low physiological compatibility, not suitable for direct use in medicaments, but can be used, for example, as a chemical reaction or as an intermediate for the preparation of pharmaceutically acceptable salts. The present invention also includes all solvates of the compounds of formula (I), such as hydrates Or an adduct of an alcohol, an active metabolite of a compound of the formula (I), and a derivative and a prodrug of a compound of the formula (I), which comprise a physiologically tolerable and separable group, such as an ester or an anthraquinone. Amines and compounds wherein the N-H group of formula 1 is substituted with an N-alkyl group such as an N-methyl or N-alkenyl group such as N-ethinyl or N-spermine oxime, including in the presence of an N-acid group A pharmaceutically acceptable salt formed on a functional group. The compound of formula (I) is a compound in which one or more of the tombs have the following definitions, and all combinations of preferred substituent definitions are the subject of the invention, with respect to all preferred compounds of formula (I), The invention also includes stereoisomeric forms and mixtures thereof in all ratios, as well as pharmaceutically acceptable salts thereof. In a preferred embodiment of the invention, the substituted bases 1 to 5, A, B, C and D and the aryl and heteroaryl groups of the formula 1 have the following definitions independently of each other, therefore, one or more The substituents R1 to R5, A, B, oxime and oxime may have the preferred definitions, better definitions, further preferred definitions, best definitions, or particularly preferred definitions provided below. R1 is preferably selected from the group consisting of: Η; CrCV alkyl, 〇1_〇: 4_alkane {Please read the back note first and then fill out this page)

1298999

An oxy group; a CF group; a pyridyl group; a (CrQr alkyl group) s(〇)m_; and an unsubstituted and at least monosubstituted phenyl group and a heteroaryl group, the substituents being selected from the group consisting of a halogen group, a pseudo i group, a crcr alkyl group, a Crcr alkoxy group, and cf3, wherein the heteroaryl group is selected from heterocyclic groups including 5 and 6-membered members having one or more selected from 5 hetero atoms including N, 0 and s R1 is more preferably h, i group or crc4-alkyl. R2 is preferably selected from the group consisting of the following groups: _ group; pseudodentate group; and cr C3-alkyl group; R2 is more preferably η. It is selected from the group consisting of hydrazine; halo; pseudohalyl; and cr c3-alkyl; R3 is more preferably hydrazine. 10 R4 is preferably selected from the group consisting of hydrazine; QQ-alkyl, CKV alkoxy; Cf3; _ group; pseudo-yl; (Ci-C4_alkyl)_s(〇)m_; and unsubstituted and at least monosubstituted phenyl and heteroaryl groups, the substituents of which are selected from the group consisting of i groups, a base, a CrCr alkyl group, a CrCr alkoxy group, and a CF3 group, wherein the heteroaryl group is selected from the group consisting of 5- and 6-membered heterocyclic groups containing one or more selected from 15 hetero atoms including anthracene, fluorene, and S; R4 is more preferably H, a functional group or a CrC4-alkyl group. R1 to R4 are each especially H. A is preferably selected from the group consisting of CH^CH〇H; It is preferably Ch2. B, C and D are preferably independently selected from each other including CH2&cH_ch3, more preferably B and C are each CH2 and D is CH2 or CH-CH3; optimum B, C and D20 are CH2. More preferably selected from the group consisting of: an Ar group or a Hetar group, both of which may be unsubstituted or have one or more substituents selected from the group consisting of: CN; ; unsubstituted and at least monosubstituted CrCr alkyl, c2_C8_ dilute, c2 < v block, CrCr alkoxy, (CrC8-alkyl) amine, two ~ 18~ 1298999 A7 B7 V, invention description (,; 7) 10 15 20 The property bureau employee consumption cooperative (Crcr alkyl) amine group, the substituent of which is selected from the group consisting of F, CrC6-alkoxy, phenoxy, (CKV alkyl) Wei, NH2, (CVCV alkyl) amine groups and A (匸1 core 6_alkyl)amino group, C3-C5-carbodienyl; phenyl; heteroaryl: phenyl- or heteroaryl-substituted CrCr alkyl; CF3; OH; phenoxy; Benzyloxy; (crc6-alkyl)COO; s(o)m(crc6-alkyl); s(o)m-phenyl; s(0)m^aryl; SH; phenylamino; benzyl (amino group); (CrC6-alkyl)-CONH-; (CrC6-alkyl)-CON(CrCr alkyl)-; phenyl_CONH-: phenyl-CON(CrC4- Alkyl)-;heteroaryl-CONH-;heteroaryl-CON(CrC4-alkyl)-;(Cl-C6_alkyl)_C0;phenyl-c〇;heteroaryl_CO; CF3-C0 -OCH2O-; -OCF2O-; -OCH2CH2O-;-CH2CH20-; COO(CrC6-alkyl); _CONH2; CONH(CrCV alkyl); -CON(di(CrCV alkyl)); CNH(NH2); -so2nh2; S02NH(CrCV alkyl); -S02NH(phenyl); -S02N(di(CVQ-alkyl)); (CrC6-alkyl)S〇2NH-; (CrC6_alkyl)S02N(CrC6- Alkyl-so2NH-;phenyl-s〇2N (Cl_c6-alkyl; heteroaryl-S〇2NH-; heteroaryl-S〇2N (Cl-c6-alkyl; and saturated or The at least monounsaturated aliphatic mononuclear 5- to 7-member has 1 to 3 heterocyclic groups selected from hetero atoms including N, hydrazine and s, and the heterocyclic group may be selected from one or more Substituting a substituent of a CrCr-alkyl group, a CrCr alkoxy group, an OH group, a ketone group, and a CF3, wherein the heterocyclic group may be condensed to the Ar group or the Hetar group as needed; wherein all of the heteroaryl group, the phenyl group, a heteroaryl-containing group and a phenyl group-containing group, which are optionally present in the substituent of the Ar group or the Hetar group, may be selected from one or more selected from the group consisting of a halogen group, a pseudohalo group, a CrCr alkyl group, and an OH group. , CVCr alkane Substituted by substituents of CF3; 19 1298999, invention description (/<P) 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing R5 is preferably selected from the following base phenyl or Hetar base, both They may be unsubstituted or carry one or more substituents selected from the group consisting of halo; CN, NH2; unsubstituted and at least monosubstituted Ci_C6_alkyl, C2_C6-alkenyl, Crc6-alkynyl, CFCr An oxy group, a (rcc4-alkyl)amino group, a bis(Q-C4-alkyl)amine group, the substituent of which is selected from the group consisting of F, Ci_c3_alkoxy, (Crcr alkyl)fluorenyl and NH2; : 3 (5-alkyldiyl; phenyl; heteroaryl: phenyl- or heteroaryl-substituted CrCr alkyl; CF3; OH; (CrC4-alkyl)COO; S(0)m(CrCr-alkane (crc4-alkyl)-CONH-; (cr C4-alkyl KONCCVQ-alkyl)_; (CrC4-alkyl)-CO; phenyl-CO; heteroaryl <:0;3-(:0;-〇〇120;-€0'20-;-〇CH2CH20-;-CH2CH2O-;COO(CrC6-^l.);-conh2;•CONHCCVCr alkyl) BuCON(二(CrC4 _Alkyl)); CNH(NH2); -S02NH2; -S02NH(CrC4-alkyl); -S02NH(phenyl); -S02N(bis(CrC4-alkyl)); (CVCralkyl)S02NH-; ( Cr Q-alkyl)S〇2N(CrCzr alkyl)-; and saturated or at least monounsaturated aliphatic mononuclear 5- to 7-members having 1 to 3 heteroatoms selected from the group consisting of ruthenium, osmium and S a heterocyclic group which may be substituted with one or more substituents selected from the group consisting of a halogen group, a crc3-alkyl group, a Crcr alkoxy group, an OH group, a ketone group and a CF3 group, wherein the heterocyclic group may be condensed as needed To the phenyl group or the Hetar group; wherein all of the heteroaryl group, the phenyl group, the heteroaryl group, and the phenyl group-containing group are optionally present in the substituent of the phenyl group or the Hetar group, One or more substituents selected from the group consisting of halo, pyrenyl, CrC3-alkyl, hydrazine H, CrC3_alkoxy and CFs; R5 is more preferably selected from the group consisting of phenyl or Hetar, Both are not available (please read the notes on the back and then fill out this page) - Order -20~ 1298999 A7 B7 V. Invention Description (/f) (Please read the note on the back and fill out this page) With one or more substituents selected from the group consisting of F; Cl; Br; C "C3-alkyl; CrC3-alkoxycarbonyl; 2-amino-3,3,3-trifluoropropyl- ; CF3 ; C3-C5-calcined diyl; phenyl; heteroaryl Octyl; heteroaryl-methyl; OH; CrC3, alkoxy; phenoxy; trifluoromethoxy; 2,2,2-5 trifluoroethoxy; (Cr(V alkyl)COO; (CrCr alkyl)fluorenyl; phenylfluorenyl; (CrCr alkyl)sulfonyl; phenylsulfonyl; NH2; (CrC4-alkyl)amine; bis(CrC4-alkyl)amine; (CrC3- Alkyl)-CONH-; (Cr c3-alkyl)-so2nh-; (CVC3-alkyl)-CO; phenyl-<:0;-00120-;-0CF20-;-CH2CH20-; COO(CrC4 -alkyl); -CONH2; -10 CONH(CrC4-alkyl); -CON(di(CrC4-alkyl)); CN;-S02NH2; -S02NH(CrC4_alkyl); -S02N(di(CrCr) Alkyl)); pyrrolidinyl; hexahydropyridinyl; fenofyl; and thiofolf group; all of which are heteroaryl, phenyl, heteroaryl-containing, and phenyl-containing groups, as needed The substituent present in the phenyl group or the Hetar group may be selected from one or more substituents including i group, pseudohalo group, crc3-alkyl group, OH, crc3-alkoxy group and CF3. Replaced; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed R5 is most preferably selected from the following groups: 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-(CrCV alkoxy)-phenyl 4 -trifluoromethoxyphenyl, 2-bromo{fluorophenyl, 2-chlorofluorophenyl, 3,4-dimethylphenyl, 2,4-diindolyl-2-methyl Phenyl, 2·trans)-4-methylphenyl, 2-carbyl"4-ethoxyphenyl, 2-methoxy- ice methylphenyl, 4-phenoxyphenyl, 3_ Fluorine_4_methylphenyl, benzo[1,3]dioxolan-5-yl, 2,2-difluoro-benzo[I,3]dioxolan-5, 2,3 _Diazolobenzoate, 1-(4-chloro-phenyl)-5-trifluoromethyl-1Η-σ-bisazolyl, 1-(4-fluoro-phenyl)-3,5-dimethyl- 1H-pyrazole_4_yl~21~ This paper is suitable for China's solid sample rate (cns) from the threat (21 (^297 mm) 1298999 Α7 Β7 5, invention description (VO), 1H-benzotriazole- 5-yl, 1HH4-yl, fluorenyl, 1-isopropyl-2-trifluoromethyl-1H-benzimidazol-5-yl, 1-methyl-3-carbonyl-1 2,3,4-tetrahydro-mouth quinalin-6-yl, 1-phenyl-5-trifluorodecyl]. Sitting on a 4-base, 2-(2-carbidyl-4-yl)-1Η-benzoxan-5-yl, 2-(4-cyano-5phenyl)-1Η-benzopyrene -5-yl, 2,4-dimethyl-o-tr tr--5-yl, 2,4-dimercapto-indolyl-5-yl, 2,4-diindenyl H5-yl, 2, 5-dimethyl-1H-^-r--3-yl, 2,5-dimercapto-1-phenyl-1H-pyrrole; benzyl, 2,5-dimercapto-1-0 ratio -4- Base methyl-1Η-ϋ ratio 17 groups, 2,5-dimercaptoyl group, 2,6-diox ratio °-3-yl, 2,6-dimethoxy group 2,6-dimethyl 10 base ratio -3-yl, 2-amino-4,6-dimercapto-bite '3-yl, 2-amino-6-gas-0 ratio -3- Base, 2-amino group than indole-3-yl, 2-chloro-6-methyl-indol-3-yl, 2 • gas ratio 4-yl, 2-cyclopropyl-4-hydrazino Sputum-5-yl, 2-diaminoamino-4-mercapto-17-secen-5-yl, 2-dimethylamino-indole-4-yl, 2-ethyl-5-methyl -2H-pyrazol-3-yl, 2-hydroxy-6-methyl:pyridin-3-yl, 2-methyl-1H-15 benzimidazol-5-yl, 2-methyl-3H-benzo Imidazol-5-yl, 2-methyl-pyridine-3-yl, 2-methyl-6-trifluoromethyl-pyridin-3-yl, 2-methyl-thiazol-5-yl, 2-fo咐-4-yl-吼11 1,4--4-yl, 2-folf-4-yl---------------------- Ralidine-1-yl-pyridyl ice group, 3,5-dimethyl-1Η-pyrazole ice group, 3-amino-5,6-dimethyl-17 ratio σ well-2-yl, 3- Amino-5-methyl-port ratio well-2-yl, 3-amino-20 pyridin-2-yl, 3-dimethylamino-4-methyl-phenyl, 3-dimethylamine Base-phenyl, 3Η-benzimidazol-5-yl, 1Η-benzimidazol-5-yl, 3-methanesulfonylamino-2-methyl-phenyl, 3-methanesulfonylamino Phenyl, 3-methyl-isoxazole-4-yl, 3-fosfos-4-yl-phenyl, 3-hexahydropyridin-1-yl-phenyl, 3-pyrrolidinyl-benzene Base, 4-(2,2,2-trifluoro-ethoxy)-phenyl, 4,6-dimethyl-~22~ This paper scale applies to Chinese National Standard (CNS) Α4 specification (210Χ297 mm) (Please read the notes on the back and fill out this page.) Order · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298999 A7 B7 V. Description of Invention (v) Acridine-3-yl, 4-Amino-2-B Sulfonamide-sulfonyl-5-yl, 4-amino-2-methylpyridin-5-yl, 4-chloro-3-indane pyridinyl-phenyl, 4_gas_3_amine sulfonate Mercapto-phenyl, 4-methyl-3-methylamino-phenyl, 4-methyl-thiazolyl, octyl-2-yl, 5,6, 7,8-tetrahydro-π-quinone, 5-aminophenyl·ιη_ 5 pyrazolyl, 5-methanesulfonyl-2-methyl-phenyl, 5-methyl-hydrazine-phenyl _ 1Η-吼. Sitting on ice base, 5-methyl-iso-spin _3_ base, 5-methyl-π ratio _3-based 5-mercapto-pyrylene-2-yl, 6-a-pyridin-3-yl , 6-cyano-pyridine-3-yl, 6-dimethylamino-pyridine-3-yl, 6-ethynyl-π-pyridyl-3-yl, 6-methoxymethyl-pyridine-3- ,6-methoxy-pyridin-3-yl, 6-methyl-2-methylamino-pyridyl10--3-yl, 6-methylamino-pyridin-2-yl, 6· Mercapto_pyridine_3_yl, bupufeptin-4-yl-pyridin-3-yl, 6-pyrrolidine-μ-yl-acridine-3-yl, imidazo[1,2-a]pyrene -2-yl, 6_trimethylmethyl is more than 唆_3_ group and mouth biting _4_ group. The heteroaryl group is preferably a 5- to 10-membered aromatic mono- or bicyclic ring containing one, one or three ring members selected from hetero atoms including anthracene, fluorene and S; the heteroaryl group is preferably selected from 15 The following radicals are included: furyl, pyrrolyl, thienyl, thiazolyl, isothiazinyl, indolyl, isoindolyl, pyrazolyl, imidazolyl, indole. Well base, outer 匕 u well base, bite base, shouting base, benzopyrene, benzoxanthene, benzoxanthyl, 4 fluorenyl, isodecyl, 喳nfu , oxazolidine, pterido, benzoxanthyl, benzophenylthio, and stilbene. The Hetar group is preferably a 5- to 10-membered aromatic mono- or bicyclic ring containing one or two or more heterocyclic groups selected from hetero atoms including anthracene, fluorene and S; the Hetar group is preferably selected from the group consisting of Including the following groups: furanyl, pyrrolyl, thienyl, fluorenyl, isothiophene, oxazolyl, isoxazolyl, pyrazolyl, oxazolyl, sulphonyl, fluorenyl, pyridyl, Pyrimidinyl, benzimidazolyl, benzoxazolyl ~23~ This paper scale is applicable to China National Pharmaceutical Corporation (CNS) VIII 4 threat (210X297 mm f (please read the back note before filling this page) Ministry of the New Economics Intellectual Property Bureau employee consumption cooperative printed 1298999

V. INSTRUCTIONS (>Λ) 10 15 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, benzoxazolyl, porphyrinyl, isoindolinyl, porphyrinyl, oxazolyl, hydrazine Base, benzofuranyl, benzothiazepine, and carbazolyl. The aryl group is preferably a phenyl group. m is preferably 0 or 2. It is also the subject of the invention that some or all of the abovementioned compounds of the formula (I) have a preferred definition, a better definition, a further definition, a best definition, or a particularly preferred definition of the above definition. According to the most preferred compound of formula (I), in any of its stereoisomeric forms or mixtures thereof in any ratio or in pharmaceutically acceptable salts, h is selected from the group consisting of: 1 '疋2,5_2 Methyl-1-anthracene-based methyl-1H-pyrrolecarboxylic acid (6,7,8,9_tetraindole benzophenone)-decylamine, 5-methyl+phenyl ♦ Each-renewed acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-decylamine, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -5H-benzocycloheptene each)__, 5-methyl-oxime + 2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene_6_yl)_醯Amine 2 comparable to 3H-benzoxanthene-5- Lai (6,7,8 fine hydrogen red cycloheptylamine, 2-methyl-1H-benzopyrene_5. Paper 7,8,9 _ four gas benzocycloheptene each base) - guanamine, 2-amino-6-gas | (6,7, lingsiqi_ _ benzo & heptene-6-yl)-nicotine 醯Amine, ν·(6,7,8,9-tetrahydro-5Η-benzocycloheptenyl) ice (2,2>trifluoro-ethoxy)_indolylamine, &pyrrole bite I (6,7,8,9-tetrahydro-5H-benzocycloheptene)-Nicotine decylamine, benzylaminomethylamino-N-(6,7,8,9 hydrogen-evil Benzocycloheptanylamine, 3-amino-5,6.dimethyl-4-shirt_(6,7,8,9,hydrogen|benzoxene | Base) over amine, 4|Ν_(6,7,8,9, hydrogen as stupid and cycloheptene ^ -24 - This paper uses Zhongguanjia standard (CNS) eight 4 threat (21GX297 mm (please read the back first) Note on this page)

V. Description of invention (>3) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999 base) 4-brown amine, > bite each bite!! ϋ (6,7,8 fine hydrogen benzocycloheptene Base)-octylamine, 2,4-dimethyl+salveric acid (6,7,8,_nitrogen_5H1 benzocycloheptyl)>_, 2_amino group-team (6, 7,8,9-tetrahydrox-benzocycloheptene-6-yl)-in accordance with the amine, 2,b dimethyl*(6,7,8,9-tetranitro-5 5H-benzo Cycloheptane 4-based final test guanamine, 3-amino _5· fluorenyl ton than ton winter carboxylic acid (6,7 yarn tetrahydrogen-benzocyclohepta-diyl)-amine, and (tetra)- Pyrite well 1 is a slow acid (6,7,8,9-tetrahydroisophenyl benzene along a hydrazine). In another embodiment of the invention, the substituent according to formula 1 and even R, A, B, C and D, and aryl and heteroaryl have the following definitions: 1 〇 R1 and R4 are each independently selected from the group consisting of H; unsubstituted and at least monosubstituted CrC1 (r: ^, C2_C1 (r alkenyl and c2_C1 (r alkynyl, the substituent of which is selected from the group consisting of F, OH, crc6-alkoxy, (Crc6-alkyl)), CN, COOR6, c〇NR7R8, unsubstituted and At least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of a base, a pyridyl group, a Ci_C3_alkanyl group, a Ci-Cr alkoxy group and a CF3 group; an unsubstituted and at least monosubstituted phenyl group and a heteroaryl group, the substituent of which is selected from the group consisting of a halogen group and a pseudohalo group , CrCr alkyl, Q-C3-aerobic and CF3; R9CO; conrWr11; COOR12; CF3; halo; pseudohalo; ΝρΠρΗ; 〇R15; s(〇)mRl6; so2nr17r18 ; ^n〇2 ; m, 20 r 2 and R 3 are each independently selected from the group consisting of the following groups: H-group; a pseudodentate group; an unsubstituted and at least mono-substituted Cl_C6-alkyl group, the substituents of which are selected from the group consisting of OH, phenyl and heteroaryl (0); (^("alkoxy; phenoxy; S(〇)mR19; CF3; CN; N02; (C"C6-alkyl)amine; bis(CrC6-alkyl)amine; Ci-C6-alkyl)-CONH-; unsubstituted and at least single ~25~ This paper is applicable to China National Standard (CNS) 八4 threat (21〇χ297 public sauce) (please read the notes on the back first) Fill in this page)

1298999 A7

The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers’ Cooperatives, printed the substitutes _CONH and phenyl-SOr〇. The substituents were selected from the group consisting of halo, pseudodentate, ch3 and methoxy; ((:κν·) Δ〇2_α ; unsubstituted and at least monosubstituted (Q-CV alkyl) C0, the substituents of which are selected from the group consisting of F, bis(CrCr alkyl)amine, pyrrolidinyl and hexahydropyridyl; 5 yl-C0, the phenyl moiety thereof may be substituted by one or more substituents selected from the group consisting of CrCr alkyl, halo and methoxy; A is selected from the group consisting of CH2, CHOH and CH-(CVCr) B is selected from the group consisting of CH2 and CH-(CrCr); C independently has the same definition as B; 10 D independently has the same definition as B; R5 is an aryl or heteroaryl group, which may be Substituted or substituted with one or more substituents selected from the group consisting of: halo; pseudo-yl; CrC1 (r-alkyl; crC5-carbolyl'phenyl; phenyl-substituted CrCr alkyl; CF3; OH; CrC1 ( r alkoxy; phenoxy; benzyloxy; CF30: (CrC1G-alkyl)COO; 15 S(0)mR20; (crci(r)alkyl; di(crc1(r)) ;(cr

Ci〇-alkyl)CONH- ; (Ci-Cig-alkyl)-CON(CrC3-alkyl)-; (C!_ C1(r alkyl)-CO ; CF3-CO ; -OCH20 ;-〇CF2 〇 _ och2ch2o-bch2ch2o-; phenylamino group · phenyl-co · · c〇OR2i; conr22r23; S〇2NR24R25; and aromatic or aliphatic mononuclear 5_ to 7 item 20 with 1 to 3 a heterocyclic group selected from the group consisting of a hetero atom of ruthenium, osmium and S, which may be substituted by one or more substituents selected from the group consisting of a ketone group, a Crcr alkyl group, a CrC3-alkoxy group and a cf3 group, wherein all phenyl groups and a phenyl-containing group which is optionally present in the aryl group or the substituent of the heteroaryl group, which may be selected from one or more selected from the group consisting of halo, pseudohalo, C1-C3-alkyl, C1- C3-alkoxy and cf3 substitution ~26~ This paper scale applies to China National Standard (CNS) 8.4 4 grid (210X297 mm) {Please read the back note first and then fill out this page)

A7

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999 base substitution; R疋H, C!-C6_alkyl or noon; R is selected from: Η; CrCV alkyl, which can be substituted by phenyl; phenyl , hydroquinone and heteroaryl; and wherein each of the above aromatic groups may be unsubstituted or have one or more substituents selected from the group consisting of a hydrazino group, a pseudo i group, a CrCr alkyl group, a CrC3-alkoxy group, and a CF3 group. R or a Ci_C6-alkyl group; R is a CrCV alkyl group which may be unsubstituted or carry one or more substituents selected from the group consisting of F, a di(CrQ-alkyl)amine group; Substituted with less than 10 monosubstituted phenyl and heteroaryl groups, the substituents are selected from the group consisting of CrC=alkyl, crc3-alkoxy, halo, pseudohalo and cf3;

RlG independently has the same definition as R7; R11 independently has the same definition as R8; R12 independently has the same definition as R6; 15 R疋 is selected from the group consisting of Η, Ci-CV alkyl; and unsubstituted and Substituted phenyl, benzyl, heteroaryl, phenyl-CO, and heteroaryl-CO, the substituents of which are selected from the group consisting of halo, pseudohalo, CrCr alkyl, crCr alkoxy and CF3, And wherein one or more of these substituents may be present; R14 is hydrazine or CrC6-alkyl; 20 R is selected from the group consisting of: hydrazine; CpCV alkyl; and substituted and unsubstituted benzyl, phenyl and heteroaryl a substituent selected from the group consisting of a halogen group, a pseudohalo group, a C1-C3-alkyl group, a C1-C3-alkoxy group, and a CF3 group, wherein one or more of these substituents may be present; R16 is selected from the group consisting of :CrCV burnt base; CF3; and substituted and unsubstituted ~27~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the back note first and then fill in this page)

1298999 5. The present invention and heteroaryl group of the invention (V), the substituents of which are selected from the group consisting of a hydrazino group, a pseudohalo-Crcr alkyl group, a Crcr-laboxy group and a CF3, and wherein one or more of these substituents may be present R17 independently has the same definition as R7; 5 R18 independently has the same definition as R8; R19 independently has the same definition as R16; R2G independently has the same definition as R16; R21 independently has the same R6 Definitions; R22 independently have the same definition as R7; 10 R23 independently has the same definition as R8; R24 independently has the same definition as R7; R25 independently has the same definition as R8; heteroaryl is 5- To a 10-membered mono- or bicyclic ring containing one or more aromatic heterocyclic groups selected from heteroatoms including n, fluorene and S; 15 are phenyl, tea-1-yl or tea_2-yl ; m*〇, 1 or 2. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, according to the compound of formula (I), preferably via thiolation of each 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine, followed by re-functionalization as needed The compound thus obtained can be subjected to thiolation by reacting the above amine with 20 acid and a suitable coupling agent such as carbodiimide, HATU or TOTU in the presence of, for example, monoisopropylethylamine. Or, by reacting the above amine with helium using a solvent such as di-methane, THF, toluene or dioxane in the presence of a base such as triethylamine, the thiolation is preferably carried out at room temperature. 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine can be used as an educt ~28~ This paper is applicable from China National Standard (CNS) A4 (210X297 mm) 1298999 A7 B7 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. 5. Description of the invention (>7) Prepared according to the method announced in the literature. Suitable methods for publication are, for example, Vejdelek, ZJ et al9 Collect. Czech. Chem. Commun 39; (1974 2819; Cannon, J. G et al. J. Med. Chem. 23 (1980) 745; Seidl, G. et al. Chem. Ber. 97 (1964) 249; or Lab, B. et al. J. 5 Med. Chem. 15 (1972) 23. The overall reaction for the synthesis of the compound according to formula (I) is known per se and can be carried out according to or similar to the winter method disclosed in the literature, for example in Houben-Weyl, Methoden der Organishchen Chemie (Methods) Of Organic Chemistry), 10 Thieme-Verlag, Stuttgart or Organic Reactions, John Wiley &

Sons, New York, depending on the individual case, in order to prevent side reactions in the synthesis of compounds, it is desirable or desirable to temporarily mask the functional groups by the addition of protecting groups and to remove them during subsequent stages of synthesis. , or a functional group in the form of a precursor, which is converted to 15 desired functional groups in a subsequent reaction step, suitable for use in each of these synthetic strategies and protecting groups and precursor groups are known to the artist, if desired The compound of formula 1 can be purified via a purification method for mussels, for example, by recrystallization or chromatography. The starting compound for the preparation of the compound of formula (I) is commercially available or can be based on or similar to the literature. The preparation of the method disclosed herein, the compound obtained by the above synthesis of green 20, is another subject of the present invention. WO 00/5197G discloses the use of a compound of the formula (11) and for the conversion of cholinergic activity. ' " Z1\ 73 ^^X-Y-Q-Z3 (II) ~29' (Please read the notes on the back and fill out this page)

1T A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298999 V. Invention Description (4) In the above formula: Z and Z are each aryl or aryl (low carbon) alkyl, or together form a low carbon extension A thiol or a low-carbon stretching group, each of which may be substituted by an aryl group or may be condensed with a low-carbon alkyl group, a low-cracking oxy group, an aryl group, an aryloxy group or a cyclic hydrocarbon of 5 generations from the base, if necessary. , Z 疋 low carbon alkyl, low carbon alkoxy, aryl, arylamine or aryloxy, each of which may be substituted by a lower alkoxy or halo group, a pyridyl group, or a pyridylamino group, X is CH or N, 10 Y is a single bond or -NH-, and A曰丨丨Q 疋-C-: For the definition of Z1 and Z2 in formula (II), the preferred low carbon alkyl group is four A methylene or pentamethylene group, preferably a low carbon fluorenyl group is a butyl group, a pentyl group or a fluorenyl pentenyl group. The preferred cyclic hydrocarbon is benzene and the preferred aryl group is Phenyl. Further, preferred compounds according to formula (II) are those wherein the lower alkylene group formed by Z1 and Z2 may be substituted by an aryl group or, if desired, substituted with a lower alkoxy alkoxide, aryl or arylamine group. The benzene is condensed, Z3 is a pyridyl group, or a pyridyl 20 amine group, each of which can be substituted with a halogen group, X is CH or N, Y is a single bond or · NH-, and Q is f-c. The thiolated 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine of formula (I) is not explicitly disclosed in WO 00/51970, and is clearly defined by WO 00/51970~3〇~

(Please read the notes on the back and fill in the form)

1298999 A7 — -----—.. — B7 V. DESCRIPTION OF THE INVENTION The disclosed compounds are not the subject of the present invention. The domain of the present invention is also derived from the 6,7, mycotetrahydro-5Η-benzoquinonecycloheptenylamine of the formula (I), any stereoisomers thereof and mixtures thereof in any ratio and Accept the use of __light#. R1

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, in which R1 and R4 are each independently selected from the group consisting of unsubstituted and at least monosubstituted CrC1 (r-alkyl, CrC1 (r-alkenyl and Q-Ckt alkynyl) , the substituent is selected from the group consisting of F, OH, CrCr alkoxy, (Cl_C8_alkyl) fluorenyl, 15 CN, COOR6, CONR7R8, and unsubstituted and at least monosubstituted phenyl and heteroaryl, which are substituted The group is selected from the group consisting of a halogen group, a pseudohalo group, a Ci_c3_alkyl group, a CrC3_alkoxy group, and a CF3 group; an unsubstituted and at least monosubstituted phenyl group and a heteroaryl group, and the substituent is selected from the group consisting of a halogen group. , pseudo-based, Ci_c3_ alkyl, CVC3·alkoxy and CF3; R9CO; CONKER11; COOR12 20; CF3; halo; pseudohalo; NR13Rl4; 〇R15; so2nr17r18; and n〇2; R2 and R3 Independently selected from the group consisting of: η; halo; aryl; unsubstituted and at least monosubstituted CrC1 (ralkyl, the substituents of which are selected from the group consisting of hydrazine H, phenyl and heteroaryl; 〇H ; CVCur alkoxy; phenoxy; ~ 31~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1298999 A7

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

S(〇)mR19 ; CF3 ; CN ; N02 ; (CrC10_alkyl)amine; bis(cv C10-alkyl)amine; (CrCV alkyl)CONH-; unsubstituted and at least monosubstituted -CONH- and phenyl-S〇r〇-, the substituents of which are selected from the group consisting of fluorenyl, pseudo-yl, CH3 and decyloxy; (CrC6-alkyl)s〇r〇_; And at least monosubstituted (CrCV alkyl) CO, the substituent of which is selected from the group consisting of F, bis(CrCr alkyl)amine, pyrrolidinyl and hexahydropyridyl; and phenyl-C0, the phenyl moiety The fraction may be substituted with one or more substituents selected from the group consisting of a crcr alkyl group, a halogen group and a methoxy group; A is selected from the group consisting of CH2, CHOH and CH-(CrC3-alkyl); 10 B is selected from the group consisting of CH2 And CH-(CrCr alkyl); C independently has the same definition as B; D independently has the same definition as b; R5 is an Ar group or a Hetar group, both of which may be unsubstituted or have one or more Substituents selected from the group consisting of i-based; pseudo-yl; NH2; unsubstituted and less than 15 monosubstituted CrC1 (r-alkyl, CrC1 (r-alkenyl, CrC1 (r alkynyl, Cr c10-alkoxy, (CVCht alkyl)amino, bis(cvc1(r alkyl)amine group, the substituents of which are selected from the group consisting of F, OH, CrCs Alkoxy, aryloxy, (cr C8-alkyl)indenyl, NH2, (CVCV alkyl)amino and di(CrC8-alkyl)amine; C3-C5-alkanediyl; phenyl; Heteroaryl: aryl- or heteroaryl-substituted 20CrC4-alkyl; CF3; N02; OH; phenoxy; benzyloxy; (Cr C1(r-alkyl)COO; S(0)mR2G; SH; phenylamino; benzylamine; (CVCur alkyl) CONH-; (CrC1(ralkylKX)N(CrC4-alkyl)-; phenyl-CONH-; phenyl-CON (CrCrane Base)-;heteroaryl-CONH-;heteroaryl-CON(CrC4-alkyl)-;(CrC1(r-alkyl)-CO;phenyl-CO~3 2~ This paper scale applies to Chinese national standards ( CNS ) A4 size (21〇X297 mm) (Please read the notes on the back and fill out this page) - Order - Line -

w In nn Hal HI 1298999 A7 B7 Description of invention U/ ) 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 'hybrid square--(3〇,0卩3-€1〇,-〇〇[12〇- ;-〇.卩2〇-;-〇CH2CH2〇. ; -CH2CH20- ; COOR21 ; c〇NR22R23 ; toilet 2); so,r25 ; r26s〇2· ; base)_; and saturated or to less a monounsaturated aliphatic mononuclear oxime to a heterocyclic group selected from the group consisting of a hetero atom including ruthenium, osmium and S, the heterocyclic group may be selected from one or more selected from the group consisting of a functional group, Substitution of a CrCr alkyl group, a CrCr alkoxy group, an OH group, a CF group, and a CF3 group, wherein the heterocyclic group may be condensed to the Ar group or the Hetar group as needed; wherein all of the aryl group, the heteroaryl group, the phenyl group, An aryl group, a heteroaryl group-containing group, and a phenyl group-containing group, which are optionally present in the Ar group or the substituent of the Hetar group, may be selected from one or more selected from the group consisting of a halogen group, a pseudohalo group, and a CVC3. Substituting a substituent of a pyridyl group, an OH group, a CrCroxy group and a cf3; R is selected from the group consisting of ruthenium, CrC1 (r-alkyl group, which may be selected from one or more selected from the group consisting of F, CrCr alkoxy and Substituent substitution of a di(CrCV alkyl)amino group; aryl-(CVCr alkyl) And a heteroaryl-(Q-C4.alkyl) group which may be substituted with one or more substituents selected from the group consisting of a halogen group, a CrCr alkoxy group and a di(CrC6-alkyl)amine group; Including: H; CrC10_alkyl, which may be substituted by one or more substituents selected from the group consisting of F, CrCV alkoxy, bis(CrCr alkyl)amine and phenyl, phenyl; hydroquinone and hetero An aryl group; and wherein each of the above aromatic groups may be unsubstituted or have one or more substituents selected from the group consisting of a ketone group, a ruthenium group, a Ci_c3 group, a CrCr alkoxy group, and a CF3 group; R疋Η or Cl -ClQ-alkyl; R疋 is selected from the group consisting of CrC1 (r-based, which can be unsubstituted or with one or more (please read the back of the note first and then fill out this page)

1298999 A7 B7 V. INSTRUCTIONS 〇) The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints a substituent selected from the group consisting of F, CrC4_alkoxy, bis(Ci_C3_alkyl)amine; and unsubstituted a phenyl group and a heteroaryl group which are at least monosubstituted, the substituents of which are selected from the group consisting of CVQ-alkyl, CrCr alkoxy, halogen 1 pseudohalo and CF3; 5 R1G independently has the same definition as R7; R11 is independent The ground has the same definition as R8; R12 independently has the same definition as R6; R疋 is selected from the group consisting of ·; CrC0-alkyl; unsubstituted and substituted phenyl, ilyl, heteroaryl, CrC6-alkyl KX), phenyl-CO and heteroaryl-10 C0, the substituents of which are selected from the group consisting of halo, pyrenyl, alkyl, CrCr alkoxy and CF3, and one or more of them may be present One such substituent; one R14 independently has the same definition as R13; R15 is selected from the group consisting of: Η; CVC1 (r alkyl; (CrCr alkoxy Krc3-15 alkyl); and substituted and unsubstituted benzyl a phenyl group and a heteroaryl group, the substituent of which is selected from the group consisting of a halogen group, a pseudohalo group, a Cl_Cr alkyl group, a Crc3_ alkoxy group, and a CF3 group, and wherein Wherein one or more of these substituents are present; R疋 is selected from the group consisting of: CrC1 (r-alkyl group, which may be selected from one or more selected from the group consisting of F, OH, CrCr alkoxy, aryloxy, (QQ-alkyl) a substituent of a mercapto group, a (Ci_20 C8-alkyl)amino group and a di(CrCr alkyl)amino group; 〇ρ3; and a substituted or unsubstituted phenyl group and a heteroaryl group, the substituents of which are selected Included from the group consisting of halo, pseudohalo, CrCr alkyl, crcr alkoxy and CF3, and one or more of these substituents may be present; R17 independently has the same definition as R7;

(Please read the note on the back and then fill out this page) Order 1298999 A7 B7 V. Description of invention (93) 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed R18 independently has the same definition as R8; R19 independently Having the same definition as Ri6; R2G independently having the same definition as R16; R21 independently having the same definition as R6; R22 independently having the same definition as R7&gt;23 independently having the same definition as R8 4 independently having Definition 5 identical to R7 independently has the same definition as R8, 6 independently having the same definition as R16; 7 independently having the same definition as R16; heteroaryl is 5- to 10-membered aromatic single- or two The ring contains one or more heterocyclic groups selected from hetero atoms including N, 0 and S; the Hetar group is a 5- to 10-membered aromatic mono- or bicyclic ring containing one or more selected from the group consisting of N, 0 and a heterocyclic group of a hetero atom of S; an aryl group is a phenyl group, a naphthalen-1-yl group or a naphthyl group; an Ar group is a phenyl group, a naphthalene group or a naphthalene-2-yl group; (5) is a ^), 1 or 2 The compound of the formula (I) is used as a pharmaceutical product, wherein one or more of the above-mentioned groups include all of the above-mentioned preferred definitions, and more preferably </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The bases r^r5, A, B, ^^ and the aryl and heteroaryl groups have the following definitions. &gt;24, &gt;25, &gt;26&gt;&gt;27&gt; -35-

(Please read the notes on the back and fill out this page)

1298999 A7 --------____B7_ V. Invention Description &quot; One~~- R1 and R4 are each independently selected from the following bases··H; unsubstituted and at least single, instead of CrC1 (r filament , c2_Cl (r_ &amp; C2_Ci "silk, the substituents are selected from the group consisting of F, 〇H, QQ-alkoxy, (CrCV alkyl) Wei, (3), COOR6, CONR7R8, unsubstituted and at least monosubstituted benzene The substituents of the group 5 and the heteroaryl group are selected from the group consisting of a halogen group, a pseudohalo group, a CrC3-alkyl group, a CrCV alkoxy group and a CF3 group; an unsubstituted and at least monosubstituted phenyl group and a heteroaryl group, which are substituted The base is selected from the group consisting of a dentate group, a pseudo-based group, a CpCr alkyl group, a C!_croxy group, and a CF3; R9CO; CONKER11; COOR12; CF3; a halogen group; a dummy _*; NR13R14; 〇R15; 16·10 S02NR17r18; And m' R2 and R3 are each independently selected from the group consisting of hydrazine; dentate; pseudohalo, unsubstituted and at least monosubstituted iCVCV alkyl, the substituents of which are selected from the group consisting of 〇H , phenyl and heteroaryl; OH; CrC6-alkoxy; phenoxy; S(〇)mR19; CF3; CN; N02; (CrC6-alkyl)amino; di(CrCV 15 alkyl)amine ;(Ci-Q-alkyl)-CONH-; unsubstituted and at least single Phenyl-CONH and phenyl-SOrO-, the substituents of which are selected from the group consisting of halo, pseudohalo, 03⁄4 and methoxy; (CKV alkyl)SOr〇-; unsubstituted and at least monosubstituted ( CrC6-alkyl)CO, the substituent of which is selected from the group consisting of F, one (C1-C3-alkyl) amine group, 吼π each sigma group and hexahydro carbene group; and benzene fluorenyl-CO, benzene thereof The base moiety may be substituted with one or more substituents selected from the group consisting of CrCr alkyl, halo and methoxy; A is selected from the group consisting of CH2, CHOH and CH-(CrCr alkyl); B is selected from the group consisting of CH2 And CH-(CrCr alkyl); C independently has the same definition as b; ~3 6~ This paper scale applies to the Middle Ages National Standard (CNS) Eight 4 Secrets (2丨0x297 mm) (Please read the back of the note first) Matters fill out this page), 11 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1298999 A7 ; ----^_______B7 V. Invention (y) —;- D independently R9 is an aryl or heteroaryl group which may be unsubstituted or have - or a plurality of substituents selected from the group consisting of i; pyranyl; CH: 1 (ralkyl; Cc burns an A; Phenyl; phenyl substituted W group 5 group; phenoxy group; benzyloxy group; cf3o: (CVCw alkyl) co〇; S(0)mR2〇; (CrCl0_院) amine group; ·院基)Amine; (Ci_

Cur-based) CONH-, (Cj-Cio-hospital)-CON(CrC3-alkyl)-;(cr

Cio-alkyl)-CO; CFrCO; -0CH20-; -〇CF2a; _ 〇CH2CH20-, -CH2CH20-; phenylamine group: stupid group _cq: c〇〇R21 10 ; conr22r23 ; s〇2nr24r25 ; 5 or 7 of the aromatic or aliphatic mononuclear group having 1 to 3 heterocyclic groups selected from hetero atoms including anthracene, fluorene and S, which may be selected from one or more selected from the group consisting of a functional group, a CrCr alkyl group, Cl_C3_Oxygen-burning: a group substituted with a CF^ substituent, which is formed by casting a phenyl group and a phenyl group containing a phenyl group, which is required to be present in the aryl group or the substituent of the heteroaryl group, and may be selected from one or more selected from the group consisting of Substituted by a substituent comprising a radical, a pseudohalo, a CrCr alkyl, a crc3-alkoxy group and a cf3; R疋H, CrC6-alkyl or octyl; R疋 selected from the group consisting of: Η; Q-C6- An alkyl group which may be substituted with a phenyl group; a phenyl 'carbonate group and a heteroaryl group, and wherein each of the above aromatic groups may be unsubstituted or the band 20 may have one or more selected from the group consisting of a halogen group, a pseudohalo group, and a group. Alkoxy and a substituent of CF3; R8 is an anthracene or a CrCV alkyl group; R9 is a Crcv alkyl group which may be unsubstituted or may have one or more substituents selected from the group consisting of F and s Amino group; and unsubstituted with ~3 7~ (please read the back) Precautions to fill out this page)

1298999 A7 B7 V. Description of the invention (乂) Less monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of CrCr alkyl, CVC3-alkoxy, halo, pseudohalo and cf3; Read the back note. Fill in this page again. R1G independently has the same definition as R7; R11 independently has the same definition as R8; 5 R12 independently has the same definition as R6; R疋 is selected from: Η; CrCV a non-substituted and substituted phenyl, benzyl, heteroaryl, phenyl-C0, and heteroaryl-C0, the substituents of which are selected from the group consisting of halo, pseudohalo, CrCr alkyl , CrCr alkoxy and CF3, and wherein one or more of these substituents may be present; 10 R14 is fluorene or CVCV alkyl; R 疋 is selected from the group consisting of η, CpCV alkyl; and; substituted; An octyl group, a phenyl group and a heteroaryl group, the substituents of which are selected from the group consisting of a fluorenyl group, a pseudohalo group, a C1-C3-group group, a Ci-C3*· alkoxy group, and a CF3 group, and one or more of which may be present These substituents; 15 R疋 are selected from the group consisting of: Ci-CV alkyl; CF3; and substituted and unsubstituted stupyl and heteroaryl groups, the substituents of which are selected from the group consisting of Fake-based, Crcr-alkyl, Crcr-alkoxy and CF3, and one or more of these substituents may be present therein; , R17 independently has the same definition as R7; Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints 20 R18 independently has the same definition as R8; R19 independently has the same definition as R16; R2G independently has the same definition as R16; R21 independently has the same definition as R6; R22 independently has the same definition as R7; ~3 8~ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1298999

V. DESCRIPTION OF THE INVENTION () R23 independently has the same definition as R8; R24 independently has the same definition as R7; R25 independently has the same definition as R8; heteroaryl is 5- to 10-membered- or two The ring contains one or more aromatic heterocyclic groups selected from hetero atoms including N, fluorene and 5 S; the aryl group is phenyl, naphthalen-1-yl or naphthalen-2-yl; m is 0, 1 or 2 . The compound of the formula (I) can be used for the regulation of the expression of the endothelium and is an important pharmaceutical compound for the treatment of various diseases. In the present invention, the treatment 10 includes the treatment and prevention of each disease. Examples of diseases which can be treated with the compound (I) according to the present invention include cardiovascular diseases such as stable and unstable angina pectoris, coronary heart disease,

Prinzmetal colic (痉挛), acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral motion, closure (PA〇D), endothelial 15 dysfunction, atherosclerosis, reocclusion, PTCA Endothelial injury, hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renal vascular hypertension, renal vascular chronic glomerulonephritis), erectile dysfunction, arrhythmia, and reduction of postmenopausal or contraception Cardiovascular risk for women with drugs. 20 Compounds of formula (I) are also useful in the treatment and prevention of diabetes and diabetic complications (renal lesions, retinopathy), angiogenesis, bronchial asthma, chronic renal failure, cirrhosis, osteoporosis, restrictive memory performance or restrictive learning ability. The car's indications are stable angina pectoris, coronary heart disease, and Nanjin pressure paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) ------------- - (Please read the notes on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, printed 0 1 m 1298999 A7 ________B7___ V. Description of invention (Μ), endothelial dysfunction, atherosclerosis and diabetes complication. The compound according to formula (I) can also be used in combination with other pharmaceutically active compounds. Preferred compounds are those which enhance the effect of the compound according to formula (I). Examples of such compounds include: statin; ACE-inhibitor; AT1 - antagonist; 5 arginase-inhibitor; PDE V-inhibitor; Ca-antagonist; alpha-blocker; recall-blocker; metimazol and similar compounds; arginine ; tetrahydrobiopterin; vitamins, especially vitamins ^: and vitamin B6; in oxalic acid. The compound of the formula (I) and a pharmaceutically acceptable salt thereof, if necessary, in combination with the 10 pharmaceutically active compound thereof, can be administered as a medicament to an animal, preferably breast-feeding, in the form of itself, a mixture containing other compounds or a pharmaceutical preparation. An animal, and especially a human, another subject of the present invention is the use of a compound of the formula 1 and a pharmaceutically acceptable salt thereof as a pharmaceutical, which is used as a transcription stimulator for endothelial NO synthase and particularly It is a use for medical treatment and prevention of the above-mentioned 15 syndromes and its use for preparing medicaments for these purposes, and another subject of the present invention is a pharmaceutical preparation (or pharmaceutical composition) containing the formula of the effective agent (I) a compound and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, that is, one or more pharmaceutically acceptable carrier materials and/or additives. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 20 The medicament according to the present invention is palatable, such as pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, water-based, alcoholic Or in the form of oily/cold, sugar, lotion or suspension, or rectal, for example in the form of a suppository, or parenteral (eg subcutaneous, intramuscular or intravenous for injection or perfusion) Solution form into ~40~^paper ΛΑApplicable to Chinese National Standard (CNS) A4iUM 21GX297 mm) 1298999

Ίο 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing, other suitable forms of medication are, for example, percutaneous or topical medications, such as in the form of soft, _, spray or percutaneous medical systems, or in the case of Or in the form of an aerosol mixture such as a micro-face, a plant or a rod; a second administration, the preferred form of administration is determined, for example, in the treatment of the disease and in the severity. The amount of the compound of the formula (I) and/or its pharmaceutically acceptable salt in medicine is usually from 〇.2 to _mg per dose, preferably from 〇5 to 5^mg, especially from 1 to 2 GG mg. However, the mosquito may be higher in the type of the medical agent. The pharmaceutical preparation usually contains 5% to 9% by weight of the formula, and the preparation of the pharmaceutical preparation can be carried out in a manner known per se. - or a plurality of compounds of formula (I) and / or pharmaceutically acceptable salts thereof and / or a plurality of solid or liquid pharmaceutical carrier materials and / or additives & auxiliary substances, and if combined with other medical or lion activities The pharmaceutically active compound can be formulated into a suitable form or administration form, and used as a medicament in human or animal medical treatment. ' For the manufacture of pills, tablets, sugar-coated tablets and hard and soft gelatin capsules' can be used to test for such as lactose, starch such as jade face decoction, talc, stearic acid or its crane, etc. The carrier of the test agent is, for example, a fat, a wax, a semi-solid and a liquid polyol natural hardened oil, etc., for preparing a solution such as a solution for injection: a milk & or a suitable carrier of a sugar-polymerizing agent such as water, Physiological sodium chloride solution, alcohols such as ethanol, glycerin, polyols, Yan sugar, invert sugar, glucose, mannitol, vegetable oil, etc., can also be used to freeze (1) compounds and their pharmaceutically acceptable surfaces and use The obtained cold-drying material, for example, is used for preparation for the injection of ~41. The paper size applies to the Chinese National Standard (CNS) Α4 specification (210χ297 public Chu) (please read the back note first and then fill out this page) d. 1298999 A7 - - - ____B7 V. INSTRUCTIONS (&lt;^) Preparations for injection or infusion, suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. In addition to the compound or compound group according to the invention and the carrier, the pharmaceutical preparation may also contain additives such as fillers, decomposers, adhesives 5 emulsifiers: wetting agents, stabilizers, emulsifiers, dispersants, preservatives. , sweeteners, _, flavorings, fragrances, noodles, thinners, buffers, solvents, solvents, agents used to achieve depositional effects, salts used to alter osmotic pressure, coatings or antioxidants . The amount of the compound of the formula (I) and/or its pharmaceutically acceptable salt is determined to be in individual cases, and is usually adjusted according to individual circumstances to achieve an optimal effect, whereby it is determined by the disease in need of treatment. Essence and severity, sputum and human need for treatment, age, weight and individual response, period of action (1), treatment is acute or chronic or prevention of medication other than formula (I) The active compound, usually administered in an amount of from 1 to 5 mg, is preferably from 1 to 100 mg/kg, preferably from 1 to 1 mg/kg, especially from 8.3 to 53⁄4 g/kg (mg in each case) Every kilogram of body weight, from the drug to an adult weighing about 75 kg, the desired result, each dose can be administered in a single dose, especially when used in large quantities, such as two, three or three independent The dose of the drug, in some cases, after 20, = _ response, may need to deviate downward or upward from the given dose per dose. | _ Formula (1) compounds can also be used in the above-mentioned Wei目@# Examples of intentional system include diagnostic purposes, as a living The use of tools, and for | example, as intermediates to make other compounds of the pharmaceutically active compound.

I 制 J J_. ~42~ This paper uses TiiiiiT^Ts) Α娜(2Η)Χ2崎)~~—- 1298999 A7 B7 V. Invention Description (Minutes) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing now The invention is illustrated in the following examples: Example: Preparation of 6,7,8,9·Four Wind-5H-Ben and 辰 庚 稀 稀 冬 将 将 I I I I I I I I I I I I I I I I I I I I I I I I I Here. . 5 liters of methanol and 9.66 g (10)·5 mmoles of isovaleronitrile were added, then 10 ml of concentrated HC1 was added dropwise for 1 〇min and the mixture was stirred at the price for 3 hours. After concentration, the second gas was used. The sulphur-sterol mixture (98:2, ν/ν) was used as the mobile phase, and the residue obtained was fractionally chromatographed on Shiqi gum. Yield: gram (6〇%) 〇10 8 g of the above intermediate Dissolved in 400 ml of glacial acetic acid, 5 ml of concentrated sulfuric acid was added and the intermediate was hydrogenated using 3*Pd/c at a pressure of 10 bar for 2 hours. After the catalyst is transferred, the mixture is poured into water and extracted with ethyl acetate, and then the aqueous layer is treated with a sodium hydroxide solution to obtain a basic layer and then 15 is extracted with di-methane, dried and concentrated. The residue was poured into ethyl acetate and etheric HCl was added to give the corresponding hydrochloride salt. Yield: 4.2 g (560%) 〇 By reducing the hydrogenation time, the following product was obtained in a similar manner: 6_Amino-6,7 ,8,9-tetrahydro-511-benzocyclohepten-5-ol 20 General procedure for the thiolated benzocycloheptenylamine 2.5 mM of each benzocycloheptenylamine 5 mg of triethylamine and 5 ml of dioxane were mixed, then 2.55 mmol of carbaryl chloride was added and stirred at room temperature for 2 hours. Then pour the resulting mixture into the ice / HC1-mixture, the resulting (please read the back of the note and then fill out this page) Order ~ 43 ~ This paper is applicable to China National Standard (CNS) Α 4 secret (21QX297 public Chu) 1298999 A7

V. INTRODUCTION OF THE INVENTION (Min) The product was extracted with ethyl acetate, dried over sulfuric acid and concentrated, and the residue thus obtained was separated by preparative HPLC. The following compounds (Examples 1-6) were obtained from the above method:

iMLL4-gas_N-(6,7,8,9·tetrahydro-5H_benzocyclohepten-6-yl)-octylamine 5 [M+HT] Measured: 284 m.p.: 165°C Preparative HPLC separation of palmar isomers (Chiralpeak AD, flow wash n-heptane·isopropanol 10:1): a) (-H-fluoro-N-(6,7,8,9-tetrahydrogen) -5H-benzocycloheptene each base)_threatene retention time: 10.11 b) (+M-fluoro good (6,7,8,9-tetrahydro-5H-benzocycloheptene_6_yl) ) _ octadecylamine retention time: 11.52 carbyl-6,7,8,9-tetrahydro-5-benzo benzocycloheptene _6-yl) + decylamine

15 Melting point·· 156°C Complex Example 3. · 4·Ga-2-mercapto-N-(6,7,8,9-tetrahydro-5H-benzocycloheptyl) 醯 + decylamine [ Μ+ΙΤ]Measured value: 314. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing time: 5.42 20 Condition: c

Mi : 2-chloro-4H(6,7,8,9_tetrahydro-5H_benzocycloheptyl _6 - decylamine _ soil > under [M+HT] Measured: 318 Retention time: 5.19 Paper is also applicable to China National Standard (CNS) into 4 threats (210X297 mm) --- V. Invention Description (Fantasy)

Conditions: C: 4-Ethoxy-N_(6,7,8,9-tetrahydro-5H_benzocycloheptene_6·Based crushed Μ+Η1 Measured value: 3.10 5 Residence time: 525 Condition: c 2,4-Fluoro-N-(6,7,8,9-tetradec-5H-benzocycloheptenyl)-Minylamine [M+H^] Measured: 302 10 Retention time: 5.30 Condition: c ^12 · (s)_2_methyl-3h-benzimidazole j-carboxylic acid (6,7,8,9-tetrazine_5Η·bengon _6_yl)_bristamine 1·2 g (6.83⁄4 mol) 2-methyl-1Η·benzoimine. Add 5-dimethylformamide (DMF) to a solution of 50-15 ml of anhydrous THF. 2.44 g (7·44 mmol) 〇_[(cyano-ethylidenemethylidene)amino]_ ν,ν,ν',ν'_tetramethylphosphonium tetrafluoroborate (TOTU) & 193 g (14·9 mmol) of ethyl diisopropylamine and the mixture was stirred at room temperature for 30 minutes, adding 1·〇g (6.2 mmol) (s)-6,7,8 , 9, Il-5H-benzoxephen-6-ylamine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 and the reaction was stirred for 3 hours, the resulting mixture was added to saturated sodium bicarbonate solution, with acetic acid Extraction of ethyl ester, drying via sulfuric acid and using methylene chloride / decyl alcohol 95:5 Chromatography on silica gel as a flow wash, yield U8 g (70%), or this compound can also be purified via preparative hplc^is, acetonitrile/water, 0.1% TFA. ~45~ This paper size is applicable to China National 榡牟(CNS) M Specification (210&gt;&lt;297 mm) 1298999 Α7 Β7 V. Description of invention (from) Melting point: 206°C W-NMR (300 MHz, d6-DMSO) ): 1.28-1.46 (m,1H,Η-alkyl), 1.80-2.13 (m,3H,H-alkyl), 2.5 (m,CH3 and DMSO), 2·72_2.90 (m,3H,H -alkyl),3··〇7_3·2〇(m,1H,H-alkyl), 3·80 (width q,iH, H-6),7.07-7.20 (m,4H,Hl,H- 2, H-3, H-4), 7.47 (d, lH, N-6'/H-7'), 7.67 (d, 1H, N-7'/H-6'), 7.98 (s , 1H, H-4'), 8.31 (d, 1H, NHCO), 12.40 (s, 1H, NH). Alternatively, the compound is synthesized using the racemic 6,7,8,9-tetrahydro-5H-benzocycloheptene-6-6-amine in the same manner and subjected to preparative HPLC (Daicel ChiralpeakAD, 20 micron, 250 x 50 mm, solvent: acetonitrile / isopropanol = 95: 5 + 0.1% diethylamine, flow rate: 50 ml / minute countercurrent mode) Separation of the resulting racemic isomer. [Μ+ΡΓ] Measured value: 320 Retention time: 8.95 15 Condition: a 5 10 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints appropriate case dad · (R) · 2-methyl benzo oxime · 5 _ The acid (6,7,8,9-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7 from the racemic amine. : 320 Retention time: 13.33 Condition: a Wukui 2*4-moly-&gt;^_(6,7,8,9-tetrahydro-511-benzocycloheptanium _6 4 prepared according to Example 7. &gt; guanamine paper Μ applies to China National Standard (CNS) A4 secret (21GX297 mm) (please read the notes on the back and fill out this page)

1298999 A7 _B7_ V. Invention description (private) (Please read the note on the back and fill out this page) [M+H&quot;] Measured value: 344 Retention time: 5.42 Condition: c Example 10: 6-Chloro-N-( 6,7,8,9-tetrakis-5H-benzocycloheptene each)-nicotine 5 decylamine was prepared according to Example 7. [M+H4]Measured value·· 301 ίRetention time: 4.96 Condition: c 10 Example 11: 2-hydroxy-6-mercapto-fluorene-(6,7,8,9-tetrahydro-5Η-benzo Cycloheptene-6-yl)-methanol was prepared according to Example 7. [Μ+Η4·] Measured value: 297 Retention time·· 4.12 15 Condition: c Example 12 ··1Η-吲哚-4-carboxylic acid (6,7,8,9-tetrahydro-5Η-benzocycloheptane The alkene)-bristamine was prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing [M+tf] Measurement: 305 20 Residence time: 4.66 Condition: c Example 13: 1H_benzotriazole-5-carboxylic acid (6,7,8,9- Tetrahydro-5H-benzocycloheptyl-6-yl)-bristamine was prepared according to Example 7. ~47~ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1298999 A7 B7 V. Invention description (w) (Please read the note on the back and fill in this page) [Μ+ΚΤ]Measured value :307 residence time: 4.26 condition: c Example 14: 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 5 (6,7,8,9-four Hydrogen-5H-benzocycloheptene-6-yl)guanamine was prepared according to Example 7. [M+H&quot;] Measured value: 434 Retention time: 5.59 Condition: c 10 Example 15: 2,6-dimethoxy-N_(6,7,8,9-tetrahydro-5H·benzocycloheptene -6-yl)-nicotine decylamine was prepared according to Example 7. [Μ+ΚΤ]Measured value: 327 Retention time: 5.55 15 Condition: c Example 16: 2-chloro-6-methyl-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene -6-yl)-prepared from the base amide according to Example 7. * Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed [Μ + ΗΓ] Measured value: 315 20 Residence time: 4.87 Condition: c Example 17: 4-methyl-2-phenyl-thiazole-5-carboxylic acid (6, 7,8,9-Tetrakis-5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. ~4 8~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298999 Α7 Β7 V. Invention description ("9) [Μ+ΗΓ] Measurement value: 363 Residence time: 5.65 Condition: c Example 18 : 2-indolyl-4·trifluoromethyl-thiazole-5-carboxylic acid (6,7,8,9-tetrahydro-5H-5benzoxylene-6-yl)-nitramine according to Example 7 preparation. [M+if] Measured: 355 Retention time: 5.17 Condition: c 10 Example 19: 5-trifluoromethyl_thieno[3,2-B]pyridine-6-carboxylic acid (6,7,8, 9-Tetra-5H-benzoxephen-6-yl)-bristamine was prepared according to Example 7. [M+tf] Measured: 391 Retention time: 4.87 15 Condition: c Example 20: 1H-吲哚-6·carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6 -Base)-Proline was prepared according to Example 7. , [M+H&quot;] Measured value: 305 20 Residence time: 4.77 Condition: c Example 21: 6-cyano-anthracene (6,7,8,9-tetrahydro-5H-benzocycloheptene-6 -Base) - Tobacco test guanamine was prepared according to Example 7. ~49~ This paper size is applicable to China National Standard (CNS) Α4 specification (210X29*7 mm) (please read the notes on the back and fill out this page) Order-Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1298999 , Invention description (young) 10 [Μ+ΕΓ]Measured value: 292 Retention time: 4.86 Condition: c · Benzo[I,2,·3]thiadiazole glacial carboxylic acid-N-(6,7,8 9-tetraoxy-:5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. [M+tT]Measured value: 324 Retention time: 5.12 Condition: e 1^1 : 2-Amino-^[-(6,7,8,9-tetrahydro-511_benzocycloheptene-6- Base)-Tobacco Testamine (Planomer I) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. ... (please read the notes on the back and fill out this page) Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs [M+IT] Measured value: 282 15 Retention time: 5.21 Condition: a Suitable case 2! : 2-Amino -Nh(6,7,8,9-tetrahydro-5H-benzocycloheptyl)········································· The resulting elimination is in the 20th structure. '疋[M+H1]Measured value·· 282 Retention time: 5.90 Condition: a , 岂: 2-amine base bucket (6,7,8,9-tetrahydro-5H-benzocycloheptene_6_ base ) The paper A degree is applicable to the Chinese national standard (CNS } A4 specification (210 X 297 mm), - mouth wm I -1 1298999 A7 B7 Ministry of Construction Intellectual Property Bureau employee consumption cooperatives printed five, invention description (%) alkali Indoleamine hydrochloride 223 mg (〇·79 mmol) of the compound of Example 24 was dissolved in 20 mL of methanol, and 0.5 mL of 2 eq. of HCl was added and partially evaporated to crystallize the title compound from the residual solution and filtered. Collection, yield: 183 mg 5 (73%) 〇 [Μ + ΕΓ] Measured: 282 tM.26 : 2_mercapto-N_(6,7,8,9·tetrahydro JH-benzocycloheptene Based on the alkali amide (p-isomer I) 'The resulting racemic iso- 10 structure was prepared and isolated from the racemic amine according to Example 7. [Μ+ΗΓ]Measured value: 281 ίWith the stay between the temples :4.27 Condition: b 宜^ : 曱--from (6,7,8,9_tetrahydro-benzo benzocycloheptene_6_yl15-alkali amide (p-isomer II) soil; 7 The racemic iso[M+tf] measurement obtained from the preparation and separation of the racemic amine :281 Retention time: 6.94 20 Condition: b. Surface 28· : 2,4-dimercapto-thiazole-5-acid (6,7,8,9-tetrahepten-6-yl)-decylamine (pair The palmomer isomer p 冓 Prepared and separated from the racemic amine according to Example 7 The resulting racemic paper is made of the same pattern (please read the back note and fill out this page)

1298999 A7 B7 V. INSTRUCTIONS (Yarn) (Please read the notes on the back and fill out this page) Measured value: 301 Retention time: 5.26 Condition: b Example 29: 2,4-Dimethyl-thiazole-5-carboxyl Acid (6,7,8,9-tetrahydro-5H-benzocyclohexane 5-hepten-6-yl)-decylamine (p-Isolomer II) Prepared and isolated from the racemic amine according to Example 7. Racemic isomer. [M+H*&quot;]Measured value: 301 Residence time: 5.99 10 Condition: b Example 30: 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (6,7,8,9 -Tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine (p. toomer I) - The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. : 15 [Μ+ΐΓ]Measured value: 346 Retention time: 5.44 Condition: a Example 31: 5-mercapto-1-phenyl-1H-pyrazole-4-carboxylic acid (·6,7,8,9- Tetrakis-5H-benzocycloheptene-6-yl)-decylamine (p. toomer II) 20 Purified and isolated from the racemic amine according to Example 7 Employee consumption cooperatives print structures. , [Μ+Ιί] Measured value: 340 Retention time: 6.28 Condition: a ~ 52~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298999 V. Invention description (Qiao) = Amine 5 = ^ _,7,8,9 She called the cyclized structure and prepared from the racemic amine according to Example 7 and obtained the racemic iso- 5 [M+H+] Measured value: 282 Retention time: 6.17 Condition: b · 5·曱基·対·2. Paper 7,8,9-tetrahydro-6-yl)-decylamine (p-isomer π) hexene _ 10 structure according to Example 7 from a racemic amine Preparation and separation of the resulting racemic measurements: 282 Retention time: 7.53 Conditions · · b 15 shot: u phenyl j three gas 曱 base. 〇 than wow winter _ (6,7 yarn four gas _ 5H-benzo Cycloheptenyl)-decylamine (p-isomer) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. . [M+H4·] Measured value: 4〇〇 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the note on the back and fill in this page) 20 Stay time: 3.64 Condition: a

Mil·· 1-phenyl-5-trimethyl-1H-pyrazole glacial carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene) 醯 醯 ( Isomer π) Preparation and separation of the resulting racemic from the racemic amine according to Example 7.

This paper is printed by China National Standard (CNS) from the threat (21Qx297 &amp; A 1298999, invention description (&gt;) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed structure. [M+FT] Measurement value: 4〇〇 detention Time: 3.81 Condition: a 治g ((基二=私_,7,8,9, hydrogen-5H_Taode compound). Ν_(6,7,8,9_tetrahydro_5Η_benzo Cycloheptadine, each of the three gas oxime 10 groups - in the base amide (the palm isomer I) 纠 / 艮 according to Example 7 prepared and isolated the racemic isomer from the elimination of the neoamine. ϊΓ]Measured value: 335 Retention time: 4.06 15 Condition: a, ··6,7,8,9-tetrahydro-benzo-cycloheptene groups>6-trifluoromethyl-in the base amide (Planomer isomer) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. tM+iT] Measured: 335 Retention time · · 5.96 Condition: a : 2-methyl -:^-(6,7,8,9-tetrahydro-511-benzocycloheptene-6-yl)_6-trifluoromethyl·in the base amide (p-isomer I) 20 paper New Lai (4) Team Sample (CNS) A4 Secret (21GX297 mm) I . 7 --- - - - -ri -I :--1 - - - 1 1 - I (Please read the notes on the back first) Fill in this page) Order 1298999

BRIEF DESCRIPTION OF THE INVENTION ($3) The resulting racemic isomer was prepared and isolated from a racemic amine according to Example 7. [M+IT]Measured value: 349 Retention time: 3.29 · Condition: a Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed: 2_methyl^(6,7,8,9-tetrahydro_511_benzo ring Heptene_6_yl)_6·Trifluoromethyl-nicotinium amide (p-isomer II) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. ', [Μ+ίΤ] Measured value: 349 Retention time: 3.82 Condition: a·· 2-dimethylamino _;^-(6,7,8,9-tetrahydro-511-benzocycloheptene) - Isonicotinic acid guanamine trifluoroacetate 'soil was prepared according to Example 148. tM+tr]Measured value: 31〇 Residence time: 1.72 Condition: d ^ v * · 24-Ν-(6,7,8,9-tetrahydro-5H_benzocycloheptene·6_US 20 test The amine was prepared according to Example 7. tM+Hl Measured: 301 Retention time: 2.40 Condition: d 10 15 ^^14« ) (210X297^—4—?------ {Please read the notes on the back first Fill in this page} Book 1298999 V. Invention Description (Reverse) ίο 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 3-Dimethylamino*(6,7,8,9, Hydrogen Stupid)-卞Indoleamine (manufactured by the racemic amine, according to Example 7, prepared from the racemic amine and isolated as racemic iso [M+H4] measured values · · 3〇9 retention time: 6.17 conditions :b Rhyme ^ ·· 3_Dimethylamine-based, 7,8,9-tetrahydro- benzophenone)-octylamine (for palmomer isomer) 衣g埽_6_based structure according to the example 7 Preparation and separation of the racemic amine from the racemic amine. [M+l·^] Measured value·································· 6,7 yarns four & g 6 meal amines (pairs of palmisomers!) heptane I was prepared and isolated from the topical neoamine according to Example 7 [M+H&quot;] Quantitative value: 283 Residence time: 5.05 Condition: b Charm: 3-amine 4 well - continuous acid (6,7,8,9_tetrahydrogen | stupid and 6-based &gt; decylamine π), - Prepared and separated from the racemic amine according to Example 7 and obtained the racemic iso-56- paper-based general-purpose Zhongguan standard (CNS__) from the threat (21GX297). Please read the back ί

Order 1298999 V. Invention Description (Government) Structure. [Μ+ΗΓ1]Measured value·· 283 Residence time·· 5.60 Condition: b. 5 Example 47: Bu)-91 One-Gan,, &amp; base-bite ice-based methyl-1H_t each-3-carboxylic acid...四虱-5!!-Benzocycloheptaine _6·yl) 醯 醯 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 10 Residence time·· 7.42 Condition: b · (=2,5· dimethyl nickname icylmethyl _m•transtracted acid (6,7,8,9-tetrahydrobenzobenzocycloheptene) ) 醯 醯 ( ( 对 ( ( ( 异构 异构 异构 异构 异构 制备 制备 制备 制备 制备 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨 叨,,. · 20 Λ · (+)_2,5_dimercapto-bubifurfuric acid (6,7,8,9-tetrahydro-5 fluorene-benzocycloheptene_6-yl)-decylamine (Pair of the isomers)) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. [Μ+ΗΤ]Measured value: 283 Retention time: 3.63 The paper scale was applicable to the Chinese country揉Standard ((210χ297 mm) 1298999 A7 B7 V. Description of invention (β) Condition: e (Please read the note on the back and fill out this page) 50 : (-)-2,5-Dimethyl-1-pyrrole-3·carboxylic acid (6,7,8,9-tetradec-5H-benzocycloheptene-6-yl)-decylamine ( Pair of palmomers II) The resulting racemic iso-structure was prepared and isolated from the racemic amine according to Example 7. [M+tf] Measured: 283 Retention time: 4.02 Condition: e Example 51 ·· 5 -Methyl-isoxazole-3-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene 10 ene-6-yl)-guanamine was prepared according to Example 7. [M+H&quot; Measurement: 271 j with retention time: 2.41 Condition: d 15 Example 52: 2,4-dimercapto-pyrimidine-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptane The ene-6-yl)-guanamine was prepared according to Example 7. [M+if] Measured: 296 Retention time: 1.99 20 Condition: d Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example 53: 6-pyrrolidine-1 -Methyl-pyridine-2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-guanamine prepared according to Example 7. [M+HT] Measured: 336 ~5 8~ This paper scale applies to China National Standard (CNS) A4 (210X297 mm) 1298999 V. Invention Description (^?) · 6-Mercapto-N-(6,75859, Hydrogen-Benzene Benzene Ring Gentamine (for palm isomer I) &lt;disgusting base), Yugen Example 7 Preparation and isolation of the resulting state structure from the racemic amine [M+tf] Measured: 281 Residual B Temple: 8.96 Condition: b ===; 7,8-benzocycloprop 10 According to Example 7 Preparation and separation of the racemic isomers obtained by the elimination of the heteropolyamine [M+HT] Measured value: 281 Retention time: 14.54 Condition: b - IV----H 11Γ1 I —i I - si &quot;3^^ ^- I 0 {Please read the notes on the back and fill out this page] 15 : 2-Amino- 4,6-dimethyl-N-(6,7,8,9-tetrahydroortho-phenylene -6-yl)-in the test of decylamine (p-isomer I) Cycloheptane prepared from the racemic amine according to Example 7 and isolated from the racemic iso-order economic department Intellectual Property Bureau employee consumption cooperative printing Structure [Μ+ΕΓ] Measured value: 310 20 Residence time: 8.13 Condition: b fMZ ·· 2-Amino-4,6-dimethylcatch (6,7,8,9_tetrahydro, 511_stupid Ethyl-6-yl)-in the case of decylamine (p-isomer jj) W According to Example 7 prepared from the racemic amine and isolated, the scale of the dilatation of the heterogeneous paper is applicable to the Chinese national standard. (CNS) A4 specification (210X297 Gongling) 1298999 A7 B7 V. Invention description (slave) Structure. (Please read the notes on the back and fill out this page) [M+H&quot;] Measured value: 310 Retention time: 13.88 Condition: b. 5 Example 58: 2,4-Dimethyl-carbazole-5-carboxylic acid (6,7,8,9-Tetrahydro-5H-benzocycloheptyl-6-yl)-nitramine was prepared according to Example 7. [Μ+ΗΓ]Measured value: 285 Retention time: 1.75 10 Condition: f Example 59: 3-Amino-5-mercapto-pyridine-2-carboxylic acid (6,7,8,9-tetrahydro-5H -Benzocyclohepten-6-yl)-nonylamine trifluoroacetate was prepared according to Example 7. [M+Mine] Measured value: 297 15 Residence time: 1.86 Condition·· f Example 60: 6-ethynyl-N_(6,7,8,9-tetrahydro-5H-benzocycloheptene_6-yl) - Nicotinamide guanamine trifluoroacetate was prepared according to Example 7. 20 [M+H^]Measured value: 291 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Retention Time: 1.79 Conditions·· f Example 61: 5-Amino-1-phenyl-1H-pyrrole-4-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine trifluoroacetate~60~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) PCT) 1298999 Α7 Β7 V. Description of the invention (rf) Prepared according to Example 7. (Please read the notes on the back and fill out this page) Measured value: 347 Retention time: 1.80 Condition: f · 5 Example 62: 4-Amino-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (6 , 7,8,9-tetrakis-5H-benzocycloheptene-6-yl &gt; decylamine was prepared according to Example 7. [M+H4! Measured: 360 Retention time: 2.86 10 Condition: f Example 63 4-amino-2-pyridin-4-yl-pyrimidine-5-carboxylic acid (6,7,8,9-tetradec-5H-benzocycloheptene-6-yl)-decylamine according to Example 7 Preparation [M+H&quot;]Measured value·· 360 15 Residence time: 2.82 Condition: f Example 64: 2-Isofos-4-yl-pyrimidine-5-carboxylic acid (6,7,8,9-tetra Hydrogen-5H-benzocycloheptene-6-ylguanamine trifluoroacetate was prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 [M+If] Measurement: 353 Residence time: 1.75 Conditions: f Example 65: 2-Phenylamino---D- _5·Weyric acid (6,7,8,9-tetraaza-5H-benzo[rhoheptene-6-yl)-decylamine trifluoroacetate ~61~ This paper size applies to China National Standard (CNS) Α4 specification (210X29*7 mm) 1298999 A7 B7 V. Invention description (A) Prepared according to Example 7. [Μ+Ιί]Measured value: 359 Time: 1.84 Conditions: f · 5 Example 66: 4-Amino-2-ϋΐ^σ定-2-yl-mouth 11 D--5-decanoic acid (6,7,8,9-tetra-rat-5IJ-benzene And cyclohepten-6-yl)-guanamine was prepared according to Example 7. [Μ+Η1] Measured: 360 ” Retention time: 2.71 . 10 Conditions: f Example 67: 3-methyl-2-pyridine-4- Base-1H-indole-5-carboxylic acid (6,7,8,9-tetraaza-5H-benzocyclohepten-6-yl)-guanamine trifluoroacetate was prepared according to Example 7. [M+ If] Measured value: 396 15 Retention time: 2.57 Condition: f Example 68: 2-(2-hydroxy-pyridin-4-yl)-1Η-benzimidazole-5-carboxylic acid (6,7,8,9_ Tetrahydro, 5H-benzocyclohepten-6-yl)guanamine trifluoroacetate was prepared according to Example 7. 20 [Μ+ΗΓ] Measured: 399 Retention time: 2.62 Condition: f Example 69: Pyrimidine-4_ Carboxylic acid (6,7,8,9-tetradec-5H-benzocycloheptene-6-yl)-guanamine trifluoroacetate~62~ This paper scale applies to China National Standard (CNS) A4 specification ( 210X297 mm) Please read the note of the back © first

I Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1298999 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (eve) Prepared according to example 7. [Μ+ΗΓ]Measured value·· 268 Retention time: 2.80 Condition: f · 5 Example 70: 2,6-Dichloro-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene • 6-Base)-Nicotine guanamine trifluoroacetate was prepared according to Example 7. [M+tf]Measured: 335 Retention time: 2.96 10 Condition: f Example 71: 2-methyl-pyrimidine-5-carboxylic acid (6,7,8,9-tetraaza-5H-benzocycloheptene -6-yl)-guanamine was prepared according to Example 7. [M+H4! Measured: 282 15 Retention time: 2.86 Condition: f Example 72: 3_Amino-5,6-dimethyl-pyridine-2-carboxylic acid (6,7,8,9_4 Hydrogen-5H-benzocyclohepten-6-yl)-nonylamine trifluoroacetate was prepared according to Example 7. 20 [Μ+ΕΓ]Measured value: 311 Retention time: 3.05 Condition: f Example 73: 2,6-bis-dimethylamino-pyrimidine-4-carboxylic acid (6,7,8,9-tetrahydro-5H _Benzocycloheptene-6-yl&gt; Indole trifluoroacetate~63~ This paper scale is applicable to China National Standard (CNS) Α4 specification (210X297 mm) Please read the back note and then page 1298999 A7 B7 V. INSTRUCTIONS (/&gt;) Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+ΗΓ] Measured value: 354 Retention time: 3.07 Condition: f · 5 Example 74: 4-Amino-2-ethylsulfonyl fluorenyl-pyrimidine-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-nonylamine trifluoroacetate Prepared according to Example 7. |&gt;1+1^] Measured value: 343 Retention time: 2.89 10 Condition: f Example 75: 6-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (6,7,8 , 9_tetrakis-5H-benzocyclohepten-6-yl)-nonylamine trifluoroacetate was prepared according to Example 7. [Μ+ΗΓ] Measured: 337 15 Retention time: 3.03 Condition: f Example 76: 6-Amidino-pyridin-2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-6yl)-guanamine trifluoroacetate Example 7 Preparation. 20 [M+H&quot;] Measured value: 297 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Retention Time: 2.80 Condition: f Example 77: 6-(4-mercapto-hexahydropyrazine small base) -pyridine-2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine ~64~ This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 1298999 A7 B7 V. INSTRUCTIONS (/3) Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+ΗΓ]Measured value: 365 Retention time: 2.59 Condition: f ' · 5 Example 78 · Biting-1-yl-N-(6,7,8,9-tetrazo-5H-benzocypinhept-6-yl)-nicotine decyl trifluoroacetate according to an example 7 Preparation [M+H&quot;] Measured value: 336 Retention time: 2.56 10 Condition: f Example 79: 5-(4-mercapto-six-nosed mouth-by-well-1-yl)-N-(6,7 , 8,9-tetra-rat-5H-benzocycloheptene-6-yl)-nicotine decylamine was prepared according to Example 7. [Μ+ΗΓ] Measured value: 365 15 Residence time: 2.51 ... Condition: f Example 80 : 5-Offort 11 lin-4-yl-N-(6,7,8,9-tetraaza-5H-benzoglyoxyl-6-*yl)-nicotine guanamine trifluoroacetate, According to example 7 . Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 [Μ+Η&quot;] Measured value: 352 Retention time: 2.57 Condition: f Example 81: 6-dimethylamino-N-(6,7,8,9-four Hydrogen-5H-benzocycloheptene-6-yl)-in the test amine trifluoroacetate~65~ This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1298999 7 Α7 Β7 V. Invention The preparation was carried out according to Example 7. (Please read the notes on the back and fill out this page) [M+H1! Measured value: 310 - Residence time: 2.44 Condition: f · 5 Example 82: 6-pyrrolidine small group-N-(6,7,8 , 9-tetrakis-5H-benzocycloheptene-6-yl)-based base amine trioxyacetate was prepared according to Example 7. [M+H&quot;] Measured value: 336 Retention time·· 2.64 10 Condition: f Example 83: 5-(6,7,8,9-tetrahydro-5H·benzocycloheptene-6-ylamino group A Ethyl)-pyridine-2-carboxylate ethyl ester trifluoroacetate was prepared according to Example 7. [Μ+ΗΓ]Measured value: 453 15 Residence time: 2.81 Condition: f Example 84 ··· 4-Amino-2-(4,4-dimethyl-2-keto-imidazolidine-1-yl)- Pyrimidine-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-ylaminoindenyl)-guanamine was prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 [M+lT] Measured: 281 Retention Time: 2.67 Condition Example 85: Imidazo[1,2-indole]pyridine-2-carboxylic acid (6,7,8, 9-Tetrahydro-5Η-benzocycloheptene-6-yl)-guanamine ~66~ This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1298999 A7 B7 V. Invention description Ujt) Prepared according to Example 7. (Please read the precautions on the back and fill out this page) [M+H&quot;] Measured value: 306 Retention time: 2.91 Condition: f · 5 Example 86: 2-mercapto-1-phenyl-1H-benzimidazole 5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. [M+H^]Measured: 396 Retention time: 2.75 10 Condition: f Example 87: 1-isopropyl-2-trifluoromethyl-1H-imidazole-5-carboxylic acid (6,7,8,9 -Tetrahydro-5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. [M+H&quot;] Measured value: 410 15 Residence time: 3.06 Condition: f Example 88: N-(6,7,8,9-tetrahydro-5H-benzocycloheptene: 6-yl)-4- Trifluoromethyl-prepared to decylamine. Trifluoroacetate, prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 [M+H4! Measured value: 335 Retention time: 2.83 Condition: f Example 89: 3,5-dimercapto-1H-pyrazole-4-carboxylic acid (6, 7,8,9-Tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine ~67~ This paper scale applies to Chinese National Standard (CNS) A4 Grid (210X297 mm) 1298999 A7 B7 V. Description of the invention (#) Prepared according to Example 7. [Μ+ΕΓ]Measured value: 284 Retention time: 2.64 Condition: f · 5 Example 90 Today Yulin-4-decanoic acid (6,7,8,9-four mice-5H-benzoglycol ≥6 • Base) _ guanamine trifluoroacetate was prepared according to Example 7. [Μ+Η&quot;] Measured value: 318 Retention time: 2.76 10 Condition: f Example 91: 5_mercapto-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene-6- The base nicotine guanamine trifluoroacetate was prepared according to Example 7. [Μ+ίΓ]Measured value: 281 15 Residence time·· 2.65 Condition: f Example 92: 2-ethyl-5-mercapto-2H-pyrazole-3-carboxylic acid (6,7,8,9-four Hydrogen-5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. 20 [M+HT] Measured value: 298 Retention time: 2.90 Condition: f Example 93 ·· 4-Methyl-[1,2,3]thiadiazole_5_carboxylic acid (6,7,8,9- Tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine ~6 8~ This paper scale applies to Chinese National Standard (CNS) A4 (210X297 mm) _--------- -- (Please read the note on the back and then fill out this page) Ordered by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1298999 A7 B7 V. Invention Description (ο) Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+Η^] Measured value: 288 Retention time: 2.85 Condition: f · 5 Example 94: 3-methyl-isoxazole-4-carboxylic acid (6 , 7,8,9-Tetrahydro-5H-benzocycloheptyl-6-yl)-bristamine was prepared according to Example 7. [M+H^] Measured: 271 Retention time: 2.28 10 Condition: f Example 95: 1-(4-Fluoro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ( 6,7,8,9-Tetrahydro-5H-benzocyclohepten-6-yl)-decylamine was prepared according to Example 7. [M+H4*]Measured value: 378 15 Residence time: 2.60 Condition: f Example 96: 2,5-Dimethyl-1-phenyl-1Η-σ ratio slightly -3-acid (6,7,8 , 9-tetramur _ 5 Η-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. 20 [Μ+ΗΓ]Measured value: 359 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Retention Time: 2.87 Condition: f Example 97: 3-methanesulfonylamino-N-(6,7,8,9- Tetrahydro-5H-benzocycloheptene-6-yl)-benzylamine ~6 9~ This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1298999 Α7 Β7 V. Invention description (α Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+ΗΓ]Measured value: 359 Retention time: 4.68 Condition: f · 5 Example 98: 4-ox-3-oxanesulfonylamino-N- (6,7,8,9-Tetrahydro-5H-benzocycloheptene-6-yl)-benzylguanamine was prepared according to Example 7. [M+rfl Measured value: 393 Retention time: 4.90 10 Condition: f Example 99: 3-methyl calcination arylamino-2-mercapto-N-(6,7,8,9-tetraaza-5H- Benzocycloheptene-6-yl&gt; Benzylamine was prepared according to Example 7. [Μ+ΗΓ] Measured: 373 15 Retention time·· 4.61 Condition: f Example 100: 4-amino-2-indenyl- Pyrimidine-5-carboxylic acid (6,7,8,9-tetrahydro-511-benzocycloheptene-6-yl)-nonylamine trifluoroacetate was prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 [Μ+ΗΓ] Measured value: 297 Residence time: 2.07 Condition: f Example 101: 6-?Fo 11 Lin-4-yl-N-(6,7,8,9-four-rat-5H-benzene And 哀 庚 庚 -6-6-yl)-nicotine decylamine trifluoroacetate ~ 7 〇 ~ This paper scale applies to China National Standard (CNS) Α 4 specifications (210X297 mm) 1298999 Α7 Α7 Β7 5, invention description (# Prepared according to Example 7. (Please read the notes on the back and fill out this page) [M+H4]Measured value: 352 Retention time: 4.40 Condition: f. 5 Example 102: 6-methoxy-N-(6 , 7,8,9-Tetrahydro-5H-benzocyclohepten-6-yl)-nicotine decylamine trifluoroacetate was prepared according to Example 7. [Μ+:ΗΓ]Measured value 297 Residence time: 4.9 10 Conditions: f Example 103: 2,6-difosfos-4-yl-pyrimidine-4-carboxylic acid-(6,7,8,9-tetrahydro-5H·benzocycloheptane The ene-6-yl)-guanamine trifluoroacetate was prepared according to Example 7. [M+if] Measured: 438 15 Retention time: 5.56 Condition ef Example 104: 2-Mercapto-thiazole-5-carboxylic acid ( 6,7,8,9-Tetrahydro-5H-benzocycloheptyl-6-yl)-bristamine was prepared according to Example 7. 20 [M+H4]Measured value: 287 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Retention time: 4.63 Condition: f Example 105: 2-(4·Cyano-phenyl)-1Η-benzimidazole_5_carboxylic acid (6,7,8,9-tetrahydro-5H-benzo ring Heptene-6-yl)-nonylamine ~71~ This paper scale applies to Chinese National Standard (CNS) ΜSpecification (210X297 mm) 1298999 A7 B7 V. Invention Description (y) Prepared according to Example 7. (Please read the back first Note: Please fill in this page again) [M+HT] Measured value: 407 Retention time: 5.02 Condition: f. 5 Example 106: 3-hexapyridine-1-yl-N-(6,7,8,9- Tetrakis-5H-benzocyclohepten-6-yl)-benzylamine was prepared according to Example 7. [Μ+ΗΓ] Measured: 349 Retention time: 4.73 10 Conditions: f Example 107: 3-( 4-Methyl-hexahydropyridin-1-yl)_N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-benzylguanamine Prepared according to Example 7. [M+H&quot;] Measured value: 364 15 Residence time: 3·49 . Condition = f Example 108: 3-isfosin_4_based_N_(6,7,8,9-tetrahydro-5H-benzene And cyclohepten-6-yl)-benzylguanamine. Prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 [Μ+ΗΓ] Measured value: 351 Retention time: 5.11 Condition: f Example 109: 4·methyl·thiazole-5-carboxylic acid (6,7,8,9- Tetrahydro-511-benzocycloheptyl·_6-yl)-bristamine~72~ This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1298999 A7 B7 V. Description of the invention (7/) Prepared according to Example 7. [Μ+Ιί&quot;] Measured value: 287 Example 110: 4,6-dimercapto-fluorene-(6,7,8,9-tetrahydro-5 fluorene-benzocycloheptene-6-yl)-nicotine Indoleamine (p-Isolomer I) 5 The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. [Μ+Η&quot;] Measured value: 295 Retention time: 10.32 Condition: b 10 Example 111: 4,6-Dimethyl-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene -6-yl)-nicotine decylamine (p-isomer II) The resulting racemic isomer was prepared and isolated from the racemic amine according to Example 7. [Μ+β]Measured value: 295 15 Residence time: 17.01 'Condition: b Example 112: 2,6-dimercapto_N-(6,7,8,9-tetrahydro-5H_benzocycloheptene _6_yl)-nicotine decylamine (pivot; construct I) 'The resulting racemic iso 20 was prepared and isolated from the racemic amine according to Example 7. [M+H&quot;] Measured value: 295 Retention time: 6.37 Condition = b Example 113: 2,6-Dimethyl-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene - 6-based ~73~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Sample clothing ------------^1-----Shenzhen (please read first Precautions on the back side of this page) 1298999 A7 B7 V. Inventive Note (&gt;) ) - Nicotinamide (for Palmomer Isomer II) (Please read the back note before completing this page) According to Example 7 The resulting racemic isomer is prepared and isolated from the racemic amine. [M+HT] Measured: 2? 5 5 Retention time: 10.41 Condition: b Example 114: (S)-3-Amino-5-methylpyrazine-2-carboxylic acid (6,7,8,9 -Tetrahydro-5H-benzocycloheptyl-6-yl)-bristamine was prepared according to Example 7. 10 [M+tf] Measured: 297 Retention time: 2.52 Condition: d Example 115: (S)-3-Amino-5,6-dimethyl-pyridine-2-carboxylic acid (6,7,8 , 9-Tetrahydro-5H-benzocycloheptene-6-yl)-decylamine 15 was prepared according to Example 7. '[Μ+ΕΓ]Measured value: 311 Retention time: 2.60 Condition: d Example 116: (S)-6-Methylamino-pyridine-2_carboxylic acid (6,7,8,9-tetrahydro- 5H-Benzene 20 and cyclohepten-6-yl)-decylamine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing was prepared according to Example 7. [M+ET] Measured value: 297 Retention time: 2.28 Condition: d ～74~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1298999 A7 B7 V. Description of invention (is) Example 117 : ( S) 6-dimethylamino-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-purine was prepared according to Example 7. [M+H^] Measured value: 3.10 5 Residence time: 1/75 Condition β· d Example 118 · (S)-6-p pirox 17 -1-yl-Ν·(6,7,8, 9-tetra-rat-5H-benzol-heptene-6-yl)-nicotine decylamine was prepared according to Example 7. 10 [Μ+Η4] Measured value: 330 Retention time: 1.82 Condition: ά Example 119: (S)-3-methanesulfonylamino-4-methyl-indole-(6,7,8,9-four Hydrogen-5Η-benzocycloheptene-6-yl)-benzylguanamine 15 was prepared according to Example 7. * [Μ+ΗΓ]Measured value: 373 Retention time: 2.26 Condition: d · \· Example 120 : (S)-2-cyclopropyl_4_mercapto-thiazole-5-carboxylic acid (6,7,8 , 9-Tetrahydro-20 5 fluorene-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. [Μ+ΗΓ] Measured value: 327 Retention time: 2.52 Condition: d ～75~ This paper scale applies to Chinese national standards (CNS &gt; A4 specification (210X297 mm) ------------ ( Please read the notes on the back and fill out this page.) 泉泉_ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1298999 V. Invention Description 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed: (8)·2,5- Dimethyl + benzene-pure - spider 3__ tetram-5-p-cycloheptene-6-yl)-guanamine was prepared according to Example 7. [Μ+ΗΓ]Measured value: 3.59 Staying time: 2.83 Condition: d Money should: (S)-2, k曱 base-calling ratio '3·Rebel acid (a, 8 stupid and cycloheptyl-6-yl) - decylamine '' was prepared according to Example 7. [Μ+ΗΓ]Measured value: 284 Retention time: 2.28 Condition: d 岂Mm : 6-methyl-2-methylamine (6,7,8,9_four gas_5H thin _6-yl)- Determination of the deuterated heterogeneous [M+HT] obtained from the racemic amine according to Example 7 and the separation of the amine (Isolation of the isomer I) from the racemic amine: 310 retention time: 9, 35 Conditions: g Example 124 ···6-Methylamino-amino-N-(6,7,8,9-tetrahydro-ethen-6-yl)-nicotine decylamine (p. 7 The resulting exodomain was prepared and isolated from the racemic amine. [Μ+ίΤ]Measurement value: 310 (6,7,8,9- Stupid and Geng Geng paper scale applicable to China National Standard (CNS) Α4 specification (210Χ297 mm) 1298999 A7 A 7 B7 V. Description of invention (; &gt;/) Residence time: 9.88 Condition: g (Please read the notes on the back and fill out this page) Example 125: (S)-N-(6,7,8,9-tetrahydro-5H-benzo ring Hepten-6-yl)-4-(2,2,2-trifluoro-ethoxy)-benzamide 5 was prepared according to Example 7. [M+H &quot;] Measured: 364 Example 126: (S) -3H-benzimidazole-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-guanamine was prepared according to Example 7. 10 [Μ+ΐΓ] measurement Value: 306 Residence Time: 3.81 Condition: d Example 127: 1-Mercapto-3-keto-1,2,3,4-tetrahydro-indole-6-carboxylic acid (6,7,8,9 -Tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine 15 Prepared according to Example 7. ♦ Measured: 350 Example 128: (S)-2-Amino- 6-gas-N-(6 , 7,8,9-tetraar-5H-benzocycloheptene-6-yl)- was prepared according to Example 7. 20 [M+H&quot;] Measured value: 316 Ministry of Economic Affairs Intellectual Property Office staff consumption Cooperative printing time: 2.52 Condition: d Example 129: (S)-2_Dimethylamino-4-methyl -thiazole-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine ~77~ This paper scale applies to Chinese National Standard (CNS) A4 (210X297 mm) 1298999 A7 A 7 B7 V. INSTRUCTIONS (V) Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+ΗΓ]Measurement value: 330 Retention time: L91 Condition: d. 5 Example 130: (S)-6-methoxy-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-in the case of the decylamine according to Example 7 Prepared. [M+H&quot;] Measured value: 297 Retention time: 2.34 10 Condition: d Example 131: (S)-3-dimethylamino-4-methyl·Ν-(6,7,8,9- Tetranitro-5H-benzocycloheptene-6-yl)-benzylguanamine was prepared according to Example 7. [Μ+Η&quot;] Measured value: 323 15 Residence time: 1.85 Condition: d Example 132: (8)-3 -Bilo 0-but-1-yl-1^-(6,7,8,9-tetrazo-511-benzo-hepten-6-yl)-benzylamine 'prepared according to Example 7. 20 [ M+H&quot;] Measured value: 335 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Residency Time: 2.71 Condition: d Example 133: (S)-6-Alkyloxy-N-(6,7,8, 9-tetrahydro-5H-benzocycloheptene-6-yl)-test Guanamine ~78~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298999 A7 A7 B7 V. Description of invention (V) Prepared according to Example 7. (Please read the notes on the back and fill out this page) [Μ+ΗΓ]Measured value: 311 Retention time: 2.00 Condition: d. 5 Example 134: 5,6,7,8-tetrahydroindole-3-carboxylate The acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-nonylamine trifluoroacetate was prepared according to Example 7. [M+H^]Measured value: 321 Retention time: 1.83 10 Condition: f Example 135: 4-mercapto-3-methylamino-indole·(6,7,8,9-tetrahydro-5H-benzo Cyclohepten-6-yl)-benzylguanamine was prepared according to Example 7. [Μ+Η4! Measured value: 309 15 Residence time: 2.15 * Condition: f Example 136: 2·Ga-5-methanesulfonylamino-N-(6,7,8,9-tetrahydro-5H- Benzocycloheptene-6-indole)-benzylguanamine. Prepared according to Example 7. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 [Μ+ΗΓ] Measured value: 393 Retention time: 2.78 Condition: f Example 137: 2-Amino-6_chloro_1^(6,7,8,9- Tetrahydro-5H-benzocycloheptene-6-yl)-in the test amine trifluoroacetate~79~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298999 B7 V. Invention Description (Λ?) Prepared according to Example 7. [Μ+ϊί]Measured value: 310 Retention time: 2.91 Condition: f. 5 Example 138: 4-Chloroaminesulfonyl-N-(6,7,8,9-tetrahydro-5H-benzocycloheptane Ace-6-yl)-benzylguanamine trifluoroacetate was prepared according to Example 7. [M+H&quot;] Measured value: 379 Retention time: 2.75 10 Condition: f Example 139: 3-methanesulfonyl-N-(6,7,8,9-tetrahydro-5H-benzocycloheptene- 6-Methyl)-benzylamine was prepared according to Example 7. [Μ+ΗΓ]Measured value: 344 15 Residence time: 2.74 * Condition: f Example 140: 5_Methanesulfonyl-2-mercapto-N-(6,7,8,9-tetrahydro-5H-benzene And cycloheptene-6-yl): benzinamide was prepared according to Example 7. 20 [Μ+β]Measured value: 358 Retention time: 2.77 Condition: f Example 141: 3,6-dichloro-pyridine-2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzo ring Heptene-6-yl)-decylamine ~80 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (please read the notes on the back and fill out this page) 4

1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1298999 Five Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing, invention description (&gt; corpse) Prepared according to Example 7. 'Measurement value: 336 Retention time: 5.19 Condition: c Application 42: 4-benzylamino-pyridyl carboxylic acid (6 heptene-6-yl)-nonylamine tetra 1L-5H-present and % The title compound was obtained from 13 (TC starts with the amine as a solvent from 4 气 讯 苯 环 庚 6 6 6 · · 6 6 , , , , , 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Crystal (four) body, the filament replaces the product at 52% yield [Μ+Ιί] Measurement: 372 Residence time: 2.00 Condition: d 1 inverted 1434 · 3_ afternoon amine-based acid (6,7,8,9· Tetrahydro- benzo benzocycloheptene-6-yl> decylamine The compound of Example 141 (383 mg, U4 mmol) in 6 ml of decylamine 耷not: stirred for 4 hours, cooled to room temperature. The residue was dissolved in ethyl acetate and washed with H.sub.2 and EtOAc (EtOAc). And 35% (Example 143B) yield to complete the crystalline solid of the title compound. [M+tf] Measured: 406 Retention time: 6.20 5 Port ratio 10 15 20 -8 l · This paper size is applicable Granary of Standards (CNS) A4 size (210X297 public widow) 1298999 A7 ______B7 V. invention is described in (charge)

Conditions: C Example 1 迎·· 6; Amine _3-Ga _° ratio lean _2_Wei acid (6,7,8,9-tetrahydro-:5H-benzocycloheptene-6-yl) - decylamine was prepared according to Example 143.A. 5 [M+IT] Measured value: 406 Retention time: 5.46 Condition: ci Example 144: 3-Amino-pyridine 1carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6 ·-)-acid amine 10 255 mg (0. 63 mmol) of the compound of the example M3 A was dissolved in 15 ml of methanol and 1 ml of dichloromethane, after adding a catalytic amount of Pd / C (10%), The reaction mixture was stirred at room temperature under H2 pressure for 3 hrs, then filtered and filtered and evaporated. [M+H4] Measured value: 282 15 Residence time: 2.58. Condition: d

Ai column 145 · 3-methanesulfonylamino group _. Bipyridine-2-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptan-6-yl)-decylamine · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in Example 144 compound (113 mg, 0.40 mmol) in a 3 ml 20 ϋ solution, add a catalytic amount of DMAP and 50.4 mg (0.44 mmol) to a solution of chlorinated chlorine in 〇·5 ml of dichloromethane. The reaction mixture was stirred at 〇C for 30 minutes and at room temperature for 5 hours. After the reaction was kept at room temperature overnight, additional 1.2 equivalents of methanesulfonium was added and the reaction mixture was stirred at 5 ° C for 1 hour. After the solvent is removed by vacuum, the crude product is dissolved in ~82~ This paper is suitable for CNS) A4 specification (210X297 mm) 1298999 V. Invention description (do) A7 B7

Ethyl acetate was printed by the Consumers' Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs and washed three times with 0. After drying through the crucible 4, 13 8 mg of the title compound was obtained as a crystalline solid. [Μ+Η^] Measured value: 360 Retention time: 2.68 5 Condition: d Suitable dish: Amino-pyridine retinoic acid (from "Book Hydrogen-Xin and Cyclo-6-yl") The compound of Example 142 was debenzylated using the methanol/formic acid (23:1) as solvent to afford compound 10 as a colorless solid. </ </ RTI> </ RTI> Μ ΗΓ ΗΓ 测量 282 282 282 : 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 d ··(R)_(+)-4-Mo-N-(6,7,8,9-tetrahydro-5H- benzocycloheptyl)-Milk amine &lt; according to Example 7 Preparation of (R)-6,7,8,9-tetrahydro-5H-benzocycloheptene respective amines [Μ+Η+] Measurements·· 344 · Residence time: 5.42 20 Condition: c : 2_( 4_Methyl-hexahydropyrrolidine small base) 1 (6,7,8,9_tetraaza-benzocycloheptene_6-yl) &gt;isonicotinamide guanamine trifluoroacetate class 200 Mg (〇·67 mmol) 2-gas _Ν-(6,7,8,9,hydrogen _5Η•benzoxanthene)-isonicotinium amide (Example 42) and 2 ml team Methylhexahydropyrrol 4 15

A4 size (210X297 mm) • -·1··_·: - -: i BI-cl ......- I - - - - I mu - IC Please read the notes on the back and fill out this page. ) -订·i&quot;n J— · -i Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1298999 A7 __ —__B7 V. Invention Description (#&gt;) Heating in an autoclave at 180°C for 8 hours, The resulting mixture was evaporated to dryness and purified using preparative HPLC (EtOAc, EtOAc/EtOAc, EtOAc [Μ+ίΓ]Measured value: 3 of 5 Retention time: 3.75 Condition: c : (+)-2-pyrrolidine small group-N-(6,7,8,9-tetrahydro-5H-benzocycloheptane The alkenyl)-iso-finalamine was prepared according to the method used in Example 148 and the separation of the palmomers was then carried out via a palm-like 10 HPLC. [Μ+ΙΤ] Measured value: 336 Retention time: 6.60 Condition: b. : (_)-2-pyrrolidine small group-N-(6,7,8,9_tetrahydro_5H_benzocycloheptene 15 The ene-6-yl)-isonicotinamine amide was prepared according to the method used in Example 148 and was subsequently separated from the palmeal isomers by anterior palm chromatography. [M+If] Measurement fill: 336 · Residence time: 8.15 20 Condition: b Guardian 151_ · (-)-2-Ilf 11 Lin-4-yl-N-(6,7,8,9_tetrazo _5H-benzocycloheptene each base) isoniacistone guanamine was prepared according to the method used in Example 148 and then separated by palmar HPLC. ~84~ This paper is applicable to China National Economic Rate (CNS) 八4 threat (21〇&gt;&lt;297 嫠) (please read the notes on the back and fill out this page)

1298999 A7 B7 V. Description of invention (Β) [M+H&quot;] Measured value: 352 Retention time: 5.25 Condition: b ! Example 1· (-+)-2-?福0林-4-基-N-( 6,7,8,9-Four Rat-5H_ 笨 j ^ 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 1&gt;1+1^]Measured value: 352 Retention time: 6.22 10 Condition: b _ in the chromatographic conditions of Example 3-152 (HPLC)

Chiralpak AD, 250 X 4·6 mm li^(Daicel), acetonitrile: isopropanol: n-g = 50:3:4, 1 ml/min 4. Chiralpak AD, 250 X 4.6 mm _Daicel, acetonitrile, 1 ml/min Merck Porospher 55 X 2 mm 5μ, gradient: 95% H20 (0.05% TFA) to 95% acetonitrile, 4 min, 95% acetonitrile, 1.5 min, 〇·5 ml/min YMC J'Spher ODS H80, 33 X 2·1 mm, 3μ, Gradient: 9〇%H2〇Conditions a Condition b Condition c Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printing Conditions d ~ 8 5~ This paper scale applies to China National Standard (CNS) A4 Specifications (210&gt;&lt;297 mm) 1298999 A7 B7 V. Invention Description (Batch) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5 (0-05%TFA) to 95% Acetonitrile, 2.5 minutes, 95% Acetonitrile, 0.8 Minutes, 1 ml/min Chiralpak AD, 250 X 4.6 mm, li^(Daicel), acetonitrile: methanol = 95:5, 1 ml/min LiChroCart 55-2, PuroSpher STAR; RP 18e (MERCK), solvent A: acetonitrile /water (90:10) +0.5% formic acid; solvent acetonitrile / water (10:90) + 0.5% formic acid; gradient: 95% B 0.5 min, 95% B to 5% B at 1.75 min, 5% B 2.5 min ; 1 ml / min Chiralpak AD, 250 X 4.6 mm, lOp (Daicel), Zheng Gengyuan · Ethanol: Methanol = 50:1:1, 1 ml / min retention time is expressed in % minutes (for each condition) Measurement of activation of eNOS transcription according to the disclosure revealed in e et al "Activation of protein kinase C alpha and / or epsilon enhances transcription of the human endothelial nitric oxide synthase gene 5', Mol. Pharmacol. 1998; 53: 630-637 Activation of transcriptional activity. In addition, the starting codon of the eNOS gene is 3,5kB long film condition e condition f condition g This paper scale is applicable to China National Standard (CNS) A4 specification (21〇X297 mm) (Please read the note on the back and then fill out this page) Order 1298999 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (κ) Section 5 'Copy, Serialize and Copy in Firefly Luciferin The enzyme expresses the plastid to monitor the activation of the eNOS promoter via the reporter (rep〇rter) gene activity, stably transfects and expresses this promoter-reporter constructed human endothelial cell line for compounding Test cells were incubated with compound (I) 18 h. 5 Dissolve the compound in sterile DMSO, allow for the final concentration of X5% DMSO in the medium, and measure the reporter gene expression using the standard luciferase test system (Promega, Cat. No E150) according to the manufacturer's instructions. In the evoked action of these cells, the ratio of the two activities 10 (transcriptional inducing ratio, TIR) is plotted as a function of the concentration of the compound in the luciferase-inducing effect of the cells cultured with the compound (I) compared with the solvent culture alone. In general, the ratio is 1 at a low concentration, and the TIR value indicates no compound effect, and extends to the maximum TIR value. (4) indicates an increase in eNOS transcription, which is determined by the graph as the ec5G value of the transcription-inducing ratio of the compound concentration function. The effect of eNOS-transcription was confirmed in a second test based on eNOS protein 15 detection. The root sputum standard method was used to isolate and culture primary human umbilical vein endothelial cells (HUVEC), and the fused cells were used. The compound was cultured for 18 hours and the winter effect of eN〇s protein expression was determined by quantitative Western blotting. After compound incubation, HUVEC was dissolved in 10 mmol. Tris-HCl, pH 8.0, 1% SDS and protease inhibitor 2 in ice-cold lysis buffer, cell lysate was subjected to standard denaturing polypropylene guanamine gel electrophoresis and blotted to nitrocellulose membrane, using specific Primary monoclonal antibodies (Transduction Laboratories, UK) and alkaline antibodies labeled with alkaline phytase (Jackson Labs) visually identify specific eN〇s protein bands and quantify them by chemical fluorescence detection. Read the notes on the back and fill out this page) «装·

, 1T ~ 87'

1298999 at B7 V. INSTRUCTIONS (η) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs The results are listed in the table below. Compound No. EC50 value (micromolar concentration) TIR(max) 1 0.02 3.3 la 0.001 3.2 lb 6.0 2.9 2 6.0 2.2 3 &lt;0,08 2.2 4 &lt;0.08 2.8 5 &lt;0.08 3.0 6 &lt;0.08 3.0 7 0.075 3.3 10 0.256 3 11 2.1 2.0 12 0.136 3.0 13 8.8 2.0 14 1.2 1.7 15 0.779 3.1 16 0.038 2.9 20 0.016 3.1 21 8.2 2.6 22 0.083 3.1 24 0.030 3.1 ~ 8 8~ (Please read the notes on the back and fill out this page. ) JT- Line « This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1298999 at B7 V. Invention Description (J7) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed compound number EC50 value (micro Molar concentration) TIR(max) 25 0.031 3.1 26 1.8 3.1 28 0.049 3.4 29 9.6 3.4 30 0.020 3.5 31 5.0 2.8 32 0.047 3 33 3.3 2.6 34 0.060 2.8 35 3.3 3.5 36 0.050 3.3 37 0.283 2.9 39 0.496 2.9 43 0.080 3.2 45 0.060 2.9 47 0.020 3.4 48 0.590 3.4 49 0.040 3 50 1.8 3 54 0.042 3.2 56 0.168 3 ~ 89' (Please read the notes on the back and fill out this page)

, 1T # This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298999 μ B7 V. Invention description u&lt;f) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed compound number ec50 value (micro-mole concentration ) TIR(max) 58 19 2.5 59 0.019 3.2 61 2.3 3.4 64 16 3.1 70 2.0 3.1 72 0.071 3.1 74 34 3.1 76 0.572 3.1 81 0.053 3.3 82 0.283 3.2 85 15 3 91 2.3 2.9 96 0.020 3 97 1.0 2.5 98 0.574 2.6 99 2.8 2.5 101 6.0 3.1 102 0.083 2.9 106 4.8 2.5 108 14 3.1 109 1.8 2.8 ~ 9〇~ (Please read the note on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297) PCT) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999. V. INSTRUCTIONS (π) Compound number ec50 value (micro-mole concentration) TIR{max) 110 1.0 3.1 112 0.040 3.1 114 0.030 2.9 115 0.020 3 116 0.150 2.9 117 0.136 3 118 0.140 3 119 0.230 3 120 0.041 3.1 122 0.015 2.85 123 0.260 2.9 124 0.006 2.9 125 0.040 3 126 0.351 2.9 127 4.9 2.7 128 0.002 3.1 129 0.100 3.1 130 0.110 3.1 131 0.440 3.1 132 0.050 3.1 , 133 0.128 3.1 ~91~ (Please read the notes on the back and fill out this page. Line _· This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) 1298999 V. Invention description (A7 B7 compound number EC50 value concentration) TIR(max) 134 3.0 3.5 135 0.589 3 137 0.090 3 138 10 3 139 1.9 3 140 1.3 3 141 0.250 3.2 142 3.0 2.5 143B 28 2.5 144 0.010 2.9 145 3.8 1.6 146 2.4 2.9 149 3.4 3 (Please read the note on the back before refilling this page) The effect of the compound according to the invention is also Can be demonstrated in the following animal models (animal experiments are based on the German Animal Protection Act and the Guide for the US National Institutes of Health) Care and Use of Laboratory Animals provides guidelines for experimental animals). 5 Animals and Treatment (Experiment A-C)

ApoE and eNOS-deficient mice (C57BL/6J background, Jackson Laboratory, Bar Harbor, Me) were used. All animals were 10-12 weeks old and weighed 22 to 28 grams. The mice were divided into 4 days before surgery. Group (apoE control group, n=10-12; apoE and compound (I), n=10-12; eNOS~92~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 4 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999 A7 B7 V. Invention description (7/) ^~- control group, n=l〇_12; eNOS and compound (I), η=10-12) and accept standard rodent Food (containing 4% fat and 0.001% cholesterol; hereinafter referred to as placebo group) or standard rodent food + compound (1) (10 or 30 mg/kg, orally). Antihypertensive effect of ApoE overwhelming mice 5 Using a computerized tail-palm system (Visitech Systems, Apex,

Nc) The blood pressure of the sensory mice was measured, and the test compound was used to treat ApAE-deficient mice and eNOS-deficient mice, and the blood pressure was compared with the results obtained with the placebo. B inhibits neuronal intimal formation and atherosclerosis (femoral circumflex) 10 Treatment of ApoE-deficient mice with each compound after 3 days (1 mg/kg/day in food), intraperitoneal injection Pentobarbital (6 mg/kg) was anesthetized and intramuscularly injected with xylazine (2 mg/kg) and the band was revealed according to Moroi et al. (J Clin Invest 101:1225-32, 1998). Placed around the femoral artery, briefly, dissecting the left femoral artery, using a 15 PE-50 tube (inner diameter 〇 · 56 mm, outer diameter 〇 · 965 mm, Becton

A non-occlusive 2 mm mm polyethylene annulus made by Diekmson, Mountain View, Ca) was placed around the artery and tied with two 7-0 sutures to separate the right femoral artery from the surrounding tissue but without a ring Band, after treatment, each compound was continuously treated for 14 days, then the animals were killed, and the aorta was taken out and the vascular NOS expression was measured by a 20-gauge Western blotting method. Both femoral arteries were collected, fixed in formalin and embedded in paraffin. 20 sections (1 μm) were cut from the annulus of the left femoral artery and from the corresponding part of the right artery, and the section was subjected to standard hematoxylin and eosin staining, using a mirror analysis computer program (LeicaQWin, Leica) Imaging Systems, Cambridge, GB) for morphological analysis, for ~93~ This paper applies to China National Standard (CNS) Eight 4 Secrets (21qx297 public) (Please read the notes on the back and fill out this page again) -Iml-- -----IT—-----^__w.. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1298999 A7

= truncated 3 area of the cavity, the inner layer of the inner tube of the neuron tube, the inner membrane of the upper nerve is defined as the area between the cavity and the inner elastic layer, and the middle layer is the area of the inner and outer elastic layers, the nerve The ratio of the intimal area of the golden tube to the mid-layer area of the jk was expressed as the ratio of the 5 layers in the endocardial/enteral tube of the neurovascular endothelium. The results obtained in the compound group were compared with those obtained in the placebo group. c. Prevention of atherosclerotic plaque formation in chronic treatment with various compounds pressed in food (^ lack of mice after 16 weeks of spermatozoa and finally kill it, remove the aorta from each mouse, fixed at 10 Formalin is embedded in paraffin, measured by lipid damage in the aorta (from the aortic arch to sputum) and analyzed by oil red sputum staining analysis. In this test, the femoral artery is used to fix each compound in the blood vessel eN〇| The effect of g expression was compared in the compound group with the results obtained in the placebo group. D Improves the coronary function of the sick ApoE-deficient mice 15 In the experiment, the old male wild &amp; C57BL/6J mice were used. River Wiga GmbH, Sulzfeld) and a 6-month-old apoE-deficient mouse (C57BL/6J background, Jackson Laboratory, Bar Harbor, Me) weighing 28 to 36 grams, dividing the mice into 3 groups (C57BL/6· , n=8; apoE control group, n=8; apoE and compound (I), n=8) and received standard 20 rodent food (containing 4% fat and 〇·〇〇1% cholesterol) or standard rodent food + each compound (30 mg / kg, orally). Sodium ketone (100 mg/kg, intraperitoneal) anesthetize the mouse and quickly remove the heart and place it in ice-cold perfusion buffer, intubate the aorta and connect it to the perfusion device (HUGO SACHS ELECTRONICS, ~94~ paper scale Applicable to China National Standard (CNS) A4 specification (21 OX297 mm) (Please read the note on the back and fill out this page) -, can be printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 1298999 A7 B7 V. Invention Description ( P) 5 10 15 20

Freiburg, Germany) immediately started at a fixed perfusion pressure of 6 mm Hg, using a modified Kreb bicarbonate buffer equilibrated with 95% 〇2 and 5% (:02 and maintained at 37.5 °C in retrograde mode Underflow of the heart. The beveled tubule (PE 50) is passed through the pulmonary vein into the left ventricle and stretched through the ventricular wall, secured to the apex via the groove end, and attached to the tip-micro pressure gauge (Millar 1.4 French), the left atrium was inserted into the same pulmonary vein and the heart was adjusted to the operating mode with a 10 mm silk fixed preload force and a load pressure of 6 mm Hg, using an ultrasonic flow probe (HSE/Transomc Systems Inc) ·) Continuous measurement of outflow and atrial flow (infl〇w), based on the difference in atrial flow and aortic flow, and all hemodynamics at a sampling rate of 1 Hz The data was digitally digitized and recorded on a PC using special software (HEM, N〇t〇c〇rd). The heart was stabilized for 30 minutes, and all functional blood movements were measured during steady state and during volume and pressure j loading. Number The left ventricular function curve was established by changing the pre-load pressure. In order to obtain the monthly il-reduction curve, the post-load was set at 6 〇 to the column and the 5 to 25 mm Hg range was adjusted to 5 mm Hg. To stabilize the heart in the baseline situation between the dust and the volume and negative &gt; ί 寺. ! #! (Please read the notes on the back and fill out this page.) Order the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives The core paper scale applies to the Chinese national standard (CNS } a4 specification (210Χ297 mm)

Claims (1)

298999 正; Bu Ke A8 B8 C8 Patent Application No. 91102290 ROC Patent Appln. No.91102290 The text of the patent application without amendments after the amendment (1) Amended Claims in Chinese End (T) (Submitted in December 1993/September 1993) (Submitted On December l〇, 2004) 10 A 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine deuterated according to formula (I), in any of its stereoisomeric forms or Mixtures of any ratio or pharmaceutically acceptable salts thereof, 15 (I) Where R1, R2, R3 and R4 are Η; 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 25 Α is selected from the group consisting of CH2 and CHOH; B, C and D are CH2; R5 is Ar-based or Hetai*-based, two Any one of which may be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo; CN; NH2; unsubstituted or monosubstituted, disubstituted or trisubstituted CrC8 via (CrC4)-alkoxy -alkyl, C2-C8-alkynyl, unsubstituted or monosubstituted, partially substituted, trisubstituted CrC8-alkoxy, (C"C8-alkyl)amine, bis(CrC8-alkyl) Amine; C3-C5-alkanediyl; phenyl; hetero 96 - 91028B - paper size applicable to China National Standard (CNS) A4 specification (210x297 mm) 1298999 Fangshen- or heteroaryl-substituted crC4-alkyl 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 -^^3 ; OK ' S(0)m-(CrC4) alkyl, where m is 0 , 1 or 2· #基;benzylamino; C00-(CrC8)-alkyl·,sow%4^amine Q)-alkyl-S〇2NH-; and saturated or monounsaturated lipid singly (1 or &amp; 1 member comprising 1 or 2 heteroatoms X 5: group including N and oxime, the heterocyclic group may be selected from one, two, three or four, including beach lanthanum, Ci-C: 3 Substituting a substituent of an alkyl group and a ketone group, wherein the heterozygous disaccharide is condensed to the Ar group or the Hetar group as needed; wherein all = aryl groups: phenyl, hetero-containing filaments and phenyl-containing groups, It is optionally 3 that the substituent of the Ar group or the Hetar group may be substituted by two substituents including a halogen group, a CN, a CKV alkyl group and an OH: group; wherein Ar is a phenyl group; Is a 5- to 10-membered aromatic mono- or bicyclic ring containing one or two <"heterocyclic groups from heteroatoms including N, fluorene and S; heteroaryl is 5- to 10-membered aromatic mono-? _ a heterocyclic group containing one or more hetero atoms selected from the group consisting of ruthenium, osmium and S. *Lu Nian's succulent, sulphurized, 0,7,8,9-tetrahydro-5 benzene, bis-2, any stereoisomeric form thereof or in any of the exemplified or pharmaceutically acceptable _, where _ R1, R2, R3 and R4 are H; A is selected from the group consisting of CH2 &amp;ch〇h; B, C and D are CH2; 1298999, the patent application A8 B8 C8 D8 is surrounded by 5 R疋Ar or Hetar, both of which may be unsubstituted or have one, one or two substituents selected from the group consisting of halo; Cn; NH2, not Monosubstituted, disubstituted or trisubstituted CrCs-alkyl, C2-C8-alkynyl, Crc8-alkoxy, (Ci.C=alkyl)amine, dioxane substituted by (CrC4) alkoxy Amino group; Q_C5_alkanedi, phenyl, heteroaryl: phenyl- or heteroaryl-substituted C1_C2-alkyl LCF3; 〇H; S(〇)m(CrC4-alkyl), wherein m is i or 2 n-based amino group; benzylamino group; C00(C丨-C6-alkyl); - 10 fine 2 '(Cl_C4_alkyl) 〇 〇; and saturated or monounsaturated = a family of mononuclear 5- or 6-members containing 15 5 2 heterocyclic groups selected from the group consisting of "NA", which may be via -, two, three or four 2 = subunits, CVC3-hospital and Substituted by a substituent of a group, 15 mils of which are to be condensed to the fluorenyl group or the Hetar group; a heteroaryl group of phenyl phenyl P, a phenyl group, a aryl group, which is optionally present in the base of the group, may be - Or two substituents selected from the group and OH; Q soil, CN, CrC3_alkyl group = Included in the 10_ member aromatic mono- or bi-ring containing -, two or three heterocyclic groups selected from Ht I, including N, ° ^ S heteroatoms. Hetar base is 5 to 1 〇 aromatic, &amp; base is = Ν, and one: ring base - according to the scope of the patent application! or guilty - stupid and cycline amine, in any 3. 20 1298999 s, the patent application scope A8 B8 C8 JD8 any ratio of mixture or a pharmaceutically acceptable salt thereof, wherein in the formula (I), R1, R2, R3 and R4 are hydrazine; A, Β, C and D are each CH2; 10 15 20 R is a phenyl group or a Hetar group, both All may be unsubstituted or carry one, two or three substituents selected from the group consisting of halo; CN; NH2; unsubstituted and at least monosubstituted CrCV alkyl (c: 4 alkoxy), c2 -c6-fast radical, CKV alkoxy, (c "C4-alkyl" amine, bis(cvc4-alkyl)amine; C3_c^diyl; phenyl; heteroaryl-phenyl- or hetero Aryl, substituted C "C2H CF3 ; 〇H ; S (〇) m (CKV alkyl), which makes 4 〇 or 2; C00 (Cl_ C, 6 alkyl) 'S〇2NH2, (c widely Cp burned Base)s〇2NH-; and saturated=unsaturated aliphatic mononuclear 5- or 6_members containing one selected from the group N a heterocyclic group of a hetero atom of hydrazine, which may be substituted by one, two, two or four selected from the group consisting of a south group, wherein the thiol group and the fluorenyl group are condensed as needed To the phenyl group or the group; wherein all of the impurities: and the group containing a phenyl group, which may be in the substituent of the phenyl group or the 3-heterocyclic group, may be in the phenyl group or the The ruthenium-alkyl group and the oh substitution are selected from heteroatoms including a halogen group, a CN group which is 5- to 1 (a), a member of the aromatic group, n, 〇 and s: two or two selected Hetar groups are 5_ to 1Gm贞4, from heterocyclic groups including a ruthenium and 8 or 2 or 3 selected W heteroatoms. -99 297 mm) This paper size applies to the Chinese National Standard (CNS) m specification A8 B8 C8 1298999 4· According to the scope of the patent scope i or 2, the 6,7,8,9-tetrahydro-5H- benzocycloheptylamine, in any of its stereoisomeric forms or in any a mixture of ratios or a pharmaceutically acceptable salt thereof, wherein in the formula (I), R1 'R2, R3 and R4 are Η; Α, Β, C and D are each CH2; 10 15 Ministry of Economic Affairs Intellectual Property Office employees The consumer cooperative prints that 20 R5 is a phenyl or Hetar group, both of which may be unsubstituted or have one, two or three substituents selected from the group consisting of F; Cl; Br; C^C3-alkyl; CrC3 - alkoxymethyl; CF3; C3-C5-calcyl; phenyl; heteroaryl; heteroaryl-methyl; OH; crC3-alkoxy; trifluoromethoxy; 2, 2, 2 _Tri-I ethoxy; Li 2; (Crc4_ fluorenyl) Months' '(CrCV alkyl) amine group; alkyl)-S02NH-; COCKCVCr alkyl); -SC^NH2; ; hexahydroquinone. a base, a sulphonyl sulphate; and a sulphonic sulphate; all of the heteroaryl, phenyl, heteroaryl-containing, and stupid-containing groups, optionally present in the phenyl or the Hetar group The substituent may be substituted with _ or a plurality of substituents selected from the group consisting of halo, CN, C1-C3-alkyl and OH; &amp;heteroaryl is selected from the group consisting of furyl, pyrrolyl, Thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, hydrazine, pyridinyl, pyridyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, Benzosulfanyl, iso-indolyl, hydrazino, carbazole, carbazyl, benzofuranyl, benzophenylthio, and carbazolyl; -100 China National Standard (CNS) A4 Specification (210x297) [298999 A8 B8 C8 D8 VI. Patent Application The Hetar group is selected from the group consisting of furanyl, pyrrolyl, thienyl, anthracenyl, isothiazide. , oxime, isoindolyl, sulfhydryl, cyanosyl, σ argon, pyrene, pyridyl, glucosinolate, benzomethanone, Benzo-indenyl, benzoxanthylpyridinyl 5, fluorenyl, isoindolyl, fluorenyl, oxazolinyl, p-fluorenyl, benzoxanthyl, benzophenylthio And 0 σ 坐 〇 〇 〇 〇 . . . . 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 a form or a mixture thereof in any ratio of 10 or a pharmaceutically acceptable salt thereof, wherein in the formula (1), R1, R2, R3 and R4 are oxime; A, Β, C and D are each CH2; R5 is selected from The following groups are included: 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl 15, 4-(Ci_C3-alkoxy)-phenyl, 4-dimethoxymethoxyphenyl, 2-&gt; Stinky _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing 4-fluorophenyl, 2-chloro-4-fluorophenyl, 3,4-dimercaptophenyl, 2,4-dimethylphenyl, 4 -Ga-2-methylphenyl, 2-yl-4-indolylphenyl, 2-indolyl-4-ethoxyphenyl, 2-methoxy-4-indolylphenyl, 3 -1-4-methylphenyl, benzo[1,3]dioxan-5-yl, 2,2-digas-benzene 20-[1,3]dioxolan-5-yl, 2,3-dihydrobenzofuran-5-yl, 1-(4-chloro-phenyl)-5- Trifluoromethyl-1H-pyrazol-4-yl, 1-(4-fluoro-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl, 1H-benzotriazole_5 -Base, 1H-port, 11 -4-yl, 111-1, pentyl-6-yl, 1-isopropyl-2-trifluoromethyl-1H-benzimidazol-5-yl, 1-methyl Benz-3-keto-1,2,3,4-tetrahydro· 101 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 9 9 9 8 9 2 AB c D VI. Application Patent scope: 咁-6-yl, 1-phenyl-5-trifluorodecyl-1H-pyrazol-4-yl, 2-(2-trans-l-11-decyl-4-yl)-1H - Benzo flavor. Sodium-5-yl, 2-(4-ranyl-phenyl)-1Η-benzimidazol-5-yl, 2,4-dimercapto-oxazol-5-yl, 2,4-dimethyl -pyrimidin-5-yl, 2,4-dimethyl-thiazol-5-yl, 2,5-dimethyl-5-yl-1 fluorene-bipirolo-3-yl, 2,5-dimethyl-1 -phenyl-1 H-portllo-3-yl, 2,5-dimercapto-1-pyridin-4-ylmethyl-1Η-pyrrolyl, 2,5-dimethyl-2Η- Pyrazol-3-yl, 2,6-dichloro-cyclopyridin-3-yl, 2,6-dimethoxy-11 ratio. D--3-yl, 2,6-dimethyl. ratio. 3-Benzyl, 2-amino-4,6-dimethyl-^ ratio 111--3-yl, 2-amino-6-gas-batch 17--3-yl, 2-amino- . Than 10 bit-3-yl, 2_gas_6-methyl-oxime. Ding-3-yl, 2_qi-. ratio. D--4-yl, 2-anoxapropyl-4-mercapto-3⁄4. Take a 5-amino group, 2-dimethylamino-4-mercapto-mouth plug. Sit on -5-yl, 2-dimethylamino-. °-4-yl, 2-ethyl-5-methyl-2H-portpyrazol-3-yl, 2-hydroxy-6-methyl-cyclopyridin-3-yl, 2-indenyl- 1Η-Benzyl porphyrin sits on a 5-based, 2-methyl-3Η-benzene yam. Sitting on a 5-base, 2-indolyl-to-mouth ratio of 15 σ--3-yl, 2-methyl-6-disorder thiol. Ding-3-yl, 2-methyl-σ plug Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed u sit-5-based, 2_norfos-4-yl-1:1 ratio -4--4-yl , 2- 福 1:1 lin-4-yl-mouth dense sigma-5-based, 2-° piroxime-l-based-to-mouth ratio. _4_ base, 3,5-dimethyl-1H-port ratio keto-4-yl, 3-amino-5,6-dimethyl-port ratio well-2-yl, 3-month Anki-5-methyl-0 ratio phen-2-yl, 3-amino-indole σ-2, dimethylamine 20 -4-methyl-phenyl, 3-dioxene Amino-phenyl, 3-indolezimidazole-5-yl, 1-indole-benzoic. Sitting on -5-based, 3-methyl-branched, arylamino-2-methyl-phenyl, 3-methanesulfonylaminophenyl, 3-methyl-isoxazol-4-yl, 3-吗福林-4-yl-phenyl, 3- 6-nine 0 to 0-l-yl-phenyl, 3-.略σσ-1-yl-phenyl, 4-(2,2,2-difluoroethoxyphenyl)-phenyl, 4,6_ -102 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1298999 A8 B8 C8 D8 VI. Patent application range Dimethyl-pyridin-3-yl, 4-amino-2-ethylsulfonyl fluorenyl-pyrimidine _5_yl, 4-amino-2- Methyl-pyrimidinyl, 4_gas_3_decanesulfonylamino-phenyl, 4-chloro-3-aminesulfonyl-phenyl, 4-mercapto-3-methylamino-benzene Base, 4-mercapto-thiazolyl, pyridin-2-yl, 5,6,7,8-tetra-5 Hydrogen-methyl sulfonamide, amino-1-phenyl-1H-.嗤-4-yl, 5-methylsulfonyl-2-methyl-phenyl, 5-methyl-1-phenyl-1-indole-pyrazole-4-yl, 5-mercapto-isoxazole 3-yl, 5-methyl-pyridine-3-yl, 5-mercapto-pyridin-2-yl, 6-chloro-pyridin-3-yl, 6-cyano-pyridin-3-yl, 6-Diaminoaminopyridin-3-yl, 6-ethynyl-pyridine-3-yl, 6-methoxy10 fluorenyl·&quot;pyridine-3-enyl, 6-decyloxy-pyridine_3 _ base, methyl-2-decylamino-pyridin-3-yl, 6-methylamino-pyridin-2-yl, 6-methyl-° ratio 疋-3-yl, 6-?福咐_4_基_u比ϋ定_3_基,6-η比洛咬小基-吼丁_3_基, 口米唑和[i,2_a]tJ比啶_2_基,卜Trii-methyl-pyridin-3-yl and pyrimidin-4-yl. 15 6·6,7,8,9-tetrahydro-5H- benzocycloheptenylamine, according to claim 1 or 2, in any of its stereoisomeric forms or in any ratio a mixture thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 2,5-dimethyl-1-pyridin-4-ylmethyl_1Η-pyrrole-3 printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economy. -carboxylic acid (6,7,8,9-tetrahydro-5-benzocycloheptene-6-yl)-decylamine, 5-methyl-1-phenyl-1indole-pyrrolidinecarboxylic acid ( 6,7,8,9-tetrahydro-5Η-benzocycloheptene each) 醯 醯, 1 哚 哚-6-carboxylic acid (6,7,8,9-tetrahydro·5Η_stupid Cycloheptene_6_ylguanamine, 5-methyl-pyridin-2-carboxylic acid (6,7,8,9-tetrahydro-5 fluorene-benzocycloheptene-6-yl)-decylamine, 2-methyl-3Η-benzo-salt-5-weilic acid (6,7,8,9-tetrahydro--103 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1298999 A B c DJ 10 15 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Base) _ gas 2 · methyl heart rhyme. Sitting money, tetrahydro-stupid and cycloheptyl)-octylamine, "better" - soil) 4 (2,2,2-I I 虱 、, 6 6 A) ww 疋... soil 1 (6 ,7,8,9-tetrahydro-5H-benzocyclol. (6W bis-J-heptenyl)-nicotinium amide, 3-amino-5,6-dimethyl-17 ratio σ Well-2-decanoic acid (6 7 δ η λ- 4_Fluorine-_78: called Yangcheng Ring Sheng 6_ base "amine 2 base H5H_benzocycloheptyl) amine, guanamine 24 - W wind benzocycloheptene each base) - benzyl bromide ° sitting acid (6,7,8,9-tetrahydro-benzo-cycloheptene: ketone) - guanamine, 2-amino group - Νlike 8,9•tetrahydro-benzocycloheptene-6-yl) rhyme _, 2,6_ dimethyl secret (6,7,8,9_tetrahydro-sodium benzodiazepine ·6· Glycosylamine, 3_amino group _5•methyl (6,7,8,9·tetrachloro-p- and cycloheptyl)&gt; decylamine, amine _(tetra)_2_neu (6'7,8 , 9 tetrahydrogen. benzocycloheptyl) styroic amine. 6,7,8,9-tetrazol-5-benzophenone of the formula (1) according to the definition of claim 142 Heptenylamine, fC Η -104 This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1298999 as B8 C8 ^ is used as a pharmaceutical product in the form of a homologue or a mixture thereof in any ratio or a pharmaceutically acceptable salt thereof. 8. The root of the patent, the scope of the patent, the 6,7,8,9, hydrogen, benzoheptylamine, in any of its stereoisomeric forms or in any of the examples Or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for stimulating expression of endothelial NO-synthase. 9. In accordance with the scope of the patent application, i.e. 6,7,8,9_tetranitro-pirin-benzoheptenylamine, in any of its stereoisomeric forms or mixtures thereof in any ratio or a pharmaceutically acceptable salt thereof for use in the manufacture of 10 agents for the treatment of cardiovascular disease, stable and restless angina, coronary heart disease, Prinzmetal colic, acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis Formation, peripheral arterial occlusion, endothelial dysfunction, atherosclerosis, reocclusion, endothelial injury after PTca, high A pressure, essential hypertension, pulmonary hypertension, secondary 15 blood pressure, renal vascular high Blood pressure, renal vascular chronic glomerulonephritis Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing clothing, erectile dysfunction, arrhythmia, diabetes, diabetic complications, nephropathy, retinopathy, angiogenesis, bronchial asthma, chronic kidney abortion, Cirrhosis, osteoporosis, restrictive memory performance, restrictive learning ability, or lowering the risk of 20 vasculature in women after menopause or taking birth control pills. 10. A pharmaceutical preparation for the regulation of eNOS expression in intradermal cells, comprising an effective amount of at least one compound of formula (1) as defined in any one of claims 1 to 6 of the patent application, in any stereoisomeric form thereof Or a mixture thereof in any proportion or a pharmaceutically acceptable salt thereof, -105 - This paper size applies to the Chinese National Standard (CNS) A4 specification (2) 0χ297 mm) 1298999 5 10 15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives 20 and pharmaceutically acceptable carriers. 11. The pharmaceutical preparation according to the scope of claim 1G of the invention, which is in the form of a pill, a lacquered tablet, a sugar-coated tablet, a granule, a hard and soft gelatin capsule, an aqueous, alcoholic or oily solution, Sugar preparations, emulsions or suspensions, suppositories, solutions for injection or infusion, ointments, tinctures: sprays, transdermal medical systems, nasal sprays, aerosol mixtures, microcapsules, implants or rods. I2·- a method for synthesizing a compound of formula 7 according to any one of claims ii 6 of the patent application, which comprises 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine and appropriate The coupling reaction of _ or county gas in the presence of a suitable and/or suitable couple of agents, the functional compound thus obtained is subsequently functionalized as needed. 13. According to the + application „ patent scope of the 1st or 21st member of the brewing 6,7,8,9-tetrahydro-5H-benzonepeptenylamine, in any of its stereoisomeric forms or in any a mixture of ratios or a pharmaceutically acceptable salt thereof, wherein in the formula (I), the group A is CH2. 14. According to the application, the range of the third or the second is 6,7,8,9_ Tetrachloro-5H-exocycloheptenylamine, in any of its stereoisomeric forms or a mixture thereof in any ratio, or a pharmaceutically acceptable salt thereof, wherein _ self-contained 4 pin bases, 2, 2 _二二并并二虱戊% 5_ base, 6-methoxymethyl-pyridine-3-yl, fluorenyl-1沁benzimidazolyl and 2-methyl-3H-benzimidazole_5_ Base. Soil 15 · According to the medium and material range 1 * 2, '6,7,8,9_tetrahydro-5H-benzoxanthylamine, in any of its stereoisomeric forms or -106 - Paper Size Standard (CNS) A4 Specification (210x297 public) - A8 B8 C8 D8 10 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printing and Printing [298999 VI. A mixture of any proportion of the patent application or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 4-fluoro-N-(6) , 7,8,9-tetrahydro-5H-benzocycloheptene_6-yl)benzylguanamine, 2-methyl-3H-benzimidazole-5-carboxylic acid (6,7,8,9- Tetrahydro-5H-benzocycloheptene-6-yl)-nonylamine and 2-methyl-1H-benzimidazole-5-carboxylic acid (6,7,8,9-tetraindole-5H-benzo) Cycloheptene-6-yl)-guanamine. 16. A 6,7,8,9-tetrahydro-5H-benzocycloheptenylamine, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, which is selected from the group consisting of Including (S)-6-methoxymethyl-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-nicotinium amide and 2-mercapto- 3H-Benzimidazole-5-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl)-guanamine. 107 This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)