TWI324999B - Compounds for treating fundic disaccomodation - Google Patents

Description

1324999

V. INSTRUCTIONS (/) 5 10 15 20 Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperatives Μ The present invention relates to a novel compound of formula (1) having a substrate relaxation property, and to a method for preparing the same, which comprises the compound The pharmaceutical composition and the use of the compound as a medicament for restoring disturbed substrate disorders. DE-2,4〇0,094, published on July 18, 1974, discloses 1-[1-[2-(1,4-benzodioxan-2-yl)_2-hydroxyethyl] with hypotensive activity] -4- hexahydro 0 ratio. Fixed base-2-benzene flavor. sit. Lin Wei. DE 2,852,945, published on Jun. 26, 1980, discloses a bismuth hexahydroquinone-based carbendazole having an antihypertensive activity. Ketone. Ep_〇, 004, 358, published on October 3, 1979, discloses N_啐cycloalkylalkylhexahydropyridine which can be used as an antidepressant and a psychostimulant. EP-0, 〇 48, 218, issued March 24, 1982, discloses N-oxides of N-salt-alkyl hexahydropyridinium having antidepressant activity. WO_93/i7〇17, published on September 2, 1993, discloses [(benzodioxan, benzofuran or benzopyran)alkylamino]alkyl substituted oxime, which acts as a selective vasoconstrictor It is used to treat conditions associated with vasoconstriction, such as migraine, clusters, and headaches with vascular disease. WO-95/053837, published on Feb. 23, 1995, discloses that dihydrobenzopyranidine derivatives also have vasoconstrictor activity. As of August 7, 1997, WCW/28157 discloses that the aminomethylbenzo dihydromethane derivative is used as a therapeutic agent for degenerative nerves of α2_adrenalin. α The compound of the present invention is different from the known compounds mentioned in the art in the structure of the divalent group _ai=a2_a3=a4_, the nature of the R5 substituent and pharmacologically ~3* The paper scale applies to the Chinese solid standard ( CNS) A4 specification (G〇x 297 public love - (please read the note on the back? Please fill out this page again) - ------- order---------- 1324999 A7 B7 economy Ministry of Intellectual Property, Staff Consumer Cooperatives, Printed, V. INSTRUCTIONS (The fact that these compounds unexpectedly have basal relaxation properties, and that the additional advantageous pharmacological properties of the compounds of the invention are little or no vasoconstrictor activity. Compound of formula (1)

Z1 Z2

-AlkL -R5 (I), 10 a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, or a quaternary salt thereof, wherein _a1 = a2 - a3 = a - is a divalent group of the formula -N=CH-CH=CH- (a-1), -CH=N-CH=CH- (a-2), -CH=CH-N=CH- (a -3), -CH=CH-CH=N- (a-4), -N=N-CH=CH- (a-5), -N=CH-N=CH_ (a-6), -N =CH-CH=N- (a-7), -CH=NN=CH- (a-8), -CH=N-CH=N- (a-9), or -CH=CH-N=N - (a-1〇); -zkz2- is a divalent group of the formula -Y'-CH(R4)-CH2--Y'-CH(R4)-0- (b-1), (b-2 ), .nni^· ϋ flu fl— e^ia^i ^^1 · IK n ^if IV nnn TI i ^^1 I (Please read the phonetic on the back first? Then fill out this page) This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1324999 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed V. Invention Description (Multiple) -Y'-CH(R4)-CH2-0- (b- 3), -Y'-CH(R4)-CH2-S-(b-4), -Y'-CH(R4)-CH2-NH-(b-5), -Y'-CH(R4)- CH2-CH2-(b-6), -Y1-CH(R4)-CH2-CH2-CH2-(b-7), -Y'-CH(R4)=CH-(b-8), -Y' -CHCRVCH-CH!- (b-9), -Y'-CH(R4)-CH=CH- (b-10), -Y1-CH(R4)=CH-CH2-CH2- (b-11) , Or Y'-CH2-CH(R4)-(a-12); wherein, where possible, one or two hydrogen atoms on the same or different carbon or nitrogen atom may be hydroxy, Cm alkoxy CM alkyl, CM Alkylcarbonyl, or optionally substituted by a dentate group, a hydroxyl group, a Cw cycloalkyl group or a phenyl group substituted with a phenyl group, y 5 Y1 is oxygen or sulfur;

Alk>CM alkylcarbonyl, carbonyl*CM alkyl, CM alkylcarbonyl (^4, carbonyl, or optionally via hydroxy, yl, amine, hydroxy (^-4 alkyl, CM alkoxy, hydroxy) Carbonyl group, cM alkyl ester group, aminocarbonyl group, mono or di(CM alkyl)aminocarbonyl group, Cm alkoxy Cm alkyl group, 0 Cm alkylcarbonyloxy group, CU4 alkylcarbonyloxy CM alkyl ester group oxygen , CN4 alkoxyimino, phenyl Cl4 alkylamino, cM alkyl ester Cm alkenyl, cyano (^-6 alkenyl or Q.6 cycloalkylcarbonyloxy CM alkyl decyloxy) Substituted Ci_6 Hyun·diyl; R1, R2 and R3 are each independently selected from hydrogen, Cl6 alkyl, C36 dilute, C|_6. The paper scale applies to China National Standard (CNS) A4 specification (210 X 297). Public hair) --------------------^--------- (Please read the phonetic on the back? Please fill out this page again) 1324999 A7 B7 V. INSTRUCTION DESCRIPTION (f) 10 15 alkoxy, hydroxycarbonyl, trihalofluorenyl, trioxalyloxy, halo, hydroxy, cyano, nitro, amine, CN6 alkylcarbonylamino, Q- 6 alkyl ester group, Cm alkylcarbonyloxy group, aminocarbonyl group, mono or bis(Q-6 alkyl)aminocarbonyl group, amine group Q-6 alkyl group, mono or di C, -6 alkyl)amino Cm alkyl, CM alkylcarbonyloxy CM alkyl oxy, or C 3-6 cycloalkylcarbonyloxy CM alkyl oxy; R 4 is hydrogen, hydroxycarbonyl, phenyl Aminocarbonyl, mono or di(CM alkyl)aminocarbonyl, Q-4 alkoxy CM alkyl, CN4 alkyl ester, N-pyrrolidinylcarbonyl, N-hexahydropyridylcarbonyl, N-high Hexahydropyridylcarbonyl, Cl-4, & aryl-based Ci_4, S, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C a Ci6 alkyl group substituted with a thiol group or, if desired, a thiol group, a murine group, a phenyl group, a mono or di(cM alkyl)amino group or a mono or di(CM alkyl)aminocarbonyl group; A- is the divalent group of the following formula—Nr-Aik2—(c-1)

(C-2) 20 (CH2)-

R6

(CH2)sr Ministry of Economic Affairs Intellectual Property Bureau employee elimination f cooperative printing R6 (c-3)

(c^) R6 (CH2)sr N-(CH2)„ (c-5) (c-6) (c-7) (Please read the notes on the back and fill out this page)

This paper scale applies to China National Standards (CNS) A4 specifications (210x2^^5" 1324999 A7 B7 5. Inventive Note (r) where m is 0 or 1;

Aik2 is a divalent group independently selected from (: "alkylcarbonyl Cm alkyl; phenyl; C3_6 cycloalkylcarbonyloxy CM alkyl oxy), optionally having one or more than one halo, hydroxy, hydroxy Carbonyl, hydroxy Q-4 alkyl, (:, .43⁄4 oxy, C1-4 alkoxy C1-4 alkyl, C|_4 flammable, Cm alkylcarbyloxy Cm acetaloxy , C>6-cycloalkyloxy-Ci.4^@| alkoxy, phenyl-substituted Qu-cycloalkanediyl; or, if desired, one or more hydroxyl, dentate, amine, hydroxycarbonyl, Hydroxy CM alkyl group, 1 〇Cm alkoxy group, Cm alkoxy group Ci_4 alkyl group, Cm group, CM group benzyloxy Cm oleyloxy group, 〇3.6 ring yard group, amine base group a mono or di(CM alkyl)aminocarbonyl substituted Cy alkyl group, or a q6 alkyl group wherein the Cw alkyl group and the carbon atom to which it is attached may form a core ring; 15 r6 is hydrogen, Cm alkyl group, Halo group, hydroxyl group, hydroxy hydrazine with alkyl group, CM alkoxy group, amino group CM alkyl group, CM calcinyl group, Cw alkylcarbonyloxy group C 4 alkyl ester group, amine group, thiol group, amine group a mono- or mono-(Ci 4 alkyl)amino group or a Q 6 cycloalkylcarbonyloxy Ci4 alkyl esteroxy group; R5 is the basis of the following formula (please read the notes on the back and fill out this page) f

^1 n n n^--"'T a n n a^i I Printed by the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1324999 10 A7 B7 5. Inventive Note (4) where η is 1 or 2; ρ1 is 0 and ρ2 is 1 or 2; or ρ1 Is 1 or 2 and ρ2 is 0; X is oxygen, sulfur, NR9 or CHN02; Y2 is oxygen or sulfur; 5 R7 is hydrogen, CN6 alkyl, C3_6 cycloalkyl, phenyl or phenylmethyl; R8 is C ^6 alkyl, C3_6 cycloalkyl, phenyl or phenylfluorenyl; R9 is cyano, Cw alkyl, C3-6 cycloalkyl, Q-6 alkyl or amine carbonyl R1 () is hydrogen or Q-6 alkane Or R9 and R10 together with the nitrogen atom to which it is attached form a pyrrolidinyl group, a hexahydropyridyl group, a high hexahydropyridyl group, a hexahydropyridinyl group, or a ruthenium group, which is burned by Ci_4 as needed. Substituted or Ci-4 alkoxy substituted; and Q is a divalent group of the following formula (please read the phonetic transcription on the back side? Please fill out this page again) t 15 -ch2-ch2- (e-1), -co- Ch2-(e-6), -ch2-ch2-ch2-(e-2), -(CH2)2-CO- (e-7), -CH2-CH2-CH2-CH2-(e-3), -CO-(CH2)2- (e-8), -CH=CH- (e-4), -CO-CH2-CO- (e-9), -CH2-CO- (e-5), - Ch2-co-ch2-(el〇), wherein one or two hydrogen atoms are on the same or different carbon atoms as needed % (^^ burn group by group or phenyl, or Q is a bivalent group of the Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed%

, or (e-H)

(e-12) -8~ This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). V. INSTRUCTIONS (7 A7 B7 The halogen group used in the above definition refers to the fluorine group, a gas group, a molybdenum group and an iodine group; the Q fluorenyl group defines a linear and 1 bond saturated hydrocarbon group having up to 4 carbon atoms, such as an anthracene group, an ethyl group, a propyl group, a butyl group, a methylethyl group 2 _A 5-ylpropyl, etc., Q_6 alkyl is meant to include (^_4 alkyl and its higher carbon homologues containing 5 or 6 carbon atoms, such as 2-mercaptobutyl, pentyl, hexyl, etc.; C3 6-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C36 alkenyl defines straight-chain and branched unsaturated hydrocarbon groups having 3 to 6 carbon atoms, such as propenyl, butenyl, pentyl Alkenyl or hexenyl; Cl 2 alkanediyl defines methylene or 10 1,2·ethyl-yl 'C!·3 sylylene defines a divalent straight or branched hydrocarbon group having 1 to 3 carbon atoms, for example a methylene group, a 1,2-ethanediyl group, a 1,3-propanediyl group, and a branched isomer thereof; a CU5 alkanediyl group defines a divalent straight or branched chain hydrocarbon group having 1 to 5 carbon atoms, For example, anthracenyl, l52_ethylenediyl, 1> 3-diyl, 1,4-butadiyl 1,5-pentanediyl and its branched isomers; Cl 6 alkane> groups include C!-5 15 alkanediyl and its higher homologues of 6 carbon atoms, such as 1,6_hex A base, etc., the term ''CO'' refers to the carbonyl group. Examples of the R5 printed by the Ministry of Economic Intelligence's Staff and Consumers Cooperatives are:

Use (CNS) A4 to hide ~ (21. x 297 (please read the back of the note first and then fill out this page)

1324999 A7 V. Description of invention (ί) 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed from ΐΐΐΓ,, stereoisomer form "mosquito formula (1) (four)" may be heterogeneous _, unless otherwise mentioned Or indicate that the chemical field of the chemical substance refers to a mixture of all possible stereochemically isomeric forms, and the subtractive compound is recorded by the molecule (4) palm isomer and palmar isomer, more specifically, The acceptor or the s_m substituent on the divalent cyclic (partial) saturated group may have a cis or trans-configuration, 'a compound containing a double bond may have stereochemistry at the double bond, and the stereotype of the compound of formula 1 The chemical lion form is well within the scope of the invention. The pharmaceutically acceptable acid addition salt as referred to above is a medically active non-toxic acid addition salt form which may be formed by the inclusion of a compound of formula (I), and a pharmaceutically acceptable acid addition salt may conveniently be obtained from a base. The form is treated with a suitable acid, for example, an inorganic acid such as a hydrohalic acid such as hydrogen acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like; or an organic acid such as acetic acid, propionic acid, hydroxyacetic acid 'lactic acid, pyruvic acid Oxalic acid (also known as oxalic acid), malonic acid, succinic acid (also known as succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, sulfonic acid, ethanesulfonic acid, benzenesulfonate Acids such as acid, p-toluenesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid, p-aminosalicylic acid, and bamoic acid. Conversely, the salt form can be converted to the free base form via treatment with a suitable base. The quaternary ammonium salt of a compound of formula (I) as used herein defines a basic nitrogen of a compound of formula (I) with a suitable quaternizing agent such as, if desired, an alkyl halide, a cyclist or an aromatic A base halide such as a methyl moth or a base-breaking reaction can be formed, and other reactants containing a good release group can also be used, for example, ------------------- ---- (Please read the note on the back and then fill out this page) This paper scales the general Chinese National Standard (CNS) A4 specifications (210 X 297 mm 丄 yyy 丄 yyy

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. = 曱 曱 黄 黄 黄 、 、, alkyl methanesulfonate and alkyl p-toluenesulfonate, quaternary & salt has a positively charged nitrogen, pharmaceutically acceptable Accepted counterions include gas ions, > odor ions, strontium ions, trifluoroacetate, and acetate. The choice of counter ions can be carried out using an ion exchange resin column. 5 The term addition salt as used hereinabove also includes the compound of the formula (I) and the class of formed > granules, such as hydrates, alkoxides and the like. The N-oxide form of the compound of formula (1) which can be prepared by methods known in the art is meant to include a compound of formula 1 wherein one of the nitrogen atoms is converted to an N-oxide by oxygen. The absolute stereochemical configuration of some of the compounds of formula (I) and the intermediates used in their preparation has not been experimentally confirmed. In these cases, the first isolated stereochemically isomeric form is referred to as "A" and the second is called "B", no further stereochemistry is specified, but the "A" and "B" isomer form 15 can be clearly identified by, for example, its optical rotation if, 'A" and, B" There is a pair of isomer relationships, and those skilled in the art can determine the absolute configuration of the compound using methods known in the art, such as X-ray diffraction. The first group of compounds are those of the formula (I). The divalent group -zLz2- is a formula (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8) 20, (b-9), (b-10) or (b-11). A valuable compound is one of the following relationships in which the compound of formula (1) applies: a) divalent group- Ζ^Ζ2- is a formula (b-Ι) or (b-2); or b) a divalent group-Zi-Z2- is a formula (b-2), (b-3), (b-4) or B-5); especially the two paper scales apply to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please Read the back of the precautions to fill out this page)

1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (π) Price base - ZLz2- is formula (b-2) or (b-3); or c) Divalent base - Ζ^Ζ2- Is a formula (b-3); d) a divalent group -a^-aW1- is a formula (a_i), (a_2) or (a_4); especially _ a = a - a3 = a4 is a formula (a-1 5 e) - valence group - A- is formula (c-1) or (c-2); OR1, R2 and R3 are each independently selected from hydrogen, Ci6 alkyl, hydroxy or halo group » g) R4 Is hydrogen; h) Aik1 is a Ci 2 alkanediyl group which is optionally substituted by a hydroxyl group, especially a human is _ 10 ch2-; 1) Aik2 is a C 3 adiyl group which is optionally substituted by a hydroxyl group, especially eight said 2 Is _(CH2)3- or -CH2-CHOH-CH2-; and/or j) R6 is a phenyl fluorenyl hydrogen. Particular compounds of formula (I) are those of formula (I) wherein the divalent group _ζι_ 15 Z2- is of the formula -〇-CH2-CH2-0- and the divalent group is of formula (η). Preferred compounds are those of the formula (I) wherein R5 is a group of formula (d-i) wherein X is oxygen, R7 is hydrogen and Q is (e_2). More preferred compounds are those of the formula (I) wherein the divalent group _ai = a2_ a3 = a4 is a formula (a·1), (a-2) or (a-4); a divalent group β-Ζ2 - is formula (b-1), 20 (b-2) or (b-4) wherein R4 is hydrogen; Aik1 is -CH2-; divalent group -A_ is formula (c-1) or (c-2) And R5 is a group of the formula (d-1) wherein X is oxygen; R7 is hydrogen and q is _1), (e-2), (e-5) or (e-7). Other more preferred compounds are those of the formula (1) wherein the divalent group _al=a2_a3=a4- is a formula (a-1), (a-2) or (a-4); the divalent group j-Z2- is (b- ~12~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) D•H ^1 ^1 ^1 ϋ iai i_i · n .^1 ϋ n emm§ - ^ I (Please read the note on the back? Please fill out this page again) 1324999 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (") 1), (b-2) or (b-4) Wherein R4 is hydrogen; Aik1 is -CH2.; divalent group_A is a formula (c-2) wherein R6 is hydroxyindenyl; and R5 is a group of formula (d-1) wherein X is oxygen; R7 is hydrogen and Q is (e-1), (e-2), (e-5) or (e-7). Still other more preferred compounds are those of the formula (I) wherein the divalent group _ 5 a^aLaka4- is a formula (a-1), (a-2) or (a-4); a divalent group - Ζ^ Ζ2- is a formula (b·1), (b-2) or (b-4) wherein R4 is hydrogen; Aik1 is -CH2-; a divalent group _A_ is a formula -CIVCHOH-CH2-; and a radical R5 is Formula (d-1) wherein X is oxygen; Rule 7 is hydrogen and Q is (e-1), (e-2), (e-5) or (e-7). The most preferred compound is the compound of formula (1) wherein the divalent group _ai=a2_a3=a4- is formula (a-1); the divalent group ϋ- is formula (b-3) wherein γΐ is 〇iR4 is wind' The monovalent group Aik1 is -CH2·; the divalent group A is of the formula (c-2) wherein m is an integer 〇; and R5 is a formula (d-Ι) group wherein the divalent group Q is (e-ι) or ( E_2). Other preferred compounds are those of the formula (I) wherein the divalent group _ a-a _a = a _ is a formula (a-1); the divalent group - Ζ^ Ζ 2 is a formula (b-3) wherein γ1 is 〇 And R4 is hydrogen; the divalent group Aik1 is -CH2-; the divalent group A is a formula (4)) wherein Aik2 is -(CH2)r; and the group R5 is a formula (d-Ι) wherein the divalent group q is (e_5)戍 (e_ 7). A preferred compound is 1-[1-[(2,3-dihydro[1,4]dioxos[2,3-bipyridin-3-yl)indenyl]_4_hexahydro 20 °°° Fixed base]-2-imyl ketone; 1-[1-[(2,3-dihydro[1,4]dioxan[2,3-sub)-[3-yl]methyl]_4_6 Hydrogen 0-pyridyl]tetrahydro-2(1H)_ phenidinone; HH[(2,3-dihydro[I,4]dioxo[2,3 clock ratio 0 _3 base) fluorenyl ]amino]propyl]dihydro-2,4(1Η,3Η)-° dense. Dingdione; and 10 15 (please read the precautions on the back and fill out this page) Order·--------_ 43- 1324999 A7 B7 V. Description of invention (10 HH[(2,3-two) Hydrogen [I,4]dioxo[2,3-7]pyridine-3-yl)indolyl]amino]propyl]-2,4-imididinedione; pharmaceutically acceptable acid plus In the form of a salt, a stereochemically isomeric form, or an N-oxide form, especially the (S)-stereoisomers of the above four compounds. The preparation of the compounds of the invention can generally be carried out via the use of a formula (ΠΙ) intermediate Alkylation of a formula (Η) intermediate wherein W is a suitable cleavage group such as a halo group such as a fluoro group, a fluoro group, a bromo-iodo group or, in some cases, a sulfonyloxy group such as methylsulfonate a reactive excipient such as an oxy group, a benzenesulfonyloxy group, a trifluoromethylsulfonyloxy group, or the like, which may be reacted in a reaction inert solvent such as acetonitrile or tetrahydrofuran, and if necessary, in a suitable test such as sodium carbonate or potassium carbonate. Oxidation in the presence of diethylamine, stirring can increase the reaction rate, the reaction can be conveniently carried out at room temperature and the reflux temperature of the reaction mixture, and if necessary, can be pressurized React in the pot. (Please read the phonetic on the back first? Please fill out this page again) 15

-Alk'-W Z2' -A-R5

(D (Π) (III) The preparation of a compound of formula (1) can also be followed by reductive alkylation of an intermediate of formula (IV) with an intermediate of formula (III) according to a reductive alkylation process known in the art, wherein Aik1 stands for direct bond or Q_5 alkanediyl. • I nnn ^OJ nnn I n I * 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

Alkl-CHO Ά-R5 (HI) (I) Alternatively, the preparation of a compound of formula (I) may also be carried out via a sulfhydryl group of formula (v) wherein Aik1' represents a di- or direct bond with an intermediate of formula (III) Appropriate -14~ The paper is suitable for the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A7 B7 V. Inventive Note (/3) Reaction in case of reaction. •~r\

-Aik1 z2- (V) ta + -A-R3 (I) (III) 10 15 20 The reductive alkylation reaction can be carried out in a reaction inert solvent such as di-methane, ethanol, methyl or a mixture thereof In the presence of a hydride such as sodium hydride, sodium cyano hydride or triethyl methoxy hydride, it is also convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as Rh/C or Pt/C. In the case of using gas as a raw material, it is advantageous to add a dehydrating agent such as aluminum butoxide in the reaction mixture, in order to avoid undesired further hydrogenation of the reactants and a part of the functional groups of the reaction product, which is also advantageous in To the reaction mixture, a suitable catalyst poison such as porphin or 啥σ林-sulfur is added. In order to increase the reaction rate, the temperature can be increased to room temperature and the reflux temperature of the reaction mixture, and the pressure of hydrogen can be increased as needed. A compound of the formula (Ia), which is defined as a compound of the formula (1) wherein the divalent group - octa- represents -NR6-CH2-CH(OH)-CHr, which can be prepared by reacting an intermediate of the formula (VI) with an intermediate of the formula (VII) The reaction is carried out in an inert solvent such as methanol and, if necessary, in the presence of an inorganic test such as sodium carbonate. 2 Λγζ,^ . /\卞/人少ΤΗ+ ^ R3 3 (VI) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed CH2—r5 (VII)

CH2-CH-CH2-R5 OH Preparation·Compound shot according to this hybrid art #基基基Ί5-1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (/<〇基之式(I The compound can be converted to the corresponding compound of formula (1) wherein R6 is hydrogen via a debenzylation reaction known in the art, and the deoctylation reaction can be carried out according to methods known in the art, for example using Catalytic hydrogenation of a suitable catalyst such as Pt/C, Pd/C in a suitable solvent such as methanol, ethanol, 2-propanol, 5 ethyl ether, tetrahydrofuran, and a compound of formula (I) wherein R6 is hydrogen can be used Alkylation of methods known in the art, such as reductive N-alkylation with a suitable aldehyde or ketone. According to the known methods of the art for converting trivalent nitrogen to its N-oxide form, It is also possible to convert the compound of the formula (1) into the corresponding N-oxidized oxime form, and the N-oxidation reaction can usually be carried out by reacting the starting material of the formula (1) with a suitable organic or inorganic peroxide, suitable inorganic Oxides include, for example, hydrogen peroxide, alkali metals or bases Metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include, for example, benzene carbon peroxyacid or dentate substituted phenylcarbon peroxyacids such as 3-gas benzene-carbon peroxyacid, 15 Oxyalkanoic acids such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide, suitable solvents are, for example, water, lower alcohols such as ethanol, and the like, hydrocarbons such as toluene, ketones such as 2-butanone, Toothed hydrocarbons such as di-methane and mixtures of such solvents. Starting materials and partial intermediates are known compounds and are commercially available or can be prepared, for example, according to conventional methods generally known in the art. The intermediate of formula (III) can be prepared according to the method disclosed in examples A.4 and A.5 of w〇_99/29687. The compound of formula (1) and a part of the intermediate may have one or more stereocenters in its structure, and exist as Ruler or 5 configuration, such as carbon source with R4 substituent ~16~

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

1324999 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives A7 B7 V. Inventive Note (AT) Sub, and carbon atoms connected to the -Alki-A-R5 part. The compound of formula (1) prepared in the process disclosed above can be synthesized as a racemic mixture of the oxime isomers which can be separated from each other according to the dissociation methods known in the art, and the racemic compound of formula (1) Upon reaction with the appropriate 5 pairs of palmitic acid, it can be converted to the corresponding non-palphaliomer salt, which can then be separated, for example, via selective or stepwise crystallization and released via the base. An alternative method for isolating the palmomeric isomer form of the compound of formula (I) comprises the use of liquid chromatography on the solid phase of the palm, the pure stereochemically isomeric form may also be derived from the corresponding pure of the appropriate starting material. Stereochemical iso 10 building form, provided that the reaction is carried out stereospecifically, preferably if a particular stereoisomer is desired, the compound will be synthesized via stereospecific preparation methods, which will facilitate the use of Palmomerically pure starting material. . The compound of formula (I), its N-oxide form, the pharmaceutically acceptable salt 15 and the stereoisomeric form have important basal relaxation properties and can be sensible by pharmacological example C-1 The monthly tension in the dog measured by the electronic constant pressure device is true. Moreover, the compounds of the present invention have other advantageous pharmacological properties, which have little or no vasoconstrictive activity and can be mediated by pharmacokinetic example C-2 "basal vasoconstriction vasoconstriction activity", confirming that vasoconstrictive activity can cause unwanted "Side effects such as coronary artery effects that can cause chest pain. In addition, the compounds of the present invention have other important pharmacokinetic properties with rapid onset and two pause retention activities without any intervening effects of CYP45〇2D6 or 3A4 (please Read the notes on the back and fill out this page. f Order ---------. ~17~

1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (4) During consumption of the diet, the substrate is also the beginning part of the stomach, slack and k for storage function, substrate disturbance > or damage The patient with adaptive relaxation has shown that it is more sensitive to gastric dilatation and exhibits dyspepsia during food digestion. Therefore, the compound that can normalize or restore disturbed basal regulation can be used to relieve the disease. Patients with dyspepsia syndrome. In view of the ability of the compounds of the invention to relax the base, the compounds are useful in the treatment of diseases or conditions associated with modulation of dysfunction, obstruction or impairment of the substrate, such as dyspepsia, premature satiety, bloating and anorexia 〇10 digestion Adverse suffocation is a motility disorder that can be caused by delayed gastric emptiness or basal relaxation of impaired food digestion, and warm i animals with dyspepsia due to delayed gastric emptiness include humans ( Generally referred to herein as patients, there is usually a normal basal relaxation and the 15 dyspepsia can be relieved via a prokinetic agent such as cisapride, which may have dyspepsia but no disturbed stomach emptiness. The dyspepsia syndrome may result from reduced hypersensitivity caused by excessive contraction of the basal or adaptive basal relaxation, and hypersensitivity caused by abnormality. The excessively contracted basal causes the compliance of the stomach to decrease, and the compliance of the stomach, It can be expressed as the ratio of the gastric volume to the pressure on the stomach wall, and the compliance of the stomach is related to the tension of the stomach 20 Its tonic contraction of muscle fibers of the proximal stomach line, the proximal end portion of the stomach after being regulated tonic contraction (gastric tone) via the reach of the reservoir function of the stomach. Patients with premature fullness can't complete the normal diet because they feel saturated before they can complete the normal diet, usually when people start to eat ~18 paper scales apply to China National Standard (CNS) A4 specifications (210 X 297 mm) --------IT--------- (Please read the note on the back? Please fill out this page again) A7

V. INSTRUCTIONS (/ 7) After printing by the Ministry of Economic Affairs' Intellectual Property Bureau employee consumption cooperative, the stomach will show a compliant pine effect, that is, the food will not be loosened to accept digestion, and the basal loosening effect will be impaired. After the obstruction of the stomach is hindered, there is no such a relaxing relaxation effect. The use of a compound of formula (I) is shown, which shows that the present invention also provides a method of treating 5 warm-blooded animals, including humans (collectively referred to herein as patients), having a modulation effect of disturbing 'obstruction or damage'. The method is to provide a patient for the treatment of conditions such as dyspepsia, premature satiety, stomach qi and anorexia. Accordingly, there is provided the use of a compound of formula (I) as a medicament, in particular a compound of formula 10 (I) for the manufacture of a medicament for the treatment of a condition in which the substrate is disturbed, hindered or excavated by food digestion, including prophylaxis and medical treatment. Sexual treatment. Impaired basal relaxation syndrome can also be caused by ingestion of chemicals such as Selective Seretonine Re-uptake Inhibitors 15 (SSRi s)' such as fluorocarbon propylamine, paroxetine' fluvoxamine, Citai〇pram and sertraline. When preparing the pharmaceutical composition of the present invention, an effective amount of the specific compound in the form of a base or an acid addition salt as an active ingredient is intimately mixed with a pharmaceutically acceptable carrier, and the carrier can be used in various forms and from the preparation to be administered. Form 20 determines that these pharmaceutical compositions need to be in unit dosage form, suitably suitable for oral, rectal or parenteral administration, for example, in the preparation of oral dosage form compositions, any conventional pharmaceutical medium may be employed. For example, in the case of oral liquid preparations such as suspensions, slurries, elixirs and solutions, water, glycols, oils, alcohols, etc. may be used, or in powders, pills, ~19~ paper scales for China. National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and fill out this page) ^^1 tlB ft > nn I =° 1324999 V. Invention Description (β) 10 15 20 Economy Department of Intellectual Property Bureau employees consumption cooperatives printing capsules and (4) the use of nails, kaolin, lubricants, adhesives, decomposers;::, sugar agents and capsules represent the most favorable: single;; The carrier usually comprises sterile water, and the intestinal tract is incorporated into other ingredients such as to promote solubility. For example, it can be used in combination: it can be added with a carrier, including a mixture of no-mix, a liquid, or a suspension for injection. In the liquid product, she (4) = 2 suitable additives of any nature 丄 2 will cause skin mization effect, the addition of radiation to promote or help to prepare the desired composition, these compositions can be used in the same formula = For example, as a transdermal patch, as a patch, as an ointment, ί(Ι) = salt formation is more suitable for the preparation of an aqueous composition due to increased water solubility. I''1 is particularly advantageous for modulating the above-mentioned pharmaceutical composition in the dosage unit and dosage of the drug, and the dosage unit used in the specification and application of the invention refers to a suitable dosage for unit administration. Physically separated, the unit 'each unit contains a predetermined amount of active ingredient calculated to produce the desired medical effect in combination with the desired pharmaceutical carrier. Examples of such dosage unit form are tablets (including twisted lines or packs). Tablets, capsules, pills, powder packaging, glutinous rice, solutions for injection or suspension, etc. and their separate weight. Clothing --------tr--------- (Please read the notes on the back and fill out this page) -20 - Paper size is applicable to the National Standard (CNS) A4 specification (21 〇X 297 公爱1324999 A7 B7 V. Invention Description (zf) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints the form of remuneration, using conventional methods, capsules or sealants, (eg _#:^ It can be connected to (4) curry, such as adhesive 5, polyethylene followed by propyl methyl fiber (such as stearic acid read or powder, lubricant ~ ', moonstone into 虱 矽), decomposing agent (for example) Tablets are coated by a method well known in the art of potato starch. 1n will be a liquid preparation for oral administration, which may be in the form of, for example, a solution, an aqueous solution, or may be present as a dry product and may be used with water or The liquid preparation can be prepared by a conventional method, and δ pharmaceutically acceptable additives such as a suspending agent (for example, sorbitol pulp, m cellulose, propyl propyl methyl fiber) can be prepared. Or hydrogenated edible fat), emulsifiers (such as lecithin or gum arabic), non-aqueous vehicles (such as almonds) , an oil ester or ethanol), and a preservative (such as methyl or propyl paraben or sorbic acid). The pharmaceutically acceptable sweetener comprises at least one strong sweetener such as saccharin, sodium saccharin or Feeding, aspartame, methyl phenylalanine, methyl sulphate, amine clock, sodium hexylamine sodium, alitame, dihydro benzophenone sweetener, monellin ), snake chrysanthemum or sucmlose (4,1',6'_three gas-4,1',6,-trideoxysucrose), preferably saccharin, sodium saccharin or calcium, and Use large volume sweeteners such as sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, grape dihydrogen glucose syrup, xylitol, caramel or honey as needed. ' 15 20 ~2l· This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) f I Book 1324999 A7 B7 V. Invention Description (>〇10 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Conveniently Using Low Concentration Strong Sweetening For example, in the case of sodium saccharin, the concentration can range from 0.04% to 0.1% (weight/volume) to the end The total volume of the preparation is based on the ratio, preferably about 6% of the low dose preparation and the high dose preparation is preferably about 〇. The large volume sweetener can be effectively used in a relatively large amount ranging from about 10%. Up to about 35%, preferably from about 1% to 15% (weight/volume). The pharmaceutically acceptable flavoring agent which masks the bitter component in the low dose formulation is preferably a fruit flavoring such as cherry, raspberry, Black currant or strawberry flavoring, a combination of two flavorings can produce very good results, and high flavoring agents may require stronger flavoring agents such as caramel chocolate tinctures, scented flavors 'fantasy' Fantasy) a pharmaceutically acceptable accentuating agent such as a flavoring agent. The concentration of each flavoring agent in the final composition ranges from 〇〇5% to K (weight/volume), which is advantageous for the use of the combination of the accelerating odorants. in use. The week does not change or lose the taste or color in the acidity of the preparation. The compounds of the invention may also be formulated as a deposition preparation, such long-acting preparations may be administered by implantation (for example subcutaneously or intramuscularly) or via intra-injection, whereby for example the compound may be combined with a suitable polymeric or hydrophobic substance (for example , an emulsion in an acceptable oil) or an ion exchange resin, or as an insoluble derivative, for example as a nearly insoluble salt. The compound of the present invention can be formulated by injection without parenteral administration, or by intramuscular or subcutaneous injection, for example, via a bolus injection or a pulse reading, and the injection can be in the form of a dose, for example, in a pro- or multiple dose. a preservative in the container, in the form of a suspension, solution or emulsion in an oily or aqueous vehicle-22-

Clothing -------- set --------- (please read the notes on the back and fill out this page) 1324999 A7

V. INSTRUCTIONS (v) 10 15 20 Ministry of Economic Affairs, Intellectual Property Bureau

And may comprise a modulating agent such as isotonic, suspending, stabilizing and/or dispersing agents, or the active ingredient may be in powder form and may be employed in a suitable vehicle such as a sterile non-pyrogen prior to use. The compounds of the invention may also be formulated for rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. 〃 The compounds of the invention may also be used for intranasal administration, for example, as a liquid spray, powder or drop. The preparation of the present invention may optionally contain an anti-flatulent agent such as dimethyl hydrazine oil, α-D-galactosidase or the like. Usually the effective medical dose is from about 0.001 mg/kg to about 2 mg/kg body weight, preferably from about 0.02 mg/kg to about 毫克5 mg/kg body weight. The county is in two fines for taking the therapy (IV). Use the following abbreviation I, for acetonitrile and r (ΓίίΓ is a chemical formula, such as CH2Cl2 for two gas NH_, TM hydrochloric acid, and second (four) T, first silk to "A," - indicates the actual stereochemistry Configuration. And the four brothers D,,, did not enter A: the example of the intermediates AJ Consumer Cooperatives printed paper scale applicable to China's national standard luxury -----丨-J叮--------- 49--------'丨丨·(Please read the note on the back? Please fill out this page again), 23~ 1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (mouth Methanesulfonate (0.012 mol) in DCM (6 ml) was added dropwise to 2,3-dihydro-1,4-dioxo[2,3-7]pyridine-3-methanol ( A mixture of 0.008 moles and triethylamine (0.016 mol) in DCM (26 mL) and cooled in ice-bath, mixture mixture was taken at 5. (: stirring for 1 hour, the mixture was filtered, and the filtered 5 liquid was washed with water and Extraction, the organic layer was dried, filtered and evaporated to dryness, and the product was used without further purification to obtain 2. y y y y y y y y y y y y y Pyridine-3-methanol phthalate ester (Intermediate u. Example A.2 a) 2,3-Dihydro-3_[(phenylmethoxy)methylg[2,3_b]pyridinium (0.0638 mol) in CH3〇H ( The mixture in 25 ml) was hydrogenated with Pd/C (2 g) as a catalyst. After hydrogen consumption (丨 equivalent), the catalyst was filtered and the filtrate was evaporated. This fraction was purified by HPLC (flow washing) : ethanol/methanol 60/40; column: chiraipakAD 20 μm), two fractions were collected and the solvent was evaporated to give 4.06 g of (S)-2,3-dihydro-1,4-dioxol and [2, 3_b] 15 ° pyridine-3-sterol (intermediate 2-a) ([a]20D=-34.33.; c=25.34 mg/5 ml of methanol) and 3.81 g of (R)-2,3-di Hydrogen-1,4-dioxo[2,3-7]pyridin-3-indole (intermediate 2-b) ([a]20D=+32.74.; c=22.60 mg/5 ml sterol· b) Mix a mixture of (intermediate 2-a) (0·023 mol) and triethylamine (〇_046 mol) in dcm 20 (4 ml) at 〇 ° C, add dropwise Mixture of sulfonium sulfonate (〇〇35 mol) in DCM (103⁄4 liters), the mixture was allowed to stand on an ice bath for 2 hours, then washed with HzO/NaCl, the organic layer was dried, filtered and evaporated. (oil) solidified in DIPE, The precipitate is filtered and dried to obtain 5 g of (3)-2,3-dihydro-1,4-dioxane and [2,3 succinylpyrimidine_3_methanol vermiculite / paper scale applicable to Chinese national standards (CNS) A4 specification (210 X 297 public) (Please read the note on the back and fill out this page) ---------tT------1—. 1324999 A7 B7

V. Description of invention (W 10 15 20 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing Acids (Vinegar) (Intermediate 3) ([a ]2〇d=-27.89.; c=25.1〇mg/5ml Methanol; melting point 136 ° C). Example A.3 a) Under a nitrogen pressure reaction, NaH 60% (0.4725 mol) was stirred in DMF (225 mL) and 2,3-pyridinediol was added dropwise. 〇 225 mol) and the mixture was stirred at room temperature for 30 minutes, the reaction mixture was cooled in an ice water bath and 1,1-dioxa-2-oxo-2-keto-ethyl was added dropwise. ι·ι25摩尔), the resulting reaction mixture was stirred at 95 ° C for 5 hours, then allowed to stand overnight at room temperature, the cooled crude reaction mixture was added to water, filtered through Celite and extracted with ethyl acetate. Dry the organic layer, filter and evaporate the solvent. The residue was purified by flash chromatography on EtOAc (br. </ br> DCM). The desired fractions were collected and evaporated to yield 4 ηg. (士)], 3--oxopenta[4,5-b]0 is less than 0-but-2-acidic acid 中间g (Intermediate 4). b) Under a nitrogen pressure, a solution of the intermediate (4) (0.042 mol) in THF (48 ml) was added dropwise to UAIH4 (IMin THF) (0.0466 m) and cooled in an ice bath. The reaction mixture was stirred at room temperature for a few hours. The reaction mixture was carefully added to a 10% NH4C1 solution and diluted with water and ethyl acetate. The reaction mixture was filtered through Celite and extracted, and the organic layer was dried and filtered. The solvent was evaporated and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. c) Stir the solution of intermediate (5) (0.018 mol) and triethylamine (0.036 mol) in 0 〇^ (80 ml) and cool with ice bath, add sulfonium oxime (0.027 mol) dropwise And the resulting reaction mixture is stirred under ice-cooling for 1 small -25 - (please read the notes on the back and fill out this page again) Shock--------Book--------- A paper is again applicable to the China National Standard (CNS) A4 Regulations & 21 〇 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed 1324999 A7 -------- SI______ V. Invention instructions (when, will be crude reaction The mixture was washed with water and brine, then extracted, and the separated organic layer was dried, filtered and evaporated to give a solvent of &lt;RTI ID=0.0&gt;&gt;醯 _ () Intermediate (Example A.4 5 a) The reaction was carried out under nitrogen pressure, and 2 propylene (9) was added dropwise to NaH 6 〇% (〇·〇〇2 MoM^DME) (5 ml) of the mixture of the mixture was stirred at room temperature for 15 minutes, and a solution of 3_(methoxymethoxy)_4_, 吼 Π Π Π ) 在 在 在 在 在The resulting reaction is stirred under reflux overnight and will The mixture was washed with water and extracted with ethyl acetate (10 ml). The organic layer was dried, filtered and evaporated to dryness, and the residue was purified by short-opening column chromatography (flow washing: hexane / ethyl acetate propyl = 90/10) '· CH 2 Cl 2 / MeOH 96/4), the product stream fractions were collected and the solvent was evaporated to give 0.18 g of 3-(methoxymethoxyoxy) 4-(2-propenyloxy)pyridine (Intermediate 7). 15 b) Add bromine (0,00092 mol) dropwise to the intermediate (7) (0.00092 mol) in DCM (2 mL), stir the reaction mixture at room temperature for 15 min and pour the mixture A saturated NaHC solution containing 10% Na2S〇4 was added, the mixture was extracted, the organic layer was dried over Na 2 SO 4 , filtered and evaporated to dryness to give 0.32 g of (±)-4-(2,3-dibromopropoxy Benzyl-3-(methoxymethoxy 20-yl)pyridine (Intermediate 8). c) The intermediate (8) (0.0248 mol), HCl (35.42 ml) and ethanol (4 ml) were stirred at room temperature overnight, the reaction mixture was concentrated in vacuo, and the concentrate was cooled in an ice water bath It is neutralized with saturated NaHC03 solution and extracted with ethyl acetate. The organic layer is dried by Na2SO4. The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mil) tT--------- (Please read the notes on the back and fill out this page) 1324999 A7 B7 V. INSTRUCTIONS (&gt;r) Filter and evaporate to dryness, and purify the residue by short open column chromatography (flow washing: CH2C12; CH2a2) /MeOH (98/2, 96/4 and 90/10)), the & pure second-stream wash and the solvent was evaporated to give 4.27 g (yield) -4- (2, 3- ss. 3-pyridinol (intermediate 9). 5, a solution of the intermediate (9) (0.0097 mol) in ethanol (5 mL) was stirred and refluxed overnight, then NaHC 〇3 (0.0097 mol) was added and the resulting mixture was stirred and refluxed overnight. The solvent was evaporated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3/2)), collect the pure stream wash and evaporate the solvent to obtain 151 g (soil)_3-(&gt;odor methyl)-2,3-dihydro-1,4-dioxo[ 2, 3-Pyramid bite (intermediate 1 〇). Example A.5 a) a mixture of 2,2-dimercapto-1,3-propanediamine (0.22 mol) and 2-propanonitrile (2 mol of hydrazine) in ethanol (250 ml) in a chamber Stir under temperature overnight, steam the solvent for 15 rounds, 2,2-dimercapto-1,3-propanediamine (〇_28 mol) and 2-acrylonitrile (0.28 mol) in ethanol (250 ml) The mixture was stirred at room temperature for 1 hour, the solvent was applied, and the residue was combined. The residue was purified by evaporation to afford 27.2 g of 3-[(3-amino-2,2-dimethylpropyl) Amino]-propionitrile (intermediate 11). b) A mixture of intermediate (11) (0.16 mol) and 1,1'-carbonyl bis-oxo-oxazole (0.16 mol 20 s) in THF (500 mL) was stirred and refluxed overnight and filtered. Drying gave 26.7 g of hexahydro-5,5-dimercapto-2-oxo-pyrimidinepropanenitrile (Intermediate 12, melting point 190 ° 〇. c) Intermediate (12) (0.12 Mo) Hydrogenation of Raney Nickel (3.0 g) as a catalyst in a mixture of CH3OH/NH3 (400 m), consumption of hydrogen (2 equivalents) ~ 27. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297)厘) (Please read the notes on the back and fill out this page) -· n Is ti ϋ -1-°',* n tl* _ Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperative Printing 1324999 A7 ______ B7 V. Inventive Note (&gt;6), the catalyst was filtered and the filtrate was evaporated to give 21.2 g of 1-(3-aminopropyl)tetrahydro-5,5-dimethyl- 2 (1H), ketone (intermediate 13). Example A.6 a) 4-Amino-1-(phenylmethyl)_4·hexa-argon π ratio methanol (〇·〇ΐ82 mol) and 2-5 acrylonitrile (0.0304 mol) in ethanol (80 The mixture was stirred and refluxed for two days, 2- acrylonitrile (2 ml) was added, the mixture was stirred and refluxed for 5 hr, then 2- acrylonitrile (2 ml) was added and the mixture was stirred and refluxed overnight, and the solvent was evaporated. The residue was purified via hydrazine on a glass filter (flow washing: CH2C12/(CH30H/NH3) 95/5), the desired fractions were collected and the solvent was evaporated to give 3-[[4- Mercapto)-1-(phenylmethyl)-4-hexahydroacridinyl]amino]-propanenitrile (Intermediate 14). b) Hydrogenation of hydrogen (2 equivalents) with a mixture of intermediate (14) (0.0159 mol) in decyl alcohol (150 ml) saturated with NH3 at 14 ° C with Raney Nickel (1/2 ft.) as catalyst. After that, the catalyst was filtered and the filtrate was evaporated to give 3.8 15 g of 4-[(3-aminopropyl)amino]-i-(phenylindolyl)- 4-hexahydropyridinol (intermediate 15) . c) 1,1'-carbonylbis-1H-. Add a mixture of the intermediate (15) (0.0137 mol) in THF (40 ml), stir the mixture at room temperature overnight, filter the precipitate, crystallize from ACN, filter, use 20 The ACN and DIPE were washed and dried to give 2. 5 g of tetrahydro-1-[4-(pyridinyl)-1-(phenylmethyl)-4-hexahydroindole. Base]-2(1H)-. Ketone (Intermediate 16, melting point 210 ° C:). d) Hydrogenating a mixture of intermediate (16) (0.0059 mol) in decyl alcohol (1 ml) with Pd/C (1 g) as a catalyst, after consuming hydrogen (1 equivalent), the catalyst was passed over. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). (Read the back note first and then fill out this page.} Clothing.-------Book--I--I--- 1324999 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (&gt;7) Filtration, evaporation of the transition solution and crystallization from ACN, yielding 0.6 g of tetrazo_1_[4_(hydroxymethyl)-4 - hexahydropyridyl]-2(1H)-. pyridine ketone (Intermediate 17, melting point 162 ° C). Example A.7 5 1 -(2-propenyl)-2,4-imidazolidindione Mixing (0.036 mol) and 3-gas phenylcarbon peroxyacid (0.043 mol, 70.75%) in DCM (25 ml) at room temperature for 2 hours, adding aqueous sodium hydrogen sulfite solution and mixing the mixture After 10 minutes, Na2C03 was added and the mixture was extracted with DCM. EtOAc (EtOAc) Imidazole. Didone (Intermediate 18). Example A.8 a) Under a stream of nitrogen The reaction was carried out and a mixture of 2-ox-3-pyridinol hydrochloride (1:1) (1.760 mol) in DMF (1 mL) was added dropwise to NaH 60% (1.934) over 3 min. Mohr) in a mixture of DMF (1200 ml) (temperature less than 27 C), the reaction mixture was allowed to be removed for 3 minutes, and added dropwise to the DMF (1 mL) (chloromethyl)_epoxy The mixture was stirred for 3 hours at 60 ° C. The mixture was cooled, water was added dropwise to an ice bath, and the mixture was extracted with DCM. The solvent was evaporated, the oil was added to the residue, and then the mixture was decanted (3 times). This fraction was combined with a similar portion and then purified by HPLC on a silica gel (flow washing: hexane/ethyl acetate g (5 〇/5 〇)), the desired fractions were collected and the solvent was evaporated to give 635 g of 2- gas-3-(oxiranylmethoxy)-pyridine (intermediate 19). b) THF (915 ml), claudinol (2.96 mol) &amp; Na〇H (2 % mol) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 male cage) (please first Read the notes on the back and fill out this page) #订--------- 1324999 A7 -------____B7_________ V. Description of invention (&gt;&lt;?) {Please read the note on the back first Please fill in the mixture of this item at room temperature (4) for 3G minutes (requires cooling to maintain the temperature below 25 C), add intermediate (19) (1.97 mol), and stir the reaction mixture at room temperature for 4 days. Water was added dropwise (required to cool) and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and evaporated, and the residue was combined with 5, and then purified by HPLC on Hexane/ethyl acetate (60/40)), collect the desired stream fraction and evaporate the solvent to give 38% 1-[(2-chloro-3-indolyl)oxy]-3_[( 3z) _3,5-hexadienyloxy]-2-propanol (intermediate 20). c) A mixture of intermediate (20) (0.034 mol) and Lawesson's Reagent (0.051 Mo 10) in toluene (750 ml) was stirred and refluxed for 16 hours, the solvent was evaporated and the residue was passed through a short open column Chromatography on silica gel (flow wash: CH2Cl2/2-acetone (100/0; 90/10)), the desired fractions were collected and the solvent was evaporated and the residue was purified by flash column chromatography Purify on silica gel (flow washing: hexane/2-acetone (95/5; 90/10)), collect 15 portions of the desired stream and evaporate the solvent to obtain 2.3 g of 2,3-dihydro-3-[ (Phenylmethoxy)methyl]-[1,4]oxazolo[3,2-b]pyridine (Intermediate 21). d) A mixture of the intermediate (21) (0.00732 mol) and FeCl3 (2.37 g) in DCM (100 ml) was stirred at room temperature for 16 h, then FeCl3 (2.37 g) was added and the mixture was stirred for a further 16 h. The reaction mixture was alkalized with NH4OH (saturated by the Ministry of Economic Affairs, Intellectual Property Office, Employees' Consumption Co., Ltd. 20) and filtered through Celite. The organic layer was dried, filtered, and the solvent was evaporated, and the residue was applied to Purification on the celite (flow washing: CH2Cl2/2-acetone (95/5)), collecting the desired washings and evaporating the solvent to give 0.93 g of 2,3-dihydro-[l,4l·l oxazole [3,2_b]pyridine-3-methanol (intermediate 22)» This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of the invention) e) Slowly add sulfonium sulfonate (0.0076 mol) to intermediate (22) (〇〇〇51 mol) and diethylamine (0.0102 mol) in DCM (50 ml). The mixture was stirred, and the mixture was stirred at 0 ° C for 2 hours. Water was added and the organic layer was dried, and then evaporated, and the solvent was evaporated to give 1.16 g of hexane: hexane and s. Determine each sterol, the acid ester (ester) (intermediate 23). Example A.9 a) Mix a mixture of NaH 60% (0.051 mol) in THF (20 ml) under 〇t: and add 3-amino-2β to bite (0,34 mol) at 0 C. The solution of the reaction mixture in THF (75 ml) was stirred at room temperature for 10 hours, and 2-(diethoxyphosphino)_2-ethyl acrylate (0 04 i) was added dropwise at 〇 °C. Mol) in THF (753⁄4: liter), the reaction mixture was stirred at room temperature for 24 hours. '1% aqueous solution of NH4C1 was added and the mixture was extracted with dCM. The separated organic layer was dried, and the solvent was evaporated. The residue was purified on silica gel by short open-column chromatography. The desired fractions were collected and 15 solvent evaporated to give 0-56 g of ethyl 2H-pyrano[3,2-b]pyridine-3-carboxylate. (Intermediate 24). b) Mix the intermediate (24) (0.0032 mol) in a mixture of methanol (anhydrous) (2 ml) and THF (anhydrous) (163⁄4 liter) at 〇 °c, then add NaBH4 (0.0128 mol) dropwise. The reaction mixture was stirred at room temperature for 5 hours, 20% aqueous solution of NH.sub.1 was added and the mixture was extracted with DCM, and the organic layer was dried, filtered and evaporated to give EtOAc &lt;RTIgt; ~b]Acridine-3-methanol (#Intermediate work. c) A mixture of intermediate (25) (0.0027 mol) in decyl alcohol (2 ml) at room temperature with Pd/C (0.04 g) After hydrogenation as a catalyst, after consumption of hydrogen (equivalent equivalent), the paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇297 mm) -----------f------ --tr---------1. (Please read the notes on the back and fill out this page) 1324999 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 V. Invention Description (Μ) Catalyst Filtration and evaporation of the filtrate gave 35 g of 3,4-dihydro-2H-pyrano[3,2-7-acridin-3-indole (Intermediate 26). d) A solution of the intermediate (26) (0.002 mol) in DCM (10 mL) was applied. Stir under the agitation, add triethylamine (0.0024 mol) and sulfonium oxime 5 (0.0024 mol) at 〇 ° C, and mix the resulting reaction mixture for 3 hours at room temperature, add saturated NaHC〇 3 aqueous solution, the organic layer was separated, dried, filtered, and the solvent was evaporated to give 049 g of 3,4-dihydro-2H-pyrano[3,2-b]pyridine-3-methanol, oxime sulfonate ) (Intermediate 27). Example A.10 '10 a) In a solution of 2-chloro-3-° than bitten amine (0. 〇465 mol) in THF (45 ml) at -78 ° C under a stream of N 2 The propyl amination chain (0.0513 mol, 2 molar concentration), the reaction mixture was allowed to warm to 〇 °c and mixed for 1 hour, then cooled to -78 ° C, then added thiol iodine (0.0582 mol), so that The reaction mixture was warmed to room temperature and stirred for 16 h, a saturated aqueous solution of nh 4 C1 was added and the mixture was extracted with 15 ethyl acetate. The separated organic layer was dried, and the solvent was evaporated and the residue was applied Purification on Shixi gum (flow washing liquid: Jiyuan/ethyl acetate 80/20), collecting the desired flow washing fraction and evaporating the solvent to obtain 5.91 g of 2-gas-N-methyl-3-π ratio amine (Intermediate 28). b) Slowly add lithium diisopropylamide (0.062 mol, 2 mol concentration) in the intermediate (28) (0.031 mol) in THF (50 ml) in a solution of _78〇c and n2 gas 20 flow. The reaction mixture was allowed to warm to 〇 ° C and stirred for 1 hour. After cooling again to _78 C, [(phenylmethoxy) decyl]-epoxyethyl bromide (0.034 mol) in THF (40). Solution of ML), warm the mixture to room temperature and mix for 16 hours, add saturated NH4CI aqueous solution and extract with acetic acid to extract ~32. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)厘) !!会--------1T---------I (please read the notes on the back and fill out this page)

V. Description of invention (A 10 15 20 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing base - lHm[2,3_b][1,4] ah _3 methanol (intermediate _). ") (〇.G1丨丨莫耳) and triethylamine (1) (four) Moer) in the (200 house liter) GC shouting drop two people (10) 6 m), the reaction mixture in (TC search Mix for a few hours, then add water, the separated organic layer is extracted with veins, green, ton, i «dissolved, and 2_85 g of 2,3-hydrogen _ 丨 曱 吼 吼 吼 吼 定 2 2 2 2 2 ] [1,4] Ten wells of methanol, oxime sulfonate (intermediate 32). Example A.11 a) 3-oxo carbon peroxyacid (_7 mol) in three gas smoldering (10) ml The solution was added dropwise to 2,3-dihydro-l,4-dioxane [2,3 姊 ratio. Each sterol 曱% acid _.0217 mol) in the trichlorocarbyl (125 ml) The solution, and it is better at room temperature, add 5 〇 ml, rail 1247 sister 2 (:: 〇 3, stir the mixture for 30 minutes, then filter it and use a mixture of DCM in methanol ( 90/10) Wash, evaporate the filtrate and purify the residue on short-term column chromatography on Shishijiao (flow wash: O^Cl AMeOH/NH3) 96/4, 95/5 and 90/10), the product stream fraction was collected and the solvent was evaporated to give 3.62 g of 2,3-dihydro-[1,4]dioxo[2,3 - b] pyridin-3-nonanol oxime sulfonate (intermediate 33) b) a mixture of intermediate (33) (0.0138 mol) and phosphonium (0.069 mol) at l ° ° C The reaction mixture was evaporated to dryness <RTI ID=0.0></RTI> , 3-Dihydro-[1,4]dioxo[2,3-b]acridin-3-indole oxime sulfonic acid (intermediate 34). This paper scale applies to China National Standard (CNS) A4. Specifications (210 x 297 mm) ------------------- Order --------I (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1324999 A7 -------- B7__ V. Invention description (shirt) Example A.12 Indifferent _9 Moel) Add dropwise to 2,3·dihydrogen· Μ_二氧^ [2 such as D-3: Methanol _9 Moule) in DCM (sub-ml) and shouting 饱和3 saturated solution (5 〇 ml) in the room, the anti-alias Warm under 5 f for 16 hours, add more __ moles and leave the reaction mixture at room temperature for 3 days, add a few drops of ΝΜ〇3 and transfer the mixture for 2 minutes' will separate the organic layer of money, Wei and the minerals were evaporated, and the residue was purified on silica gel by short open column chromatography (flow washing: CH2Cl2/CHsOH 100/0; 98/2), and the desired fraction was collected and the solvent was evaporated. , 1 〇 gave 0-9 g of 7-bromo-2,3-dihydro-[1,4]dioxyg and [2,3-b]pyridin-3-methanol (intermediate 35). b) Add the chlorinated chlorine (0.0054 mol) dropwise to the intermediate (35) (〇 〇〇 36 mol) and diethylamine (0_0 〇 72 mol) in DCM (50 ml) at 〇. The mixture is allowed to be stirred, and the reaction mixture is stirred at 〇 ° C for 3 minutes, then extracted with water 15 to separate the organic layer, dried, and the solvent is evaporated to obtain 1. 〇 7 g of 7_&gt; , 3-diindole-[1,4]dioxygen and [2,3-7] quinone than _3_methanol phthalate (intermediate 36). Example A.13 a) Adding gas (1,1-dimercaptoethyl)difluorenyl _ Shi Xia (〇 〇 2〇 Mo ear) dropwise

20 to intermediate (38) (0.010 mol) and full (0.020 mol) in DMF (100 ml), the reaction mixture was stirred at room temperature for 16 hours, the solvent was evaporated and the residue dissolved in water /ethyl acetate, the organic layer was separated, dried, filtered, and the solvent was evaporated, and the residue was purified on a celite by short open-column chromatography (flow washing: hexaethyl acetate 9 〇 / 1) 〇), the paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1IIIII — — — — &gt; II Lane 1 III Weng|||||1|_ (Please read the back Note: Please fill out this page again} 1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7___ V. Invention description (α) 40). Example 14.14 a) In the intermediate (2-a) (〇.〇3mol) in DCM (50 ml) and saturated Na2C03 (50 ml), add Mo (0·09 Mo) dropwise and The reaction mixture 5 was stirred at room temperature for 6 hours, then a solution of Na 2 SO 3 (10%) was added and the mixture was stirred at room temperature for 15 minutes, then neutralized with a saturated Na 2 CO 3 solution and the aqueous layer was extracted with DCM. The separated combined organic layers were dried, filtered and evaporated, and the residue was purified on EtOAc (EtOAc: EtOAc (EtOAc) The fractions were washed and the solvent was evaporated. The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc , 27 g of (s)_7_ side-2,3--虱-[1,4]-oxygen and [2,3-b]0 ratio bit -3-sterol (intermediate 41) and 0·26克之8_漠-2,3-Dihydro-[1,4]dioxanthene and succinylpyrazine_3•methanol (in 15 substances 42). b) In the mixture of intermediate (42) (0.0014 mol) and triethylamine (〇〇〇28 mol) in ^^;^ (53⁄4 liter), slowly add ochre yellow to chlorine at room temperature ( 〇〇〇21 Mohr), the reaction mixture was mixed for 16 hours, extracted with water, the separated organic layer was dried, filtered and the solvent was evaporated to give 〇·42 g (幻_8_漠_ 20 2,3-二Hydrogen-[Μ]dioxo[2,3-7]pyridine.3-3-methanol oxime sulfonate (branched) (Intermediate 43). Example A.15 a) Diethyldithiodicarboxylate A solution of (0.1572 mol ml) was added dropwise to 4-gas-3-pyridinol (0 1429 mol), 2 propylene small alcohol ~37. This paper was used in China National Standard (CNS) A4 specification (210 Χ 29Γ) ^Τ -----------— ----- --Book - -------· (Please read the notes on the back and fill out this page) 1324999 Ministry of Economic Affairs Intellectual Property Bureau Employees' consumption cooperatives printed A7 B7 V. Invention instructions (#) (0.1572 mol) and triphenylphosphine (0.1572 mol) in THF (276 ml) cooled in an ice-water bath and a mixture under nitrogen flow, will form The mixture was stirred in an ice-water bath for 15 minutes and stirred at room temperature overnight, and the mixture was concentrated under vacuum. The residue was washed with a saturated Na 2 CO 3 solution, and the mixture was extracted with DCM and the separated organic layer was dried, filtered and evaporated to dryness, and the residue was added to DIPE and the solid formed was filtered and decanted. The filtrate was evaporated to dryness <RTI ID=0.0></RTI> and the residue was taken to diethyl ether and the solid was filtered and evaporated. The filtrate was evaporated to dryness. - Acetone such as /1; 98/2), a 10 stream fraction was collected and the solvent was evaporated to give 7.9 g of 4-y- 3-(2-propenyloxy)-pyridine (Intermediate 44).

b) Benzyl alcohol (0.0698 mol) was added dropwise to a mixture of NaH 60% (〇. 11 mol) kDME (丨 70 mL) under nitrogen flow and the mixture was stirred at room temperature for 30 min and then added dropwise Intermediate (44) (0.046 mol) in DME 15 (1702⁄4 L) and the obtained mixture was stirred and refluxed overnight. The cooled reaction mixture was washed with water and extracted with ethyl acetate. The separated organic layer was dried and filtered. The solvent was evaporated to dryness and the residue was purified eluting eluting eluting eluting 90/0/10), the product stream fraction was collected and the solvent 20 was evaporated to give 6.2 g of 4-(phenyl decyloxy)-3-(2-propenyloxy)-pyridine (intermediate 45). c) Add bromine (0.025 6 mol) dropwise to a solution of intermediate (45) (0.0256 mol) in DCM (64 mL) and stir the mixture at room temperature for 3 min. NaHC03 solution and a few drops of Na2S03 solution ~38~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ------------------- — (Please read the notes on the back and fill out this page) 1324999

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions, 07) 黯; monthly washing and extraction, separating the timing layer, transitioning and evaporating the solvent, and passing the residue through short open column chromatography Purified on silica gel (flow washing: D ^ CM / MeOH 1 〇〇 / 〇; 99 / 1;, the product stream fraction was collected and the solvent was heated to give 6.68 g of 3-(2,3-di- propyloxy) Base X phenyl 5 methoxy)- ♦ (Intermediate 46) d) Partial addition of FeCl3 in a solution of intermediate (46) (0.0166 mol) in DCM (270 mL) (0_〇33 Mo The mixture was stirred at room temperature overnight, and the reaction mixture was added to a saturated NH4C1 solution and a sodium potassium tartrate diluted solution, and then filtered through a stone bath, and the solvent was evaporated to dryness. The liquid was evaporated to dryness and the residue was added to &lt;RTI ID=0.0&gt;&gt; Dry, wash the residue with water and extract with DCM, dry the separated organic layer, filter and evaporate the solvent and leave the residue Column chromatography was carried out on silica gel (flow 15 liquid: ethyl acetate / (MeOH / NH3) 96 / 4), the product stream fraction was collected and the solvent was evaporated to give 0.52 g of 2-(bromomethyl)- 2,3-Di-argon-[1,4]dioxo[2,3-c]pyridine (intermediate 47). Example A.16 a) Slowly add 5-di-spray (0.063 mol) to (2-propan-1-ol 20 (4.03 mol) of TC and stir the mixture for 1 hour at room temperature, Then join

NaH 60% (0.126 mol) and the reaction mixture was stirred and refluxed for 48 h, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and evaporated to dryness. The analytical method was purified on Shishijiao (flow washing liquid: jiayuan/ethyl acetate 50/50), and the required paper size was collected for Chinese national standard (CNS>A4 specification (210 X 297 mm) --- -------I-----------Book--------- (Please read the notes on the back and fill out this page) 1324999 A7 Ministry of Economic Affairs Intellectual Property Office staff Printed by the Consumer Cooperative 5, the invention instructions (secret) wash and evaporate the solvent to give 2.3 g of 5-(2-propenyloxy)-pyrimidine (intermediate 48) b) in the intermediate (48) (0.0169 mol) Add bromine (0·0186 mol) to a solution of DCM (250 ml) and mix the reaction mixture for 1 hour at room temperature. The solvent was saturated with Na2CO3 solution and a few drops of Na2S03 solution (1%) Extraction, the separated organic layer is dried, filtered and the solvent is evaporated to dryness, and the residue is purified on silica gel by short open-column column chromatography (flow washing: hexane/acetic acid Vinegar 66/33; 50/50), collect the desired fractions and evaporate the solvent to give 3.85 g of 3-(2,3-di-propylpropoxy)-by-bit (intermediate 49). CH3C03H 35% (0.0246 mol) was added dropwise to a solution of intermediate (49) (0.0123 mol) and H2S04 (0.0135 mol) in water (5 ml) and the reaction mixture was stirred at room temperature for 16 h. The mixture was extracted with ethyl acetate and the separated organic layer was dried <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 95/5), collect the desired fractions and evaporate the solvent to give 2 3 3 g of 5 _(2,3 _dibromopropoxy) / (3 H) oxazinone (intermediate 5 〇) 〇d) A mixture of the intermediate (50) (0.0091 mol) and NaHC03 (〇. 〇 113 Mo) in ethanol (100 ml) was stirred and refluxed for 16 hrs, the reaction mixture was cooled to room temperature and solvent was evaporated. The residue was dissolved in water and ethyl acetate. The separated organic layer was dried, filtered, and evaporated to dryness. The residue was purified on silica gel using short open-column column chromatography (flow washing: hexane/acetic acid)Vinegar 66/33; 50/50), collect the desired washing fraction and evaporate the solvent to obtain 1.1 g of 7-(bromomethyl)-6,7-dihydro-[1,4]dioxane. [2,3-d]pyrimidine (in 10 15 20) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) —I--------------- Order ί—I—I (please read the note on the back and then fill out this page) 1324999 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Print A7 B7 V. Invention Description (V) Interliment 51). f Example A.16 a) Reaction under a stream of argon, stirring a mixture of 1-amino-3-dinonylaminopropanone (0.195 mol) in ethanol (225 ml) at room temperature to give acrylic acid B 5 ester (〇. 2 mol) was poured into the mixture and the reaction mixture was stirred at room temperature overnight, and the residue was purified by column chromatography on silica gel (flow washing: CH2C12 / hexane / CH3 〇 H 50 /45/5), collect the desired fractions and evaporate the solvent to give 27 g of N-[3-[bis(phenylmethyl)amino]propyl]|ethyl alanate (intermediate 52) . · 10 b) Mix the intermediate (52) in ethanol (150 ml), mix the mixture with HC1/2-propanol (±60 ml) + water (2 ml, stir the mixture for 5 minutes, The solvent was evaporated at 60 ° C, ethanol was added to the residue, the solvent was evaporated, a mixture of decyl alcohol in water (70:30; 200 ml) was added to the residue and the mixture was stirred, then slowly warmed until completely dissolved, acidified The solution was added dropwise to a solution of KOCN (0.100 mol) in a mixture of decyl alcohol in water (7 〇: 3 Torr; 1003⁄4 liters) (under argon pressure for 3 )), and the pH was disturbed at room temperature. From ±8 to ±6, the reaction mixture was stirred at room temperature for 9 hours, more KOCN (0.32 g) was added and the reaction mixture was stirred at room temperature for 9 minutes, and more KOCN (0.9) was added. The reaction mixture was stirred at room temperature for 20 minutes, then stirred at 95 ° C for 6 days. The reaction mixture was cooled, then concentrated EtOAc (20 mL), and the mixture was stirred at 95 ° C for 2 hours. Then, it was allowed to stand at room temperature overnight, the precipitate was filtered, the filtrate was stirred and cooled on an ice bath for 3 hours, and the resulting sediment was obtained. Filtration and drying gave 19.6 g of 1-[3-[bis(phenylmethyl)amino]propyl]dihydro-~41~ -----------^^--- -----Order--------- (Please read the note on the back and fill in this page again) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Gong Chu) 4999 A7 B7 Five inventions description (Industrial Intelligence Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs printed 2,4(1H,3H)-pyrimidinedione (intermediate 53). c) Intermediate (53) (0.010 mol) in sterol ( A mixture of 15 〇 ml) was hydrogenated in S (TC with Pd/C (10%, 1 g) as a catalyst. After hydrogen (2 eq.) was consumed, the catalyst was filtered and the filtrate was evaporated, toluene was added and rotary evaporation was carried out. Azeotropy on the apparatus, the residue was dried under a gentle stream of nitrogen over the weekend, benzene was added and azeotroped on a rotary evaporator, the residue was stirred in (50 ml), and Na 〇 CH3 (0.504 g) was added and The reaction mixture was stirred under a nitrogen atmosphere for 1 hour, more methanol (25 mL) was added and the mixture was stirred for 30 min, and the precipitate was filtered and evaporated under vacuum to give 1.54 g of 1-(3-aminopropyl base Dihydro-2,4(1H,3H)-pyrimidinedione (intermediate 54) B. Preparation of quinone final compound Example B.1 Intermediate (1) (0.00815 mol), 1_(3_amine Mixture of propyl)tetrahydro-2(1H)-pain beta ketone (0.00815 mol) and CaO (0.022 mol) in THF (26. 5 ml) in a Parr apparatus at 100 ° C overnight, Excessive CaO filtration is removed, the filtrate is evaporated to dryness, and the residue is purified on silica gel by short-opening column chromatography (flow wash 1 : CH 2 Cl 2 /CH 3 〇H 90/10 and flow wash 2 : CH 2 Cl 2 / ( CH3〇H/NH3) 96/4), the pure flow fractions were collected and the solvent was evaporated, and the residue was purified again by HPLC on a thimble (flow wash: CH2Cl2/(CH3〇H/NH3) 93/ 7), the pure stream washing fraction was collected and the solvent was evaporated, the residue was crystallized from DIPE, and the precipitate was filtered and dried to give 0.88 g of (±)-1-[3-[[(2,3-dihydro-1) ,4-dioxaindolo[23b]25pyridin-3-yl)methyl]amino]propyl]tetrahydro-2(1H)pyrimidinone (Compound 〇10 15 20 -42- This paper scale applies to China Standard (CNS) A4 specification (2丨0X297 mm)

1324999 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (0/ ) Mix a mixture of intermediate (6) (0.0092 mol) and intermediate (13) (0.0183 mol) at 1〇〇. (: stirring for 2 hours, the crude reaction mixture was purified on silica gel by short open tube chromatography (flow washing: CH2C12/CH3OH90/1〇) 5 'Collect the desired flow fraction and evaporate the solvent to remove the residue It was washed with DIPE and then dried to obtain 148 g of (±)-l-[3-[(l,3-diazino[4,5-b]11-bito-2-amino)amino]propyl ] tetrahydro _5,5-diindenyl 2 (1H) _ ♦ 嗣 (Compound 10). f Example B.3 10 2_(Bromomethyldihydro-2Η-pyrano[2,3-b Mixture of pyridine (0.007 mol) and 1-(3-aminopropyl)tetrahydro-2 (1 - fluorenone (0.014 mol) at 100 C for 2 hours, add the crude reaction mixture to DCM The obtained solid was filtered and discarded, the filtrate was evaporated, and the residue was purified on silica gel using short open-column column chromatography (flow washing: ch2ci2/ch3oh 15 84/16, CH2Cl2/(CH3OH/NH3) 9 (V10), collect the purest flow washing fraction and evaporate the solvent, dissolve the residue in ethanol and convert it to oxalate (1:1), then filter and recrystallize from ethanol to obtain 〇·45g (5) small [3_[[(3,4_Dihydro-2仏〇 is more than [2,3 -b]pyridine-2-yl)indolyl]amino]propyl]tetrahydro-2(1H) - Micidone oxalate (1:1) (Compound 9). 20 Example B.4 2,3-Dihydro-N-(phenylindenyl)-1,4-dioxan [ 2,3-b]. Stir the mixture with 3-methylamine (0.0059 mol) and intermediate (18) (0.00497 mol) in methanol (30 ml) and reflux overnight. Purification on silica gel by short open column chromatography (flow wash: CH2Cl2/2^ This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) -------- --------- (Please read the notes on the back and fill out this page) 1324999 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 V. Invention Description (0) Ketone 96/4, 90Λ0 and 80 /20, then CH2C12/CH30H 96/4 and 90/10), the product stream fractions were collected and the solvent was evaporated to give 1.29 g of (±)-1-[3-[[(2,3-dihydro-1, 4-Dioxo[2,3-bH pyridine-3-yl)methyl](phenylindenyl)amino]_2_Zhao propyl]_2,4-imidyldione (Compound 12) 5 Example B.5 A solution of compound (12) (0.0031 mol) in methanol (40 ml) was hydrogenated in a Parr apparatus at 50 ° C using Pd/C (10%, 0.13 g) as a catalyst. After hydrogen (1 equivalent), The catalyst was filtered and the filtrate was evaporated. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc: EtOAc: EtOAc (EtOAc) The solvent was evaporated to give 0.3 g of 1-[3-[[(2,3-dihydro-1,4-dioxo][2,3-b]acridin-3-yl)methyl]amine ]]-2-Light propyl]-2,4-σ 〇 〇 sit 嗣 (Compound 13). Example 6.6 Potassium hydroxide (0.0022 mol) in ethanol was added to compound (44) (0. 0 〇 12 mol) of 15 in ethanol, and the reaction mixture was stirred at 50 ° C for 4 hours. Stir at room temperature overnight, evaporate the solvent and purify the residue on RP BDS (Hyperprep C18 (100 angstroms, 8 micron), stream wash: H2 〇/CH3CN (0 min) 100/0, (24 Minutes 63/37, (24.01-32 minutes) 〇/1 〇〇), the product stream fractions were collected and the solvent was evaporated to give 0.050 g of compound (5 〇). Example B.7 Reaction under nitrogen pressure. Compound (R268652) (0.0037 mol) was stirred in THF (120 mL) and cooled on ice. 2 molar concentration solution) and the reaction mixture paper size is applicable _ home standard (CN_ii) A4 specification (10) X 297 mm) ---- I----丨丨! ------ 丨丨 ------ ------ --- (Please read the note on the back and fill out this page) 1324999 A7 V. Invention Description (phantom) Stir at room temperature for 1 hour, The mixture was stirred and refluxed for 5 hours, then stirred at room temperature over the weekend, then stirred and refluxed overnight, finally cooled to room temperature, more lithium borohydride (〇. 〇〇 74 Mo) was added and the mixture was stirred. And refluxing overnight, then cooling to room temperature, adding water, the mixture was assayed with 5 % NaH, then the organic solvent (THF) was evaporated and the residue was purified by column chromatography on silica gel (flow wash: Ch2ci2/ch3oh 95/5), collect the desired flow fraction and evaporate the solvent, dissolve the residue in a small amount of ACN, warm to complete dissolution, then cool on ice bath, filter the resulting precipitate, wash and Dry, #到〇·7g compound (51) 5 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example Β.8 Compound (60) (0.0091 mol). Chiraipak gossip via high-performance liquid phase Purification by chromatography and separation (flow washing: C5H2〇H/CH3CN (64/36)), collecting product stream And the solvent was evaporated, and the residue was dissolved in ethanol and converted to oxalate (1:1) to give 7 g of compound (9) [a] 2QD = -42.50 (c = 25.06 mg / 5 ml CH3〇H), melting point 212 C, and 0.9 g of compound (28), [a] 2〇D=+4277C) (c=2 liters to CH3〇H), 216aC. Shouting 5 examples B.10 The intermediate (3) _ Moer), 1-(4-hexahydro ♦ grouping > 2-sided, ketone _ Moer) and the system called _ Moer and touched 6G He, = Qing, the separated organic layer is dried, and the residue is purified on the Shiqi gum by tube chromatography. (Flowing liquid: - 4S- This paper scales the standard when it is suitable for S (CNS- 〉A4 specifications (10) (Please read the notes on the back and fill out this page)

1324999 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (Μ) CH2Cl2/CH3〇H 95/5) 'Collect the desired flow wash and evaporate the solvent to solidify the residue in DIPE, filter and Drying gave 613 g (483%) of compound (19) (yield: 132t; [α]' = 41.70% = 24.34 mg / 5 ml in methanol). 5 Example Β.11 A mixture of intermediate (54) (0.0058 mol) in dioxane (4 ml) was added, and a mixture of intermediate (3) (0.029 mol) and CaO (2.4 g) was added. The reaction mixture was stirred at 14 (TC for 16 hours, the solvent was evaporated, DCM and water were added to the residue, the separated organic layer was dried, filtered and evaporated, and the solvent was evaporated. Purify on silica gel (flow wash. CH2Cl2/(CH3〇H/NH3) 90/10), collect the product stream wash and evaporate the solvent, dissolve the residue in ethanol and convert to oxalate (1:1) The formed sediments were filtered and dried to obtain 1.5 gram of (8)-1-[3-[[(2,3-dihydro[1,4]dioxo[2,3]-bi-pyridine- 3-yl) fluorenyl]amino]propyl] 15 Dihydro-2,4(1Η,3Η)-l-pyridinedione (Compound 25), mp 186 ° C; [α] 20 〇 = -37.46. = 26.56 mg / 5 ml in DMF. Example B.12 a) Intermediate (3) (0_041 mol), benzylamine (0.041 mol) and NaHC03 (0.11 mol) in dioxane (1 The mixture of 〇〇ml) was stirred and refluxed for 48 hours. The solvent was evaporated and the residue was dissolved in water and DCM. The organic layer was dried, filtered, and the solvent was evaporated. The residue was purified on EtOAc EtOAc EtOAc EtOAc EtOAc -2,3-Dihydro-N-(phenylindenyl)-[1,4]dioxo[2,3-b]pyridine-3-methylamine (Intermediate 55). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-----I! i 丨I ——丨-book-------- (Please read the back of the note first) 1350999 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (ο b) Dissolve Intermediate (55) (0.0195 Mo) in Ethanol (50 mL) and Add 2_Acrylonitrile (0.02 mol) and the reaction mixture was stirred and refluxed overnight, then 2- acrylonitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed for 2 hours, then 2- acrylonitrile (〇 〇 莫 2 Mo) was added. The reaction mixture was stirred and refluxed for 6 min 5 hrs, then EtOAc (0 EtOAc) was then taken and the mixture was stirred and refluxed overnight. The solvent was evaporated and the residue was purified by column chromatography The flow washing liquid: CH2Cl2/CH3OH97/3), the product stream fraction was collected and the solvent was evaporated to obtain 6.0 g of (S)-3-[[2,3-dihydro[1,4]dioxane[2] , 3 姊 啶 _ 3- 3- 3- 3- 3- ] ] ] ] ] ] ] ] ] ] 。 。 。 。 。 。 。 。 10 c) Hydrogenation of a mixture of intermediate (56) (0.0195 mol) in methanol (400 ml) saturated with Li 3 with Raney nickel (1 g) as a catalyst, after consumption of hydrogen (2 equivalents), the catalyst Filtration and evaporation of the filtrate, the residue was purified by column chromatography on silica gel (flow washing: CH2C12/(CH3〇H/NH3) 90/10), the product stream fraction was collected and the solvent was evaporated. 2.7 g of (S)-N1-15 [(2,3-dihydro[1,4]dioxo[2,3-b]pyridin-3-yl)indolyl]-anthracene phenylmethyl) - 1,3-propanediamine (intermediate 57). d) Dissolve ethyl monobromoacetate (0.0032 mol) in THF (30 mL) and slowly add this solution dropwise to intermediate (57) (0.0032 m) and triethylamine (0.0048 m) in THF (50 ml) mixture, the reaction mixture was stirred at room temperature overnight, the solvent was evaporated, the residue was partitioned between water and DCM, the organic layer was separated, dried, filtered and evaporated. Chromatography on silica gel (flow washing: CH2CV(CH3〇H/NH3) 99/1), collecting the desired fractions and evaporating the solvent to give 0.8 g of -[[3-[[(2, 3-Dihydro[1,4]dioxygen and [2,3-b]~47~ This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) (please read the back note first) Please fill out this page again)

1324999 f A7 l ______B7 ____ V. Inventive Note (46) Pyridin-3-yl)indenyl](phenylindenyl)amino]propyl]amino]-acetic acid ethyl ester (Intermediate 58). e) A mixture of intermediate (58) (0.002 mol) in dioxane (7.3 ml) and THF (2.4 ml) was stirred at room temperature and trimethyldecane isocyanate 5 (0.0023 mol) was added. The reaction mixture was stirred and refluxed for 1 hour, the solvent was evaporated, the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The separated organic layer was dried, filtered and evaporated to give 0.4 g of (S)-l-[3-[[(2,3-dihydro[1,4]dioxyg[2,3-b] ] 10 0 than p--3-yl)methyl](phenylmethyl)amino]propyl]-2,4-° methanedine 2 (intermediate 59) ° f) intermediate (59) (0.001 mol) A mixture of methanol (5 ml) was hydrogenated with Pd/C (0.2 g) as a catalyst. After hydrogen (1 equivalent) was consumed, the catalyst was passed over and the percolate was evaporated. The residue was dissolved in ethanol and converted to ethyl hexanoate (1:) to give 3.3 g of compound (30), melting point i 90 ° C; [ a] 20 D = -35.99 ° (C = 24.87 mg / 5 ml in DMF). Tables F-1 to F-7 list the compounds prepared according to one of the above examples, using the following abbreviations: .C2H2O4 represents oxalate. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (2) 0 x 297 mm) 1324999 A7 B7 V. Description of the invention (β) Table F-1

κΧ〇J i V ~4 9~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --------I---------- ------- Line ^^^- (Please read the note on the back and fill out this page) Compound number example number -S =3. -2l =3.- -Q- Physical data (melting point °c) 1 B.1 -N=CH-CH=CH- _(CH2)r Melting point 77.5 2 B.1 -N=CH-CH=CH- -(CH2)3- (A);.QH204(1:1) ; [a] 2V +44.40° (c=24.66 mg/5 ml sterol) 3 B.1 -N=CH-CH=CH- -(CH2)3-(B);.C2H204(1:1); Melting point 203; [a] 2 () D = -44.65 ° (c = 24_75 mg / 5 ml of sterol) 4 B.1 -N=CH-CH=CH- -CH2-C(CH3)2-ch2- C2H204 (1:1); melting point 164.9 5 B.1 -CH=CH-CH=N--CH2-C(CH3)2. ch2- - 6 B.2 -N=CH-CH=CH- -ch2- Co- C2H204(1:1) 7 B.2 -N=CH-CH=CH- -CH2-CH2-CO- - 8 B.3 -CH=N-CH=CH- -(CH2)3- •C2H2 〇4(l:l) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Print 5 Clothing 1324999 A7 _B7 V. Invention Description (I) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Compound Number Example Number -a 丨=a2-a3= A4- -Q- Physical data (melting point.c) 25 B.11 -N=CH-CH=CH- -CH2 -CH2-CO- (S); C2H204 (1:1); mp 186; [a] 2GD = -37.46 (c = 26.56 mg / 5 ml DMF) 26 B.2 -N=CH-CBr=CH- -(CH2)3- •C2H2〇4(l:l) 27 B.9 -CH=N-CH=CH--(CH2)3: (A); C2H204(1:1); melting point 212;[a 2V=-42.50° (c=25.06 mg/5 ml CH3OH) 28 B.9 -CH=N-CH=CH--(CH2)3-(B); C2H204(1:1); melting point 216; [ a ]20d= +42.77° (c=25.72 mg/5 ml CH3OH) 29 B.3 -N=CH-N=CH- -(CH2)3- •C2H204(1:1) 30 B.12 -N =CH-CH=CH--ch2-c〇-(S);.C2H204(1:1); mp 190; [a]20D=-35.99. (c=24.87 mg/5 ml DMF) 60 B.3 -CH=N-CH=CH- -(CH2)3- - (Please read the notes on the back and fill out this page) -I a^inn· n I—an 1^1 nn _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A7 B7 V. Invention Description (Cf) Table F-2

Compound example - a1 = a2 - a3 = a4 - -Q - physical data number (melting point °c) 9 B.2 -N=CH-CH=CH- -(CH2)3- •c2h2o4(i:i); Melting point 195.7 5 Table F-3 (Please read the notes on the back and fill out this page) 2i Compound number Example number - a1—a2-a3=a4- -Q- Physical data (melting point °c) 10 B.2 -NCH -CH=CH- -CH2-C(CH3)2-ch2- - 11 B.2 -N=CH-CH=CH- -(CH2)r •C2H204(1:1) Table F-4

Order --------4 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed examples of examples - a1 = a2-a3 = a4- R6 - Q- physical data number (melting point ° C) 12 B.4 -N=CH-CH=CH-benzyl-ch2-co- - 13 B.5 -N=CH-CH=CH- Η -CH2-CO- - This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) 1324999 A7 _B7 V. Description of invention (妓) Table F-5

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Compound Numbers Example Number - a1=a2- a3=a4- -Aik1-A- -Q- Physical Data (Melting Point °c) 14 B.2 -N=CH- CH= CH- -CH2-n^&gt;- -(ch2)2- - 15 B.1 -N=CH-CH=CH- -(ell·), melting point 160°c 16 B.1 -NCH- CH=CH - OloH -(ch2)3- (A); melting point 160 ° C; [ α ] 20 〇 = +30.11 ° (c = 23.75 mg / 5 ml of methanol) 17 B.1 -N=CH- CH=CH- _cHrrOc N~f '-OH -(CH2)3-(B); melting point 165 ° C; [ α ] 20 〇 = -30.11 ° (c = 9.30 mg / 5 ml of methanol) 18 B.1 -N=CH- CH =CH- -CH2-N^y~ -(CH2)2- (A); melting point 132 ° C; [ a] 20 D = +38.88 ° (c = 24.95 mg / 5 ml of methanol) ~ 52 ~ (please read first Note on the back side of this page) ----I----订·----I--- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A7 B7 V. Description of invention (r/) Printed by the Consumers’ Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

Compound number example number -al=a2- a3=a4- -Aik1-A- -Q- Physical data (melting point °c) 19 B.10 -N=CH- CH=CH- -CHZ~N^ — -(ch2 ) 2-(S); melting point 132°c; [ a] 20D=-41_70° (c=24.34 mg/5 ml sterol) 20 B.1 -N=CH-CH=CH- -CH 2-N ( —〉- -(CH2)3- Melting point 200°C 21 B.1 -N=CH-CH=CH- -ch2-n^)- -(CH2)3- (A); Melting point 195°C; [α ]20〇= +38.51° (c=25.97 mg/5 ml sterol) 22 B.10 -N=CH-CH=CH- —ch2-n^ — —(ch2)3- (S); Melting point 195° C;[ α]20〇= -41.90° (c=24.82 mg/5 ml methanol) 23 B.2 -N=CH- CH=CH- -ch2-n^— -ch2- co- •C2H204 (1: 1) 31 B.9 -N=CH- CH=CH- - COOC2H5 -ch2-n^^— -(CH2)r (A-trans) 32 B.9 -N=CH- CH=CH- .COOC2H5 -(CH2)3- (B-trans); melting point 180 °C ~53~ (please read the notes on the back and fill out this page)

Γ . HI 1· nn 】'· nnnn 1^1 n ϋ I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A7 B7 V. Invention Description (P) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed Compound Number Example Number -a1=a2- a3=a4- -Aik1-A- -Q- Physical Data (melting point °c) 33 B.9 -N=CH- CH=CH- _^cooc2h. -CH plant-(CH2)3- (A-cis); melting point 150 ° C 34 B.9 -N=CH- CH=CH- _^COOQH· ^η2λΖ/ -(CH2)3- (B-shun 35 B.3 -CH=N- CH=CH- -ch2-/^&gt;- -(CH2)2- - 36 B.3 -CH=N- CH=CH- -ch2-/^&gt; — —(CH2)2- - 37 B.2 -N=CH-CH 二CH- -ch2-.^~~ch2- -(CH2)2- - 38 B.2 -N=CH- C(CH3) = CH- -ch2-/^)- -(ch2)2- 39 B.2 -N=CC1- CH=CH- -(ch2)2- - 40 B.8 N(0)=C H- CH= CH- -ch2-/^)- -(CH2)2- •H20(l:2) 41 B.3 -N=CH- N=CH- -(CH2)2- - ~54~ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Package--------Book--------- (Please read the back Note: Please fill out this page again) 1324999 A7 __B7 V. Invention Description (〇) Ministry of Economic Affairs Intellectual Property Bureau employees Co., Ltd. printed compound number example number -a 丨==a2-a3=a4- -Aik1-A- -Q- Physical data (melting point °c) 42 B.2 -N=CH- CH=CBr ,2_n〇- -(CH2)2-(A) 43 B.9 -NCH- CH=CH- _^OH -CHj-N y-CH2~~ -(CH2)3- [B-[1(B),3ALPHA, 4BETA ]] 44 B.9 -N=CH- CH=CH- _&lt;COOC2H5 -(CH2)3- [B-[1(B),3ALPHA, 4ALPHA]] 45 B.9 -CH=N- CH=CH - -ch2-n^)- -(ch2)2- (A); Melting point 206°C 46 B.9 -CH=N- CH=CH- -'ch2-n〇— -(CH2)2- (B ); melting point 206 ° C 47 B.9 -N=CH-CH di CH- _^OH —ch2-n ch2—-(CH2)3- [A-[1(B),3 ALPHA, 4BETA]] melting point 194 48 B.9 -N=CH- CH=CH- /COOC2H5 -ch2-n^)— -(CH2)3- [A-[1(B),3 ALPHA, 4ALPHA]] 49 B.6 -N =CH- CH=CH- -ch2-n^J)— -(CH2)3- [A-[1(B),3ALPHA, 4BETA]] 50 B.6 -N=CH- CH=CH- -ch2 -nV— -(CH2)3- [B-[1(B),3ALPHA, 4BETA]] 51 B.7 -N=CH- CH=CH- /^^0H -ch2-n^J)— -( CH2)3- [A-[1(B),3 ALPHA, 4ALPHA]] ~55~ (Please read the notes on the back and fill out this page)

Order ---------Line J This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A7 B7 V. Invention Description (you) Table F-6

Compound number example number -a1=a2-a3=a4 - -Aik1-A- -Q- Physical data (melting point °c) 24 B.2 -N=CH- CH=CH- —ch2-/ — —(CH2) 2- - 5 Table F-7

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Compound No. Example No. r2 R3 3 -Q- Physical Data (melting point °C) 52 B.2 |Γ&quot;Τ〇Ί,Μ人. CHrNH—(CH2)3— NS —(CH2)3-(Α);·〇2Η2〇4 53 B.2 吣人(ch2)3—— NS -(CH2)3- (B);C2H2〇4 54 B.2 ch3 -(CH2)2- - 55 B.2 ch3 (PY Ί 1 person ch2-nh-(ch2)3—-(CH2)r - · II I----book.----- --- (Please read the note on the back and fill out this page.) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 1324999 A7 B7 V. Invention Description (iT)

5 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 10

Physical data (melting point.c) 56 B.2

57 B.9 58 B.9 59 B.2 C, Pharmacology|Example = Tensileness cannot be measured by manometry, so electrons can be used to test the pharmacological mode of the compound and to have a 'median tone, stomach tension and See the effect of the tension, 'The constant pressure device includes an air injection system, which is connected to the stomach in a fixed pressure by a double-chamber 14_F(10)ch polyethylene tube and super (four) soft poly thief (maximum volume. The change in gastric tension is measured by the volume of the air volume of the bag, and the constant pressure device maintains a fixed pressure (preselected) in the bag filled with soft milk to the inside of the stomach, and the volume of air in the bag is changed via the feedback system. The constant pressure device measures the gastric peristalsis activity according to the change in the volume of the stomach (reduced or increased, respectively) under the force of the fixed stomach. -57-

This paper-like money _ (CNS) A4 fm (210 χ 297 ΓPlease read the notes on the back and fill out this page) ----Book---------Line* A7 B7 V. Invention Description (β q Included - connected via electronic #Continuation 11 to the air injection suction ί'ίίί, money table and injection age riding through the double-cavity polythene tube meat vinyl bag, on the dial of the constant (four) towel can choose stomach underwear Maintain the value of the force. 5 The small female hound with a weight of 7-17 kg is trained to stand quietly in the pavl〇v I's implanted in the stomach tube under general anesthesia and aseptic, after a median laparotomy, in ^atarjet God At 2 cm above, the stomach wall was cut longitudinally between the larger and smaller curves, and the catheter was fixed to the stomach wall via a double-stringed string suture and passed through the residual wound in the left rib 10 to return the dog for two weeks. p At the beginning of the test, open the catheter to remove any gastric juice or food residue. If necessary, wash the stomach with 4G to 5 ml of lukewarm water, and place the ultra-thin clothes on the stomach base through the stomach catheter. During the experiment, it was easy to open the bag in the stomach and inject the volume of 400 ml into the bag twice. - Beta field for a maximum of 90 minutes during the stabilization period at 6 mm Hg (about 81 kpa). The monthly volume under pressure is stable during 15 minutes. The subcutaneous drug-like duodenal (ID) test compound is used to examine the test compound. The change in volume of the lunar month is usually 〇63 mg/kg. If the test compound shows activity in the test, the other doses and routes of administration are tested. Table c_2〇1 summarizes the test compound for SC or ID (〇63 mg/kg) After that, the average maximum change of the base slack volume during the festival is printed in the H's Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative. ~58- This paper scale applies the China National Standard (CNS) A4 specification (21〇X 297 public) Chu) 1324999 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (&gt;^7) Table ci: 10 Compound No. 4 10 13 sc Path ^CIDID — Sc —— _ sc ID Maximum volume change (ml) - Maximum change in compound numbering pathway volume (ml) 156 --- 16 ID 156 245 —— _ 18 ID 21 327 ^ ~_ 22 ID 81* _301 24 ID 35 78 25 I .D. 226* 31 ------ 30 ID 163* 118 Volume*: Maximum change measured with test compound at a concentration of 〇.〇4 mg/kg C.2 Substrate H Full-tube shrinkage method, Shishi w Hang the basal artery segment taken from the pig (anesthetized with sodium pentobarbital) for recording in 11 materials _ etc., immersing the specimen in Krebs-HenseleiW: ^ 'Let the lining hold and add 19 Cut a mixture of 2_5% c〇2 and sing the specimen (4) to a stable base tension of 2 grams. The specimen was shrunk with serotonin (3xl〇-7 molar concentration), the response to the addition of blood/months was measured and the serum was then removed by washing. This step was repeated until a stable simplification was obtained, and then the test compound (4) was applied to the organ pool. The contraction of the specimen is measured, and the contraction response is expressed as a percentage of the response to the previous serotonin. 〇 EE &gt; 5G value (molar concentration) is defined as the test compound causing serotonin------ ----Line win (please read the note on the back and fill in this page) -59- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public $ 1324999 A7 _B7__ V. Invention description (r&lt; f) Obtain a 50% contraction response concentration and estimate the ed50 value from experiments with three different specimens. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints good----------------- --Book ·-------I (Please read the phonetic on the back? Please fill out this page again) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1324999 〆kl ΒΪ DS Patent Application No. 90111411 ROC Patent Appln. No. 90114911 Approved application. Li Yiwei Chinese text one attachment (3) Amended Γ.^ίτης in Chinese — ΚηπΙΥϊΤΠ VI. Patent application scope (Republic of China 98 Submitted on October 15th) (Submitted on October 15, 2009) 1. A compound λ of formula (i) Zl Z2· -Aik1—A--Rs (I), R3 a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, or a quaternary ammonium salt thereof, wherein akaLaka4- is a divalent group of the formula -N=CH-CH=CH- (a-1), or -CH=N-CH=CH-(a-2) ' zLz2- is a divalent group of the following formula - Y'-CHCR^-C^-O- (b-3), or -Y]-CH(R4)-CH2-CH2-(b-6), Y1 is oxygen; Aik1 is Cw alkanediyl; R1 R2 and R3 are each independently selected from hydrogen; R4 is hydrogen; -A- is a divalent base of the following formula: Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing - lj? - Aik2- (c-1) R6 (c- 2) -61 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 Α8 Β8 C8 D8 VI. Patent application scope where m is 0 or 1; Aik2 is a mono-substituted Cm alkyl group ; R6 is hydrogen, hydroxy, hydroxy Cm alkyl or Cm alkyl ester group; R5 is a base of the formula (dl) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints X is oxygen; R7 is hydrogen; and Q is a divalent group of the formula -CH2-CH2-CH2-(e-2), -CH2-CO- (e -5), or -(CH2)2-CO- (e-7). 2. A compound according to claim 1 wherein R5 is a group of formula (d-1) wherein X is oxygen and Q is a group of formula (e-2) or (e-5). 3. A compound according to claim 1 wherein the divalent group -a^a2-a^=a4- is of the formula (a-1) or (a-2) and the divalent group -A- is a formula (c) -2), and is a group of formula (dl) wherein X is oxygen; R7 is hydrogen and Q is (e-2), (e-5) or (e-7). 4. A compound according to claim 1 wherein the compound is 1-[1-[(2,3-dihydro[1,4]dioxo[2,3-b]pyridin-3-yl) ) methyl]-4-hexahydropurine bite]-2-ρ rice sniff. Ketone; 1-[1-[(2,3-dihydro[1,4]dioxo[2,3-b]indoledin-3-yl)indolyl]-4-hexahydron ratio Biting base] tetrahydro-2(1Η)-°^α- ketone; -62 - This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1324999 A8 B8 C8 D8 VI. Patent application scope 1-[ 3-[[(2,3-Dihydro[1,4]dioxo[2,3-b]acridin-3-yl)methyl]amino]propyl]dihydro-2,4 ( 1H,3H)-pyrimidinedione; and 1-[3-[[(2,3-dihydro[1,4]dioxo][2,3-b]acridin-3-yl)methyl] Amino]propyl]-2,4-imidazolidindione; a pharmaceutically acceptable acid addition salt, stereochemically isomeric form, or N-oxide form. A pharmaceutical composition for treating a condition associated with a disturbed substrate disorder, comprising a pharmaceutically acceptable carrier and a compound having a therapeutic amount according to any one of claims 1 to 4 of the patent application. 6. A compound according to any one of claims 1 to 4 which is used as a medicament. 7. A process for the preparation of a compound of formula (I) according to claim 1 wherein a) is in the reaction of an inert solvent and, if appropriate, in the presence of a suitable test, formula (II) Intermediate alkylation, Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, the reaction inert solvent is selected from acetonitrile or tetrafurfuran; the suitable base is selected from sodium carbonate, potassium carbonate, calcium oxide or triethylamine; the temperature is from room temperature to reaction. Within the range of the reflux temperature of the mixture; b) or, if desired, converting the compound of formula (I) to an acid addition salt or, conversely, converting the acid addition salt of the compound of formula (I) to free-63 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1324999 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed six, apply for patent range of alkali form; and if necessary, prepare Its stereochemically isomeric form. This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)