TW442485B - Pyrano, piperidino, and thiopyrano compounds and methods of use - Google Patents

Abstract

A compound having formula I, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; m is 1 or 2; m+n is not 3; A is NR2, O or S; A' is NR3, O, S or CR4R5; D is C(O); D' is C(O), S(O), or S(O)2; R1 is phenyl substituted with one or two of the following substituent(s): halogen, NO2, CN, CF3, and OH, thienyl substituted with nitro, or benzothidiazole; R2 and R3 are hydrogen, C1-4alkyl or phenyl-C1-4alkyl; R4, R5, R6 and R7 are hydrogen, or C1-4alkyl; and with the proviso that A"" is CR4R5 when D' is S(O) or S(O)2. The said compounds may be useful in hyperpolarizing cell membranes, opening potassium channels, relaxing smooth muscle cells, and inhibiting bladder contractions.

Description

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 Λ7 ^ Α7 _ B7 V. Description of the Invention (1) The present invention is a part of the serial application of US Patent Application No. 09 / 181,690 filed on October 28, 1998. It is incorporated herein by reference. TECHNICAL FIELD Novel dihydropyridine compounds and their derivatives can open potassium channels and can be used to treat various medical conditions. BACKGROUND OF THE INVENTION Potassium channels play an important role in regulating cell membrane stress. When the unloading channel is opened, the potential across the cell membrane can change and lead to a more polarized state. Several diseases or conditions can be treated with therapeutic agents that open potassium channels; see (K. Lawson, Pharmacol. Ther., Vol. 70, 39.63 (1996)); (DR Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat., Vol. 18, pp. 1093-1102 (1994)); (M. Gopalakrishnan et al. 'Drug Development Research, Vol. 28, pp. 95-127 (1993)); (JE Freedman et al., Neuroscience , Vol. 2, 145-152 (1996)); (D'E. Nurse et al., Br. J. Urol, Vol. 68 ''27 -31 (1991)); (BB Howe et al., J. Pharmacol Exp. Ther ', vol. 274' 884-890 (1995)); and (D. Spans wick et al., Vol. 390, pp. 521-25 (1997, February 4 El)). These diseases or conditions include asthma, epilepsy, hypertension, male sexual dysfunction, female sexual dysfunction, migraine, functional bowel disorder, and neurodegeneration. Potassium channel openers can also be used as smooth muscle relaxants. Since urinary incontinence can be derived from the autonomous and uncontrolled contraction of bladder smooth muscle, potassium channel openers can over-polarize bladder cells and their ability to soothe smooth muscle provides a way to reduce or prevent urinary incontinence. This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) This page) 44248 5 A7 _____ B7 V. Description of the invention (2) Journal of Cardiovascular Medicine 8:11 68-1 175 (1986) Rowan Press, New York, Ep

0059291, EP 87051738, US 4,321,384, US 4,551,534, US 4,596,873 and 118 4,618,678 all disclose 4- (aryl) -4,5,6,7,8-hexahydro-2-alkyl-5-oxo- 7-naphthyridine carboxylate can be used as an antihypertensive agent as a calcium entry blocker. The compound of the present invention is novel and can make the cell membrane excessively polarized to 'open potassium channels and sooth smooth muscle cells' to inhibit bladder contraction and can be used to treat diseases that can be relieved by opening potassium channels. ’Summary of the invention In the main specific examples of the present invention, the compound of the present invention has f, please read the note on the back before filling in this page)

Ordered by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, or medically acceptable salts, fermented amines, esters, or prodrugs thereof, where η is 0-I; m is 1-2; A is selected from NR2 and 〇 And S; A 'is selected from the group consisting of NR3, 0, S and CR4R5; D is selected from the group consisting of <: 112 and C (0); D' is selected from CH2, C (0) , S (0) and S (0) 2;

Ri is selected from the group of aryl and heterocyclic groups; I and R3 are independently selected from hydrogen, alkoxyalkyl, alkyl, arylalkyl, and naphthenic-5- This paper is in accordance with China's Zhou Jia standard (CNS ) A4 specification (210 X 297 public love) 4 42 48 5 a? B7 V. Description of the invention (3) group, cycloalkylalkyl, self-alkyl, heterocycloalkyl, hydroxyl, superburning group, ~ 2122 and ^ Ethyl group 1) 2) alkynyl group, wherein 2) 1 and ethane 2 are independently selected from the group consisting of gas, ammonium group, alkylcarbonyl group, aryl'arylalkyl group and formamyl group; R > 4 And K · 5 are independently selected from the group consisting of hydrogen and alkyl; Chi 6 and R7 are independently selected from the group consisting of hydrogen and alkyl; but when D is CH2, then D 'is not CH2; and when D1 is S ( 0) or S (0) 2, then A is CR4R5. Detailed description of the invention All percentages, patent applications and documents described in this specification are fully incorporated herein by reference. In the case of inconsistencies, this disclosure (including definitions) will be persuasive. It should be understood that the foregoing detailed description and drawings are for illustration only and are not intended to limit the present invention, which is only defined by the scope of the application, patent, and equivalents. Various changes and modifications of the specific examples disclosed are those skilled in the art. Those who do not limit their chemical structure, substituents, derivatives, intermediates, synthetic methods, formulations and / or methods of use may make such changes and modifications without departing from the spirit and scope of the invention.

In the main specific example of the present invention, the compound of the present invention has the formula I Ministry of Economy, Intellectual Property and Property Bureau

A

------- " ------- Order --------- line (please read the precautions on the back before filling this page) Consumption cooperation Du printed or medically acceptable Sex salt 'donkey amine, vinegar, or its prodrug, of which -6- this paper size applies _ National Standard (CNS) A4 specifications (21CU 297 public love) 4 42 48 5 A7 B7 V. Description of the invention (4) Is 0-1; m is 1-2; A is selected from the group of NR2, 0, and S; A 1 is selected from the group of NR3, 0, S, and CR4R5t; D is selected from (: 出 and C (0 ); D 'is a group selected from CH2, C (0)' S (0) and S (0) 2;

Ri is selected from the group of aryl and heterocyclic groups; R2 & R3 is independently selected from hydrogen, alkoxyalkyl, alkyl, arylalkyl, cyclohexyl, cycloalkylalkyl, alkyl, A group of heterocycloalkyl, hydroxy, hydroxyalkyl, -NZih and (NZ, ZO) alkyl groups, wherein ZilZa is independently selected from纰 group; chi 4 and R5 are independently selected from the group of hydrogen and alkyl; R6 and R7 are independently selected from the group of hydrogen and alkyl; but when D is (: 112, D1 is not CH2; and when D1 When S (O) or S (0) 2, then A1 is CR4R5. In another specific example, the present invention discloses a compound of formula π or a pharmaceutically acceptable salt, amidine, ester, or prodrug thereof: 1 L -------- I --- fH · --I I --- Order --------- (Please read the note on the back * Hua Xiang before filling this page) Wisdom of the Ministry of Economic Affairs Printed by the Consumer Affairs Cooperative of the Property Bureau.

Is A. In the meaning of the definition, if the Π magic formula is η and transitive ^, combined with R7 ', 6R in the' 1MJ 1 public R body r I with D-this paper standard China National Standard (CNS) A4 specifications ( 210 X 297 g) 442 48 5 A7 B7 Printed by the Industrial Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (5 NR2; and A ,, D ,, Ri, ρ η 2, feet 6, R7, m and η is as defined in Formula I. In another embodiment of the present invention, the compound has Formula II, where A is 0 and ^ order ^.

The compound has formula II, where A is S and A D ′, 1, 1, 117, 11 », and 11 as defined in formula 1. In another specific example, the present invention discloses a compound of formula in or a pharmaceutically acceptable salt, amidine, ester 'or a prodrug thereof:

A

Where A A D, Ri, R7, m and η are as defined in Formula I, but are not CH2. In another embodiment of the present invention, the compound has Formula III, wherein A NR2, and AD'R1, R2, R6, R7'm and η are as defined in Formula I 'In another embodiment of the present invention, the compound has Formula III' In I, A is 0 and A ′, D1, R !, R6, r7, m and η are defined by the formula Γ. In another specific embodiment of the present invention, the compound has the formula III, in which A is s and A ', D', R], R6, R ?, m & n are defined as formula ^. In another specific example, the present invention discloses a compound of formula IV or a pharmaceutically acceptable salt, amidine, ester, or a prodrug thereof: 8- This paper size is applicable to the Chinese National Standard (CMS) A4 specification (21 × 297 mm) Love) —------ — I — * i ------- Order --------- line (please read the note I on the back before filling out this page) Ministry of Economy Wisdom “24 8 5 A7 _ B7” printed by the Property Cooperative Consumer Cooperative V. Invention Description (6)

Wherein A, A1, D_ 'Ri, R6, R7, m and η are as defined in Formula I. In another specific example of the present invention, the compound has formula IV, where A is NR2; A is NR3: and R! 'R2'R3, ruler 6 and R7 are as defined in formula I. In another embodiment of the present invention, the compound has formula IV, wherein A is NR2; A 'is NR3; R6 is hydrogen; R7 is hydrogen; and Ri, ruler 2 and R3 are as defined in formula I. In another embodiment of the present invention, the compound has the formula IV, where A is NR2; A1 is 0; and the ratio, R2 ′, and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula IV, wherein A is NR2; A 'is S; and Ri, R2, Rule 6 and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has formula IV, wherein A is 0; A 'is NR3; and R], R3, ruler 6 and r7 are as defined in formula I. In another embodiment of the present invention, the compound has formula IV, wherein a is 0; A 'is NR3; R6 is hydrogen; R7 is hydrogen; and rar3 is as defined in formula I. In another specific example of the present invention, the compound has the formula IV, where A is 0; A1 is 0; and -Ri, R15 and the definitions of formula I. In another embodiment of the present invention, the compound has formula IV, wherein eight is 0; A_ is 0: R6 is hydrogen; R7 is hydrogen; and 1 ^ is as defined in formula I. In another specific example of the present invention, the compound has formula IV, in which eight is 0; -9- this paper size applies to the national standard CCNS) A4 specification (210 ^ 297 mm) • »---- HIIIIJI —- ------- Order · -------- (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 42 4 8 5 a:- --- B7 V. Description of the invention (7) A 'is S; and Ri, ruler 6 and R7 are as defined in Formula J. Another 'specific example' of the present invention is: a compound having the formula w, where ... is s 'Re is hydrogen ·' R? Is hydrogen; and R is as defined by the formula. In another embodiment of the present invention, the compound has the formula 1 ¥, where A is S: A 'is NR3; and R, R3, Chi 6 and & are as defined in Formula j. — In another embodiment of the present invention, the compound has formula j V, where A is s; A is 0; and, rule 6 and r7 are as defined in formula [. In another embodiment of the present invention, the compound has the formula 1 ¥, where eight is 5; A is S; and R ′ is as defined in Formula I. In another specific example, the present invention discloses a compound of formula V or a pharmaceutically acceptable salt, amidine, ester 'or a prodrug thereof:

Where A 'A., R,' R61R7 are as defined in Formula I. In another specific example of the present invention, the compound has the formula V 'wherein A is NR2; A' is NR3; and R'2, R3 ', and R6 are as defined in Formula I. In another embodiment of the present invention, the compound has the formula V 'wherein A is NR2; A1 is 0; and &, R2, Gen6 and r7 are as defined in Formula I. In another embodiment of the present invention, the compound has the formula V 'wherein A is NR ?; A' is 0; R6 is hydrogen; R7 is hydrogen; and R2 is as defined in formula Ϊ. In another specific example of the present invention, the compound has the formula V, where A is NR; -10- The paper size is applicable to the national standard (CNS) A4 specification (210 X 297 mm) I 1 II l · I-- --I: --------Order --- 1 ---- i < Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (8) A 1 is S And R ,, R2, ruler 6 and R7 are as defined in Formula I; (Please read the notes on the back before filling this page) In another specific example of the present invention, the compound has formula V, where A is NR2; A 'is CR4R5; and Ri, R2, R4, R5, R6, and R7 are as follows: Definition of I. In another embodiment of the present invention, the compound has formula V, where A is NR2; A1 is CR4R5, R4 is · iL; R5 is rat; Rg is wind; R7 is wind; and Ri and R2 are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is 0; A 1 is NR3; and Ri, R3, 116, and R7 are as defined in formula I. In another embodiment of the present invention, the compound has formula V, wherein A is 0; A ′ is NR3; is nitrogen; R7 is martial arts; and R i and ruler 3 are as defined in formula I. In another embodiment of the present invention, the compound has formula V, wherein A is 0; A 'is 0; and R !, R6 & R7 are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, where A is 0; A 1 is 0; R_6 is JL; β · 7 is wind; and R! Is as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is 0; A ′ is S; and R !, 116 and R7 are as defined in formula I. In another embodiment of the present invention, the compound has formula V, wherein A is 0; A is CR4R5; and R4, R5, ruler 6 and R7 are as defined in formula I. In another specific example of the present invention, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the compound has formula V, where A is 0; A is CR4R5; R4 is wind; anti-5 is wind; anti-6 is rat; R7 is wind; And Ri are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is S; A 1 is NR3: and R !, R3, ruler 6 and R7 are as defined in formula I. In another specific example of the present invention, the compound has the formula V, where A is S; -11-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 442 48 5 A7 B7 Intellectual Property Bureau of the Ministry of Economic Affairs Printing of clothing by employee consumer cooperatives V. Description of the invention (9) A 'is 0; and R !, 116 and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is S; A ′ is S; and Ri and R61R7 are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is S; A 1 is CR4R5; and R !, R4, R5, R6, and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has formula V, wherein A is S; A1 is CR4R5; R4 is oxygen; R5 is nitrogen; ruler 6 is gas; K · 7 is nitrogen; and R1 is as defined in formula I. In another specific example, the present invention discloses a compound of formula VI or a pharmaceutically acceptable salt, amidine, ester, or prodrug thereof:

Wherein A, A ,, &, 116 and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is NR2: A 'is NR3; and Ri, R2, R3, R6, and R7 are as defined in Formula I. -In another specific example of the present invention, the compound has formula v, wherein A is NR2; A 'is 0; and Ri, R2, ~, and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is " NR2, A1 is S; and Ri, R2, Re and R7 are as defined in Formula I. In another specific example of the present invention, the compound has formula VI, where A is -12- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) (Please read the precautions on the back before filling this page) ; Is> 4 8 5 A7 _B7 V. Description of the invention (1〇) NR2; A 1 is CR4R5: and Ri, ruler 2, R4, R5 'Re and ruler 7 are determined by formula I (please read the note on the back first) Please fill out this page). In another embodiment of the present invention, the compound has Formula VI, wherein A is NR2; A1 is CR4R5; R4 is murine; Rs is murine; Re is nitrogen; ruler 7 is nitrogen; and R2 is as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is 0; A 1 is NR3; and R !, R3, 116, and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is 0; A1 is NR3; Re is a mouse; R? Is a mouse; and Ri and R3 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is 0; A_ is 0; and R, R 6 and 117 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is 0; A_ is S; and R, 116 and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has the formula VI, wherein A is 0; A_ is CR4R5; and Ri, R4, R5, 116, and R7 are as defined in formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is 0; A 1 is CR4R5; R6 is hydrogen; R7 is hydrogen; and R! 'R4 and R5 are as defined in Formula I. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs In another specific example of the present invention, the compound has Formula VI, where .A is S; A is NR3; and R, R3, 116, and R7 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is S; A_ is 0 :, and Ri, feet 0 and 117 are as defined in Formula I. In another embodiment of the present invention, the compound has Formula VI, wherein A is S; A 1 is S; and R, R 6 and R 7 are as defined in Formula I. -13- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 4 42 4 8 5 A7 B7 V. Description of the invention (11) (Please read the precautions on the back before filling this page) In another embodiment of the present invention, the compound has Formula VI, wherein A is S; A is CR4R5; and R !, R4, R5, 116, and 117 are as defined in Formula I. In another embodiment of the present invention, the compound has formula VI, wherein A is S; A1 is CR4R5; R4 is the base; rule 5 is nitrogen; R0 is nitrogen; is wind; and Ri is as defined in Formula I. In another specific example, the present invention discloses a compound of formula VII or a pharmaceutically acceptable salt thereof, SI; an amine, vinegar, or a prodrug thereof:

Wherein A ′ R i, R4, R5, ruler 6 and R7 are as defined in Formula I. In another specific example of the present invention, the compound has formula VII, wherein A is NR2; and Ri, R4, K · 5 ′ and R7 are as defined in Formula I. In another specific example of the present invention, the compound has formula VII, where A is NR; is nitrogen; Rs is iL; K · 6 is · SL; R7 is wind; and Ri and K · 2 are as defined in Formula I. In another embodiment of the present invention, the compound has formula VII, where A is 0; and R, R4, R5, ruler 6 and R7 are as defined in formula I. In another embodiment of the invention, the compound has formula VII, where A is 0; R4 is hydrogen; Rs is hydrogen; Rs is hydrogen; is hydrogen; and Ri is as defined in formula Ia In another embodiment of the invention, the compound Has formula VII, where A is S; and R, R4, R5, 116, and R7 are as defined in formula I -14- This paper size applies the Chinese National Standard (〇KS) A4 specification (210 X 297 mm) 442485 Λ7 137 Five 'invention description (12) is a shaking system, the present invention discloses a compound of formula νπ1 or its medically accessible 'Sexual salt, eramine, cool, or its prodrug.

R4 Rs Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs? ^ Where A, R ,, R4, R5, ruler 6 and R7 are as defined by the formula. In another specific example of the present invention, the compound has the formula νπι, wherein A NR2: and R, R2, R4, r5 ′, and I are as defined in formula 丨. In another embodiment of the present invention, the compound has the formula VIII, wherein A, B2; R4 is hydrogen; Rs is hydrogen; is hydrogen; L is hydrogen; In another specific example of the present invention, the compound has the formula νπι, wherein A 0; and R 4 ′ R 5 ′ 6 and R 7 are as defined in formula 丨. In another specific example of the present invention, the compound has the formula νιπ, where A 0: R 4 is hydrogen; R 5 is hydrogen: r 6 is hydrogen; R − is hydrogen; In another specific example of the present invention, the compound has the formula νιπ, where A is s; and R !, R4, R5, 116, and r7 are as defined in the formula 〖. Another specific embodiment of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula ι-νιπ or a pharmaceutically acceptable salt thereof, amidoamine or a combination thereof and a pharmaceutically acceptable carrier. Another specific example of the present invention relates to a method for treating male sexual dysfunction, which includes the following compounds: V η Ι Ι — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — —————— — — — — — — — — — — — — — — — — — — — — — — — — — — — — (Fill in this page) Guan Jiaxian (Cqing-15- A7

^ 4248 1 (but not limited to) a method for male erectile dysfunction and premature ejaculation, which method comprises administering a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt thereof, amine, ester, or prodrug thereof. Another specific example of the invention relates to a method for treating female sexual dysfunction, including but not limited to female sexual coldness, insufficient clitoral erection, vaginal congestion, difficulty in sexual intercourse and vaginal spasm. A compound of Formula I-VIII or a pharmaceutically acceptable salt thereof, 'amidamine, ester Λ, or a prodrug thereof. Another specific example of the present invention relates to a method for treating asthma, epilepsy, hypertension, Raynaud's syndrome 'migraine, pain, eating disorder, urinary incontinence, functional bowel disorder' neurodegeneration and shock, the method comprising And a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt thereof, glutamine, I, or a prodrug thereof. The present invention utilizes novel intermediates to make compounds of formula I. In particular, intermediates of formula IX can be used in the production of synthetic industrial compounds. F Please read the notes on the back before filling out this page) · ά Ν 印, printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Online Economics ^ IX, where A is Selected from the group consisting of 0, s, and NR2; 112 of which is selected from the group consisting of hydrogen, alkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, hydroxy, Hydroxyalkyl, -NLZaKCNZiZJ alkyl group's tZiKZs are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, and oxyaryl 16- This paper size applies to China National Standard (CNS) A4 (210 x 297) (Centi) 442485 Α7 ___ Β7 V. Description of the invention (14) Groups of foundation pits and bases. Definition of terms The term "'alkenyl" as used herein means a straight-chain or branched nicotyl group containing 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by removing two hydrogens. Representative examples of alkenyl include, but are not limited to, vinyl '2 propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2 -Fluorenyl-1 · heptenyl, 3-decenyl and the like. As used herein, alkoxy " means that an alkyl group defined herein is bonded to the parent molecule via an oxy moiety / Polyoxy Representative examples include (but are not limited to) methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and the like. As used herein, "alkoxyalkoxy" means an alkoxy group as defined herein is obtained by binding another alkoxy group to the parent molecule. Representative examples of alkoxyalkoxy groups include (but are not limited to) The third butoxyfluorenyloxy group, 2-ethoxyethoxy group, 2-methoxyethoxy group, methoxymethoxy group, etc. As used herein, alkoxyalkynyl means as defined herein It is obtained by bonding the oxyalkoxy group to the parent molecule via an alkyl moiety. Representative examples of the alkoxyalkoxy group include (but are not limited to) a third butoxymethoxymethyl group, and an ethoxymethyl group. Oxymethyl, (2-methoxyethoxy) methyl '2_ (2-methoxyethoxy) ethyl, etc. As used herein, " sulphonyloxy " refers to Tiger oxygen is obtained by bonding to the parent molecule through a pit moiety. Representative examples of alkoxyalkyl include, but are not limited to, third butoxymethyl, 2-ethoxyethyl, and 2-fluorenyl Ethyl, methoxymethyl, etc. -17- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before reading (Write this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs * J ^ -nm. ^ 1 I n III—-----*---------- ϋ. ^ 1 D. ^ 1 I . ^ 1 1 442485 A7 B7 V. Description of the Invention (15) "Alkoxycarbonyl" as used herein means an alkoxy group as defined herein is obtained by bonding the alkoxy group to the parent molecule via a carbonyl moiety. Representative examples of oxo groups Including (but not limited to) methoxycarbonyl, ethoxycarbonyl, third butoxycarbonyl, etc. As used herein " alkoxycarbonylalkyl " means that an alkoxycarbonyl group as defined herein is bound via an alkyl moiety It is obtained from the parent molecule. Representative examples of alkoxycarbonylalkyl include (but are not limited to) 3-oxooxycarbonylpropyl, 4-ethoxyalkylbutyl, and 2-tertiarybutoxy The term " alkyl ", as used herein, means a straight or branched hydrocarbon group containing from 1 to 10 carbon atoms. Representative examples of alkyl include (but are not concerned with) methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, isobutyl, third butyl, n-fluorenyl, isopentyl Base, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl Wait. "Alkylcarbonyl" as used herein refers to an alkyl group as defined herein obtained by bonding to the parent molecule through a carbonyl moiety. Representative examples of alkylcarbonyl groups include, but are not limited to, ethylamido, 1-oxopropyl, 2 , 2-dimethyl-1-oxopropyl, 1_oxobutyl, 1-oxopentyl, etc. The "Alkylcarbonylalkyl" as used herein is printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Represents an alkylcarbonyl group, as defined herein, obtained by bonding to the parent molecule through an alkyl moiety. Representative examples of alkylcarbonyl include, but are not limited to, 2, oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl, and the like. As used herein, " carbocarbonyloxy " means an alkylcarbonyl group, as defined herein, obtained by bonding to the parent molecule through an oxo group. Representative examples of Machinyloxy group '18-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 male cage) 4 2 4 8 5 A7 B7 V. Description of the invention (16) Including (but not limited to) ) Ethyloxy, ethylhexyl, tert-butyl condensate, etc. As used herein, "alkylsulfinyl" refers to a group in which an alkyl group, as defined herein, is bound to a parent molecule via a sulfinyl group. Representative examples of alkylsulfinylfluorene include, but are not limited to, methylarylene, ethylidene, and the like. "Alkyl group" as used herein means that the alkyl group as defined herein is obtained by bonding to the parent molecule through a phenyl group. Representative examples of alkylsulfonyl groups include (but are not limited to) methyl phenyl group, Ethyl ethyl group, etc. "Alkylthio" as used herein refers to a group in which an alkyl group as defined herein is bonded to the parent molecule via a thio moiety. Representative examples of alkylthio include, but are not limited to, methylthio Group, ethylthio group, third butylthio group, hexylthio group, etc. As used herein, the term "alkynyl" means a straight-chain or branched hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of blocks include, but are not limited to, ethylene, 1-propanyl, 2-propanyl, 3-butynyl, 2-pentynyl, butynyl, etc. as used herein " Aryl 11 represents a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include molyl, benzyl, Θ, naphthyl, phenyl, tetramethylene, and the like. The aryl group of the present invention may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, .Alkyl, Alkylcarbonyl, Alkylcarbonyloxy, Alkylsulfenyl, Alkyl, Alkylthio, Alkynyl, Aryl, Azide, Aryloxo, Aryl • Base 'aryloxy, complex' cyano, methylenyl, halide, haloalkyl, from alkoxy, hydroxyl, alkyl, fluorenyl, nitro, phenyl, -19- Applicable to China Garden Home Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs nnn-> -r- " J_ ln--In I .--n-I--ϋ l ft ---- 4 42485 A7 V. Description of the invention (17 (please read the precautions on the back before filling this page) (Where Rso and RS1 are independently selected from hydrogen, alkyl, carbonyl, aryl, aralkyl, and methylamino), and (where R82 and R_83 are independently selected from hydrogen, alkyl, aryl, and aralkyl). &Quot; Fang Alkoxy, which means that an aryl group as defined herein is bonded to the parent molecule via a tiger oxygen group as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-fluorene 2-ylpropyl, 5-phenylpentyloxy, etc. As used herein, "arylalkyloxycarboxy" means an arylfluorenyl group, as defined herein, bonded to the parent compound via a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include (but are not limited to) benzyloxycarbonyl, fluorenyl-2-methoxymethoxycarbonyl, etc. As used herein " arylalkyl " means that an aryl group as defined herein is An alkyl group is bonded to the parent molecule. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthyl-2.ylethyl, as used herein "&Quot; Arylcarbonyl " means an aryl group as defined herein is bonded to the parent molecule via a carbonyl group as defined herein. Representative examples of arylcarbonyl groups include (but are not limited to) benzamidine, benzamidine and the like. "Aryloxy" used in this article printed by the Ministry of Intellectual Property Bureau's Consumer Cooperatives means that A radical is bonded to the parent molecule via a lactyl group as defined herein. Representative examples of aryloxy groups include (but are not limited to, radicals, each oxy group, 3-bromophenyllactyl '4-a-p-phenyloxy, 4-methylbenzene Oxy, 3,5-dimethoxyphenoxy, etc. As used herein, " aryloxyalkyl " means an aryloxy group as defined herein is bonded to the parent molecule through an alkyl group as defined herein. Aryloxy Representative Examples of Basic Burning Packages 20- This paper size applies to Chinese national standards (CNS> A4 size (210 X 297 mm) 44248 5 A7 B7 V. Description of the invention (18) Contains (but is not limited to) 2-benzyloxy Ethyl, 3-fluoren-2-ylfluorenylpropyl, 3-bromophenoxymethyl, and the like. As used herein, uazido means -N3 group. As used herein, "carbonyl" means -C (0)-group. As used herein, "carboxy" means -C02H group. As used herein, " carboxyalkyl group " means a carboxy group as defined herein is bonded to the parent molecule through an alkyl group as defined herein. Representative examples of carboxyalkyl include (but are not limited to) carboxymethyl, 2-carboxyethyl, 3 -Carboxypropyl, etc. "Cyano" as used herein represents -CN.-"Cyanoalkyl" used in woodwork means that the cyano group defined herein is bonded to the parent molecule through the oxo group defined herein Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl '2 · cyanoethyl' 3 -cyanopropyl, etc. As used herein " cycloalkyl " means containing 3 to 8 carbons A saturated cyclic hydrocarbon group. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl'cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. As used herein, "cycloalkylalkyl" means a cycloalkyl group as defined herein is bonded to the parent molecule through an alkyl group as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl , 2-cyclobutylethyl, cyclopentylfluorenyl, cyclohexylmethyl, 4-cycloheptylbutyl, etc. As used herein " fluorenyl · 'means -C (〇) H group. As used herein 1 halo " or "halogen 11", -Br, -I or -F. As used herein, " haloalkoxy " means that at least one halogen, as defined herein, is bonded to the parent molecule through an h-lactyl bond as defined herein. Representative examples of self-oxygen include (but are not limited to) methoxymethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl-21-This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 male cage) (Please read the notes on the back before filling out this page) Duty printing of employee cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs nnn nJ-_ ° J «1 nn II-I-III n I in--- κ I-I nl---u If n Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 442485 A7 V. Description of the invention (19) Oxy-pentafluoroethoxy etc. As used herein, " fluorinated alkyl " means that at least one halogen as defined herein is bonded to the parent molecule through an alkyl group as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-fluoro-3-fluoropentyl, and the like. As used herein, " heterocycle, " means a monocyclic or bicyclic system. A monocyclic ring system is, for example, any 5- or 6-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0.3 double bonds. Representative examples of monocyclic systems include, but are not limited to, 4 butane, uf heptane, aziridine, diazepine, 1 > 3-dioxane, dioxane, dioxane, squeak 'Imidazole, imidazoline, imidazolidine, isoxazole, isoxazole, isoxazoline, isoxazolium, isoxazoline, isoxazoline, morpholine, oxadiazole Porphyrin, pyrazol, azazoline, humazidine, hexahydropyridine_'hexahydropyridine, slightly ran, pyrhexyl'ezole, pyrazole 4, pyrazolidine, pyridoxine, pyrimidine, dagen, pyrrole, pyrrole Porphyrin, Pyrrolidine, Tetrahydrofuran, Tetrahydrop-phenene, Tetra-n-well 'Tetra, P-Di-det, P-Di-t-bit, P-Tet-e, P-Tetrol, Tetradiazoline , P thiazolyl, thiazolyl, thiazoline, thiophene, thiomorpholine, thiomorpholine hydrazone, pyran, sangen, triazole 'trithiacyclohexane, and the like. Examples of bicyclic systems are any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or other monocyclic system as defined herein. Representative examples of bicyclic systems include, but are not limited to, benzimidazole, benzopyrazole, benzopyrimidazole, benzopyrene, thiophene, benzopyrazine diazole, benzohumazole, benzopyran'benzopyran Benzene, Benzamidine, Benzene # Nisaki Geng, 丨, 3-Benzamidine dioxane, oxoline, oxazole, oxindole, 4indolin, Θ 丨 indole, stub-22-. _ · _ _ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ·· -n I l · — n ϋ I ^ · I n ϋ i-aJI-ft-I n II I ( Please read the precautions on the back before filling this page) 442485 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (2〇) Pyridine, isobenzophenone, isophenylpyridine, isoindene Indole, Isotolin, Isoquinine '§Tai Teng, yong 幷 U Bidian, P Kui Lin, p Kui Ji, 4 Yin, Lin, Jun Junlin, Tetrahydroisoquinoline, Tetrahydroxoline, Aromatic pyridine and the like. The heterocyclic group of the present invention may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkenyl'alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, Alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinyl, alkylthio, alkynyl, aryl, azide, arylalkoxy'arylalkoxycarbonyl, Arylalkyl, aryloxy, carboxyl, cyano, methylol, autoalkyl, alkoxy-, hydroxyl, hydroxyalkyl, fluorenyl, nitro, sulfo, sulfonate,- NR80N8 丨 (where _RS (^ RS1 is independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, aralkyl, and formamyl), and _C (0) NR82R83 (where r82 and r83 are independently selected from hydrogen, alkane Group, aryl and aralkyl). "Heterocycloalkyl" as used herein means a heterocycle as defined herein is bonded to the parent molecule through an alkyl bond as defined herein. Representative examples of heterocycloalkyl include (but Not limited to) pyridin-3-ylmethyl, 2-pyrimidin-2-ylpropyl, etc. As used herein " hydroxy " means a OH group. As used herein, hydroxyalkyl, means a hydroxy group as defined herein Via this An alkyl group as defined herein is bonded to the parent molecule. Representative examples of alkyl group include (but are not limited to) methylol, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl Etc. As used herein, " lower alkyl " means an alkyl subgroup and a straight or branched hydrocarbon group containing 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl , Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, etc. -23- This paper size is applicable to the national standard (CNS) A4 specification (210 x 297 mm) Γ L -------- I --- One -------- Order --------- Line (Please read the precautions on the back before filling in this page) 4d248 5 A7 B7___ V. Description of the invention (21) The "thiol group" used in this article means the -SH group. (Please read the "I" on the back before filling out this page.) The "nitro" used in this article means the -N02 group. The " N-protecting group " or " nitrogen protecting group " is used in the synthetic procedure to protect the amine group against undesired reactions. The N-protecting group includes carbamate, amidine Contains heteroaryl groups, N-alkyl Biology, amine group is acetal derivative, N benzyl derivative, imine derivative, enamine derivative and N-heteroatom derivative. The preferred N-protecting group is formamidine, acetamidine, benzyl Fluorenyl, pentamyl, benzenesulfonyl, benzyl, triphenylmethyl, third butoxycarbonyl (Boc), fluorenyloxycarbonyl (Cbz), etc. Conventional N-protecting groups are disclosed in TH Greene and PGM Wuts' Organic Synthesis Protecting Group, Second Edition, published by John Wiley & Sons, New York, which is incorporated herein by reference. As used herein, "-NZiZ2" means that /, and / 2 are bonded to the parent molecule through a nitrogen atom. Z! &Amp; Z2 is independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, aryl, and methyl Brewing base.—NZ] Z2 Representative examples include (but are not limited to) amine, amine, methylamine, acetamido, acetamido, etc. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (NZ, Z2) alkyl, as used herein, means -NZβ as defined herein is bonded to the parent molecule through an alkyl bond as defined herein. Representative examples of (NZ ^ 2) alkyl include (but are not limited to) amines Methyl, dimethylaminofluorenyl, 2- (amino) ethyl, 2- (dimethylamino) ethyl, etc. As used herein " oxo · • means = 0 group. As used herein "oxy" " means -〇- 基. As used herein, " sulfinylfluorenyl 11 represents the -s (o)-group. As used herein, " sulfo, 1 represents -S03H. -24- This paper size is applicable to 1 National Standard (CNS) A4 specification (210x 297 meals) 4 4248 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (22)“ sulfonic acid ”used in this paper Esters " represents _S (0) 2OR96 group, where Rg6 is selected from the group consisting of alkyl, aryl, and aralkyl as defined herein. As used herein, "sulfo" means -S〇2- . As used in this article, "thio" means -S-group. As used herein, medically acceptable prodrug " means within the scope of reasonable medical judgment that it is 'suitable for contact with humans and lower animal tissues without adverse toxicity and irritation' allergic reactions, etc., and has corresponding reasonable benefits / These prodrugs of the compounds of the invention in dangerous proportions and effective for the intended use, and the zwitterionic state of the compounds of the invention if possible. The poor drug of the present invention can be quickly converted into the parent compound of the above formula by hydrolysis in blood. A detailed description can be found in (τ Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Volume 14 of the Ac's Conference, and Biotransformable Vectors for Drug Design Edited by Edward B. Roche, American Medical Association and Pergamon Publishing Press (1987)). The present invention includes a medicinal active metabolite formed by in vivo conversion of a compound of formula [mu] v [pi]. As used herein, a medicinal metabolite refers to a compound that is a compound formed by biological transformation in the body. Biotransformation is described in more detail in The Pharmaceutical Standards for Goodman and Gilman's Treatment, 7th ed. The compounds of the present invention can exhibit stereo p isomers when asymmetric or palm centers are present. These stereoisomers have a "R'1 or" S " configuration depending on the structure of the substituents around the carbon atoms. The present invention includes various stereoisomers and mixtures thereof. Stereoisomers include Enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Compounds of the invention ^ Individual stereoisomers can be obtained from commercially available asymmetric or palmar centers Start 2 Synthetic preparation, or prepare racemic mixture, and then use the technique to analyze the paper. The paper size is applicable to China @ 家 standard (CNS) A4 specifications (210--I --- f — 11 !! * · ---- --- —Order ----- --- (Please read the notes on the back before filling out this page) -25- 44248 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (23 ). The analytical methods such as (1) enantiomers are attached to the opposite assistant, and the mixture of non-isomeric isomers is separated by recrystallization or chromatography. And self-agents release optical purity products or (2) separate the optical enantiomeric mixture directly on the palmar pipette column Preferred compounds of formula I include (but are not limited to): 5- [3-brook-4- (di | 1methyl) benzyl] -5,10-dihydro-111,311-dioxan [3 , 4-b: 4,3-e] pyridine-4,6 (7H, 9H) · diketone, 5- [4-fluoro · 3- (2-furanyl) phenyl] -5,10-dihydro -1Η, 3Η · disulfanil [3,4-b: 4,3-e] pyridine-4,6 (7Η, 9Η) -dione, 5- [3- (2-creanyl) -4 -Methylphenyl] -5,10-dihydro-111,31 ^ -di11-sulphano [3,4-b: 4,3-e] pyridine-4,6 (7Η, 9Η) -dione , 5- (5 -Xi-4-lact-2-ylphenyl) -5,10-dihydro-1Η, 3Η-diI »Diranyl [3,4-b: 4,3-e] Pyridine-4,6 (7Η, 9Η) -dione, 5- (4-fluoro-3-isophoryl epitope) -5,10-dirat-1Η, 3Η- 二 "展 RAN 幷 [3 4_ 5- (4-methyl-3-nitrophenyl) -5,10-dihydro-1H, 3 hydrazone-dihydrofuran [3-a: b, 4,3-e] pyridine-4,6 (7Η , 9Η) -diketone, 5- [3-Ga-4- (trifluoromethyl) phenyl] -5,10-dihydro · 1Η, 3Η-dibromo [3,4-b: 4, 3-e] pyridine-4,6 (7Η, 9Η) _diketone, 5- [3 · iodo-4- (trifluorofluorenyl) phenyl] -5,10-dihydro-1Η, 3Η-dibromo Porula [3,4-b: 4,3-e] pyridine-4,6 (7Η, 9Η) -dione, 5- (3-£ 4-methylbenzyl) -5,10- Dihydro-1Η, 3Η- 二 υ exhibition Benzo [3 4 · b: 4,3-e] pyridine-4,6 (7Η, 9Η) -dione, 5 · (3-ίodor-4-phenylphenyl) -5,10 -diwind-1Η ， 3Η- 二 叫 然 幷 [3,4-b.4 3-e] -26- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)-i I -I 1 nnn tl I · II · * -OJI I n] II (Please read the notes on the back before filling this page) A7 B7 Five 'invention description (24) pyridine-4,6 (7H, 9H) -dione ,. 5 -(4-bromo-3-chlorophenyl) -5,10-dihydrodihydropyrano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione, 5- [心 气 -3- (trifluorofluorenyl) phenyl] -5,10 · dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine-4,6 ( 7H, 9H) -dione, 5- (3-bromo-4-methylphenyl) -5,10-dihydro-1H, 3H-dipiperano [3,4_ 1?: 4,3-6 ] Yodo-4,6 (711) 911) -di_ '5- (3,4-dibromophenyl) -5,10-dihydro-111,311-disulfanyl [3,4-1 ): 4,3-6] pyridine-4,6 (7H, 9H) -dione, —9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexa Hydrogen-1H-pyrrole [3,4-b] [l, 7] naphthyridine-1,8 (4H) -dione, 5- (3-bromo-4-fluorophenyl) -5,8,9 , 10-tetrahydro-1H-pyrano [3,4-b] [l, 7] naphthyridin-4,6 (3H, 7H) _diketone, 5- (3-; benzene Radical) -5,10-diwind-1Η, 3Η · di-p-sepamidine [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione, 9- (3 -Bromo-4-fluorophenyl) -5,9-dihydro-3H-furanyl [3,4-b] pyrany [4,3-e] pyridine-1,8 (4H, 7H) -di Ketone, 9- (3-bromo-4-fluorophenyl) -2,3,5,9-tetrahydropyrrole [3,4-b] 4ano [4,3-e] pyridine-1,8 (4H, 7H) -diamine, 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro p ratio ytterbium [3,4_b] [i 6] Pyridine-1,9 (2H, 5H) -dione, 10- (3-Han-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-1H--dihydropyrano [4 3-b] [1,7] Piperidine-1,9 (511) -dione, 10- (3-bromo-4-fluorophenyl) -3,4,6,10-tetrahydrodipipe幷 [3,4_b: 3,4-e] py-27- This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page) Economy Printed by the Consumer Cooperative of the Ministry of Intellectual Property Bureau 01 I · _ _--I n I, ί r— ί n-»ι nnn ^ 1- n ϋ 1 1 ^ 1 n-nn # 42485 A7 __ B7 V. Description of the invention (25) Pyridin-1,9 (5H, 8H) -diketone, 10- (3-bromo-4-fluorophenyl) -3,4,6,10-tetrahydro-211-, sulfanil [3, 4-1)] [1,6] Phenidine-1,9 (5H, 8H) -dione 10- (3-Bromo_4 · fluorobenzyl) · 3,4,6,10 · Tetrahydrobran [4,3-b] p-Cyrano [4,3-e] pyridine-1,9 (5H, 8H) -diketone, 5- (3-bromo-4-fluorophenyl) -7,7-dimethyl. . , ", ^ (^ Hexahydrobenzo) [1,7] pyrimidine-4,6 (1H, 7H) -dione, 9- (3-bromo-4-fluorophenyl) -2,3, 5,9-tetrahydro-4H-phenofluorene [3,2-b] p-Cyrano [4,3-e] pyridine-8 (7H) -one 1,1-dioxide, _ 1〇_ (3 · bromo-4-fluorophenyl) -3,4,6,10-tetrahydro-2H, 5H-dipyrimidine [3,2-b: 4,3-e] pyridine-9 (8H) -Keto 1,1-dioxide, and 5- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5,8,9,10-tetrahydro_11 ^ pyran 幷 [ 3,4-b] quinoline-4,6 (3H, 7H) -dione or a pharmaceutically acceptable salt, ester, amine or prodrug thereof. A better compound of formula I includes (but is not limited to): 5- (3-Bromo-4-fluorophenyl) -5,10-dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -Diketone, 5- (3-bromo-4-fluorobenzyl) -2,3,5,8,9,10-hexahydrophenylhydrazone [1 ^ [1,7] quamidine-4,6 (1H , 7H) -dione, 5- (3-bromo-4-fluorophenyl) -2-methyl-2,3,5,8,9,10-hexahydrobenzo [13] [1,7] Phenidine-4,6 (1H, 7H) -dione, 5- (3-bromo-4-fluorophenyl) -2,3,5,8,9,10-hexahydropyrido [3,4 tons ] [1,7] Benzidine · 4,6 (1Η, 7Η) -dione, (-)-5- (3-bromo-4-fluorophenyl) -2,3,5,7,8,9 -Hexahydro-111-cyclopentane hydrazone [15] -28- The paper size applies to the Chinese national standard (CNs7a_4 specifications (210 X 297 mm) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy---III---II II--I _ -III nn ϋ .1 ϋ n-4 42 4 8 5 A7 B7 V. Description of the invention (26) [1,7] pyridine-4,6-dione, (+) · 5- (3-bromo-4-fluorophenyl ) -2,3,5,7,8,9 · ττ oxygen-1H-cyclopentane and [b] [1,7] Nagoto-4,6-dione, (-)-5- (3- Bromo-4-fluorophenyl) -2,3,5,8,9,10-hexahydrobenzidine [b] [17] pyrimidine-4,6 (1H, 7H) -dione, (+) -5- (3-bromo-4 · fluorophenyl) -2,3,5,8,9,10-hexahydrophenylhydrazone [|)] [1,7] pyrimidine-4,6 (1H, 7H) -diketone, 10- (3-Mo-4-fluorophenyl) -3,4,6,7,8,10-7T Oxythio [3,2-b] [1,7] Pyridine-9 (5H) -one U-dioxide'-9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrofluorenphenamidine [3, 2-1)] [1,7] Piperidine-8 (4H) -one 1,1-dioxide, 9 · (3-bromo-4-fluorophenyl) -2,3,5,9-tetra Hydrogen-4H-pirano [3,4-b] 4phenanthrene [2,3-e] pyridine-8 (7H) -one 1,1-dioxide, (+)-9- (3-bromo -4-fluorophenyl) -2,3,5,9-tetrahydro-4H-piranofluorene [3,4_b] 4 phenhydrazone [2,3-e] pyridine-8 (7H) -one 1,1 -Dioxide, ( -)-9- (3-bromo-4-fluorophenyl) -2,3,5,9-tetrahydro-4H-piranopyrene [3,4_b] pyrimidinepyrene [2,3-e] eridine -8 (7H) -one 1,1-dioxide, 9- (3-cyanophenyl) -2,3,5,9-tetrahydro-4H-pyrano [3,4-b] pyrimidine And |; 2,3-e] pyridine-8 (7H) -one 1,1-dioxide, (+)-9- (3-cyanophenyl) -2,3,5,9-tetrahydro- 4H-pirano [3,4-b] fluoreno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide, (-)-9- (3-cyanophenyl ) -2,3,5,9-tetrahydro-4H-piperano [3,4-b bispheno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide , 9- (4-Ga-3-nitrophenyl) -2,3,5,9-tetrahydro-4H-pirano [3,4-b] pyrimidine-29- This paper is applicable to China Standard (CNS) A4 size (210x297 mm) (Please read the notes on the back before filling out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs and Consumer Cooperatives -n rn —I—-iw-ej · II-n 1 1 · I-II 1---.-HI ni ^ i I-1 n ^ p— .--Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 ^ 148 5 a; B7 V. Description of the invention (27) 幷[2,3-e] pyridine-8 (7H) -one 1,1 'dioxide, (+) 4- (4-chloro-3-nitrophenyl) -2,3,5,9-tetra Hydrogen-4H_piperano [3,4-b] pyrimidine pestle [2, 3-e] pyridine-8 (7H) -one 1,1-dioxide, (-)-9- (4-gas-3-nitrophenyl) -2,3,5,9-tetrahydro_ 411_piperano [3,4_b] phenofluorene [2,3-e] pyridine-8 (7H) -one 1,1-dioxide, 5- (3-bromo-4-fluorophenyl)- 5,8,9,10-tetrahydropiperidine [3 4_b] quinoline_ 4,6 (3H, 7H) -dione, 10- (3-bromo-4-fluorophenyl) -3,4 , 6,10-tetrahydro_2H 5H piperane [3 4_b oxetane [2,3-e] pyridine-9 (8H) -one 1,1-dioxide, 5_ (3_bromo-4 -Fluorophenyl) -5,10-dihydro_1 H, 3H_piperano [3 4_b] i (Cyrano [4,3-e] pyridine-4,6 (7H, 9H) -dione ， 5- (3-Bromo-4-fluorophenyl) -5,7,8,9-tetrahydrocyclopentane 幷 [} 5] piran 幷 [4,3_6] Hipido_4,6 (1H , 3H) difluorene, 5- (3-bromo-4-fluorophenyl) -5,8,9,10-tetrahydro_11 ^ piperane [3,4_1)] [〗, 7] Hysteria 4,6 (3H, 7H) -difluorene, 9- (3-bromo-4-fluorophenyl) -5,9-dihydro-3H-furanyl [3,4-b] pyrano [4, 3-e] p ratio bite -1,8 (4H, 7H) -diploid, 9- (3-brook-4-fluorobenzyl) -2-fluorenyl-2,3,5,9-tetrazine. Dimin 幷 [3,4-b] p Billoxan [3,4-e] pyridine-1,8 (4H, 7H) -dione, 9- (3-bromo-4-fluorophenyl) -2 , 3,5,9-tetrahydropiperano [3,4-b] pyrrolo [3,4-e] pyridine-1,8 (4H, 7H ) -Diketone, 5- (4-Ga-3-nitrophenyl) -5,10-dihydro-1H, 3H-dipiperano [3,4_ b: 4,3-e] pyridine-4 , 6 (7H, 9H) -dione, 5- (J-lylphenyl) -5,10-dihydro-1H, 3H-di-p-citrulline [3,4-b: 4,3-e ] -30- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) · 呓, —J n-n. II nl ^ i 一 -OJ ϋ u IE 1 I ΐ I (Please read first Note on the back, please fill out this page again) A7 _B7 V. Description of the invention (28) Pyridine-4,6 (7H, 9H) -dione, 5- (4 -Ga-3-benzyl) -5,10- Diazo-1 H, 3H-dibromo [3,4-b: 4,3-e] p ratio bite-4,6 (7H, 9H) -difluorene, 5f (5-bromo-2-hydroxy Benzyl) -5,10-dihydro-1Η, 3Η-dipiperan 幷 [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione, 5- [4 -Fluoro-3- (trifluoromethyl) phenyl] -5,10-dihydro-111,315-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H , 9H) -diketone, 5- (3,4-difluorophenyl) -5,10-dihydro-1Η, 3Η · dipiperan 幷 [3,4-b: 4,3-e] pyridine- 4,6 (7H, 9H) -diketone, -5- (2,1,3-benzyldiazolyl-5-yl) -5,10-dihydro-1Η, 3Η-dipiperan 幷 [ 3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione, 5- (5-nitro-2-p-thiophene ) -5,10-diazine-1H, 3H-diρ diamidine [3,4-b: 4,3-e] t ^ -4,6 (7H, 9H)-: _, 5- ( 5 -nitro-3 -p sephenyl) -5,10-diaza-1H, 3H-dihydrofuran [3,4 · 乜: 4,3- 伫] bamboo syndrome-4,6 (711 , 911) -dione, (+)-9- (4-fluoro-3-iodophenyl) -2,3,5,9-tetrahydro-4H-pirane [3,4-b] thiophene [2,3-e] eridine-8 (7H) -one 1,1-dioxide, (-)-9- (4-gas-3-ίphenylphenyl) -2,3,5,9 -Tetrahydro- 4H -Luran 幷 [3,4-b] Phenylpyrene [2,3-e] p-pyridine-8 (7H) -one 1,1-dioxide, employee of Intellectual Property Bureau, Ministry of Economic Affairs Consumption cooperation printed by Du (please read the precautions on the back before filling this page) (+)-5- (3-Ga-4-fluorophenyl) -2,3,5,7,8,9-hexahydro -1H-cyclohexane 幷 [b] [1,7] pyrimidine-4,6-dione, (-)-5- (3-chloro-4-fluorophenyl) -2,3,5,7 , 8,9-hexahydro-1H-cyclohexane [b] [1,7] pyrimidine-4,6-dione, 9- (3-bromo-4-fluorophenyl) -5,6, 7,9-tetrahydrofuran hydrazone [3,4-b] [l, 7] pyridine · -31-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) Λ42485 Α7 Β7 V. Description of the invention (29) 1,8 (3H, 4H) -dione, (+)-9- (3- > odor-4-fluorophenyl) -5,6,7,9-tetrahydrocrano [3 , 4_b] [l , 7] Tea bite-18 (311,411) -dione, (-)-9- (3- Mo-4-fluorophenyl) -5,6,7,9-tetrahydroxanthine [3,4_b] [], 7] Listine-1,8 (3H, 4H) -dione, 5- (3-bromo "4-fluorophenyl) -7,7-dimethyl-5,8,9,10- Tetrahydro · Dipyran [3,4-b] pyridin-4-4,6 (3H, 7H) -dione,, (9R) -9- (3-bromo-4-fluorophenyl) -5,9 -Dihydro-3H-furan hydrazine [3 4 hepta] piranidine [4,3-e] pyridine-i, 8 (4H, 7H) -dione, (called -9_ (3_ Mo + fluorophenyl) · 5,9 · Dihydro · 3Η-furan 幷 [3 4_b] Pyridoxine [4,3-e] pyridine-i, 8 (4H, 7H) -dione, 1 · (3-Ga-4- Fluorophenylbenzopyridine-1,9 (5H, 8H) -dione, 10- (3,4-difluorophenyl) _3,4,6,10, tetrahydro_2H_piperano [3, 4 b] [i 6] Pyridine-1,9 (5H, 8H) -dione, 10- [4-Ga-3_ (trifluorofluorenyl) phenyl] _3,4,6,1__tetra Hydrogen-2h piperano [3,4-b] [l, 6] pyridine-l, 9 (5H, 8H) -dione, 10- (4-Ga-3'ylphenyl ", Sunda The Department of Hydrogen Printing is murmuring, 6] Bite -1,9 (5H, 8H) -dione, 10- (3,4-Dimophenyl) _3,4,6,10 · Tetrahydro- 2H-piranopyridine [3 4_b] [16] pyridine-1,9 (5Η, 8Η)-: _, 10- (5-nitro-3_sulfenylpyridine-1,9 (5H, 8H ) -Dione, 5- (3-Mo · 4_ Fluorophenyl ^ ... tetrahydro-cucurbitar ^ heart cut quinoline · -32- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling (This page) --- III Order -----. Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (30) 4,6 (3H, 7H) -dione, 5- (3- Bromo-4-fluorophenyl) -5,7,8,9-tetrahydrocyclohexane 幷 [b] pyran 幷 [4,3_e] pyridine-4,6 (1H, 3H) -dione, and 10 -(3-Mo-4-fluorophenyl) -3,4,6,10-tetrahydro-211-tripanine [3 4-13] [16] Sign bite -1,9 (5H, 8H)- Dione or its pharmaceutically acceptable salts, esters, amines or prodrugs Compounds of the invention: The compounds and processes of the invention will be more easily understood from the following synthetic reaction schemes and methods that illustrate the preparation of the compounds of the invention. -The compounds of the invention can be prepared by various synthetic routes. Representative procedures are shown in Reaction Diagrams -45. Reaction Diagram 1 (Please read the notes on the back before filling this page) · α ⑴ R ^ HO (2) o ^

(3)

Re

The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Online Economy printed eight, eight, zero, zero, eleven [, 116, ruler 7, „1 and 11 of the general formula (4) dihydropyridine as defined in Formula 1, which can be reacted as It is prepared as shown in Figure 1. The carbonyl compound of the general formula (丨), the aldehyde of the general formula (2) and the carbonyl compound of the general formula (3) are combined in a solvent such as ethanol under heating in the presence of gas to obtain the general formula ( 4) Dihydropyridine-33- This paper size is applicable to Chinese National Standard (CNS) A4 specifications < 210 X 297 public love) 44248 5 A7 B7 V. Description of the invention (31) Reaction diagram 2

A dicarbonyl compound of the general formula (8) in which A is as defined in Formula I can be prepared as shown in Reaction Scheme 2. Wherein A is selected from S or NR2 & R2, the ester of the general formula (5) as defined in formula I can be calcined with gas acetone to obtain a ketoester of the general formula (7). The ketoester of the general formula (7) can be cyclized in the presence of 絵 such as potassium tert-butoxide to obtain a dicarbonyl compound of the general formula (8). Another method for preparing ketoesters of general formula (7) can be used. Where A is 0 and the general formula (6) radon gas prepared as described in (Terasawa, Journal of Organic Chemistry (1997), 42,1163-U69) can be obtained by treating with dimethyl zinc in the presence of a palladium catalyst. Esters of the general formula (7). Reaction Diagram 3 (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

ο Η) c (2 R1

3 N

"A = A_AR1 is defined as the formula (10). The symmetric dihydropyridine can be prepared as shown in the reaction diagram 3. Two equivalent formula (8) dicarbonyl compounds can be dissolved in ethyl acetate. (Standard ms) A4 ^ / y NJ < υ 1 FREE V π ί

--n I-II I-OJ «H--n I [I-I-] n 1 > 1 --t I. ^ 1-K----nf _ _ n _ _ I 44248 5 A7 B7 5. Description of the invention (32) The alcohol is treated with an acid of the general formula (2) and 1 equivalent of ammonia under heating to obtain a symmetric dihydropyridine of the formula (10). Reaction Figure 4

Among them, A, A1 and ruler as defined in formula I (10) dihydro p ratio lake can be prepared as shown in Figure 4. The dicarbonyl compound of the general formula (8) can be treated with ammonia in a solvent such as ethanol under heating, and then an aldehyde of the general formula (2) and a diweil compound of the general formula (1 1) are added to obtain a dihydrogen of the formula (10) P than lake. (10) Reaction diagram 5

(Please read the notes on the back before filling out this page) * The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed A, VIII, and 1 where formula (14) dihydropyridine can be prepared as shown in Figure 5 Got. One of the dicarbonyl components (8) or (〖3) can be treated with ammonia under heating, and then an aldehyde of the general formula (2) and other dicarbonyl compounds (8) or (13) can be obtained to obtain the formula (丨 4) dihydrogen. Pyridine. The dicarbonyl compound of the general formula (13) can be prepared as described in (d'Angelo, Tett Lett. (1991), 32, 3063-3066; Nakagawa, Heterocyclic (1979), 13, 477-495). -35- This paper size is in accordance with Chinese Standard (CNS) A4 (21 × 297 mm) -II-I— I -I-_ II--I ϋ 1 tn -9 I ^ Β— ϋ κ ·-J * 44248 5 A7 B7 V. Description of the invention (33)

Reaction Figure 6

(16) (17) (18) Π9) A ketone of the general formula (19) in which m is 1 or 2 can be prepared as shown in the reaction diagram 6 in a solvent such as ethanol to reduce the ketone with sodium borohydride (or other) ( 16), to obtain the alcohol (1 7) ', which can be oxidized to the corresponding amidine (1 8) using an oxidizing agent such as hydrogen peroxide with sodium tungstate catalysis. Oxidation (18) using Jones reagent etc. to obtain the required cymbal (19). Reaction Scheme 7 0 R: 〇 You: W (19) (20) where A and m are as defined in Formula (2) dihydropyridine can be prepared as shown in Reaction Scheme 7. The dicarbonyl compound of the general formula (8) is treated with ammonia in a solvent such as ethanol under heating, and then (2) and ketone sulfone (19) are added to obtain a dihydropyridine of the general formula (20). An additional heating step with an acid such as HC1 may be required to drive the reaction to completion. Reaction Figure 8

-36- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 public love) ί Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Bureau Staff Consumer Cooperatives

"248 5 A7 _B7_ " " Another method for preparing the lake can be described in the reaction diagram 8. The enamine of the general formula (22) is treated with the compound (2) and the carbonyl compound (3) in a solvent such as ethanol under heating to obtain the general formula (4). Dihydropyridine Reaction Scheme 9

(8) (23) (24) The enamine ketone of the general formula (24) in which A is as defined in Formula I can be prepared as shown in Reaction Scheme 9. The dicarbonyl compound (8) is treated with an alcohol such as ethanol in the presence of an acid catalyst such as p-toluenesulfonic acid to obtain a vinyl ether of the general formula (23) wherein R is a lower alkyl group. The vinyl ether of the general formula (2 3) can be treated with ammonia in a solvent such as methanol to obtain the ketamine of the general formula (24). Reaction diagram 1 0

Among them, A, VIII 'and the ruler, another preparation method of the dihydropyridine of the general formula (10) as defined in the formula I can be described in the reaction scheme 10. Treated with enolone of general formula (24) with aldehyde (2) and dicarbonyl compound (丨 丨) in a solvent such as ethanol under heating Mm) c Jing first read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs I: OJI ϋ I-ϊ) II n «V n--I ^^ 1 lr >-1 ^ 1 442485 A7 ___ _B7 V. Description of the invention (35) General formula (1 0) dihydropyridine. Reaction · Figure 1 1 ^ Η〇 + 〇

(24) (2) (26)

The dihydropyridine of general formula (28) wherein A, heart and claw are as defined in formula I can be prepared as shown in FIG. 11. Treatment of the ketamine of the general formula (24) with an aldehyde (2) and a dicarbonyl compound of the general formula (26) in a solvent such as ethanol under heating in the presence of a base such as triethylamine gives half of the general formula (27) A mixture of amine aldehyde and dihydropyridine of general formula (28). Hemiamine aldehyde (27) can be heat treated in an alcohol such as ethanol in the presence of an acid such as HC1 to obtain a dihydrop-pyridine of the general formula (28). Reaction diagram 1 2

(Please read the precautions on the back before filling out this page) The Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs has printed the general formula (2〇) dihydropyridine of A'KKm as defined in Formula I. The preparation method can be as follows. The reaction is illustrated in Figure 12. Treating the amidines of general formula (24) with aldehydes (2) and ketones (19) in a solvent such as ethanol under heating in the presence of triethylamine, to obtain hemiamines of general formula (30) and Eq. (20) Second command to bite. Hemic acid (30) and (20) dihydroepine can be heated by HC1 in alcohol such as ethanol ^ -38-Too large paper size Applicable to China National Standard (CNS) A4 (210 X 297 cm) -j -1 I ^ -OJf-nn. ^ 1 I 1- n II— I. ^ 1 I--II-nn > n ϋ. ^ 1 n 442485

V. Description of the invention (36) General formula (2 0) dihydropyridine Reaction diagram

(14) where a, A., and R are as defined by formula r (14) Another bite in the wind. The preparation method can be like the reaction diagram! 3mentioned. The enamine copper 'of the general formula (24) is treated with the aldehyde (2) and the bis (2) compound in FIG. 5 in a solvent such as ethanol in the presence of triethylamine under heating to obtain the general formula. (14) Dinitrogen? Specific response diagram 1 4

OR (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (33) Brominating agent

H2NR3 (36)

(37)

0 -39 This paper size applies to the national standard (CNS) A4 specification (210 X 297 mm) VI '(nn .n-J n I-]! ^ — ≪ 1 Ln nn I n I »Γ— 442485 A7 B7 V. Description of the invention (37) The dihydropyridines of the general formulae (37) and (38) in which A, core and ruler 3 are as defined in the formula can be prepared as shown in Figure 14. General formula (24) Amineone can be treated with aldehyde (2) and acetamidoacetic acid ester of general formula (32) in which R is a lower alkyl group to obtain dihydropyridine of general formula (3 3). Dihydrogen of general formula (3 3) Pyridine can be treated with a brominating agent such as N-bromosuccinimide or pyridinium tribromide in a solvent such as methanol, ethanol, isopropanol, or aerosol to obtain the dihydropyridine of general formula (3 5). (3 5) Dihydropyridine can be heat treated with a primary amine or ammonia of the general formula (36) in a solvent such as ethanol to obtain the general formula (3 7) dihydropyridine. The general formula (3 5) dihydropyridine can be simple Dihydropyridine of the general formula (3 8) is obtained by heating or heating in a solvent such as chloroform. Reaction Scheme 1 5

(40) (4) wherein A, A ', D, D, ruler 1, ruler 6, 117, 111, and 11 have the general formula (4) of dihydropyridine as defined in Formula 1, and another method for preparing the same can be shown in Reaction Scheme 1 5 stated. The carbonyl compound of the general formula (1) can be heated in a solvent such as ethanol to obtain the dihydropyridine of the general formula (4) while (2) and the enamine of the general formula (4〇). Please fill in this page for attention) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

pt > ^ 1 1 ^ 1 II nt— «^ 1 —I n 1 ^ 1 _ 442 48 5 A7 R7 V. Description of the invention (38) where A, Ri and m are as defined in formula I. General formula (28) Another preparation method for the dihydro p ratio bite can be as described in the reaction diagram 15. The dicarbonyl compound of the general formula (1) can be heat-treated in a solvent such as ethanol with the aldehyde (2) and the amine cycloalkenone of the general formula (42) to obtain the dihydropyridine of general formula (28). Aminocyclofluorenone of the general formula (42) is commercially available as 3-amino-2-cyclohexan-1-one (Huka) or as described in (Synthesis of Kikani, B. (1991), 2 176). General preparation. Reaction Diagram 1 7

V

(19) ROH acid

V

(44) NH,

V

(45) (Please read the notes on the back before filling this page)

OR NH, as described in the reaction scheme of FIG. 17, wherein the dilute amine of the general formula (45) in which m is an integer of 1-2 can be prepared as in the reaction scheme of FIG. The carbonyl compound (19) can be converted into an intermediate enol ether of the general formula (44) and then into an enamine of the general formula (4 5). Reaction Diagram 1 8

'H ^ 1 一 ° J * —I 1 * I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (8) CHO (2) η2ν

(45)

Among them, A, Xin and !!! Another preparation method of the general formula (20) dihydrofluorene »bifluorene as defined in Formula I can be described in the reaction diagram 18. The diketone of the general formula (8) can be heat-treated in a solvent such as ethanol in the presence of a base such as triethylamine with aldehyde (2) and amine sulfonium (45), -41-This paper size applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 442 48 5 A7 B7 V. Description of the invention (ii) Hemiamine aldehyde of general formula (30) and dihydropyridine of general formula (20) are obtained. Hemiamine aldehyde (30) and dihydropyridine (20) can be heated in HC1 in a solvent such as ethanol to obtain dihydropyridine of general formula (20). Scheme 1 9 Λ + CHO (8) (2)

(47)

(37) P8) {Please read the notes on the back before filling out this page) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed A, R! And & General Formulas (37) and (38) as defined by Formula I Another method for preparing dihydropyridine can be described in the reaction scheme shown in FIG. 19. The diketone of general formula (8) can be treated with (2) and aminocrotonate of general formula (47) in which R is a lower alkyl group, and dihydropyridine of general formula (33) can be obtained, which can be as shown in Figure 14 General treatment to obtain the general formula (3 7) and (3 8) dihydropyridine. Reaction diagram 2 0 rD (1)

O

Ry HN,

RiCHO + such as ~ K 〇 (2) (49)

D

42- The size of this paper applies the national standard (CNS) A4 specification (210 X 297 mm) 1: OJI nfn 1 ^ 1 I n I nn I—in · n ^ n ϋ 1 L nnnn-1 n · 4 42 48 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ----- B7________ V. Description of the invention (40) where A, A1, D, D., R |, R6, R7, m and η are as shown in Formula I Another method for preparing dihydropyridine of the general formula (4) is defined as shown in the reaction diagram of FIG. 20. The carbonyl compound of the general formula () can be in the presence of ammonia in a solvent such as ethanol with the general formula (49) a, / S-unsaturated ketone is heat treated to obtain dihydropyridine of general formula (4). Reaction diagram 2 1

m (53) (54) wherein A, Rj, and m are as defined in Formula I, and another preparation method of the dihydro p ratio bite can be as described in the reaction chart 21; Lufenone sulfide (16) can be treated with a secondary amine such as morpholine, pyrrolidine or hexahydropyridine to obtain enamine (5 丨), which can be condensed with aldehyde (2) in a suitable organic solvent to obtain the general formula (52) of the sulfide. The sulfide of the general formula (5 2) can be oxidized with an oxidizing agent such as m-gas peroxybenzoic acid to obtain a sub-minus of the general formula (53). The fluorene of the general formula (53) can be obtained by heating the dicarbonyl compound (8) and a gas source such as ammonia, ammonium acetate or ammonium hydroxide in a solvent such as ethanol or a similar alcohol solvent, acetonitrile or dimethylformamide. Formula (5 4) Erqi Edian 3 -43- The paper size is applicable to Chinese National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page)

J 1 IIII I-*-r ° J «— — — In ----I-I — < III---- II I 1-l I i _ _ _ _ _ _ I 442485 A7 B7 V. Invention Explanation (41) Reaction Figure 22

The carbonyl compound (56) can be treated with an aldehyde (2) using an Aldol reaction to obtain a ketone of the general formula (5 7). The Aldol reaction and the conditions for this reaction are known to those skilled in the art. Preferably, the ketone of the general formula (57) can be prepared by converting (56) to morpholine 'pyrrolidine or hexaargon's enamine' followed by direct reaction with aldehyde (2). The ketone of general formula (5 7) can be treated with dione of general formula (8) and ammonia to obtain dihydropyridine of general formula (58). Reaction Figure 2 3

(49) wherein A, A ', D'D1, Ri, R6, R7'm and η are as defined in the formula (4), another preparation method of dihydropyridine can be as shown in reaction FIG. The enamine of the general formula (2 2) can be heat treated in a solvent such as ethanol with the general formula (49), A-unsaturated ketone to obtain the dihydropyridine of the general formula (4). -44-Paper size Applicable national standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs * IIIIII [III ---— II I III 111 *! [1-1 IL [—-1lllf] l [— 44248 5 A7 --- B7 V. Description of the invention (42) Reaction diagram 2 4 ά ♦ ΝΗ〇U)

Among them, another preparation method of A,: ^ and dihydropyridine of general formula (54) as defined by formula I can be as shown in reaction diagram 24. The enamine butterfly of the general formula (7) may be heated in a solvent such as ethanol or a similar alcohol solvent, acetonitrile or dimethyl methylamine to obtain a compound of the general formula (54). Hydropyridine. Reaction Figure 2 5

D CHO (60) (2)

ΝΗ,

< Please read the notes on the back before filling out this page) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed eight of them, eighteen, eighteen, eighteen, eighteen, seventeen, seventy-one, and eleven as defined in Equation 1. (62) Dihydropyridine can be prepared as shown in Reaction Scheme 25. The carbonyl compound of the general formula (60) can be treated with aldehyde (2) as described in (Eiden, F ,, Liebigs Ann. Chem., (1984), Η, 1759-1777) to obtain the general formula (61) aj-unsaturated ketone. The general formula (6 I) Shen, /?-Unsaturated ketone can be heat treated with a carbonyl compound of the general formula (3) in a solvent such as ethanol in the presence of ammonia to obtain the general formula (62) dihydropyridine ° -45- The scale meets China National Standard (CNS) A4 specifications (210 X 297 mm), · nn 1i n ϋ n ^ 6JI 1 n ϋ n! —JII k — — * 442485 A7 B7 V. Description of the invention (43. Reaction diagram 2 6 h2n

r6 (40) (61)

Among them, A, A, 0 ', 111, ruler 6, ruler 7, | 11, and 11 have the general formula (62) dihydropyridine as defined in Formula 1. Another method for preparing dihydropyridine can be as shown in reaction FIG. 26. The dihydric ketone of general formula (6 U β, / 3 -unsaturated ketone can be heat treated in a solvent such as ethanol- with the general formula (40) enamine to obtain dihydrogen ratio ratio of general formula (62). Reaction Figure 2 7 Βη

6 (6 ο

6) (Please read the notes on the back before filling out this page} Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where A 1, + D, D 1, Ri, R2, R6, R7, m and η are defined as Formula I The general formula (67) dihydroeodonate can be prepared as shown in the reaction diagram 27. The general formula (6 4) dihydropyridine obtained according to the foregoing reaction diagram can be treated with vinyl formate to obtain the general formula (6 5) Hydropyridine. General formula (6 5) Dihydropyridine can be acid such as hydrochloric acid. 46- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)

i ^^ 1 m ^^ 1 1 ^ 1 · I nt · nia ^ i n. ni 1 nnn IP ^ 11 II. ^ 1. I 44248 5 A7 B7 V. Description of the invention (44) Aprotic solvents such as water or methanol Heat treatment to obtain dihydropyridine of general formula (6 6). The general formula (6 6) dihydrogen p specific bite can be used. Alkylation using standard chemical methods known in the art. Reaction Figure 2 8

BnN

HBr acetic acid

(Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed A, D, D1, 1, R6 '(^, plus and η as defined by Formula I (71) And (72) dihydropyridine can be prepared as shown in Reaction Figure 28. As shown in the previous reaction diagrams, especially the dihydrogenated bismuths of the general formula (68) prepared by the reaction diagrams 11 and 16 can be demethylated as in the reaction diagram 27 and then (8) -phenylmethanol gas formate ( Prepared from () _ 8-phenylmethanol) in a solvent such as tetrahydrocrane, digas methane or aerosol, or directly treated with (-)-8-phenylmethanol gas formate to obtain the general formula ( 69) and (70) mixture of diastereomers urethane ^ (69) and (70) diastereomers were separated on silica gel by column chromatography and then hb ^ processed in acetic acid to obtain the enantiomers of general formulas (71) and (72) dihydropyridine 3 47- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1- ------- Order ---------- Line! 142485 A7 B7 V. Description of the invention (45) Reaction diagram 2 9

< Please read the precautions on the back before filling this page.) A, A, Ri, and m are the general formula (75) dihydropyridine of formula (I). Dihydropyridine of general formula (74) can be reduced to obtain dihydropyridine of general formula (75). -Preferably, this conversion can be accomplished by (7 4) conversion to imine ether with trimethyl or triethyloxotrifluoroborate and reduction with sodium borohydride. Alternatively, the carbonyl group can be converted to a thiocarbonyl group using Lawson's reagent. Desulfurization of sulfur carbonyl can be accomplished by Raney nickel under hydrogen pressure. The desulfurization reaction can also be completed by adding amusement teeth such as nail pits to sparse species and then reducing with sodium borohydride. The carbonyl group can also be reduced to methylene under the conditions described in (Lakhvich, F.A. et al., Journal of Organic Chemistry USSR (English translation) 25 (1989) 1493-1498). Response diagram 3 0 Response diagram 29 Printed by the Economic and Intellectual Property Bureau Staff Consumer Cooperative

Wherein A, Ri, and m are of the general formula (20) as defined by the formula (2). Another method for preparing the two gas p ratio syndrome can be described in the reaction chart 30. General formula (77) -48- degrees prepared from the aforementioned reaction chart_Zhongguanjiaxian (CNS > A4 size (210 X 297 mm) 44248 5 A7 B7 V. Description of the invention (46) Dihydropyridine can be shown as the reaction chart The general treatment (2 0) dihydroeruclide is obtained by treating as described in 2 9. (Please read the precautions on the back before filling out this page> Many of the starting aryl groups and Aryl aldehydes are commercially available or can be synthesized by procedures known in the chemical literature. Suitable references for the production of aryl and heteroaryl acids are found in the following paragraphs or examples. For starting materials not described in the literature, The following reaction diagram is intended to illustrate its preparation by a general method. The brewing process used to synthesize many of the preferred compounds of the present invention can be found in the following document: References for Consumer Cooperation, Intellectual Property Bureau, Ministry of Economy, Pearson, Org. Synth. Coll., Section V. Volume (1973), 117; Nwaukwa, Tetrahedron Communication (1982), 23, 3131; Badder, Journal of the Indian Chemical Society (1976), 53, 1053; Khanna, Journal of Medicinal Chemistry (1997), 40, 1634; Rinkes, Reel Trav. Chim. Pays-Bas (1945), 64, 205; van d er Lee, Reel. Trav. Chim. Pays-Bas (1926), 45, 687; Widman, Chem. Ber. (1882), 15, 167; Hodgson, Journal of the Chemical Society (1927), 2425; Clark, Journal of Fluorochemistry (1990), 50, 411; Hodgson, Journal of the Chemical Society (1 929), 1 63 5; Duff, Journal of the Chemical Society (1951), 1512; Crawford, Journal of the Chemical Society (1956), 2155; Tanouchi, Journal of Medical Chemistry ( 1981), 24, 1149; Bergmann, Journal of the American Chemical Society (1959), 81, 5641; Others: Eistert, Chem. Ber. (1964), 97, 1470; Sekikawa, Bull. Chem. Soc. Jpn. (1959) , 32, 551 ° This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 442 4 8 5 A7 Β7 V. Description of the invention (47

R 10 reaction diagram 3 1

R 10 Μ 12 Η, ". (80) Η ^ Ο (81)

R 10 rct or (82)

(Please read the precautions on the back before filling in this page.) Among them, Rio is: ¾ self-based, slab-based, tooth-based, air-based, oxygen-based, sulfur-based, -NZ1Z2 and -C (0 ) The group of NZiZ2, where 2 ^ and 2; 2 are independently selected from the group of hydrogen, alkyl, gallyl, aryl, arylalkyl, and formyl, and t2 is selected from the nitro 'halide Among the general formula (8 1) of the radical and the scorch group, the p-substituent can be prepared according to the method described in Reaction Figure 31. A pair of _ of the general formula (8〇) or a corresponding acetal-protected aldehyde (where r is an alkyl group or an oxygen atom attached thereto) of the general formula (82) forms a 5- or 6-membered ring, starting with 1 (3-dioxane has been calcined preferably)) An electrophilic aromatic substitution reaction can be performed to obtain a protected aldehyde of the general formula (8i) or the general formula (83). Preferred protecting groups for compounds of the general formulae (82) and (83) include difluorenyl or diethylacetal or 1,3-dioxane. These protecting groups can be introduced at the beginning and at the end. Removal by known methods of organic chemistry is used to obtain substituted aldehydes of the general formula (8 丨). -50- From the Applicable Family Standard (CNS) A4 Regulations ⑽χ 挪 公公 爱) Order --------- Online 丨 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 44248 5 _B7_____ V. Invention Explanation (48) Reaction Figure 3 2 ^ 10 ίτΡΐ2 HO 人 〆CHO (88) where R10 is selected from the group consisting of alkyl, alkyl, alkoxy, alkoxy, alkoxy, alkylthio, -NZ 〖Z2 And -CCCONZjs group, where: ^ and xin are independently selected from the group consisting of hydrogen, aryl, alkynyl, aryl, -aryl aryl, and formyl, and R12 is selected from nitro and halo And alkoxycarbonyl of the general formula (8 8) can be prepared according to the method described in Reaction Figure 32. The meta-substituted phenol (86) is reacted with a base such as sodium hydroxide and a reagent such as three gas methyl alcohol or three methyl alcohol (known as

Reimer-Tiemann) and transformed into pair-substituted salicylates (87). Another set of reaction conditions includes reactions with magnesium methoxide and para-aldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). The aldehyde (87) can be subjected to electrophilic aromatic substitution reaction conditions to obtain para-di-salicylaldehyde in the general formula (8 8). Reaction Figure 3 3 HCT v H0j (89) (88) where Rio is selected from the group consisting of alkynyl, sulfanyl, 1¾, oxo, oxo, thio, _NZ 〖Z2 and -0 (0) A group of ^ 72, in which 2 丨 and 22 are independently selected from 51 of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formamyl-This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) —

(Please read the precautions on the back before writing Qi Gong)

— — — — — — — IT0J (I-*-I --- I

CHO

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 4'1, 44248 5 A7 B7 V. Description of the invention (49) The group and RI2 are selected from the group consisting of nitro, fluorenyl, and alkylcarbonyl Another method for preparing the general formula (8 8) can be as described in the reaction chart 33. In the meantime, the age of p-di-substituted '(8 9) can be obtained by reacting with a base such as sodium hydroxide and a reagent such as methane or tribromoxane (called Reimer-Tiemann) to obtain the second formula (88) Substituted salicylaldehyde. Another set of reaction conditions includes reactions with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823) e Reaction Figure 3 4

Br j10 〇 rV12 ‘rVR12 y RO OR RO Eight OR X Η 人. (90) (83) (81) where is selected from the group consisting of alkyl, haloalkyl, chlorine, fluorine, haloalkoxyoxy, alkylthio, nitro, alkylcarbonyl, arylcarbonyl, NZ, Z2 And -CCCONZiZ group, wherein ZilZs is independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and RIC is selected from alkyl, hydroxyalkyl, and alkylthio The benzaldehyde of the general formula (81) can be prepared according to the method shown in Reaction Scheme 34. The protected benzaldehyde of the general formula (90) (where R is an alkyl group or the The oxygen atoms together form a 5- or 6-membered ring, preferably 1,3-dioxane) which can be converted to a 3,4-disubstitution of general formula (83) by conversion to an intermediate lithium or magnesium derivative Benzaldehyde, followed by reaction with suitable electrophilic groups such as Vietnam, dioxo disulfide, Weinreb amines, dimethylphosphonium amines, alkylamino, or other electrophilic groups followed by deprotection of the acetal The benzaldehyde of formula (8 1). -52- This paper size is applicable to Chinese national standard (CNS> A4 size (210 X 297 mm) < Please read the precautions on the back before filling this page) · '1丨 — — — — — Order, --II I --- '^ 丨 4 4248 5 A7 ____B7 V. Description of the invention (50) Reaction Figure 3 5

(92) (83) (81) wherein R10 is selected from the group consisting of alkyl, gas, fluorine, fluorenyloxy, alkoxy, alkylthio'-NZA and-(: (0) Z | & Z2 is independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl-, arylalkyl, and formyl, and Ru is selected from alkyl, hydroxyalkyl, Alkylthio, alkylcarbonyl 'and stilbene group of another formula of the general formula (81) is as shown in the reaction of Figure 35, the protected benzaldehyde (wherein r is an alkyl or Form a 5- or 6-membered ring with the oxygen atom attached to it, preferably, 3 · dioxane) can be treated by the reaction as shown in Figure 34 to obtain a benzyl compound of the general formula (8 丨) Reaction diagram 3 6 (Please read the precautions on the back before filling out this page) -H ί— I 扈 IIII-Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

(95) wherein Rio is selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, alkyl, aryl, alkoxy, nitro, alkoxy, and alkane- 53 This paper size applies Chinese National Standard (CNS) A4 (210 x 297 public love) 4 4248 5 Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumer Cooperative Association, Λ7 B7 V. Description of Invention (5!) Sulfur-based, -NZtZ2 and- A group of C ^ CONZes, wherein Z 丨 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and methylamino, and Ri 3 is selected from alkyl, aralkyl And benzaldehyde of the general formula (95) from alkyl (wherein the preferred alkyl group is selected from the group consisting of difluoromethyl, 2,2,2-trifluoroethyl and bromodifluoromethyl) can be based on the reaction diagram Prepared by the method described in 36. The 3-hydroxybenzaldehyde of the general formula (94) can be suitably an alkylating agent such as fluorenyl bromide, methyl iodide, 2-iodo-trifluoroethane 'gas difluoromethane or dibromodifluoromethane in a base such as potassium carbonate, Treatment with potassium tributoxide or sodium third butoxide yields benzaldehyde of general formula (95). The synthesis of usable 3-hydroxybenzaldehyde of general formula (94) can be found in the following references: Journal of Chemical Society (1923), 2820; Journal of Medicinal Chemistry (1 986), 29, 1982; Monatsh. Chem. (1963), 94, 1262; Justus Liebigs. Ann. Chem. (1897), 294, 381; J. Chem. Soc. Perkin Trans. 1 (1990), 315; Tetrahedron Communication (1990), 5495; J. Chem. Soc. Perkin Trans. 1 (1981), 2677 0 reaction diagram 37 OH Rl3, 〇rV12 —— Λ V v 0 human Η Ο ^ Η. (97) (98) where Rl2 is selected from hydrogen, hydrazine, and radical A group consisting of S-based, aryl, heteroaryl, cyano, alkynyl ', alkoxy, nitro, alkoxy, alkylthio' -NZiZ2 and -CCCONZiZs, of which 4 and 22 is independently selected from -54- This paper is K-degree compatible with Chinese National Standard (CNS) A4 (210 x 297 mm) ~~ (Please read the note on the back? Matters before filling out this page) mnunn ^ -OJr tt I n 1 k II n II I--1— * 1 JI ί.---·: »^ 1 I-^ 1 .. ^ 424 8 5 a? B7 V. Description of the invention (52) (Please read the back first Please fill in this page if you are not interested) Gas, alkyl, alkylcarbonyl, aryl, arylalkane And formyl groups and RI 3 are selected from pit group, aryl group, and dentate group (of which the preferred halogen pit group is selected from difluoromethyl, 2,2,2-trifluoroethyl And bromodifluoromethyl) can be prepared according to the method described in Reaction Scheme 37. 4_ Hydroxybenzaldehyde of general formula (97) can be suitable as alkylating agent such as fluorenyl bromide, methyl iodide, 2-iodine--two gas acetone, gas one gas entertaining In the presence of potassium, potassium third butoxide or sodium third butoxide, benzaldehyde is given by the general formula (9 8). The synthesis of 4-hydroxybenzaldehyde of general formula (97) can be found in the following references: Angyal, Journal of the Chemical Society (1950), 2141; Ginsburg, Journal of the American Chemical Society (1951), 73, 702, Claisen, Justus Liebigs. Ann. Chem. (1913), 401, 107; Nagao, Tetrahedron Communications (1980), 21, 4931; Ferguson, Journal of the American Chemical Society (195〇), 72, 4324; Barnes, Journal of the Chemical Society (1950 ), 2824; Villagomez. Ibarra, Tetrahedron (1995), 51, 9285; Komiyama, American Chemical Society Stem, (1983), 105, 2018; DE 87255; Hodgson, Journal of the Chemical Society (1929), 469; Hodgson Journal of the Chemical Society (1929), 1641. Reaction Figure 3 8

(10 °) (81) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where Ri0 is selected from the group consisting of hydrogen, alkyl, sulfonyl, aryl, and heteroaryl-55- This paper is applicable to China 囵Home Standard (CNS) AJ specification (210 X 297 g) ^ 4248 5 A7 B7 V. Description of the invention (53 > aryl, cyano, alkyl, fluorenyl, alkoxy, nitro, alkoxy , Thiol, -NZιZ2 and -C ^ CONZiZ2, in which ζ! &Amp; Z2 is independently selected from the group consisting of hydrogen, alkyl, carbonyl, aryl, aryl, and methyl Another method for introducing a benzyl 3 -position substituent in formula (81) can be described in reaction scheme 38. This method (also known as the Sandmeyer reaction) involves the addition of a 3-amine of general formula (100) with sodium nitrite. The conversion of phenylbenzaldehyde to the intermediate azide salt ° can be treated with odor or moth to obtain brooks or moths. The Sandmeyer reaction and the conditions for this conversion are known to those in the field of organic chemistry. The types of Re substituents introduced include cyano, hydroxy, or halo. In order to successfully perform this conversion, it is advisable to protect the protected acid under certain conditions. Sandmeyer reaction is performed. Then the obtained iodide or bromide can be treated with unsaturated halides, triacids or tin reagents in the presence of a catalyst such as tris (triphenylphosphine) red (〇) to obtain benzene of general formula (81) Formaldehyde. Azide sulfonium salt can also be directly treated with unsaturated dentate, boric acid or tin reagent in the presence of a palladium catalyst such as tris (triphenylphosphine) palladium (0) to obtain benzoic acid of general formula (81). 3 9

(102) (81) wherein Ru is selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, alkyl, haloalkyl, halo, haloalkoxy, nitro, and alkoxy Base'ane-56- This paper size 剌 Zhongguanjia standard rate (CNS) A4 size ⑵ D x 297 public love) (Please read the note on the back ¥ item before filling out this page) I > -II 1 II t 1 »I --- [II- I, Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 42485 Α7 Β7

V. Description of the invention (54) a group of thio, -NZιZ2 and -qCONZiZ :, wherein Z1 & Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formamyl Another method for introducing a substituent at the 4-position of benzaldehyde of the general formula (81) can be described in the reaction scheme 39. This method (also known as Sandmeyer reaction) involves the conversion of 4-aminobenzidine of general formula (1) to the intermediate azide radium salt followed by azide hydrazone salt in a manner similar to that shown in Figure 38 deal with. The type of the substituent (1) introduced in this manner includes a cyano group, a hydroxyl group, or a substituent. The Sandmeyer reaction and the conditions under which this transformation is carried out are well known in the art of organic chemistry. In order to carry out this conversion successfully, it is advisable to carry out the Sandmeyer reaction on the protected aldehyde under certain conditions. Scheme 4 0 NH2 human 〇cf3 U 1) Ac20 2) BuLi, DMF 3 3 H2SQ4 4) Sandmeyer 4-bromo-3- (trifluorofluorenyloxy) benzaldehyde or 4-chloro-3- (trifluoromethyl) Oxy) benzaldehyde can be prepared as described in Scheme 40. Commercially available 4-bromo_2- (trifluoromethoxy) aniline can be protected on the amine group by a suitable N-protecting group such as ethenyl or a third butoxycarbonyl group known in the field of organic chemistry. Bromine can then be converted into lithium or magnesium derivatives and reacted directly with .dimethylformamide to give 4-amino-protected 3- (trifluoromethoxy) benzaldehyde derivatives. The N-protecting group is removed, and then the amine is converted into a bromide or gaseous substance through the Sandmeyer method in FIG. 38, followed by hydrolysis of dioxane to obtain 4-bromo-3- (trifluorofluorenyloxy) benzaldehyde or 4 -Ga · 3- (Three-57- This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297)) (Please read the precautions on the back before filling this page) Staff Consumption of Intellectual Property Bureau of the Ministry of Economic Affairs Printed by a cooperative

I & 'n n u _ ^ i I. 1 n n n 1 ^-«^ 1 n n In-n 1 n I 442 485 Δ7 B7 V. Description of the invention (55) Fluoromethoxy) benzaldehyde. Reaction Figure 4 1 Γ3 cf3 rS rV. 2 fVNO: y V 〇a〇h 0 OH OH cf3 CF3 A ^ NH2 rVx -iV V ^ vl OH X OH I CHO Π04) (105) (Please read the notes on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Bureau Consumer Consumption Cooperative Stamp * 1 ^ where X is a general formula (105) 4-trifluorofluorenylbenzyl selected from the group consisting of oxo, nitro, and halo, which can be prepared according to the method shown in Figure 41. 4-Trifluoromethylbenzylic acid was first nitrated using conditions known in the literature such as nitric acid and sulfuric acid, and the carboxylic acid group was reduced with borane to obtain 3 · nitro-4-trifluoromethylbenzyl alcohol. From this, benzyl alcohol can be obtained by violent oxidation with typical reagents such as dioxide to obtain 3_nitro_4_trifluoromethylbenzaldehyde. Nitrobenzyl alcohol can be reduced to aniline using any of a number of conditions for performing this conversion, with the preferred method being a nitrogenation reaction over a palladium catalyst. Tylamine can be converted to a halo or cyano substituent using the Sandmeyer reaction described in Reaction Figure 38. The benzyl alcohol of the general formula (104) can be oxidized using known conditions such as bell dioxide or Swern conditions to obtain the benzaldehyde of the general formula (104). For certain aromatic ring substituents of the compound of the present invention, it is better to use -58-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love)

-OJ · n-I-. I l II nrn-HI nn I---IX nn I Hi ϋ-I 44248 5 Λ7 B7 V. Description of the invention (56) After incorporating the core structure of the present invention, an aromatic ring substituent is carried out The conversion reaction. Therefore, the compounds of the present invention can be reconverted to other different compounds of the present invention. These transformation reactions include StiUe, Alder, and Heck coupling reactions, all of which are known in the field of organic chemistry. The following shows some representative methods for converting the compounds of the invention into other compounds of the invention. Reaction Figure 4 2 D >

1. Di-tert-butyl dicarbonate DMAP, MeCN 2. Pd (PPh3) 4. R12Sn (R) 3 DMF, 110 ° C}

(Please read the notes on the back before filling out this page.) The consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed eight of them, '0, 0, 116, feet 7, 11, and 111 as defined in Equation 1, 1110 Selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, aryl, fluorenyl, gas, fluorine, alkoxy, nitro, alkoxy 'alkylthio, and -c (o) nz〗 The group of z2 'wherein z! & z2 is independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, aryl gauge and methyl group, and Rn is selected from hydrogen , Hydroxy, alkoxy ', alkoxy and aralkoxy' feet 12 are two of the general formula (108) selected from the group consisting of alkyl, vinyl, aryl, heteroaryl ', cyano, etc. | Pyridine It can be prepared according to the method described in Reaction Figure 42. Where X is a compound of formula (107) selected from the group consisting of bromine, trifluoromethanesulfonate and trifluoromethanesulfonate, protected with a third butoxycarbonyl (Boc) group using standard procedures. Aryl bromide, decomposed compounds or trifluorophosphonium sulfonic acid S can be used in a solvent such as dimethyl methylamine in the presence of a catalyst, as appropriate -59- This paper & degree applies Chinese National Standards (CNS) A4 specifications (2) 0 X 297 mm) A7 B7 V. Description of the invention (57) Tin 'butterfly acid or unsaturated dentate reagent is heated to perform a coupling reaction to obtain a dihydrogen p ratio of the general formula (1 08) The conversion reaction conditions of Lake 11 can also be used to remove the Boc protecting group. Reaction Figure 4 3

1. Dicarbonate of dicarbonate DMAP, MeCN 2. Pd (PPh3) 4, Rl2Sn (R) 3 DMF, 110 0 C ί

(Please read the-; i item on the back before filling in this page> Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where A, A ', D, D', R6, R7, m and n are defined as i尺, 〇 〇 is selected from hydrogen, alkyl, alkanyl radical, alkyl, aryl, heteroaryl, cyano, alkyl, gas, fluorine, alkoxy, nitro, alkoxy Group of alkyl, alkylthio and -CCCONZiZ2, wherein z! &Amp; z2 is independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl'aryl'arylalkyl, and formamyl, and Rn is selected from hydrogen , Hydroxy, alkoxy, haloalkoxy, and aralkoxy 'R12 are dihydrogen p ratios of general formula (U1) selected from alkyl, vinyl, aryl' heteroaryl, cyano, and the like. Prepared according to the method described in Reaction Figure 43. Where X is a compound of general formula (11) selected from bromine, Hong and triflate using standard procedures with a third butoxycarbonyl (Boc) protection. Aryl bromide Compounds, iodides or trifluoromethanesulfonates can be obtained by heating in a solvent such as dimethylformamide in the presence of a palladium catalyst with a suitable tin, boric acid or unsaturated sodium compound reagent for the coupling reaction. Formula (111) Dihydrop-pyridine. This conversion reaction condition is also carried out -60-This paper size applies the Chinese National Standard (CNS) A4 specification (210x 297 public love) Order --------- line 丨 -I n D n —l · I __ n I tr n · 44248 5 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (Qiu)

Removal of Boc protecting group · Figure 4 4

(107)

1, 2nd, 3rd Ding, DMAP, MeCN 2.Pd (PPh3) 4 I] R'Zn CFs

Wherein A, A1, D, D1, R6, R7, m and n are as defined in Formula I, 1110 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, A group of alkyl, chlorine, fluorine, alkoxy, nitro, alkoxy, alkylthio and ^ (CONZiZs, where ζ ^ Z2 is independently selected from argon, alkyl, alkylcarbonyl, aryl ' The group of arylalkyl and methylamidino, a dihydropyridine of the general formula (113) selected from the group consisting of hydrogen, hydroxyl, alkoxy, haloalkoxy, and aralkyloxy, can be described according to the reaction FIG. 4 4 It is prepared by a method in which X is a compound of the general formula (丨 07) selected from bromine, iodine and triflate using standard procedures and protected with a second butoxy group (Boc). Flumesulfonate can be heated in a solvent such as dimethylformamide in the presence of a palladium catalyst with a suitable zinc reagent to perform a coupling reaction to obtain a dihydropyridine of the general formula (丨 13). This conversion The reaction conditions can also be used to remove the B0C protecting group. The meta-substituent type can be introduced in this way to include a trisaminopropenyl group and more preferably a trifluoropropenyl group. 61-Applicable to this paper standard National Standard (CNS) A4 Specification (210 X 297 mm) (Please read the precautions on the back before filling this page) Order --------- line-442485 A7 B7 V. Description of Invention (59) Reaction Figure 4 5

< Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where A, A ', D, D_, R6, R7, m and η are defined as in Formula I' Rule 10 From hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, fluorenyl, gas, fluorine, alkoxy, nitro, alkoxy, alkylthio, and- The group of CCCONZJz, wherein ZiKZ is independently selected from the group consisting of hydrogen'alkyl'alkylcarbonyl, aryl, arylalkyl, and formamyl 'Rll is selected from hydrogen, hydroxyl, alkoxy, halooxy Dihydropyridines of the general formula (116) based on aryl and aralkoxy groups can be prepared according to the method described in the reaction FIG. 45. Wherein X is a dihydropyridine of the general formula (110) selected from bromine, iodine and trifluoroformate, protected with a third butoxycarbonyl (B0C) group using standard procedures. Aryl bromide, iodide or triflate can be heated in a solvent such as dimethylformamide in the presence of a palladium catalyst with a suitable zinc halide reagent to perform a coupling reaction to obtain the general formula (丨16) Dihydropyridine. This conversion reaction condition can also be used to remove the Boc translation protecting group. The kind of the para-substituent which can be introduced in this manner includes a tridentate propionyl group and more preferably a trifluoropropenyl group. -62- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2) χ 297 mm Λ42 Λ8 〇A7 V. Description of the invention (60) In addition to using the method described in Reaction Figure 28, Individual enantiomeric compounds of the invention can be separated by palmar chromatography. The following methods are intended as illustrations of the scope of the invention and are not intended to limit its scope. Furthermore, all conditions in this article are incorporated herein by reference. Example 1 1- · (3-brook-4-fluorophenyl) · 5, ΐ〇-dihydro_1H 3H_dipiperanofluorene f3,4-b: 4,3-el pyridine-4.6 (7H, 9H) -Dione tetrahydropiperan-3,5-dione (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1 169) (1.2 g, 10.5 mmol), 3-bromo-4-fluorobenzaldehyde (1.1 g, 5.4 mmol) and a solution of 2.0 M ammonia in ethanol (8 ml, 16 mmol) were heated in a sealed tube to 80 ° C for 6 hours and then cooled to ambient temperature. The insolubles were filtered off and the filtrate was evaporated to dryness. The residue was purified by silica gel flash chromatography (5% methanol / methane gas) to obtain an orange foam, which was dispersed in ether and ethyl acetate to obtain the title compound (m mg mp > 250 ° C) as an orange solid. ; MS (APCI (+)) m / z 392 (MH) ';] Η NMR (DMSO-d6) ό 4.06 (s, 4H), 4.41-4.60 (AB qu, 4H), 4.94 (s, 1H), 7.19-7.32 (m, 2H) S 7.42 (dd, 1H), 10.12 (br S >1H); Analysis and calculation of C17H13BrFN04 · 0.5 H20 値: C, 50.64; H, 3'49; N, 3_47. Measured 値: C, 50.66; H, 3.56; N, 3.90. Example 2 5- (3-Bromo-4-fluorophenyl) -2,3,5,8,9,10-hexahydrobenzene hydrazone "bUl, 71 haha = 4,6ΠΗ, 7Η) -dione hydrochloride-63- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)- ----- Order .------- * 丨 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs I) i. N I 0L. Ϋ I tt i < 442485 V. Description of the invention (61)

Example 2 A 2- 2--5- (3-Mo-4-Qibuji) -2,3,5,8,9,10-7T Fengmu 幷 | ~ bl 『l ， 71 咗 咗 -4,6ΠΗ , 7Η) -dione hydrochloride 3-amino-2-cyclohexamidine-butanone (0.55 g, 5,0 mmol) '3-Bromo-4-fluorobenzaldehyde (1.01 g, 5.0 mmol) Ear) and a solution of N-benzylhexahydroeridine-3, 5-dione (Ziegler, Journal of the American Chemical Society (1973), 95, 7458-7464) (1.01 g '5.0 mmol) in a sealed tube Heat in ethanol (10 ml) for three days, then cool to ambient temperature. The solvent was evaporated and purified by flash chromatography on silica gel (5% methanol / dioxane) to give the title compound (0.84 g), which was converted to the HC1 salt. mp 240-24TC; MS (DCI / NH3) m / z 481 (M + H); NMR (CDC13) (free base) β 2.0 (m, 2H), 2.67 (m, 2H), 2,48 (m, 2H), 3.05-3.48 (m, 4H), 3.70 (m, 2H), 5.1 (s, 1H), 6.05 (bs, 1H), 6.99 (t, 1H), 7.32 (m, 6H), 7.41 (dd , 1H); C25H22BrFN202. Analysis and calculation of HC1: C, 57.99; H, 4.48; N, 5.41. Found 値: c, 57.87: H, 4.46; N, 5, 35.

Example 2 B 5- (3-Bromo-4-fluorobenzyl) -4,6-dioxo-3,4,5,6,7,8,9,1〇-octa (phenylhydrazone [^ 1 「 1.71 Free base (0.40 g, 0.83 mmol) of the product of Example 2A of pyridin-2 (111) -vinyl formate was dropped in digas methane (50 liters) with ethyl vinegar acetate (0.085 ml) ) Process and stir overnight at ambient temperature. Evaporate the solvent and purify by silica gel flash chromatography (5:95: j ethanol / dichloromethane / saturated hydroxide) to obtain the title compound (〇 2 5 -64- paper size Applicable to Chinese national standards (CNSM4 specification (210 X 297 mm) '---- < Please read the notes on the back before filling this page)

^ -----— Order II ---- IIIII A7d 4 2 4 8 5 η? 5. Description of the invention (62 gram) MS (ESI (+) m / z 461 (M + H) +: lH NMR (CDCI3) δ 2.08 (m, 2H), 2.4 (m, 2H), 2.55 (m, 2H), 3.9 (d, 1H), 4.15 (d, 1H), 4.43 (d, 1H), 4.57 (d, 1H), 4.75 (d, 1H), 4.85 (d, 1H), 5.12 (s, lH), 6.9 (t, 1H), 7.14 (m, 1H), 7.3 (m, 1H), 7.48 (m, 1H) ). Example 2 C5- (3-bromo-4-fluorobenzyl) -2,3,5,8,9,10-hexahydrobenzene hydrazone [^ >〗 〖〗 〖7, 7】 Trimidine · 4.6ΠΗ .7))-Diketone hydrochloride Example 2B (0.25 g) in ethanol (20 ml) was treated with 6 M (20 ml) and heated to reflux for 1.5 hours. Ethanol was distilled off, and the water-cooled portion was basified with 1 N sodium hydroxide. The alkalized solution is prepared with _ * $ ~ 气 甲 p t (3 Χ). The combined two-gas methane is concentrated and taken at work (100: 90: 1 ethanol / digas-methane / saturated ammonium hydroxide), pure, Xianlianshexuan (0.10 g), which is converted into Hydrochloride. The formula is mp 220-222〇C; MS (ESI (+)) m / z 391 (M + H) +: MS (ESI (-)) m / z 389 (MH) '; NMR (DMSO-d6 ) (Free base) β 1.72-2 〇 Liquid 1 compound (please read the precautions on the back side before filling in this page ^ -------- Order --------- line— Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2), 2.51 (m, 2H), 3.17 (s, 2H), 3.58 7.19 (m, 2H), 7.4 (m, 1H), 9,6 (s, 1H) Analysis and calculation of ClsH15N2FBr02. HC1: c 6.51. Measured 値 ·· C, 50,73; H, 4.34; N, 6 i8 4-89 (S, 50 · 67; H, 3 78; N. 65- This paper size applies to China National Standard (CNS) A4 specifications (210 ^ 297 Gongchu) A7 4 4248 5 __B7___ V. Description of the invention (63) Example 3 3- (3-Mo-4-apigenyl) -2-methyl-2,3,5,8,9, A solution of 10-ττ carbamidine-4,6 (1H, 7HV diketohydrochloric acid Example 2 C product (0.10 g) in methanol (4 ml) with 37% formaldehyde aqueous solution (0.4 ml), Treat with sodium cyanoborohydride (23 mg) and glacial acetic acid (dropwise to pH 5) and stir overnight at ambient temperature. The reaction mixture was concentrated and partitioned between aqueous sodium bicarbonate solution and methane gas. The methane gas layer was Drying over sodium sulfate 'filtration and evaporation of the solvent gave the free base of the title compound (70 mg). The free test was converted to the hydrochloride salt and recrystallized from ethanol / ¾. Mp 248-250 ° C; MS (APCI (+)) m / z 405 (M + H) +; NMR (DMSO-d6) (free 絵) J 1.78-2.0 (m, 2H), 2.22 (m, 2H), 2.29 (s, 3H), 3.1 (m, 2H) , 3.5 (m, 2H), 4.83 (s, 1H), 7.15 (m, 1H), 7.2 (t, 1H), 7.37 (dd, 1H), 9.72 (s, 1H); C19H17N2FBr02 · HC1 Analytical calculation 値: C, 51.78; H, 4.11; N, 6.35. Found 値: C, 51.73; H, 4.40; N, 6.21. Example 4 5- (3-Bromo-4-fluorophenyl)- 2,3,5,8,9,10-hexahydropyridine 弁 3.4-13 丨 1.7

-4,6 (1H, 7H) -dione dihydrochloride Example 4 A 2,8-Difluorenyl-5- (3-bromo-4-fluorobenzyl) -2,3,5,8,9 , 10-Hexapyridine hydrazone [3, t blH, 71 Pyridine-4,6 (1H, 7H) -dione N-L-Hexyl hexahydro p ratio bite-3,5-dione (Ziegler, American Chemical Society Journal (1973), 95, 7458-7464) (2.2 g, 10 mmol), 3-bromo-4-fluorobenzene-66-This paper size applies to China National Standard (CNS) A4 (210x 297 mm) < Please read the precautions on the back before filling this page) -n II Γ— A DJ · nn It f line 丨 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 442485 Α7 Β7 V. Description of the invention (64) Formaldehyde (1.02 G, 5_0 mmol) and a 2.0 M solution of ammonia in ethanol (2.5 ml) was heated in 70 ° C ethanol (10 ml) for three days. The reaction mixture was cooled to ambient temperature and concentrated. The residue was purified by chromatography on silica gel (5% ethanol / dioxane) to give the title compound (0.62 g). MS (ESI (-)) m / z 570 (Μ-Η) ·; 'H NMR (DMSO-d6) d 2.97 (d, 2H), 3.16 (m, 2H), 3.42 (m 3H), 3.61 (q , 4H), 4.82 (s, 1H), 7.13 ^ 7.42 (ra, 13H), 9.32 (s, 1H).

Example 4 B 5- (3-'; Smell-4-fluorobenzyl) -4,6-dioxo-4,5,6,7,9,10-sixth order, 11 ^ and 314_ 乜 1 "1,71 pyridine-2,8 (111,31 ^ -dicarboxylic acid diethyl product of Example 4A (0-5 g, 0.87 mmol) in digas methane (5 ml) in a solution of Ml, 1.9 mmol) and stirred overnight at ambient temperature. The solvent was evaporated and purified by flash chromatography on silica gel (8: 2 ethyl acetate / hexane) to give the title compound (0.3 g). MS (ESI (+) ) m / z 532 (M + H) +; Printed NMR (DMSO-d6) 3.95 (d, 2H), 4.2 (d, 2H), 4.46 (d, 2H), 4.65 (d, 2H), 4.77-4.94 (m, 4H), 5.15 (s, 1H), 7.0 (t, 1H), 7.1 (d, 1H), 7.14 (d, 1H), 7.32 (m, 1H), 7.4 (m, 1H).

Example 4 C 5- (3-Bromo · 4-fluorophenyl) -2,3,5,8,9,10-Hexapyrido 丨 3.4 氺 1 丨 1,7〗 ^-4,6 ( A solution of 111,7-indionedione-dione di-stilbene Example 4B (0.22 g, 0.41 mmol) in ethanol (5 ml) was treated with concentrated hydrochloric acid (0,10 ml) and refluxed for 3 hours, and cooled to the temperature of the garden- 67- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 A7 ___B7___ 5. Description of the invention (65) degrees and treated with ether. Collect The obtained solid precipitate was dried to give the title compound (0.12 g). MS (ESI (-)) m / z 391 (MH) ';' H NMR (DMSO-d6) δ 3.78 (q, 4H), 4.22 (q, 4H), 4.95 (s, 1H); 7.22 (t, 1H), 7.32 (m, 1H), 7.48 (dd, 1H), 11.48 (s, 1H); C17H15N302FBr2HCl Analysis and calculation 値: C, 43.90;;, 3 '68; N, 9.03. Found 値: C, 44.45; H, 3.86; N, 8.75. Example 5, (-)-5- (3-bromo-4-fluorophenyl) -2,3,5,7 , 8,9-hexahydro-1 ^^-cyclopentane 幷 "1 > 1 丨 1,71

Examples of pyridine-4,6-dione hydrochloride 5 A 2-benzyl-5- (3-bromo-4-fluorobenzyl) -2.3,517,8,9-hexahydro-1H-cyclopentane # [131 『1,71 Pyridine-4,6-dione 3-amino-2-cyclopenten-1-one (Kikani, BB ·, Synthesis (1991), 2, 176) (0.97 g, 10 Mmol), 3-bromo-4-fluorobenzaldehyde (2.0 g, 10 mmol) and N-benzylhexahydropyridine-3,5-dione (Ziegler, Journal of the American Chemical Society (1973), 95, 7458-7464) (2.2 g, 10 mmol) was heated under reflux for 7 2 hours, then cooled to the ambient solid temperature < = evaporated solvent and flash chromatography (5% ethanol / digas methane) on sand rubber ) Purification gave the title compound (3.0 g), which was converted to the HC1 salt. MS (ESI (-)) m / z 465 (MH) ';! H NMR (DMSO-d6) S 2.28 (m, 2H), 2.5-2.7 (m, 2H), 3.〇7 (AB qu, 2H ), 3.4 (ms 2H), 3.65 (s, 2H), 4.65 (s, 1H), 7, l5. -68- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm)- --- l · -----—---- \ --------- ι_π --------- I (Please read the precautions on the back before filling this page) 442485 A7 B7 V. Description of the invention (66) 7.45 (m, 8H), 10.25, (s, 1H) °

Example 5B 5- (3-bromo-4-fluorobenzyl) > 4, ^ 1 oxo · K3 4 5 6 789 octadecantine [~ bl 『l, 71 each bite-2-carboxylic acid (ir, 2S ′ 5R) -5-methyl-2- (1-methyl-fluorenylphenyl) cyclohexyl ester Example 5A Product (1.9 g, 4.0 mmol) in THF (30 ml) 8-phenylmethanol formate (prepared from (_) _ 8_phenylmethanol as described in Yamamota, γ, Journal of the American Chemical Society (I " 2), 1M, 121-125)) (1.45 g '4.92 Millimol) of THF (10 ml), stirred at ambient temperature for 3 days and partitioned between aqueous sodium bicarbonate solution and dioxane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the diastereomers. Aminomethyl®a vinegar mixture of the structures. The diastereomeric mixture was subjected to column chromatography (20% hexane / ethyl acetate) on the gel to obtain the less polar title compound (0.32 g). And a mixed fraction containing two diastereomers (09 g). MS (ESI (-)) m / z 635 (MH) '; * H NMR (DMSO-d6) 0.8 (m, 4H), 1.1 (s, 3H),] AS (m? 2H), 1.22 (s, 3H), 1.6 (m, 2H), 1.8 (m, 1H), 2.02 (m, 2H), 2 > 3 ( m, 2H), 2.6 (m; 1H)? 2.75 (m, 1H), 3.02 (d, 1H), 3.62 (d, 1H), 3.9 (d, 1H), 4.58 (d, 2H), 4.68 (s, 1H), 7.02- 7.38 (m, 8H).

Example 5 C M3-Ci-4-fluorophenyl) -4,6-digaso-S ^^ hydrogen_211 · Cyclopentol is called "1? 7] Chajun-2-carboxylic acid nR-2S 5R) -5_methyl-g ^ (1-methyl small phenylethyl) cyclohexyl ester Example 5 The diastereoisomeric mixture of B was recrystallized from ethanol, which is better than -69- This paper is applicable to China Standard (CNS) A4 specification (21〇X 297 mm) (Please read the notes on the back before filling this page) '·' -------- Order --------- line f -Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-ni ϋ I (VII — 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 442 48 5 A7 ___B7_ V. Description of the invention (67) Polar diastereomers Title compound (0.45 g). MS (ESI (-)) m / z 635 (MH) '; lH NMR (DMSO-d6); 0.82 (d, 3H), 1.02 (s, 3H), 118 (s, 3H), 1.18 (m, 2H), 1.58 (m, 2H), 1.68 (s, 1H), 1.98 (m, 2H), 2.3 (m, 2H), 2.61 (m, 1H), 2.75 (m, 1H ), 3.2 (m, 1H), 3.6 (m, 2H), 4.0 (m, 1H), 4.52 (m? 2H), 4.55 (s, 1H), 6.45 (m, 1H), 6.82 (m, 2H) , 7.1 (m, 2H), 7.25 (m, 2H), 7.41 (m, 1H).

Example 5 D (-)-5- (3-Mo-4-gas epitope) -2,3,5,7,8,9-Hexagas-1 only-Cyclopentanolization 1 丨 1,71 荇Yodo-4,6-dione hydrazone hydrochloride Example 5B product (0.32 g, 0.52 mmol) was treated with 48% hydrobromic acid in acetic acid (4 ml), heated to 50 ° C for 4 hours, and cooled to the surroundings Temperature, neutralized with concentrated ammonium hydroxide, and extracted with digas methane (3x). The combined organic layers are dried and dried with sulfur; The residue was subjected to flash chromatography (10% ethanol / ammonia-saturated methane) in gluing gel to obtain the title compound (0.10 g) as a free base, which was converted into the hydrochloride salt. [a] 20D -125.880 (DMSO); MS (ESI (-)) m / z 375 (MH) '; 4 NMR (DMSO-d6) (free base) Θ 2.28 (t, 2H), 2.53-2.76 (m , 2H), 3.18 (st 2H), 3.62 (d, 2H), 4.67 (s, 1H), 7.22 (d, 2H), 7.45 (d, 1H), 10.1 (s, 1H); C17H13N2FB1O2. HC1. 0.5 H2O analysis: 値: q, 48.43; h, 4.08; N, 6.28. Measured 値: C, 48’42; H, 3.59; N, 6.64. -70-This paper size applies to the national standard (CNS) A4 specification (2i0X 297 mm) (Please read the precautions on the back before filling this page); -------- Order --- ------ line — A7 ------- B7_____ V. Description of Invention (68) Example 6

Lt) -5- (3-Bromo-4-fluoromatohexahydropentane < bl > l, 71 Benzidine-4,6-dione hydrochloride Example 5C Product (0'25 g, 0.41 mmol Ear) of acetic acid (3 ml) was treated with 48% hydrobromic acid, heated to 5 (rC for 3 days. The reaction mixture was cooled to ambient temperature, neutralized with concentrated hydroxide, and extracted with methane gas. Combined organic The layer was dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography on silica gel (10% ethanol / ammonia-saturated methane) to give the title compound (0.070 g) as the free base, which was converted to the hydrochloride 5 U ] 20D +117.64. (DMSO); MS (ESI (-)) m / z 375 (MH) ';' H NMR (DMSO-d6) (free base) β 2.28 (t, 2H), 2.52-2.65 (m , 2H), 3.18 (s, 2H), 3.52 (d, 2H), 4.68 (Sj 1H), 7.2 (m, 2H), 7.43 (d, 1H), 10.1 (s, 1H); C17H13N2FBr02 HC1. 0.5 H2 ◦Analytical calculation: 値: C, 48.43; H, 4,08; N, 6.28. Measured 値: C, 48.83; H, 3.97; N, 6.32. Example 7 (-) _ 5 彳 3-Bromo-4-fluorophenyl ) -2.3,5,8,9,10-hexahydroben # 丨 1 ^ 『1,71naphthyridine-

Examples of 4,6 (1H, 7H) -dione hydrochloride 7 A 5-Π-Bromo-4-phenyl) -4,6-dioxo-3,4,5,6,7,8, 9,10-octahydrophenylhydrazone 71 Imididine-2 (1HV formic acid nR, 2S, 5R) -5 · methyl-2- (1-methyl-1-benzylethyl) cyclohexyl ester according to Example 5 B The method described deals with the product of Example 2 (1.23 g '2.5 -71-this paper is suitable for financial standards (CNS) A4 Lin (2〗 GX 29 / public)) (Please read the precautions on the back before filling (This page) ^ -------- Order --------- Line — Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 A7 V. Description of Invention (69) • —Bu --- ---------- Dream-- ί Please read the urgent notes on the back before filling in this page). Diastereomeric mixtures were subjected to column chromatography on gelatine (4: 1 ethyl acetate / hexane) to give the title compound (0.32 g) with less polar diastereomers and more polar diastereomers. Enantiomers (0.30 g). MS (ESI (-)) m / z 649 (MH) '; iH NMR (CDC13) ί 0.88 (d, 3H), 0.9 (m, 1H), 113 (m, 1H), 1.19 (s, 3H), 1.28 (m, 2H), 1.32 (s, 3H) t 1.72 (m, 2H), 1.88 (m, 1H), 2.05 (m5 3H), 2.38 (m, 2H), 2.51 (m, 2H), 2.72 ( d 1H), 3.56 (d, 1H), 3.82 (d, 1H), 4.71 (m, 2H), 5.07 (s 1H) 6.92 (t, 1H), 7.12 (m, 1H), 7.28 (m, 6H) . ’

Example 7 B 5- (3-Bromo-4-fluorobenzenedioxo-3,4,5,6.7.8,9-10-Bayou Xiaoshe Phenidine-2 (1HV formic acid (1R.2S.5RW The more polar diastereomer (0.30 g) of 2-A-n-methylethylethyl) cyclohexyl ester Example 7A was recrystallized from digas methyl ether to obtain the title compound (0.24 g). Line-MS (ESI (-)) m / z 649 (MH) '; NMR (CDC13) ί 0.88 (d, 3H), 0.92 (m, 1H), 113 (s, 3H), 1.18-1.32 (m, 6H), 1.73 (m, 2H), 1.92 (m, 1H), 2.05 (m 3H) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 2.38 (m, 2H), 2.53 (m) 2H), 2.81 (d , 1H), 3.2 (d, 1H), 3.9 (d, 1H)} 4.56 (d, 1H), 4.75 (m, 1H), 5.1 (s, 1Η), 6.41 (tj 1H)) 6 8 (m, 2H), 7.05 (in, 1H), 7.12 (d, 1H), 7.31 (news, ih) 7 4 (m 1H), 7.5 (d, 1H).

Example 7 C (-)-5- (3-French-4-town, Benji) -2,3,5,8,9,10 06 1 Tomb of Zhibai Tomb--72- This paper is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

4 pay S A7 _B7__ 5. Description of the invention (7〇) 4,6 (1H, 7H) -dione hydrochloride n The product of Example 7 A (0,32 g) was treated according to the method described in Example 5 D to obtain the free base. The title compound (0.125 g) 'was then converted into the hydrochloride salt. [α] 20Ό -10 ° (CH3CN); MS (ESI (-)) m / z 389 (MH) ': lHNMR (DMSO-d6) (free base) 1.72-1.99 2.22 (t, 2H), 2.98 (m , 1H), 3.15 (s, 2H), 3.4 (m, 2H), 3.57 (s, 2H), 4.88 (s, 1H), 7.18 (m, 2H), 7.4 (d, 1H); C18H15BrFN202 ♦ HC1 analysis Calculate 値: C, 50.67: H, 3.78; N, 6.57. Measured radon: C, 50.18; H, 4.22; N, 6.16. Example 8 (> +)-5- (3-Bromo-4-fluorophenyl) -2,3,5,8,9,10-hexahydrobenzene , 6ΠΗ, 7Η) -dione hydrochloride_ The product of Example 7B (0.24 g) was treated according to the method described in Example 5D to give the title compound (0.070 g) as the free base, which was then converted to the hydrochloride salt. [A] 20D + 9.52 ° (CH3CN); MS (ESI (-)) m / z 389 (MH) .; lH NMR (DMSO-d6) δ 1.75-1.98 (m, 2H), 2.25 (t, 2H), 2.95 (s, 1H), 3.15 (s, 2H), 3.45 (m, 2H), 3.57 (s, 2H), 4.89 (s, 1H), 7.17 (m, 2H), 7.39 (d, 1H), 9.6 (s, 1H ); C18H16BrFN202 HC1 Analytical calculation: 値: C, 50.67; H, 3.78; N, 6.57. Found 値: C, 50.54; H, 4.05; N, 6.32. Example 9 10- (3-Bromo-4-Gasyl) -3.4.6.7,8, ί〇-Hydrogen-2H · 喽 RAN 弁 丨 3.2-b〗 丨 1,71 -73- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ( (Please read the precautions on the back before filling this page) -------- Order --------- Online 丨 Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Society 442485; V. Description of the invention (71) Pyridine-9 (5H)- Ketone 1.1-digas hydrazone hydrochloride '" · "-I, —

Example 9A 7-fluorenyl-10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydrocytidine [3,2-biri, 71 naphthyridine-9 (5H) -one 1,1-dioxide i N -benzylhexahydropyridine-3,5 · dione (Ziegler, Journal of the American Chemical Society (1973), 95, 7458-7464) (0.55 g, 2.5 A solution of mM) in ethanol (5 mL) was treated with 2.0M ammonia in ethanol (1.25 mL, 2.5 mM), stirred in a sealed tube for 30 minutes, and tetrahydrothiran-3-one-ΐ, ι Treated with dioxide (0.36 g '2.5 mmol), treated with 3-bromo-4-fluorobenzoic acid (0511 g, 2.51 ¾ mole)' at 48C for 48 hours, cooled and concentrated. The residue was purified by silica gel flash chromatography (5% ethanol / dichloromethane) to give the title compound (0.50 g). MS (ESI (-)) m / z 517 (MH) ';' H NMR (DMSO-d6) ά 2.18 (m, 2H), 2.42 (m, 2H), 2.95 (m 2H), 3.15 (m, 4H ), 3.42 (m, 2H), 3.6 (q, 2H), 5.0 (s, 1H). 7.18-7.5 (m, 8H), 9.5 (s, 1H).

Example 9 B 10- (3-Bromo-4-fluorobenzyl) -9-oxo-3,4,6,8,9,10-hexag.-2H-pyran # L3,2-b] " l, 71 pyridine-7 (5H) -vinyl formate l, i-diphosphonium sulfide Example 9A product (0_48 g, 0.92 mmol) in THF (5 ml) solution with vinyl formate (0.10 ml, 0.94 mmol) was treated and stirred overnight at ambient temperature. The solvent was evaporated and purified by flash chromatography on silica gel (ethyl acetate followed by 10% ethanol / dichloromethane) to give the title compound (205 g). MS (ESI (-)) m / z 497 (MH) '; -74-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) )

nnn I nnn IIII n II — Li — 1 I nn. A7 442485 B7_ V. Description of the invention (72) 4 NMR (DMSO-d6) ί 2.21 (m, 2H), 2.68 (m > 2H), 3.18 (m, 2H ), 3.28 (m, 2H), 3.5 (m, 1H), 3.75 (q; 2H), 4.11 (s, 2H), 5.08 (s, 1H), 7.28 (m, 2H), 7.41 (d, 1H) , 9.5 (br s, 1H).

Example 9 C 10- (3-bromo-4-fluorophenyl) · 3,4? 6? 7 ^ §_7Ι〇-color complex ^ 211 • thiopyrene 弁 q 2 tea bit-9 (5H) -one 1 A solution of the 1-dioxide b sulfonate Example 9B product (0.25 g) in ethanol was treated with 6N HC1 (1 ml) and refluxed for 2 hours', cooled to ambient temperature and concentrated. The residue was purified by flash chromatography on stone gum (15% ethanol / ammonia saturated with ammonia) to give the title compound (0.09 g) as the free base, which was converted into the hydrochloride salt. MS (ESI (-)) m / z 425 (MH) '; NMR (DMSO-d0) (free base) d 2.2 (mf 2H), 2.6 (m, 2H) 3.15 (s, 2H), 3.22 (m, 2H), 3.52 (d, 2H)} 5,02 (s, 1H), 7.22 (m 2H), 7.4 (m, 1H), 9.5 (br s, 1H). C17H16N2FBrS03 · HC1 · 0.5 C2H5OH Analytical calculation 値 .c 44.41; Η, 4.14; N, 5.75 '· Cl, 7.28 a Measured 値: c, 44.80; h 4.16; N, 5.68; Cl, 7.40 ° Example 1 0 9- [3-Bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothiophene 幷 丨 3,2_ | ^ 丨 1,71 tea shout_ 8 (4H)- Ketone 1J-dioxide salt conversion Example 10A A solution of tetrahydrobiphene-3 -alcohol tetrahydrophene-3-one (10.2 g '100 mmol) in ethanol (100 ml) slowly Treated with sodium borohydride (4'3g '114 millimoles), at Zhou Yuanwen -75- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back before filling (This page) * ^. 1 I ---- I ^ --------- 1 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 A7 B7 V. Description of the invention (73) Stir for 1 hour, Concentrated to a volume of about 50 ml, treated with water (400 ml) and extracted with monogas (3x). The combined two gas pit layers were washed in HC1, and dried (MgS〇4) '; It was taken up and concentrated to give 9.0 g of the title compound as a clear oil, which was used in the next step without purification.

Example 10B Tetrahydropyrimidin-3-ol-M-dihydride Example 10A (10.0 g, 96.0 mmol), sodium tungstate dihydrate (0.315 g, 0.96 mmol) and acetic acid (7.5 ml , 130 mol) in water (42 liters) was treated dropwise with 30% hydrogen peroxide (31.6 g, 280 mol) at 0 ° C for 1 hour and stirred at 0 ° C for 30 minutes, Stir for 45 minutes at ambient temperature, transfer to a 100 mm X 190 mm crystallization dish and concentrate on a steam bath to obtain the title compound as an oil, which was used in the next step without purification.

Example 10C Four wind ρ-phenphen-3- 嗣 -1,1-di-emulsion Example 10B A mechanically stirred solution of the crude product in acetone (300 ml) in 2 hours with Jones reagent (2.7M, total 30) (Ml) treatment until it continued to brown, stirred for 1 hour, slowly treated with isopropanol (7.5 ml), incubate for 5 minutes' diluted with acetone (400 ml) and removed the road salt through celite. The filtrate was concentrated and chromatographed on silica gel (1: 1 hexane: ethyl acetate) to give 5.88 g of the title compound. NMR (CDC13) 3 3.08 (t, 2H), 3.58 (t, 2H), 3'70 (s, 2H).

Example 10D 6_benzyl_9 · (3-bromofluorophenyl) _2,3,5,6,7,9-hexahydro 0 box Fyme "3 -76- This paper size applies to Chinese National Standards (CNS) A4 specifications (210 X 297 mm) {Please read the notes on the back before filling out this page) ------- Order If — — — — — — — Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 442 48 5 A7 B7 V. Description of the invention (74) [U71Benzidin-8 (4H) -one 1, [] -dioxide N-fluorenyl hexahydrop-pyridine_3,5-dione (Ziegler, American Association Journal (1973), 95, 745 8-7464) (0.55 g, 2'5 mmol) in ethanol (5 ml) was treated with 2.0 M ammonia in ethanol (1.25 ml, 2.5 mmol). Stir in a sealed tube for 4 hours, treat with the product of Example 10C (0.33 g, 2.5 mmol), treat with 3-bromo-4-fluorobenzaldehyde (0.51 g, 2.5 mmol) and stir at 75 ° C 4 8 hours, cooled and concentrated. The residue was purified by rapid chromatography on silica gel (5-10% ethanol / dichloroform) to give the title compound (0 28 g). MS (ESI (-)) m / z 501 (MH) ';' H NMR (DMSO-d6) ά 2.8 (m, 1H), 3.0 (m, 2H), 3.08 ^ 3.3 (m, 2H), 3.42 ( m, 3H), 3.62 (m, 2H), 4.85 (S) 1H), 7.2-7.48 (m, 8H), 9.98 (s, 1H).

Example 10E 9- (3-bromo-4-fluorobenzyl) -8-oxo-2,3,5,6,7,9-hexa || .4 phenoxide "32_ | ^ Π, 7" -6 (4H) -vinyl formate M-dioxide Example 10D (0.22 g, 0.43 mmol) in digas methane (5 ml) solution of vinyl chloroformate ml, 0,94 mmol ) Process and incubate overnight at ambient temperature. Dilute with Ichiran Ain and wash with aqueous sodium carbonate solution. Separate the methane layer, dry over sodium sulfate, filter and concentrate to give the title compound (0.28 g). -)) m / z 497 (MH) '; * H NMR (DMSO-de) ^ 2.88 (m, 2H), 3.1 (m, 3H), .3,5 (m, 1H), 3.75 (q, 2H ), 4.12 (s, 2H), 4.9 (s, 1H), 7.29 (m5 2H), 7.48 (d, 1H), 10.1 (s, 1H). -77- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210 x 297 male cage) (Please read the precautions on the back before filling this page)

; 仏 -----— Ϊ— Order ------- 11 ^-I Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 44248 5 A7 B7 V. Description of the Invention (75)

Example 10F 9-Π-bromo-4-fluorophenyl) -2.3.5,6,7,9: hexahydro "cephene 弁 3,2-bl" l, 71 pyridine-8C4HV ketone 1.1-dioxide Example 10E A solution of the product 10E in ethanol (5 ml) was treated with 6N HC1 (1 ml) and refluxed for 3 hours, cooled to ambient temperature and concentrated. The residue was subjected to flash chromatography on silica gel (10% ethanol / ammonia). Saturated digas methane) was purified to give the title compound (0.070 g), which was converted to the hydrochloride salt. MS (ESI (-)) m / z 411 (MH) ": NMR (DMSO-d6) i 2.75 (m , 2H), 3.02 (m, 1H), 3.15 (s, 2H), 3.58 (m, 3H), 4.87 (s, 1H), 7.25 (d, 2H), 7.43 (d, 1H), 9.9 (s, 1H); C16H 丨 4BrFN2S03 · HC1 · 0.5 Analysis of C2H5OH5: c, 43.19; H, 3.84: N, 5.93; Cl, 7.50. Found 实: c, 43,69; H, 3.85; N, 5.83; Cl , 7.66. Example 1 1 9- (3-Bromo-4-fluorophenyl) · 2,3,5,9-tetrahydro-4H-piperane 3.4-bl

[2,3-el pyridine-8 (7H) -rim 1J · dioxide example 11A (2-oxopropoxy) methyl acetate 2M difluorenyl zinc in toluene solution ml, 42 mmol) under nitrogen Cool to o ° C., Treat with trans-benzyl (gas) bis (triphenylphosphine) palladium (π) (〇57 g, 76mmol), and treat with 2- (aeromethylmethylmethoxy) Methyl acetate (12.6 g, 70 mmol) was treated dropwise at 0.5 h.匸 Stir 〇5 hours' Stir at the garden temperature for 16 hours, take 1MHC1 (40 ml) and then eat -78- {Please read the precautions on the back before filling this page) -------- Order ·- ------ line ί printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 7 9 2 X 10 (2 grid 0- η / 0 '1 ^ Ϊ-1-442 48 5 A7 ---- 5 Description of the invention (76) Treated with brine (20 ml). The organic layer was dried (MgS04), filtered and concentrated the β residue on silica gel and purified by flash chromatography (丨: 2 ethyl acetate / hexane) to obtain the title compound. (5.2 g). Example II Β 1 Lunan-3.5MΗ.6Η) -diketone solution of the product of Example 11A (5.0 g, 34 mmol) in ether (40 ml) in 2.5 hours Drop to! M potassium tert-butoxide (34 ml in tert-butanol) in 0 C ether solution (270 ml). The mixture was treated with i M HC1 (120 mL) and then with ethyl acetate (250 milliwells) and brine (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (twice, 250 ml). The combined organic layers were washed with brine (2 ×, 60 ml), dried (MgS04), filtered, and concentrated (maintaining a low temperature of 4 (rc) to obtain the title compound (Terasawa, organic, about 30% pure). Chemical Journal (1977), 42, 1163-1169) 'It can be purified by chromatography on silica gel using 2000: 1: 1: 1 ethyl acetate, acetic acid: water: hexane to obtain the title compound.

Example 11C -Amine-2H-Xan-3 (6H) -one The product of 30% purity of Example 11B was treated with benzene (60 ml), followed by ethanol (20 ml) and p-toluenesulfonic acid (100 mg). ) Treatment, followed by heating to reflux for 6 hours and shrinking. The product 5_ethoxy_2Η_piperan · 3 (6H) · one was treated with 2 M ammonia in methanol (100 ml), and stirred! 6 hours and concentrated. The residue was purified by flash chromatography on silica gel (5% and then 10/0 methanol / dioxane) to give the title compound (1.3 g). MS (DCI / NH3) m / z 114 (M + H) +, 131 (M + NH4) +; -79- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) C, please first (Please read the notes on the back and fill in this page) ί -------- Order --------- Online — Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 Employee Consumption of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the cooperative A7 B7 V. Description of the invention (77) Ή NMR (DMSO-d6) ^ 3.80 (s, 2H), 4.19 (s, 2H), 5.01 (Sj! H)} 7.01 (bs, 2H) =

Example 11D Fluorophenyl) -2,3,5,9-tetrahydro "3,4-bh thiophene # [2,3-e ~ | pyridine-8 (7H) -one-1" -di ^^^ Example Lie products (1.5 grams, u millimoles), 3_bromo_4_fluorobenzaldehyde (32 grams, 16 millimoles), tetrahydrophene · 3_oxodeca 丨 _dioxide (miscellaneous Journal of Cyclic Chemistry, Volume 27, prepared as described on page 1453 (199 °)) (18 g, 13 mmol) and triethylamine (0.93 ml, 6.6 mmol) in ethanol (20 ml) The mixture was stirred in a 8 (TC sealed tube for 60 hours, cooled and concentrated to dryness. The residue was treated with ethanol (50 ml) and then 1 MHC1 (5 ml in Etsutsu, 5 ml) and heated to reflux for 5 minutes and maintained at ambient temperature. 3 hours. The resulting solid was collected by filtration, washed with acetonitrile, and changed in the air / θ, and explored for 16 hours. The title compound (3.2 g) was obtained. Mp > 260 ° C; MS (ESI (+)) m / z 414 (M + H) +, 431 (M + NH4); MS (ESI (-)) m / z 412 (MH) '; 丨 H NMR (DMSO-d6 ”2.85 (m, 1H), 3.08 (m, 1H), 3 ⑸ 42 (m, 2H), 4.03 (s, 2H), 4.49 (AB q, 2H), 4'90 (s, 1H) .7 27 (m 2H), 7.45 (dd5 1H ), 10.14 (s, 1H); '·' C16H13 Analytical calculation for N04SFBr: C, 46.39; H, 3.i6; N 3 38. Found: C, 46.25; H, 3.24; N, 3.26. 'Example 1 2 (+)-9- (3-Bromo-4 -Fluorophenyl) -2,3,5,9-tetrahydro-4H-should _ -80 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) --JI —-hi — ~ I —If—. ^ ---— — — — — — — — IIIIIC Please read the notes on the back before filling out this page) Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs 44248 5 A7 _ — B7 V. Invention Instructions (78)

幷 U, 3-elpyridine · 8 (7Η) _one 1,1-dioxide solid tree 12 A 9 -_ (_ 3_-xi-4-fluorophenyl) -8-oxo-2.3.5,7 , 8,9-Hexafluorene-4 only-Amino acids 丨 3,4-1) 1 Benzene 幷 『2,3-e〗 Pyridin-4-methyl base nR.2S, 5R) -5-A 2- (1-Methyl-1-phenylethyl) cyclohexyl phosphonium, 1-diphosphonium compound under nitrogen at 0eC in Example iid (1.58 g, 3,7 mmol) in THF (40 Into a suspension), a solution of potassium tert-butoxide in 1M THF (4.1 ml) was added dropwise over 5 minutes. The mixture was stirred at ambient temperature for 30 minutes 'cooled to 0C' with 8-phenylmethanol lactate (as described in Yamamotto, Y., Journal of the American Chemical Society (1992), 114, 121-125) Prepared from (-)-8-phenylmethanol) (1.31 g, 4.4 mmol) in THF (20 ml) for 5 minutes, stirred at the garden temperature for 16 hours, and heated in digas (150 ml) Dilute and wash with sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with two-gas methane gauge (50¾ liters). The combined organic layers were dried (Mgs04), dried and concentrated. The residue was purified by flash chromatography on a colloidal gel (3: 2: 1 aeroform / hexane / ether) to obtain 0.98 g of the less polar diastereomer a MS (ESI (+)) m / z 672 ( M + H) +, 689 (M + NH4) +: MS (ESI (-)) m / z 670 (MH) —.

Example 12B 9-(_ 3-Mo-4-fluorophenyl) -8-oxo-2,3,5,7,8,9-hexahydro-41 ^-^^ 3: 丨 3 4_h 丨 毽 phen 幷[2,3-e] pyridine-4 · carboxylic acid (1R, 2S.5R) -5-methyl = ^ phenylethyl) cyclohexyl acetate 1,1-dioxide_ The impurity of Example 12A is more polar and non- Enantiomers were rechromatographed on silica gel (3: 2: 1 aerosol / hexane / acetic acid) to obtain 1 _ 0 grams of more pure pure anisotropy isomers -81-This paper size applies Chinese national standards (CNS) A4 specification (210 X 297 mm) *. Jllhll — 1— —--- 仏 · I ------,-I I --- t I (Please read the notes on the back before filling This page) 442485 A7 B7 V. Description of the invention (79) Structure. MS (ESI (+)) m / z 672 (M + H) +} 689 (M + NH4) +; MS (ESI (·)) m / z 670 (M-H).

Example 12C (± hg- (3.r. Mo-4-fluoro: Benzyl) meaning -tetrahydro-sister-piperan and trans ^^^^ 2,3-elpyridin-8 (7H) -Ketone M-Dihydrogenation Example 12A (0.98 g '1.4 mmol) in a methanol / digas solution (40 ml / 10 ml) was degassed in nitrogen to 25% methanol sodium formate ( 30 drops), stirred for 16 hours, filtered through a 45 mm syringe syringe and concentrated to 5 ml of methanol. The precipitated solid was collected by filtration, washed with methanol and dried in the air for 16 hours to obtain the title compound 36g). [A] 23D +117. (DMSO, c 0.925); MS (ESI (ten)) m / z 414 (M + H) +, 431 (M + NH4) +; MS (ESI (-) ) m / z 412 (MH) ';' H NMR (DMSO-d6) 2.85 (m, 1H), 3.08 (m) 1H), 3.33-3.42 (m, 2H), 4.03 (s, 2H), 4.49 ( AB q, 2H), 4.90 (s, 1H), 7.27 (m, 2H), 7.45 (dd, 1H), 10.14 (s, 1H); C16H13N04SFBr Analysis and calculation 値: C, 46.39; H, 3.16; N, 3.38 Measured plutonium: C, 46.07; H, 3.02; N, 3.19. Example 1 3 (-)-9- (3-Bromo.-4-Gabenzyl) -2,3,5,9-tetrahydro-4H -旅 喃 丨 3,4_b ~ | 远 芬 # [2.3-el pyridin-8 (7H) -one 1, di dioxide Example 12B (1 (0 g, 15 mmol) was treated as described in Example 1 2C to obtain the title compound (0.40 g). -82- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) (Please (Please read the notes on the back before filling this page) Λ --------- Order --------- line — printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 A7 B7 V. Description of the invention (8G) [a] 23D -117. (DMSO, c 1.01): MS (ESI (+)) m / z 414 (M + H) +, 431 (M + NH4) +; MS (ESI (-)) m / z 412 (MH) ·; 'H NMR (DMSO-d6) δ 2.85 (m, 1H), 3.08 (m, 1H), 3.33-3.42 (m, 2H), 4.03 (s, 2H), 4.49 ( AB q, 2H), 4.90 (s, 1H), 7.27 (m, 2H), 7.45 (dd, 1H), 10.14 (s, 1H);

Ci6H13N04SFBr Analytical calculation C: C, 46.39; H, 3.16; N, 3.38. Found 値: C, 46.12; H, 3.23; N, 3.34. Example 1 4 · 9- (3-Cyanobenzyl) -2,3,5,9-tetrahydro-41 ^ -Xanan 幷 3,4-131 »Cyno " 2,3-61 pyridine- 8 (7H) -one M-digas compound Example 11C product (0.74 g, 6.5 mmol), 3-cyanobenzaldehyde (1.0 g, 7.8 mmol), Tetrahydropcetin The mixture of oxo- 丨 shan dioxide (0.87 g, 6.5 mmol) and triethylamine (0.45 ml, 3.2 mmol) in ethanol (20 ml) was stirred in a sealed tube for 60 hours, Cool and collect the solid by filtration and wash with ethanol. The solid was treated with ethanol (30 ml) and 1M HCI ('4 ml in ether) and heated to reflux for 5 minutes and maintained at ambient temperature for 16 hours. The title compound (1.4 g) was collected, washed with ethanol and dried in the air for 16 hours. MS (ESI (+)) m / z 360 (M + NH4) +; MS (ESI (-)) m / z 341 (MH) _; H NMR (DMSO-d6) ά 2.86 (m, 1H), 3.09 (m, 1H), 3.38 (m, 2H), 4.02 (s, 2H), 4.49 (AB q, 2H), 4.97 (s, 1H), 7.49 (t, 1H), 7.56-7.68 (m, 3H) , 10.14 (s, 1H); -83-This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) (Please read the precautions on the back before filling this page)

-i ------ Order --------- Line J Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs * '1 ^ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 442485 A7 ---- B7 V. Description of the invention (81) c ”H14N204S. 0.25 EtOH analysis and calculation 値: C, 59.4; H, 4.41; N, 7 92. Measured 値: C, 59.19; H, 4.40: N, 7.88. Example 1 5

(± 1-9- (3-cyano-phenyl) -2,3,5,9-tetrahydrone, -411-piranofluorene [3,4-131 side pheno f2,3-el pyridine-8 ( 7H) -keto 1.1-dioxide example 15A ilD-cyanobenzene) -8 • oxo-2.3,5,7,8,9-hexahydro-4H-pirane 幷: 查 全 _ 幷 r2, 3-el pyridine-4-carboxylic acid (1R.2S.5RV5-methyl-2-Π-methyl-1-1-phenylethyl) cyclohexyl ester 1.1 -Earth oxide product of Example 14 (1.3 g, 3.8 Millimoles) were treated as in Example 12A and UB to give 0.50 g of the less polar diastereomer and 0.50 g of the more polar diastereomer. (Less polar diastereomers) MS (ESI (+)) m / z 618 (M + NH4) +; MS (ESI (-)) m / z 599 (MH) ': (more polar Diastereomers) MS (ESI (+)) m / z 618 (M + NH4) +; MS (ESI (·)) m / z 599 (M-Η).

Example 15B (+)-9- (3-Cyanobenzyl V2,3,5,9-tetrahydro-4H-piranofluorene f2,3-el pyridine-8 (7H) -one 1,1-dioxide Example 15 A suspension of the less polar diastereomer (0.50 g, 0.83 mmol) in methanol (10 ml), with methanol (30 drops) containing 25% sodium methoxide Processing, stirring for 16 hours, filtering through a 45 mm syringe filter and -84- This paper size applies to China National Standard (CNS) A4 (210x297 mm) ί-^---Mi ----— —Order --------- line (please read the notes on the back before filling this page) 4 8 5 A7 B7 V. Description of the invention (82) Concentrated to dryness and treated with ethanol (20 ml), Heat on a steam bath until the start of crystallization and let stand at the ambient temperature for 5 hours. The solid was collected by filtration, washed with ethanol and dried in the air for 16 hours to give the title compound (015 g). [A] 23d + 105 ° (DMSO; c 1.0); MS (ESI (+)) m / z 360 (M + NH4) +; MS (ESI (-)) m / z 341 (MH) ';' H NMR (DMSO-de) ^ 2.86 (m , 1H), 3.09 (m, 1H), 3.3g (m 2H), 4.02 (s, 2H), 4.49 (AB q, 2H), 4.97 (s, 1H), 7.49 (t) iH) 7.56-7.68 ( m, 3H), 10.14 (s, 1H); C17H14N204S Analytical calculation: 値: C, 59.64; H, 4.12; N, 8.U. Measured 値: C, 59.39; Η, 4.25; N, 7.80. Example 1 6 (-)-9- (3-air base groups ) -2,3,5,9-tetrahydro-4H- * diamidine 弁 3,4-b] p * —fen- 幷 f2,3-e1 pyridine-8 (7HV ketone 1,1-digas Example 1 5A A more polar diastereomer (0.50 g, 0.883 mole) in methanol (30 ml) and digas methane (5 ml) in a suspension containing 25% sodium methoxide Treated with methanol (10 drops), stirred for 16 hours, filtered through a 45 mm syringe filter, treated dropwise with acetic acid until the yellow color disappeared, concentrated to dryness, treated with ethanol (30 ml), and heated on a steam bath until the beginning Crystallize and leave at ambient temperature for 5 hours. Collect the solid by filtration, wash the strip with ethanol, and dry in the air for 16 hours to obtain the title compound (0.18 g). [A] 23D 1030 (DMSO, c 1.0) ; MS (ESI (+)) m / z 360 (M + NH4) +; MS (ESI (-)) m / z 341 (MH) '; -85- This paper size applies to Chinese National Standard (CN'S) A4 Specifications (210 X 297 mm) -l · I I- II --- I! — "^ --- I ---- Order --------- Line— (Please read the back first Please fill in this page again) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 442485 Α7 B? 5. Description of the invention (83) iH NMR (DMSO-d6) is 2.86 (m, 1H), 3.09 (m, 1H) , 3 3 § ^ 2H), 4.02 (S, 2H), 4.49 (AB q, 2H), 4.97 (s, 1H), 7 49 (t, 1H) '7-56-7.68 (m, 3H), 10.14 (s, 1H); ''. 0.5 H20 Analytical calculation 値: C, 58.86; H 4 21. N 8.08. Found 値: c, 58.90; H, 4.48; N, 7.80. 'Example 1 7?-(4-fluoren-3-arylphenyl) -2,3,5,9-tetrahydro-411- |; > Nongran # 『3 ^^ 1; ^ | ^ 4 i2J -el Pyridin-8 (7H) -one 1,1-dioxide Example 11C product (0.74 g, 6.5 millimolar plant, 4-gas-3_cerylbenzoic acid (1.5 g, 7.8 millimolar) '' A mixture of tetrahydrophene-3-oxo-U-dioxide (0.87 g, 6'5 mmol) and triethylamine (0.45 ml, 3_2 mmol) in ethanol (20 ml) Treated as in Example 11D, which was purified by flash chromatography on syrup (5% methanol / dichloromethane) and crystallized from ethanol to give the title compound (1.46 g). MS (ESI (+)) m / z 414 (M + NH4) +; MS (ESI (-)) m / z 395 (MH) " 'H NMR (DMSO-d6) ^ 2.80-2.93 (m, 1H), 3.01-3.13 (m, 1H ), 3.39 (t; 2H), 4.04 (s, 2H), 4.49 (AB q, 2H), 5.02 (s, 1H), 7.58 (dd, 1H), 7.69 (d) 1H), 7.86 (d, 1H ), 10.22 (s, 1H); C16H13N206SC1 Analytical calculation 値: C, 48, 43; H, 3.30; N, 7.06. Found 値: C, 48.13; H, 3.38; N, 6.79. Example 1 8 (+)- 9- (4-Gas-3-nitrophenyl) -2,3,5,9-tetrahydro-4H-piperan # 『3,4-bP & phene 幷 丨 2,3-elpyridine-8 ( 7HV Ketone M-Dioxide -86- This paper size applies to Chinese national standards (CNSM4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) ^--------Order ------ --Line—Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4424 8 5 Α7 __ Β7 V. Description of Invention (84)

Example 18A 9- (4-Ga-3-Askylphenyl) -8-oxo: 2,3,5,7,8,9-hexahydro-41 ^ -slightly fluorene P, 4-bh r2.3-e1 Pyridine-4-carboxylic acid (lR, 2S, 5R) -5-methyl-2_Π-methyl-1-benzylethyl ¾ Hexyl acetate 1,1-dioxide Example 1 of 7 The product (1.3 g '3.3 mmol) was treated as in Examples 12A and 12B to give 0.71 g of the less polar diastereomer and 081 g of the more polar diastereomer. (Less polar diastereomers) MS (ESI (+)) m / z 672 (M + NH4) +: MS (ESI (-)) m / z 653 (MH) '; (more polar Diastereomers) MS (ESI (+)) m / z 672 (M + NH4) +; MS (ESI (-)) m / z 653 (MH).

Example 18B (+)-9- (4-Gas-3-nitrophenyl) -2,3,5,9-tetrahydro-4H-ouranino 丨 pheno 丨 2,3-elpyridine, 8 ( 7))-Keto-1, dioxide Example 18A The less polar diastereomer (0 71 g, M mmol) was treated as in Example 16 to give the title compound (0.23 g). [Shen] 23d +75. (C = 1.0, DMSO); MS (ESI (-)) m / z 395 (MH) "; Η NMR (DMSO-d6) ό 2.80-2.93 (m, 1H), 3.01-3.13 (m, 1H ), 3.39 (t, 2H), 4.04 (s, 2H), 4.49 (AB q, 2H), 5.02 (s, 1H), 7.58 (dd, 1H), 7.69 (d, 1H), 7.86 (d, 1H ), 10.22 (s, 1H); Ci6H13N206SC1 analysis and calculation 値: c, 48.43; H, 3.30; N, 7.06. -87- This paper is compatible with China National Standard (CNS) A4 (210x297cm ^ < Please read the unintentional matter on the back before filling in this page)

i ------ Order * ------- II Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 44248 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economy A7 B7 V. Description of the invention (85)値: C, 48.26; Η, 3.48; N, 6.98. Example 1 9 (-)-9- [4-Gas-3-nitrophenyl) -2.3.5.9-tetrafluorene-41?-呱 咗 # 丨 3.4-1? 14—phene 幷 2.3-el pyridine- 8 (7HV, 1,1-dioxide Example 18A, a more polar diastereomer (0.11 g, L2 mmol)) was treated as in Example 16 to give the title compound (0.29 g). [ο:] 23d -74 ° (DMSO, c 0.97); MS (ESI (+)) m / z 414 (M + NH4) +; MS (ESI㈠) m / z 395 (M-Η) ·; lH NMR (DMSO-d6) ά 2,80-2.93 (m, 1H), 3.01-3.13 (m, 1H), 3.39 (t, 2H), 4.04 (s, 2H), 4.49 (AB q, 2H), 5.02 ( s, lH), 7.58 (dd, 1H), 7.69 (d, 1H), 7.86 (d, 1H), 10.22 (s, 1H); Analysis and calculation of Ci6Hi3N206SCl 値: C, 48.43; H, 3.30; n, 7.06. Measured tritium: C, 48.42; H, 3.31; N, 6.91. Example 2 0 5- (3- "Smell-4-fluorobenzyl) -5,8,9,10-tetrahydro-1H-sound 弁 丨3 4_b] n set of '# 4,6 (3H, 7H) -dione Example lie product (0'23 g, 2.0 mmol), 3-Cr · 4-fluorobenzaldehyde (0.49 g, 2.4 mmol) ), 1 mixture of hexamethylene dioxane (023 g, .20 mmol) and triethylamine (0.14 ml, 1.0 mmol) in ethanol (4 ml) sealed tube at 80 ° C Stir for 60 hours and cool to ambient temperature. The resulting solid was collected by filtration, washed with ethanol, dissolved in a mixture of Dimethyl Acetone / Methanol (4: 1), and heated on a steam bath to remove the Dimethyl Amine and make It crystallizes for 4 hours. Collect the crystals after washing with methanol 'and dry in the air -88-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 〈Please read the precautions on the back before filling (This page)

— — — — — —— Order ---- I --- I A7 442485 _______B7 _______ V. Description of the invention (86) The title compound (0.37 g) was obtained by drying for 16 hours. MS (ESI (+)) m / z 392 (M + H) +; MS (ESI (-)) m / z 390 (MH) '; * H NMR (DMSO-d6) ά 1.76-2.01 (m, 2H ), 2.25 (t, 2H), 2.43-2.64 (m, 2H), 4.01 (s, 2H)? 4.48 (AB q, 2H), 4.90 (s, 1H), 7.20 (m, 2H), 7.39 (del , 1H), 9.82 (bs 1H); C18H15N03FBr Analytical calculation 値: C, 55.12; H, 3.85; N, 3.57 Measured 値: C, 54.99; H, 4.04; N, 3.49. Example 2 1 '10- (3-Bromo-4-fluorophenyl) -3,4,6,10-tetrahydro-211,511-pirane 弁 3,4-131 唣 唣 幷 2,3-elpyridine -9 (8H) -one 1,1-dioxide Example 11C product (0.23 g, 2,0 mmol), 3-bromo-4-fluorobenzyl (0. · 49 g '2.4 mmol ), 〖, 1_dioxo tetragas_ι_ρ 塞安 _3_ snapper (D0 (jd JH, Journal of Heterocyclic Chemistry (1990), 27, 1453-1456) (0.30 g, 2.0 mmol) and A mixture of ethylamine (0.14 ml, 1.0 mmol) in ethanol (4 ml) was treated as in Example 14 to give the title compound (0 25 g). MS (ESI (+)) m / z 428 (M + Η ) \ 445 (Μ + ΝΗ4) +; MS (ESI (-)) m / z 426 (MH) *; NMR (DMSO-d6) ^ 2.22 (m, 2H), 2.41-2.56 (m, 1H), 2.64 (dt, 1H), 3.09-3.35 (m, 2H), 4.02 (s, 2H), 4,43 (AB q, 2H), 5.06 (s, 1H), 7.25 (m, 2H), 7.41 (dd, 1H), 9.67 (bs, 1H);

Cpii15N04SFBr Analytical calculation 値: c, 47.68; H, 3.53; N, 3.27. Found 値: C, 47.36; H, 3_65; N, 3,06. -89- Lai Jia Standard (CNS) A4 Specification (210x 297 Public Love) in this paper preparation standard {Please read the notes on the back before filling this page) ---- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ·- ------- I ------- 442485 A7 B7 V. Description of the invention (87) Example 2 2 Odor 4-fluorophenyl) -5,10-dihydro · -1Η, 3Η-piper幷 "3,4-bl-disyrano'4,3-M pyridine-4,6 (7H, 9H) -dione Example 11C product (0.23 g '2.0 mmoles), 3-mo-4-fluoro Benzyl (0.49 g '2.4 mmol), cethan-3,5-dione (Fehnel, EA ·, Journal of the American Chemical Society (1955), 77, 4241-4244) (0.26 g, 2_0 mmol) Ear) and triethylamine (0.14 ml, 1.0 mmol) in ethanol (4 ml) were treated as in Example 20 to give the title compound (0.37 g). MS (ESI (+)) m / z 410 (Μ + Η) +, 427 (Μ + ΝΗ4) +; MS (ESI (-)) m / z 408 (MH) ';' H NMR (DMSO-d6) δ 3.12 (d, 1H), 3.50 (d, 2H), 3.81 (dd, 1H), 4.03 (s, 2H), 4.48 (AB q, 2H), 4.97 (s, 1H), 7.20 (ddd, 1H) , 7.26 (t, 1H), 7.40 (dd, 1H), 9.98 (bs, 1H);

Ci7H13N03SFBr Analytical calculation 値: c, 49.77; Η, 3.19; N, 3,41. Found 値: C, 49.43; H, 3, 28; N, 3, 21. Example 2 3 5-Q · Mo-4-fluorophenyl) -5,7,8,9-tetrahydrocyclopentane [bl piperanopyridine-4,6 (1H, 3H) -dione Ministry of Economic Affairs The Intellectual Property Bureau employee consumer cooperative printed examples of 11C products (0.23 g, 2.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.49 g '2.4 mmol), 1,3-cyclopentanedione ( A mixture of 0.20 g, 2.0 mmoles) and triethylamine (0.14 ml, 0.00 mmol) in ethanol (4 ml) was treated as in Example 14. The solid was dissolved in a mixture of digas methane / methanol (4: 1), heated on a steam bath to remove digas and to crystallize for 4 hours. The crystals were collected by filtration, washed with methanol, and dried in the air. I 6 小 -90- __ This paper size is applicable to China National Standard (CNS) A4 (210 X 297 male cage) 442485 Α7 Β7 V. The description of the invention (88) The title compound (0.14 g). MS (ESI (+)) m / z 378 (M + H) +, 395 (M + NH4) +; MS (ESI (-)) m / z 376 (MH) '; NMR (DMSO-d6) J 2.31 (t, 2H), 2.59 (dt, 1H), 2.73 (dt, 1H), 4.04 (s, 2H), 4'53 (AB q, 2H), 4.71 (s, 1H), 7.22 (m, 2H), 7.43 (dd, 1H), 10.36 (bs, 1H); C17H13N03FBr Analytical calculations: C, 53.99; H, 3, 46; N, 3'70. Found 値: C, 53.68; H, 3.63; N, 3.63. Example 2 4-

5- (3.bromo-4-fluorophenyl) fluorene 9,10-tetrahydro-1H-piranylhydrazone IIi_4-blLL7] pyrimidine-4,6 (3H, 7HV dione hydrochloride example 24A 8-benzyl -5- (3-brook-4-fluorophenyl) -5,8,9,10-tetrafish-114_tripamidine "3,4-1 > 1 Γ1,71 naphthyridine-4,6 (3H , 7H) -diketone Example 11C product (0.13 g, 1.1 mmol), 3-bromo-4-fluorobenzaldehyde (0.28 g '1.4 mmol), N-fluorenylhexahydropyridine_3,5 -Dione (Ziegler, Journal of the American Chemical Society (1973), 95, 7458-7464) (0.23 g, 1.1 mmol) and triethylamine (0.14 ml, 1.0 mmol) in ethanol (3 ml) The mixture in was treated as in Example 2 A to give the title compound (5 g). MS (ESI (+)) m / z 483 (M + H) + s 505 (M + NH4) +; MS (ESI (-)) m / z 481 (MH) ..

Example 2 4 B Tris (3-bromo-4-fluorophenyl) -4,6-dioxo-4.5,6,7,9.10-hexamidine-11! -Piperane f3,4-b ~ [| L, 71 phenylpyridine-8 (3H) _vinyl formate-91-This paper size is applicable to the national standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page )

^ · I— H ^ 1] ^ —OJ1 n II Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs — Hi n I n II i-A7 4 42 48 5 ____B7 _ V. Description of the invention (89) The product of Example 24A ( A solution of 0,29 g, 0.69 mmoles in methane (4 ml) was treated with ethyl chloroformate (0-10 ml, 1.2 mmoles) and treated as in Example 2B. Purification by flash chromatography (EtO Ac) on silica gel gave the title compound (0.13 g). MS (ESI (+)) m / z 463 (M + H) +, 480 (M + NH4) +; MS (ESI (-)) m / z 461 (M-H)-.

Example 24C 5- (3-Bromo-4-fluorophenyl) -5.8,9,10-tetrahydro_1 H-piranofluorene 3T4-bin, 71 naphthyridine-4,6 (3H, 7H) -di Ketohydrochloride Example 24B in ethanol (10 ml) was treated with 6N HC1 (5 ml), refluxed for 3 hours and concentrated. Purified by flash chromatography on silica gel (10% methanol / ammonia-saturated methane). The title compound (0.080 g) was obtained, which was converted into the hydrochloride salt. Mp 232-235 ...; MS (ESI (+)) m / z 393 (M + H) +, 410 (M + NH4) +; MS (ESI (-)) m / z 391 (MH) '; * H NMR (DMS0-d6) 3.78 (AB q, 2H), 4.07 (s, 2H), 4.19 (s, 2H) S 4.54 (AB q, 2H), 4.95 (s, 1H), 7.27 (m, 2H), 7.46 (dd, 1H), 9.86 (bs, 2H), 10.71 (s, 1H); C17H14N203FBr · H20.0_25 EtOH analysis calculation 値: c, 45.77; H, 4.06; N, 6.10. Found 値: C, 45.89; H, 4.23: N, 5.91. Example 2 5 9- (3-Bromo-4-fluorobenzyl) -5,9-dihydro-3H -Furano 丨 3.4-bl piperane 丨 4,3-el pyridine-1,8 (4H, 7H) -dione-92- This paper size applies to China National Standard (CNS) A4 specifications < 210 X 297 male Li) --- J ------ ^ ------- order --------- line — < Please read the notes on the back before filling (Buy) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 442485 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (90)

t Μ 25 A 4- (3-’/ Oxid-4-fluorophenyl) -2-methyl-5-gas-substituted 4,5,6,8-tetrachloro-pyrene

Jj, 4-bl Pyridine-3-methyl formate tetrahydroxyl 17 South-3,5-di_ (Terasawa, Journal of Organic Chemistry (1977), 42, 1 163-1169) (1.4 g, 12 mmol) The mixture of 3-bromo-4_fluorobenzyl (3.0 g '15¾ mole), 3-amino crotonic acid methyl ester (14 g, 12 mmol) and ethanol (10 ml) was as in Example 2 A deal with. Purification by flash chromatography on silica gel (1% followed by 2% and then 5% methanol / methane) gave the title compound (2.4 g) as a solid. -tnp 206-208 ° C °

Example 25B 4-Q-Bromofluorophenyl) -2- (bromomethyl) -5-msa hydrazone-IH-Wl A solution of 0.87 g, 2.2 mmoles in aerosol (0 ml) was cooled to -1 (TC 'treated with pyridine (0.21 ml, 2-6 mmoles) followed by pyridinium tribromide (0.84 g, 2.6 millimoles), stirred for j hours, diluted with dichloromethane (150 mL) and washed with 1NHCI (25 mL). The organic layer was dried (MgS04), dried and concentrated. The residue was ground into gum Purification by flash chromatography (1% followed by 2% methanol / digasmethane) gave the title compound (0.68 g) as an oil.

Example 25C Bromo-4-fluorophenyldihydro-3Ηfuranpiran dagger read: -1,8 (4H, 7H) -dione. Example 25B product (0.30 g '0.63 mmol) was pure heated to 13 (^ 15 分 -93- This paper size applies the national standard (CNS) A4 specification (210 X 297 mm)) (谙 Please read the notes on the back before filling this page) 44248 5 A7 _ B7 V. Description of the invention (91) (Please read the Weeping Matters on the back before filling this page) and cool to ambient temperature .. The residue is treated with digas methane and the resulting solid is collected by filtration, washed with digas methane and dried to obtain a white solid The title compound (0.074 g). Mp 166-168 ...; MS (ESI (+)) m / z 380 (Μ + Η) +, 397 (M + NH4) +; MS (ESI (-)) m / z 378 (MH) ';! H NMR (DMSO-d6) 6 4.06 (s, 2H), 4.54 (AB q, 2H), 4.75 (s, 1H), 4.88 (d, 1H)} 5.03 (d, 1H ), 7.28 (d, 2H), 7.48 (d, 1H), 10.50 (s, 1H).-

CmHhNCUFBi · Analytical calculation 値: c, 50.55; H, 2.92; N, 3 ′ ° 8 ° Measured 値: C, 50.28; H, 3.03; N, 3.61. Example 2 6 • Wire. 9- (3-> 4--4-fluorophenyl) -2 -methyl-2,3,5,9-tetrahydrobranthene 丨 Ltbitr ratio heparin "3,4- el Pyridine-1,8 (4H, 7H) -dione Example 25B product (0.16 g '0_34 mmol) and a 2M solution of methylamine in methanol (3'5 ml' 7.0 mmol) was stirred at a garden temperature of 16 Hours and concentrated. The residue was purified on silica gel (5% followed by 10% methanol in dichloromethane) to give an oil, which was crystallized from ethanol, collected by filtration and dried to give the title compound (0.016 g) as a white solid. MS (ESI (+)) m / z 393 (M + H) +; MS (ESI (-)) m / z 391 (MH) ';' H NMR (DMSO- d6) J 2.81 (s, 3H), 3.98 (d, 1H), 4.03 (s; 2H), 4.15 (d, 1H), 4.50 (AB q, 2H), 4.75 (s, 1H), 7.23 (m) 2H), 7.46 (dd, 1H), 10.11 (s, 1H); -94- This paper size applies to China's national standard specifications (210 x 297 mm) 442485 A7 B7 Printed by Agricultural Consumers ’Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Description of the invention (92)

Ci7HMN203FBr '0.5 H20 Analytical calculation 値: c, 50.76; H, 3.76; N, 6.96. Found 値: C, 50.64; H, 3.66; N, 6.59. Example 2 7 9- (3.Bromo-gas-fluorophenyl) -2,3,5,9-tetrahydroxan # 丨 3,4-blpyrrolo 丨 3_4-e ~ | pyridine-1,8 (4H, 7ID-Diketone Example 25B product (0.22 g, 0.46 mmol) was treated in a metal agitated reactor with a 1: 1 ammonia / methanol mixture (600 ml) at a peripheral temperature for 2 5 days. The solvent was evaporated and the residue was purified by chromatography on silica gel (5% followed by 1% methanol in dichloromethane) to give the title compound as a solid (0026 g). Mp > 260 ° C; MS (ESI (+)) m / z 379 (M + H) +, 396 (M + NH4) +; MS (ESI (-)) m / z 377 (MH) ';' H NMR (DMSO-de) ^ 3.90 (d, 1H), 4.03 (s, 2H), 4.07 (d, 1H), 4.50 (AB q, 2H), 4.75 (s, 1H), 7.19-7.29 (m, 2H), 7.44 (dd, 1H) 5 7.59 (s; 1H ), 10.09 (s, 1H);

Ci6H12N203FBr. 0.5 H20 Analytical calculation 値: C, 49.50; H, 3.38; N, 7.22 = Measured 値: C, 49.34; H, 3.26; N, 7.21. Example 2 8 5- (4-Gas-3-nitrophenyl) -5,10-dihydrodi-9 bases Nan 3,4-b: 4 3-el pyridine-4,6 (7H, 9H ) -Dione tetrahydroanurin-3,5-difluorene (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1169) (0.27 g, 2,4 mmol), 4-gas-3-nitrate A mixture of benzaldehyde (0.54 g, 2.9 mmol) and the product of Example 11C (0.27 g, 2.4 mmol) in ethanol (3 ml) was heated to 80 ° C for 60 hours and allowed to stand in Zhouyuan-95- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) —: lll · — — — — — — — h ^ * i-IIIII '— —If — —--- (Please read first Please fill in this page on the unintentional matter on the back) 442 48 5 Α7 Β7 V. Description of the invention (93) Let the temperature stand for 5 hours. The solid was collected by filtration, washed with ethanol, dissolved in 1: i methanol / digas methane, filtered, heated on a steam bath (replacement of digas methane with formic acid and concentrated the mixture to about 5 ml) and allowed to stand at ambient temperature. Leave for 2 hours. The resulting solid was collected by filtration, washed with methanol and dried to give the title compound (0.061 g). mp > 260 DC; MS (ESI (+)) m / z 377 (M + H) +; MS (ESI (-)) m / z 375 (MH) " H NMR (DMSO-de) ^ 4.06 (s, 4H), 4.51 (AB q, 4H), 5.02 (s, 1H), 7.54 (dd, 1H), 7.68 (d, 1H), 7.79 (d, 1H), 10.18 (bs, 1H); '

Cl7H13N20CI analysis: c: c, 54.20; H, 3.48; N, 7_44. Measured radon: C, 53 · 84; Η, 3.81; N, 7.14. Example 2 9 5-p-cyanofluorenyldihydropiperane "3.4_b: 4 3_el pyridine-4,6 (7Η, 9Η) -dione tetrahydroxan-3,5-di snapper (Terasawa, organic Journal of Chemistry (1977), 42, 1163-1169) (0.27 g, 2.4 mmol), 3-cyanobenzyl (0.54 g '2.9¾ Mol) and the product of Example 11C (0.27 g, 2.4 mmol) A mixture of mol) in ethanol (3 ml) was heated to 80 ec 60 hours, cooled and concentrated. The β residue was purified by chromatography on a syrup (5% methanol in dioxane) to obtain the product. Filter in 1: 5 methanol / digasmethane, concentrate on a steam bath to remove dichloromethane, and leave to stand at ambient temperature for 16 hours. Collect the solid obtained by filtration and wash with methanol and dry to give the title compound. (〇〇62g). -96- This paper is suitable for China National Standard (CNS) A4 (210x297 mm) {Please read the precautions on the back before filling this page) ^ ------- Order --I ------ Line · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Du A7 B7 V. Description of the Invention (94) mp >260T; MS ( ESI (+)) m / z 323 (M + H) +; MS (ESI (-)) m / z 321 (MH) '; NMR (DMSO-d6 ”4.05 (s, 4H), 4.51 (AB q, 4H), 4 99 (s, 1H), 7,48 (m, 1H), 7.54-7.64 (m, 2H), 10.12 plus, 'ih)'; '

CmHm ^ O4 analysis: ，: C, 67.08; H, 4.38; N, 8 69. Measured 値: C, 66.76; H, 4.67; N, 8.56 «Example 3 0 Iodophenyl) -5,10-dihydro-bite ratio -4,6 (7H, 9H) -di gg ^

Example 30A 3-Amino-4-fluorophenylhydrazone 1 3-Amino-4 · fluorobenzoic acid (15 g, 97 mM, & &, 丄 ^. V. · Da Wu) in tetrahydrofuran at 0 C was treated with 1.0 mM boron pit-tetrahydrofuran complex (50 ml), stirred overnight in the room, and then treated with 130 ml of 1.0 M shed dry-tetrahydrofuran complex, stirred for 10 hours, The reaction was stopped by adding methanol, stirred at room temperature for 3 hours, concentrated and partitioned between aqueous sodium hydrogen carbonate solution and dichloromethane. Separation—chloromethane layer, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate / hexanes 1: 1) to give 7.0 g of the title compound. '* H NMR (CDCI3) cf 4.58 (s, 2H), 6.67 (br m, 1H) 6 81 1H), 6.95 (t, 1H) «(df Example 30B 4-fluoro-3-iodobenzyl alcohol Example 3 〇A product (7.0 grams, 50 millimoles) in water (loo milliliter) between 0 -97- This paper size applies to China Standard S (CNS) A4 specifications (210 * 297 mm) I — II — I — I — —— I '仏 .--- I — II! 1111111 (Please read the notes on the back before filling out this page) 442 4 8 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Note (95) C is slowly treated with concentrated sulfuric acid (30 ml) at a rate to maintain the temperature below 10 X followed by dropwise treatment with sodium nitrite (3.45 g, 50 mmol). This solution is then added to potassium iodide ( 8.13 g of a solution of 50 mol) in water (15 ml), heated to 60 ° C for 2 hours, cooled and extracted with dichloromethane. The dichloromethane layer was washed with 10% sodium hydroxide, Washed with 1 M sodium thiosulfate, washed with 10% hydrochloric acid, washed with aqueous sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated. The residue was subjected to flash chromatography on silica gel (ethyl acetate / hexane 7: 3) Purification yielded 6.4 g of the title compound. LH NMR (CDC13) ^ 1.69 (t, 1H), 4.66 '(d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H)-

Example 30C The product of Example 4B, 4-fluoro-3-Linyijia, 30B (6.4 g, 26 mM) was treated with short dioxide (4.5 g '50 mM) in aerobic simulation (300 mL), and stirred Overnight, an additional portion of nitric oxide (2.25 g) was processed to 'search and mix overnight and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate / hexane: 4) to obtain 9 g of the title compound. H NMR (CDC13) δ 7.23 (t, 1H), 7.89 (m, 1H), 8.32 (dd, 1H), 9.91 (s, 1H).

Example 30D 5 Bis (4.-fluoro-3-methylphenyl) -5; 10-trihydro · ιΗ < 3Ηdipiperan # 丨 3 4-b: 4J_el pyridinedione 30% purity Example 11B product ( Tetrahydropiperan_3,5_dione) (Terasawa, Journal of Organic Chemistry (1977), 42,1163-1169) (0.365 g, 2.4 mmol-98-This paper is in accordance with China National Standard (CNS) A4 (21〇X 297 public love) C Please read the notes on the back before filling in this page}

^ "F ------ Order -------- I 4 42 4b 〇A7 __ B7 V. Description of the invention (96) ears) Example 30C product (0.20 g, 0.80 mmol) and examples A mixture of UC product (0,090 g, 0 80 mmol) in ethanol (2 ml) was treated as in Example 29 to give the title compound (0.087 g) as a white solid a mp > 260 ° C; NMR ( DMSO-d6) δ 4.05 (s, 4H), 4.50 (AB q, 4H), 4.90 (s, 1H), 7.15 (t, 1H), 7.20 (m, 1H), 7,57 (dd, 1H), 10.10 (bs, 1H): MS (ESI (+)) m / z 442 (M + H) +; MS (ESI (-)) m / z 440 (MH) ';' C17H13N04FI analysis calculation 値: c, 46.28 H, 2,97; N, 3.17. Measured radon: C, 45.38; H, 3.68; N, 2.91. Example 3 1-Hydroxyphenyl) -5,10-dihydro-1H, 3H-dipiperan 幷 f3_4'b: 4 3 · 6ΐ pyridine-4,6 (7Η, 9 二) -dione, employee of Intellectual Property Bureau, Ministry of Economic Affairs Consumer Cooperative Seal * J ^ Example 11B product with 30% purity (tetrahydropiperan-3,5-dione; j (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1 169) (0.81 g, i 7 MM) '5-bromosalicylaldehyde (0.43 g' 2.2 mol) and the mixture of the product of Example 11C (0.20 g '1.7 mol) in ethanol (4 ml) was heated to 80.60 hours Then, it was left to stand at the solid temperature for 4 hours. The obtained solid was collected by filtration, washed with ethanol and dried to obtain the title compound (0.12 g).

mp > 260 ° C MS (ESI (+)) m / z 392 (M + H) +; MS (ESI (-)) m / z 390 (MH) '; »H NMR (DMSO-d6) d 4.03 (s, 4H), 4.48 (AB q? 4H) 4 93 (s -99- This paper size applies to Chinese national standard < CNS) A4 specification (210 X 297 mm) 442485 A7-B7 Intellectual Property Bureau of Ministry of Hydrocarbons Printed by employee consumer cooperatives 5 Take the fifth, invention description (97) 1H), 6.66 (d, 1H), 7.07-7.15 (m, 2H), 9.50 (s, 1H), 10.09 (bs, 1H); CpHuNOsBr analysis and calculation 値: C, 52.06; H, 3_60; N, 3.57. Measured radon: C, 51 · 81; H, 3.45; N, 3.48. Example 3 2 5-"4-Fluoro-3bis (trifluoromethyl) phenylμ5, ι〇-Diargondipiperan 幷 3,4-b: 4,3-el pyridine-4,6 (7H , 9H) -diketone 30% purity Example 1 1 B product (tetrahydroxan-3,5-second brew 1) (Terasawa, Journal of Organic Chemistry (1977), 42,1163-110) (0.81 g, 1.7 millimoles), 4 ~ bromotrifluorofluorenyl) benzaldehyde (0.42 g, 2.2 millimoles) and the mixture of the product of Example 11C (0.20 g, 1'7 millimoles) in ethanol (4 ml) as in the example The title compound (0.12 g) was obtained as a white solid (mp.> 260 ° C; MS (ESI (+)) m / z 3B4 (M + H) +, 401 (M + NH4) +; MS (ESI (-)) m / z 382 (MH) '; lH NMR (DMSO-d0) d 4.06 (s, 4H), 4.51 (AB q, 4H), 5.01 (s, 1H), 7.40 (t, 1H), 7.52 (d, 2H), 10.11 (bs, 1H); C18H13N04F4 analysis and calculation 値 · c, 56.40; H, 3.42; N, 3.65. Measured 値 ·· C, 56.13; Η, 3.62; N, 3.45. Example 3 3 5- (3,4-Difluorophenyl), 5,10-dihydro_1trans311-dipiperan # "3.4-13: 4,3-4pyridine-4,6 (7H, Example 9B product of 9HV diketone 30% purity (tetrahydrop citralan_3,5_dione) (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1169) (0.81 g, 1.7 mmol • 100 -(Please read the back of the page; I will fill in this page first) -------- Order --------- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 442 4 6 5 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (98) ears, 3,4-digas benzamidine (0.39 g, 2'2 millimoles) And a mixture of Example UC product (0.20 g, 1.7 mmol) in ethanol (4 ml) was treated as in Example 31 to give the title compound (0.15 g) as a white solid. Mp > 260 ° C; MS (ESI ( +)) m / z 3 66 (M + H) +, 383 (M + NH4) + MS (ESI (-)) m / z 364 (MH) ·; * H NMR (DMSO-d6) ά 4.05 (s , 4H), 4.50 (AB q, 4H), 4.94 (s, 1H), 7.19 (dd, 1H), 7.36 (d, 1H), 7.53 (d, 1H), 10.12 (bs, 1H). C17H13N04C12. 0.375 C2H6O analysis and calculation: C, 55.60; H, 4.01; N, 3.65 »Measured erbium: C, 55.21; H, 3.64; N, 3.36» Example 3 4 5- (2 丄 3-Benzamidine, No. diazol-5-yl) -5,10-dihydro-1Η, 3Η · Dipiperano-3.4-b: 4,3-e ~ | Hampi Bite-4,6 (7H, 9H) -Dihydrotetrahydropiperan-3,5-dione (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1169) (0.27 g, 2.4 mmol), 2,1,3-benzopyridazol-5- 曱 ^ (Gasco, AM Eur. J. Med. Chem. Chim. Ther. (1996), 31, 3-10) (0.54 g, 2.9 mmol) and the product of Example 11C (0.27 g, 2.4 mmol) in ethanol. (3 ml) was treated as in Example 29 to obtain The title compound as a solid (0.088 g). Mp > 260 OC; MS (ESI (-)) m / z 338 (MH) '; NMR (DMSO-d6) ^ 4.08 (s, 4H), 4.54 (AB q , 4H), 5.06 (s, 1H), 7.61 (m, 2H), 7.79 (d, 1H), 10.23 (bs, 1H); -101-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm), hip t ^ i «Ί —r- I. nnn ϋ I n If I 1 ϋ nn 一 -βι II— ϋ i] I (Please read the precautions on the back before filling out this page) 442 48 5 A7 ______B7____ 5. Description of the invention (99) C ”H13N3〇5. 0. 5 Analysis and calculation of C2HeO 値: c, 59.15; H, 4.26; N, 11.83. Found 値: C, 59.09; H, 4.32; N, 11.99. Example 3 5 5bis (5-nitro-2- »sedenyl) -5'10-difluorene-ih, 3H-dioxan # [3,4-b: 4,3-el pyridine-4.6 ( 7H, 9H) -diketone Example 30B Purity Product (Tetrahydrotripan · 3,5-dione) (Terasawa, Journal of Organic Chemistry (1977), 42, 1163-1 169) (0.60 g, 1 · 3 millimoles) '5-nitro-2-carboxaldehyde (0.25 g, 1.6 millimoles) and a mixture of the example product (0.15 g, 1.3 millimoles) in ethanol (3 milliliters) as in Example 2 The title compound was obtained as a solid (0.087 g). MS (ESI (+)) m / z 366 (M + NH4) +; MS (ESI (-)) m / z 347 (MH) ';' H NMR (DMSO-d6) ά 4.10 (dd, 2H), 4.17 (d, 2H), 4.52 (AB q, 4H), 5.22 (s; 1H), 6.86 (dd, 1H), 7.93 (d, 1H), l0-35 (s, 1H); C15H12N206S. 0.25 H20 0.25 C2H60 analysis and calculation 値: C, 51.10; H, 3.87; N, 7.69. Found 値: C, 51.04; H, 3.92; N, 7.41. Example 3 6 5 彳 5-Nitro-3-pyridinyl V5,10 · dihydro · 1Η, 3Η-dipiperanopyridine-4,6 (7H, 9H) -dione Example 30% purity (Tetrahydropiperan-3,5-dione) (Terasawa, Journal of Organic Chemistry (1977), 42, 1 163-1 169) (0.60 g, 1.3 mmol

Ear), 2-nitropyrimidin-4-carboxaldehyde (0.25 g '1.6 mmol) and Example 11 C -102- _ This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) ( Please read the notes on the back before filling out this page) • 4 * 111 ---- Order · ί — — · 丨 — I- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy f «+ q- q. Ο u442485 A7 _ B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. V. Invention Description (100) A mixture of the product (0.1 5 g '1.3 mmol) in ethanol (3 ml) was treated as Example 29 to obtain the solid title compound ( 0.084 g). mp > 260 ° C '· MS (ESI (+)) m / z 366 (M + NH4) +; MS (ESI (-)) m / z 347 (MH)';] H NMR (DMSO-d6) d 4.09 (AB q, 4H), 4.50 (AB q, 4H), 5.01 (s, 1H), 7.58 (d, 1H), 7.76 (d, 1H), 10.15 (bs, 1H); C | 5H | 2N2 〇6S. 0.25 H20 Analytical calculation 値: C, 51.06; h 357; N 7.94. Found 値: C, 51.33; H, 3.78; N: 7.57. Example 3 7 Pyridine-8 (7HV ketone 1,1-dioxide I Example 37A9- (3_-bath-4-fluorophenyl) -8-oxo-2,3,5,7,8,9-six-1 -4 only, Lu Nan 幷 "3,4- 乜 1 乜 phen_ 幷 丨 2,3-el pyridine_4 · Third butyl formate ···" _ dioxide Example 12C product (0.040 g, 0.096 mmol Ear), a mixture of tert-butyl dicarbonate (0'12 g, 0.55 mmol) and 4-dimethylaminopyridine (0.0020 g, 0.016 mmol) in acetonitrile (3 ml) and stirred at ambient temperature 2 hours and concentrated. The residue was purified by chromatography on gel (2: 1 followed by 1: 1 hexane / ethyl acetate) to give the title compound (0,035 g), which crystallized after standing. MS (ESI (+)) m / z 531 (Μ + ΝΗ4) +. Example 3 7B Fluoro-3 _- (trimethylstannyl) phenyl 1-8-oxo_13.5,7,8,9-hexahydro-4Η-1 # · Nan 丨 3,4-blp thiophene 幷 "2,3-el ρ ratio bite-4-carboxylic acid third butyl ester 1, bu di-103- ---: --------- > -------- Order --------- line (Please read the precautions on the back before filling this page) This paper size is applicable to the national standard (CNS) A4 specification (210x297 mm) ) 442485 A7 _- _B7_ V. Description of the invention (101) Product of oxide example 37A ( · 035 g, 0.068 mmol) in anhydrous ^ Renji. A mixture of No. 2 (1 ml) was treated with hexamethyltin (〇14 ml, 0.05 mmol) in nitrogen to (Triphenylphosphine) palladium (〇) (0.050 g, 0.0043 mmol) treated 'stirred at 100 ° C for 1 hour, cooled to ambient temperature and concentrated. The residue was chromatographed on silica gel (3 j Hexane / ethyl acetate) purification gave the title compound (0.031 g) 'which crystallized upon standing. MS (ESI (+)) m / z 598 (M + H) +.

Example 37C g- (4-.Air moth phenyl) -2,3,5,9-tetrahydro-4H-pirane 幷 3.4-hl 忒 L ?, 3-el pyridone M-digaside Example 37B A mixture of the product (0.023 g, 0.038 mmol) in 1% acetic acid in methanol (25 ml) was treated with N-gassuccinimide (〇ο〗 〇g, 0.077 mmol) ) Treatment 'followed by treatment with sodium sulphate (0.011 g, 0.077 mmol) and stirring for 10 minutes' to grind sodium thiosulfate pentahydrate (200 g, 0.080 mmol) ) Work up, stir for 10 minutes and concentrate to dryness. The residue was treated with trifluoroacetic acid (3 ml) 'and stirred at ambient temperature for 15 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 ml), heated gently on a steam bath for 1 minute, cooled to ambient temperature and concentrated to dryness. The residue was chromatographed on silica gel (containing 2% methanol followed by 5% methanol). (Methane) to give the title compound (0.0156 g). mp &gt; 260 ° C; MS (ESI (-)) m / z 460 (MH) '; NMR (DMSO-d6) β 2.77-2.90 (m, 1H), 3.01-3.14 (m, 1H), -104 -This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) (Please read the precautions on the back before filling this page) ^ -------- Order ------- --Line—Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 42 4 8 5 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (10.2) 3.32-3.43 (m, 2H), 4.02 (s, 2H), 4.49 (AB q, 2H), 4.87 (s, 1H), 7.16 (t, 1H), 7.24 (m, 1H), 7.59 (dd, 1H), 10.13 (bs, 1H); C16H13N04SFI Analytical calculations: C, 41, 66; H, 2.84; N, 3.04. Measured radon: C, 41.28; H, 2.79; N, 2.87. Example 3 8 5- (3-Chloro-4-aminophenyl) -2,3,5,7,8,9-hexahydro-111-cyclopentane <^ &gt; 1 丨 1,7: | benzene Example of pyridin-4,6-dione hydrochloride 38A 2-benzyl-5- (3-fluoren-4-fluorophenyl) -213,5,7,8,9 "hexahydro-11 ^ -cyclopentane Alkyl "1) 1 [1,71 pyridine-4,6-dione 3-amino-2-cyclopenten-1-one (Kikani, BB, Synthesis (1991), 2, 176) (0.78 g , 8 mmoles), 3-gas-4-fluorobenzaldehyde (1.12 g, 8 mmoles) and N-benzylhexahydropyridine-3,5-dione (Ziegler, Journal of the American Chemical Society (1973) , 95, 7458-7464) (1.78 g, 8 mmol) in ethanol (8 ml) was treated as in Example 5A to give 1.8 g of the title compound. MS (ESI (-)) m / z 421 (MH) '; lH NMR (DMSO-d6) ^ 2.3 (m, 2H), 2.5-2.72 (m, 2H), 3.07 (Abqu, 2H), 3.5 (m , 2H), 3.67 (s, 2H), 4.65 (s, 1H), 7.15 (s, 1H), 7.42 (m, 7H), 10.28 (s, 1H). Example 38B 5 · (3-Gas-4-fluorobenzyl) -4,6-dioxo-1,3,4,5,6.7.8.9-octadecane-2! 1-oxane hydrazone [bin. 71 pyridine-2-carboxylic acid (lR, 2S, 5R) -5-methyl-2-α-methylphenylethyl) cyclohexyl ester Example 38A product (1.8 g, 4.3 mmol) as in Example 5B Processed 0.2 -105- ------------- ^ -------- Order --------- Line 1 (Please read the precautions on the back before filling (This page) This paper is in accordance with the Chinese national standard (CNSM4 specification (210 X 297 mm) 442485 A7

5. Description of the invention (103) grams of the title compound with less polar isomers. MS (ESI (-)) m / z 589 (M-H) '〇

Example 38C 5- (3-1 ^ -4-1, ^ &amp;)-2? 375? 778? 9- ^ γ_4 ^ ιΗ _ ^^ fbiri.7l ^ pyridin-4,6 ~ dione Example 38B product (0.2 G, 0.33 mmol) was treated with 48% hydrogen bromide in acetic acid (4 ml), stirred for 72 hours, neutralized with concentrated ammonium hydroxide, and extracted with methane (3x). The combined organic layers were dried (Na2SO4;), filtered and concentrated. The residue was purified on silica gel (10% ethanol / ammonia-saturated methane) to give the title compound (0.03 g) 'which was converted into the HC1 salt. MS (ESI (-)) m / z 331 (MH) '; Ή NMR (DMSO-d6) 2.28 (t, 2H), 2.52-2.7 (m, 2H), 3.18 (s, 2H), 3.6 (m, 2H), 4.68 (s, 1H), 7.2 (m, 1H), 7.23 (t, 1H), 7.32 (dd, 1H), 10.18 (s, 1H);

CnHMNsFCIO〗 · HC1 _ 2H20 Analysis and calculation 値: c, 50.49; H, 4.51: N, 6.73. Found 値: c, 49.52; H, 4.26; N, 6.09. Example 3 9 9- (3-Bromo_4-di | benzene_4) -5,6,7,9

Example of 1,8 (3H.4HV dione hydrochloride 39A 7-fluorenyl-4- (h bromo-4-fluorophenyl) _2-methyl-5-oxo-1.4.5,6,7,8 -Hydrogen "1,71 articles: Pyridin-3-carboxylic acid methyl acetate 3-aminocrotonic acid methyl ester (0.58 g, 5 mmol), 3-bromo-4-fluorobenzaldehyde (1_0 g '5 mmol Mol) and N-benzylhexahydropyridine-3,5-dione (Ziegler, -106-) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the note on the back first Please fill in this page for more information) i ------ Order --------- line — printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed A7 B7 Instructions (104) Journal of the American Chemical Society (1973), 95, 7458-7464) (1.1 g, 5 mmol) in ethanol (5 ml) in a sealed tube. Heat to reflux for 24 hours and concentrate. Residue The title compound (1.3 g) was obtained as a yellow foam by dissociation and purification on silica gel with 5% ethanol / digas methane. MS (ESI (-)) m / z 467 (M-Η)-.

f Example 39B ^! _ benzyl-9- (3-bromo-4-fluorophenyl) -l6,7 8 • tetrapyran 弁 n “⑴ 丨 丨 7】 zidine-1,8 (3H, 4H )-A solution of the product of diketone Example 39A (3.1 g, 6.3 mmol) in chloroform (50 ml), cooled to 0 ° C, and treated with 90% pyridinium tribromide (245 mg, 69 mmol), Warm to ambient temperature, stir for 16 hours and wash with water. Separate the gas-imitation layer, dry (MgS04), filter, reflux! 6 hours and cool in an ice bath. Collect the resulting precipitate by filtration and dry to obtain the title of brown crystals Compound (2) g. MS (ESI (-)) m / z 467 (MH) ';! H NMR (DMSO-d6) 3.08 (AB q, 2H), 3.5 (d, 2H), 3.65 (d 2H ), 4.7 (s' 1H) '4.9 (AB q, 2H), 7.3 (m, 7H), 7.47 (m iH) 10.1 (1H).'),

Example 39C 2- (3-Bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuran gg π] 萁 咗 1,8 (3Η · 4Η) -dione hydrochloride Example 39B product (0.35 g, 0.75 mmol) was treated in digasmethane (10 ml of the solution was treated with vinyl formate (0_1 ml, 2 mmol), stirred at ambient temperature for 16 hours, concentrated to dryness, and Ethanol (丨 〇mL) treatment, to -107- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm). ». -4 ---------- order ---- ----- Line 丨 (Please read the precautions on the back before filling in this page) A7 442485 _ B7__-V. Description of the invention (105) 6NHC1 (3ml) Treatment refluxed for 5 hours and concentrated to dryness. The product was purified on silica gel (10: 90: 1 ethanol / digas methane / saturated ammonium hydroxide) to obtain the title compound (0.08 g), which was converted into the HCI salt. (-)) m / z 377 (MH) ';' H NMR (DMSO-d6) 3.2 (s, 2H), 3.62 (s, 2H), 4.7 (Sj 1H) 4.83 (d, 1H), 4.99 (d , 1H), 7.27 (m, 2H), 7.49 (dd, 1H), 1025 (s, 1H) »S 'CMHnNJBrCh' HCI. 0.5 C2H5OH Analytical calculation 値: c, 46 65; H, 3 .45; N, 6.40. Found 値: C, 46.99; H, 3.69; N, 6, 42. Example 4 0 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuran幷 丨 3,4-1 &gt; 1 丨 1.71Pyridine- 丨 一

Example of 1,8 (3H, 4H) -dione hydrochloride 40A 9- (3-bromo-4-fluorophenyl) -1,8-dioxo-1,4,5,7.8,9-hexahydro Furan # ί &gt; 1Γ1,71 Naphthyridine-6 (3H) -formic acid (lR.2S.5R) -5-methyl-2- (1, methyl, ethyl --- mono-) cyclohexane acetate A solution of the 39C product (1.46 g, 2.13 mmol) in tetrahydrocran (70 ml) with 8-phenylmethanol vinegar (eg Yamamoto, Y., Journal of the American Chemical Society (1992), II4, 121- Treated as (125) (made from (-)-8-phenylmethanol) (1.1 g, .3 74 mmol), refluxed for 36 hours, filtered to remove unreacted starting materials and concentrated. The residue was purified on silica gel (9: 9: 2 dichloromethane / ethyl acetate / hexane) to give the less polar diastereomeric title compound (0.46 g). -108- This paper size applies to Chinese National Standard (CNS) A4 (2) 0 X 297 mm. F Jing first read the precautions on the back before filling out this page} ------- Order ----- ---- Printed by the Employees 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by 442485 A7 _B7_______ V. Description of the invention (106) MS (ESI (-)) m / z 635 (M -Η) ·.

Example 40B 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuran # 丨 3.4- | ^ [1,71 pyridine-1,8 (3H, 4H) -dione hydrochloride鞔 Example 40A product (0.4 g '0.63 mmol) treated with 48% hydrobromic acid (0.5 ml) in acetic acid (2 ml), heated to 60 ° C for 5 hours, cooled to ambient temperature, and saturated with hydrogen Neutralize with ammonium oxide and extract with aerosol (10 mL). The organic layer was dried (MgSOO 'filtered and the residue was concentrated on silica gel (20: 80: 1 ethanol / digasmethane / saturated ammonium hydroxide) to obtain unreacted starting material (0,21 g) and the title. Compound (0.05 g), which was converted to the HC1 salt. MS (ESI (-)) m / z 379 (MH) '; 4 NMR (DMSO-d6) (free base) d 3.25 (s, 2H), 3.68 (s, 2H), 4.7 (s, 1H), 4.85 (d, 1H), 4.98 (d, 1H), 7.28 (m, 2H), 7.5 (dd, 1H), 10.23 (s, 1H);

CieHiiN2BrF03. HC1 · H20 Analytical calculation 値: c 44 42; H 3.26; N, 6.47. Measured radon: C, 44.74; H, 3.93; N, 6.51. Example 4 1 5-fluoren 3-bromo-4-fluorophenyl) -7,7-dimethyl-5,8,9,10-tetral-fluorene-sulfuranf3,4-bl quinoline- 4,6 (3Η, 7Η) -difluorene example lie product (0.16 g '1.4 mmol), 3-bromo_4-benzaldehyde (0.29 g' 1.4 mmol), 4,4-dimethyl A mixture of -1,3-cyclohexanedione (20 g '1.4¾ mol) and ethanol (18¾ liter) was heated to 60 hours, cooled, concentrated to give an oil and 3: 1 ethanol / The second puzzle is scattered (3χ). -109- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) J ------------ .4 -----.--- Order --- ------ Line · (Please read the precautions on the back first and fill in this page) 4 4248 5 A7 -------- B7______ V. Description of the invention (107) The solid obtained is dried to give a yellow solid The title compound (0 11 g). mp &gt; 260 aC; (Please read the notes on the back before filling this page) MS (DCI / NH3) m / z 420 (M + H) +; * H NMR (DMSO-d6) d 9.76 (br s, 1H), 7.38 (dd, 1H, J = 6.8, 2.0 Hz), 7.24-7.13 (m, 2H), 4,88 (s, 1H), 4.46 (AB q5 2H, JAB = 11.2, dvAB = 15'9 Hz), 4.01 (s, 2H), 2.68-2.48 (m, 2H), 1-78 (t, 2H), 0.98 (s, 3H), 0.93 (s, 3H); 13C NMR (DMSO-d6) β 199.7, 191.2, 155, 9, 149.9, 144 5, 131.9, 128.5, U6.2, 110.1 '108.6, 10'2' 107.0, 71.2, 63.2, 39.6, 34.0, 31.4, 24.7, 24.0, 23.1; C20H19BrFNO3 Analytical calculation 値: c, 57.16: H, 4.56; N, 3.33. Measured 値 · C, 57.10; Η, 4.70; N, 3.19. Example 4 2 [9R) -9- (3-Bromo-4-fluorenyl 1) -5,9-di III-3 fluorene-pyran # r3,4-bl Meow [4,3-e] pyridine-1, 8 (4H, 7HV diketone, Intellectual Property Bureau, Ministry of Economic Affairs, Employees' Cooperatives, printed Chiralpak AS column (5.0 cm inside diameter, 50 cm length, 20 micron packing) on 80:20 hexane: ethanol flow rate Enantiomers of Example 25C were separated by palladium chromatography at 117 ml / min as mobile phase. A total of 227 mg in 100 ml of hot ethanol (three injections of 20 ml, 40 ml and 40 ml) The faster-moving isomer was purified by chromatography on silica gel using dichloromethane with 1% -2% and 5% methanol to give the title compound (0.080 g). MS (ESI (+)) m / z 380 (M + H) +, 397 (M + NH4) +; MS (ESI (-)) m / z 378 (MH) '; -110- This paper size applies to China National Standard (CNS) A4 (210 x 297) (Mm) 4 4248 5 Printed by A7, Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs 5. Description of the invention (108) iH NMR (DMSO-d6 ”4.06 (s, 2H), 4.54 (AB q, 2H), 4.75 ( s 1H), 4.88 (d, 1H), 5.03 (d, 1H), 7.28 (d, 2H), 7.48 (d, 1H) 10.50 (s, 1H); '

CisHnNC ^ FBr _ 0.1875 CH2CI2 Analytical calculation 値: c, 49 〇9; H 2.89; N, 3.54. Found 値: C, 49.11; H, 2.93 U17. '' Multiple example 4 3 (9S) -9-(_ 3-Rabbit-4-fluorophenyl) -5,9 di ^ -3H_furan # 丨 3 into u 0,3-el pyridine-1,8 (4Η 7))-Diketone Example 42 The slower shifting isomer in the procedure described in Example 2 gave the title compound (0.080 g). MS (ESI (+)) m / z 380 (M + H) +, 397 (M + NH4) +; MS (ESI (·)) m / z 378 (MH) .; NMR (DMSO-d6) d 4.06 (s, 2H), 4.54 (AB q, 2H), 4.75 (s 1H); 4.88 (d, 1H), 5.03 (d, 1H), 7.28 (d, 2H), 7.48 (d, 1H), 10.50 ( s, 1H);

Cl6HuN04FBr * 0.125 CH2Ci2 * Analytical calculation: c, 49.56; h 2.90; N, 3.58. Found 値: C, 49, 54; H, 3.07; N, 3.27. Example 4 4 10- (3-Gas-4-fluorophenyl) -3,4,6,10-tetrahydro-211-sulfanyl [3-4- | 31, 1,61 (5H, 8H) -dione Example 11C Product (0.023 g, 0.2 mmol), Hexahydropyridine-2, Cardiodione (Nakagawa, S., Heterocyclic (1979), 13, 477-495) (0.23 G, 0.2 mmoles), 3-gas-4-fluorobenzaldehyde (0'032 g, 0.2 mmoles), and ethanol (2 ml) were heated at 80 ° C for 60 hours and cooled to ambient temperature. Over 111 paper sizes are applicable to China National Standard (CNS) A4 specifications (210 X 297 public love) J .--------- ^ -------- Order -------- -Line — C Please read the notes on the back before filling in this page) 44248 5 Economy Zou Intellectual Property Bureau Printed by the Consumer Cooperative A7 B7 V. Description of the invention (1Q9) The solids collected by filtration, washed with ethanol and dried in the air The title compound was obtained: · MS (APCI (+)) m / z 349 (M + H) +; MS (APCI (-)) m / z 347 (MH) ';' H NMR (DMSO-d6) ό 2.34- 2.57 (m, 2H), 3.13-3.28 (m, 2H), 4.00 (s, 2H), 4.45 (AB q, 2H), 4.96 (s, 1H)) 7.08 (d, 1H), 7.17 (ddd, 1H ), 7_26 (t, 1H), 7.28 (dd, 1H), 9.55 (s, 1H). Examples 4 5 10- (3,4-dichlorophenyl) -3,4,6,10-tetrahydro-211- &gt; diran # f3.4-bin, 61g_ Example 1C of pyridinedione is like Example 4 4 Treated, but replaced 3,4--4-benzylhydrazone with 3,4-digas benzyl to obtain the title compound. MS (APCI (+)) m / z 365 (M + H) +; MS (APCI (-)) m / z 363 (MH) ';' H NMR (DMSO-d6) d 2.36-2.58 (m, 2H), 3.14-3.26 (m, 2H), 4.00 (AB q, 2H), 4.45 ( AB q, 2H), 4.96 (s, 1H), 7.09 (d, 1H), 7.17 (dd, 1H), 7.34 (d, 1H), 7.49 (d, IH), 9,57 (s, 1H). Example 4 6 10- 丨 4-Gas-3- (trifluoromethyl) phenyl 1-3,4,6,10-tetrahydro-2H-slightlyn 幷 3,4-bm, 61 Phenidine-1 , 9 (5H, 8H) -dione Example 11 C was treated as in Example 44 except that 4-chloro-3- (trifluoromethyl) benzaldehyde was used instead of 3-gas-4-fluorobenzaldehyde to obtain the title compound . MS (APCI (+)) m / z 399 (M + H) +; MS (APCI (-)) m / z 397 (MH) '; -112- This paper standard uses Chinese National Standard (CNS) A · ! Specifications (210 X 297 mm)

Lk -------- Order --------- line-f Please read the notes on the back before filling out this page} 44248 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (11〇) 'H NMR (DMSO-d6) c? 2.36-2.58 (m, 2H), 3.15-3.26 (m, 2H), 4.00 (AB q, 2H), 4.45 (AB q, 2H), 5.02 (s, 1H), 7.11 (s, 1H), 7.46 (dd, 1H), 7'59 (d, 1H), 7.63 (d, 1H), 9.60 (s, 1H). Example 4 7 10- (4-Ga-3-t-phenylphenyl) -3,4,6,10-tetrahydro-2! 1-Xanan 幷 3_4_] 31 [1,61 pyridine-1,9 (5H, 8H) -diketone Example 11C was treated as in Example 44 except that 4-gas-3-nitrobenzyl was used instead of 3-gas-4-fluorobenzaldehyde to obtain the title compound. MS (APCI (-)) m / z 374 (MH) '; XH NMR (DMSO-d6) ^ 2.42-2.57 (m, 2H), 3.16-3.30 (m, 2H), 4.01 (AB q, 2H), 4.46 (AB q, 2H), 5.03 (s, 1H), 7.12 (d, 1H), 7.52 (dd, 1H), 7.64 (d, 1H), 7.76 (d, IH), 9.62 (s, 1H) 0 Example 4 8 10- (3,4-monobenzyl) -3,4,6,10-tetrahydro-2! 1-pyranosine [3,4_5] | ~ 1,61 theanidine dione Example 11C Treated as in Example 4 but replacing 3_a-4-fluorobenzaldehyde with 3,4-diphenylbenzene to give the title compound. MS (APCI (+)) m / z 453 (M + H) +; MS (APCI (-)) m / z 451 (MH) '; * H NMR (DMSO-d6) ά 2.41-2.57 (m, 2H ), 3.18-3.26 (m, 2H), 4.00 (AB q, 2H), 4.45 (AB q, 2H), 4.93 (s, 1H), 7.09 (bs, 1H), 7.12 (dd, 1H), 7.49 ( d, 1H), 7.61 (d, 1H), 9.56 (s, .1H) 0 Example 4 9 10- (5-nitro-3-distenyl) -3'4,6,10-tetrahydro-2H -Piran 弁 丨 3,4-bl 『l, 61 This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) ------------ ^ ------ --Order · -------- Lines &lt; Please read the notes on the back before filling out this page) 4 4248 5 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (111) Ethylidine-1.9 [5Η, 8Η) -dione Example 11C was treated as in Example 44. However, 5-nitroporphine-3_formaldehyde was used instead of 3-gas-4-fluorobenzoic acid to obtain the title compound. MS (APCI (+)) m / z 348 (M + H) +; MS (APCI (-)) m / z 346 (MH) ';' H NMR (DMSO-d6) d 2.39-2.54 (m, 2H ), 3.19-3.30 (m, 2H), 4.02 (s, 2H), 4.42 (AB q, 2H), 5.00 (s, 1H), 7.09 (d, 1H), 7.48 (d, 1H), 7.75 (d , 1H), 9.69 (bs, 1H) »Example 5 〇g —- (3-Ao-4-fluorobenzyl V5,8,9,10-tetra-I.-1H-thiopyran 4,6 (3H, 7m-diketopan-3,5-dione (Fehnel, EA ·, Journal of the American Chemical Society (1955), 77, 4241-4244) (0.12 g, 1.0 mmol), 3-bromo · 4-fluorobenzene A mixture of formaldehyde (0,20 g, 1.0 mmol), 3-amino-2-cyclohexene-1-fluorene (0u g, j 0 mmol) and ethanol (5 ml) was heated in a sealed tube To 80.60 hours and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and dried in the air for 16 hours to give the title compound (01 3 g). MS (APCI (+)) m / z 408 (M + H) +; MS (APCI (-)) m / z 406 (MH) '; * H NMR (DMSO-d6) ^ 1.77-1.88 (m, 1H), 1.89-1.98 (m, 1H), 2.25 (dd, 2H), 2.46-2.62 (m, 2H), 3.10 (dd, 1H), 3.48 (ddd, 2H), 3.82 (d, 1H), 4.96 (s, 1H), 7.15-7.24 (m, 2H), 7.41 (dd, 1H), 9.71 (s , 1H);

CuHuBrFNOsS analysis and calculation 値 · C, 52.95; H, 3.70 u 43. -114- This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 1I1-IIII1 — — — — — — — — — — — — Order. 1111—Ϊ (Please read the notes on the back first Please fill in this page again for matters) 4 42 4 8 5 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (112) Actual measurement: C, 52.81; H, 3.79; N, 3.17. Example 5 15- (3 ~ bian-4 -gasylphenyl) -5,7,8,9 -tetrazine; pentamidine [~ b〗 Tr celan 幷 丨 4,3-e ~), bite -4,6 (1H, 3H) -Difluorene 11Selenium-3,5-Difluorene (Fehnel, EA, Journal of the American Chemical Society (1955), 77 4241-4244) (0.12 g, 1.0 mmol) ) Treated as in Example 50, except that 3-amino-2-cyclopentan-1-one was substituted for 3-amino-2-cyclohexyl-1-fluorene to obtain a solid. The solid was purified by chromatography on silica gel with 1: 1 acetone: dichloromethane to give the title compound (0.13 g). 'MS (APCI (+)) m / z 394 (M + H) +; MS (APCI (-)) m / z 392 (MH) *; lH NMR (DMSO-d6) ^ 2.28 (t, 2H); 2.48-2.73 (m, 2H), 3.14 (dd, 1H), 3.47 (dd, 1H), 3.54 (dd, 1H), 3.82 (dd, 1H), 4.72 (s, 1H), 7.18-7.25 (m, 2H), 7.42 (dd, 1H); 10.27 (s, 1H); Ci7H 丨 3N02SFBr analysis and calculation 値: C, 51.79; H, 3.32; N, 3.55. Found 値: C, 51.46; H, 3.49; N, 3.39. Example 5 2 10- (3-Bromo-4-fluorophenyl) -3,4,6,10-tetrahydro-2H-piranofluorene "3,4-blH, 61 Example 1C as Example 4 It was treated as usual, but 3-bromo-4-fluorobenzaldehyde was used instead of 3-gas-4-fluorobenzaldehyde to obtain the title compound (0.79 g). MS (APCI (+)) m / z 393 (M + H ) +; MS (APCI (-)) m / z 391 (MH) *; 'H NMR (DMSO-d6) δ 2.38-2.60 (m, 2H), 3.18-3.26 (m, 2H), -115- J — · --------— I— -------- t --------- I (Please read the notes on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 442485 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (113) 4.00 (s, 2H), 4.45 (AB q, 2H), 4.95 (s, 1H), 7,14 (s, 1H), 7.16-7.28 (m, 2H), 7.41 (dd, 1H), 9.59 (s, 1H); C17H14N203FBr Analytical calculation: C, 51.93; H, 3.59 N, 7.12. Measured C: C, 51.68; H, 3.83; N, 7.10. However, channel opening activity was measured. Excessive polarization analysis of membranes was performed using primary cultured guinea pig urethral bladder (GPB) cells to evaluate potassium channel opening activity of compounds. Preparation of the bladder flat For muscle cells, male guinea pigs (Hartley, Charles River, Wellington, MA) weighing 300-400 grams were removed from the urethral bladder and placed in an ice-cooled Ca2 + -free Krieber solution (composition, millimolar equivalent (mM) : KC1, 2.7; KH2P04, 1_5; NaCl, 75; Na2HP04, 9.6: Na2HP04 7H20, 8; MgS04, 2: glucose, 5: HEPES, 1 0; pH 7.4). Isolate cells by enzyme dissociation (Klockner) , U. and Isenberg, G ', Pflugers Arch. (1985), 405, 329_339). The bladder was cut into small fragments and cultivated with 1 mg (mg / ml) collagenase (Sigma, Saint Louis, M0) and 0.2 per ml. In 5 ml of Kleiber solution of mg / ml protease (Calbiochem, La Jolla, CA), stir in a cell incubator. The mixture was then centrifuged at 13,000 xg for 5 minutes, and the pellets were resuspended in Dubeck scales. Residual enzymes were removed in PBS (GIBC0, Gaitherberg's MD) and centrifuged. Cell pellets were resuspended in 5 ml growth medium (composition: Dubeck's modified Eagle's medium 'supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 100 units / ml streptomycin, and 0.25 mg / ml amphoteric mold (Supply) and -116- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----; ------- II. ^ -------- Order- -------- Line (please read the precautions on the back before filling this page) A7 442485 B7 --------- V. Description of the invention A burette was used to dissociate the suspension and dissolve it through a polypropylene mesh sieve (Spectrum · 'Houston, TX). The cell density was adjusted to 100,000 cells / ml by resuspension in growth medium. Cells. A black 96-well plate (Packard) at a density of 20,000 cells / hole was placed on a transparent bottom for study of membrane efficacy and maintained in a cell incubator containing 90% air: 10% OO2 until confluent. Single-cell mouse anti-human-α-smooth muscle actin (Biomeda, Faust City, c A) was used to confirm the cells as smooth muscles by cell scaffold staining. Dynamic analysis system based on bis-oxonol dye DiBAC (4) 3 (molecular probe) on 96-hole cells' Screening using luciferin imaging sheet reader (FLIPR) (K.S_ Schroeder and other biomedical screening Journal, Vol. 1, pp. 75-81 (1996)) measures the functional activity of potassium channels by assessing membrane efficacy. DiBAC (4) 3 is an anionic potency measuring probe, which is distributed between cells and extracellular solutions in a manner related to membrane potency. Increased membrane potency (such as κ + depolarization) results in more probes being distributed in the cells; this is measured by the increase in fluorescence due to the interaction of dyes with intercellular fluids and proteins. Conversely, a decrease in membrane potency (potassium channel opener and excessive polarization) shows a decrease in luminescence. Fusion guinea pig urethral bladder cells cultured in a 96-well plate with a black transparent bottom with 200 ml of 5 &quot; M DiB AC (4) 3 analysis buffer (composition, mM: HEPES, 20; NaCl, 120; KC1, 2; CaCl2, 2; MgCl2'1; glucose, 5; pH 25 at 25 ° C) and wash the cells twice Incubate at 37 ° F with 180 ml of buffer in the incubator to ensure that the dye is distributed throughout the membrane. 5 minutes after the green reference line is fluorescent, directly on the cell-117- This paper size is applicable to the 0 national standard (CNS) A4 specification (210 X 297 gM) Please read the precautions on the back before filling this page) '' --------- Order --------- Line 丨 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 44248 5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (115) A reference or test compound prepared by adding 10-fold concentration to the analysis buffer. Follow the fluorescent change for another 25 minutes. Correct any excessively polarized responses to any background noise and reference compounds at 10%! 1075 (selected as 1000 /.) (A powerful opener of the smooth muscle κατρ channel (Quast et al.'S Molecular Pharmacology 'Vol. 43, 474-481 (1993))) Nominal response to observation . Routinely, 5 concentrations of P1075 or test compound (logarithmic or semi-logarithmic dilution) were evaluated and the maximally stable state of excessively polarized 値 (expressed as% relative to P1075) was plotted as a function of concentration. The EC50 (concentration of 50% of the maximum response to the test-test sample) was calculated by nonlinear regression analysis using a 4-parameter S-shaped program. Record the maximum ju M EC5Q response of each compound (represented by P1075. / 〇) "Compound raw material solution was prepared in 100% DMSO and further diluted in analysis buffer and added to a 96-well plate. Guinea pig bladder (GPB) Cell membrane hyperpolarization (ΜΗΡ) Example number Maximum response (% P1075) EC50 (m Μ) 1 96 0.027 2 88 0.65 3 41 27 4 21 5 97 0.19 6 83 1.0 7 75 0.57 8 33 5.0 9 89 _2.6 -118- This paper size applies to the Chinese National Standard (CN'S) A4 specification (210 X 297 meals) --ΙΙΙΙΙ—— — —k * · —----- Order ------- --Line &lt; Please read the notes on the back before filling this page) 442485 A7 B7 V. Description of Invention ("6) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 10 87 1.4 11 104 0.023 12 101 0.014 13 101 0.24 14 99 0.40 15 90 0.64 16 57 8.8 17 93 0.0042 18 95 0.058 19 94 1.8 20 93 0:03 5 21 79 0.066 22 85 0.046 23 82 0.040 24 74 0.73 25 106 0.0098 26 90 0.013 27 87 0.97 28 98 0.064 29 87 1,1 30 84 0.0074 31 83 1.3 32 102 0.015 33 92 0.0034 34 8 8 0.091 35 98 0.025 36 98 0.082 37 105 0.00064 38 82 0.39 -119- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1 ^ 1 nna ^ inn I- II In I I «J i I PI —-1 n--II (Please read the notes on the back before filling out this page) 44248 5 A7 B7 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (117) Γ --- 丨_ 39 80 0.68-one 40 111. 0.32 ----- 41 66 0.071 102 0.026 43 98 0.011 44 96 45 85 0.20 46 83 0.34 47 91 0.49 48 91 0.084 49 85 2.3 50 108 0.084 51 88 0.12 52 105 0.38 in vitro Functional models use tissue strips obtained from Landrace mouse bladder to evaluate the functional clock channel opening activity of compounds. Landrace mouse bladder was obtained from 9-30 kg female Landrace rats.

Landrace mice were anesthetized with an intraperitoneal injection of a barbitur solution (JA Webster, Sterling MA). The entire bladder was removed and immediately placed into a Kleiberlinger's bicarbonate solution (composition, MM: NaCl, 120, NaHC0'2 0; glucose '1 1; KC1, 4 7; CaCl :, 2.5; MgS04, 1.5 ·, KH2P04, 1_2; K2EDTA, 0.01; equilibrated with 5¾ C02 / 95% 02; pH 37 at 37 ° C). Propranolol (0.004 mM) was added to all analyses to block the 々-adrenoceptor. Discard the diagonal and round parts. Cut 3 to 5 mm (20 mm) wide and 20 mm long strips from the remaining tissue in a circular manner. Remove the mucosal layer. Fixed at one end -120- This paper size is applicable to China Store Standard (CNS) A4 (210 X 297 mm) -------------^ -------- Order --- ------ I (Please read the precautions on the back before filling out this page) 442483 A7 B7 V. Description of the invention (彳 18) To the slide rod and the other end is fixed with a reference preload of 1.0 grams to Glass FT03 transmitter. Two parallel platinum electrodes were included on the slide bar to provide 0.05 Hz, 0.5 millisecond electric field stimulation at 20 volts. This low frequency stimulus produces a stable twitch response of 100-500 centigrams. The tissue was equilibrated for at least 60 minutes and perfused with 80 mM KC1. A control concentration response curve (cumulative) was generated for each tissue using potassium channel opener P1075 as a control agonist. p75 is used in a range of concentrations between 0-9 and 10 5 M. The logarithmic volume is 1/2, and the twitch of the stimulus is removed in a dose-dependent manner. After a 60 minute washout period, a concentration response curve (cumulative) was generated for the test agonist in the same manner as the control agonist P1075. Report the maximum potency of each compound (expressed as a% relative to p75). Use "ALLFIT" (American Journal of Physiology, DeLean et al., 235, E97 (1980)) to calculate 50% of the maximum drug response required. The dose of the drug is expressed as Pd2 (negative logarithm). The agonist potency is also expressed as the relative index of P1075. The index is calculated by dividing pio75tED5Q by the EDS0 of the test agonist in the established tissue. Each tissue is only The indices obtained for each test agonist 'JL tissue are averaged to provide an average efficacy index. The data are shown in Table 2. Table 2 -------- II--I ^ ------ -Order · -------- I (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Landrace Mouse Bladder's example pD2 index number J (% P1075) 1 97 ---- 6.9 0.36 2 99 5.8 0.041 5 100 --------- 6.4 0.16 -121-Private paper ruler 44248 5 A7 B7 V. Description of Invention (119) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6 100 5.4 0.022 7 97 5.4 0.040 8 90 5.2 0.023 9 82 3.9 0.0015 10 96 4.3 0.0028 11 91 6.8 1.2 12 85 7.2 3.3 13 98 5.9 0.13 15 100 5.7 0.027 18 100 7.3 1.6 19 100 6.0 0.70 20 93 5.6 0.43 22 100 5.6 0.027 24 100 6.0 0.055 28 94 6.7 0.42 29 89 5.8 0.075 30 100 7.6 1.1 31 85 5.1 0.065 32 100 6.3 0.41 33 93 5.9 0.27 34 93 7.0 0.96 35 100 7.4 1.8 36 100 6.5 0.24 37 95 7.3 2.1 38 80 5.3 0.024 39 96 5.6 0.036 40 91 6.0 0.13 42 95 6.2 0.17 43 88 6.7 0.68 -122- ----------- I- ----- Order --------- Line 丨 (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 44248 5 A? B7 V. Description of the invention (120) 47 96 6.2 52 99 5.3 Consumption cooperation among employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the company 0.28 0.069 As shown in Tables 1 and 2, the compounds of the present invention reduce the cystic stimulus contraction by opening potassium channels and can therefore be used to treat symptoms and / or diseases that can be prevented or relieved by potassium channel openers. In this article, "pharmaceutically acceptable carrier" means a non-toxic inert solid semi-solid or liquid filler, diluent, encapsulating substance, or any kind of formulation aid. Some examples of substances that can be used as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and low-sugar sugar; powders such as corn powder; and horsetail potato powder; cellulose and its derivatives such as sodium carboxymethyl cellulose, beta Base cellulose and cellulose B Sa 'powder yellow gum; malt; gelatin; talc; excipients such as cocoa butter and suppository tincture; oils such as peanut oil, cottonseed oil, tsai flower oil, sesame oil, olive oil, corn Oils and sensible oils; glycols such as propylene glycol; vinegars such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; water without pyrogens; etc. Zhang salt solution; Ringer's solution 'ethanol and salt refractory buffer; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents' sweet Flavors, flavoring and flavoring agents, preservatives and antioxidants may also be present in the composition at the discretion of the formulator. The invention provides a pharmaceutical composition comprising a compound of the invention formulated with one or more non-toxic pharmaceutically acceptable carriers. This pharmaceutical composition can be formulated as a solid or liquid for oral administration, for parenteral or rectal administration. Including one or more of the compounds of formula I-VIII prepared and one or more non-123- This paper size applies to Chinese National Standard (CNS) A4 specifications (2〗 0 X 297 mm) (Please read the note on the back first (Fill in this page again)

· I. ^ 1-OJI I n I * 1 n II 442 48 5 A7 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economy Within the scope of the present invention. This pharmaceutical composition can be formulated as a solid or liquid for oral administration, parenteral or rectal administration. The pharmaceutical composition of the present invention can be administered orally, parenterally, intracranially, intravaginally, intraperitoneally, locally (by powder, ointment or drops) to humans and other mammals, or administered intraorally or nasally. 4 As used herein, "parenteral" means that the head medicine mode includes intravenous, intramuscular, intraperitoneal, intrathoracic, subcutaneous, intraarticular injection or infusion. The pharmaceutical composition of the present invention for parenteral #channel injection includes medicine Bacteria-prepared aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders are acceptable for reinstatement in sterile injectable solutions or dispersions. Suitable examples of aqueous non-aqueous carriers, diluents, solutions or vehicles include water , Ethanol 'evening alcohol (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable: oil (such as olive oil), and injectable organic esters such as ethyl oleate. For example, by applying a coating agent such as egg Phospholipids, in the case of dispersions, can maintain proper fluidity by maintaining the required particle size and the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersions A variety of antibacterial agents and anti-bacteria agents such as p-hydroxyphenyl ester, gas butanol, phenol, sorbic acid, etc. can surely prevent microorganisms. It can also include isotonic agents such as sugars, gasification sodium, etc. Delayed absorption agents such as ¥ stearic acid reduced gelatin can be used to make delayed absorption injectable pharmaceutical bones and multi-purpose acids. In some cases, 'in order to prolong the efficacy of drugs', it is often necessary to slowly absorb the drug from subcutaneous or intramuscular injection. Drugs. This can be obtained by using -124- ^ Paper Ruler National Standard (CN &amp; A4 Specification ⑵G χ 297 ----% ----- I ------ 1-- ----------- * ^ 1 f Please read the notes on the back before filling in this page) 442485 A7

V. Description of the invention (Ί22) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs shall print the seal of the cooperative cooperative * '1 ^ crystalline or amorphous material liquid. Drug absorption depends on its dissolution rate and therefore on the size and state of the crystals. Alternatively, the delayed absorption of a parenterally administered pharmaceutical dosage form can be accomplished by dissolving or suspending the drug in an oily vehicle. In addition to the active compounds, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan anhydride esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, Yellow gum and its mixtures. If desired and for more effective distribution, the compounds of the present invention can be incorporated into slow-release or targeted delivery systems, such as polymer matrices, microlipids, and microspheres. Bactericidal agents are incorporated into a solid germicidal composition for sterilization, which can be dissolved in sterile water or some other sterile injectable medium before use. ~, The active compound may also be in a microcapsule state, if necessary, with one or more of the above-mentioned excipients. The solid dosage forms of lozenges, sugar-coated tablets, capsules, pills, and granules can be prepared by coating agents and shells, such as casings, release-controlling coating agents, and other coating agents known in the field of pharmaceutical formulation. In this solid dosage form, the activated human can be mixed with at least one inert diluent such as sucrose, lactose or starch. This dosage form may also include substances other than inert diluents under normal operation, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also include buffering agents. It may in turn include opacifying agents and may also allow the composition to release only the active ingredient or preferably in a delayed manner in certain parts of the intestinal tract. Examples of usable inclusion compositions include polymeric substances and waxes. 125- This standard is applicable to China National Standard G: NS> A4 (210 X 297 g) ------------ ^ --------- * · -11-- ------- 1 (Please read the notes on the back before filling this page) A7 B7

44248 5 V. Description of the invention (123) The accumulative accumulation type can be obtained by forming a microencapsulated matrix of a drug in a biodegradable polymer such as polylactic acid and polyglycolic anhydride. Depending on the ratio of drug to polymer and the nature of the polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Accumulation Injectable formulations can also be made by encapsulating the drug in microlipids or microemulsions that are compatible with human tissues. Injectable formulations can be sterilized, for example, by retaining bacterial filter paper or by incorporating a bactericide in a germicidal sterilization composition, and dissolved in sterile water or some other sterile injectable medium before use-. Injectable preparations such as sterile injectable aqueous or oleaginous suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterilizable &gt; main injection solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, usp and isotonic sodium vaporized solution. In addition, it is customary to use a sterile fixed oil as a solvent or suspension medium. For this purpose, any brand of fixed oil may be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectable preparations. Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In this solid dosage form, the active compound is combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) an excipient or diluent such as starch, lactose, sucrose'glucose, mannitol And salicylic acid; b) binders such as carboxymethyl cellulose, alginate, gelatin 'polyvinyl erogen> _' sucrose and acacia; c) wetting agents such as glycerin; -126- Applicable to China National Standard (CNS) A4 specification (210 x 297 mm) ---- Γ I ----- II; clothing -------- order --------- I f Please read the note on the back first? Please fill in this page again) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 44248 5 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs B7___ V. Description of the invention , Tapioca or cassava starch, alginic acid, some silicates and sodium carbonate; e) solution delaying agents such as bonded alkanes; f) absorption enhancers such as quaternary compounds; g) humectants such as fresh phytol and Glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using, for example, excipients such as lactose and high molecular weight polyvinyl alcohol. Solid dosage forms of bonding agents, dragees, capsules, pills, and granules can be prepared by coatings and shells, such as enteric coatings and other coating agents known in the pharmaceutical formulation field. It may in turn include opacifying agents and also allow the composition to release only the active ingredient or preferably in a delayed manner in certain parts of the intestinal tract. Examples of usable inclusion compositions include polymeric substances and waxes. Compositions for rectal or vaginal administration are preferably suppositories, which can be obtained by mixing the compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a solid at ambient temperature but a liquid at body temperature and therefore at Rectal or vaginal preparations are suppository waxes which dissolve and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and mussels. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, Agents and emulsifiers such as ethanol, isopropyl alcohol 'ethyl carbonate', ethyl acetate, benzyl alcohol, ethyl benzoate, propylene glycol '1,3-butanediol, dimethylformamide, oils (especially cotton) , Groundnut, corn, young sprouts, olive -127- (Please read the notes on the back before filling out this page) This paper size is suitable for financial standards (CNS) A4 (210 X 297 public love) Intellectual Property Bureau of the Ministry of Economic Affairs Printed by employee consumer cooperatives 442485 A7 ___B7 V. Description of the invention (125) Fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and their mixtures. In addition to the inert diluent, the oral composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, wall flavors and flavoring agents. Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, gift creams, 'emulsions, gels, powders, solutions, sprays, inhalants, or patches. The beta active ingredients are then sterile under medical conditions and acceptable for medical use. The carriers are mixed and any desired preservatives or buffers can be mixed if desired. Ophthalmic formula 'ear drops, eye ointments, powders and solutions are also within the scope of the present invention. Ointments, pastes, creams and gels may contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols , Silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof. The powders and mists may contain, in addition to the compound of the present invention, excipients such as sugar, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or a mixture thereof. Sprays may also contain conventional propellants such as chlorofluorocarbons. Pastes have the benefit of known compounds for controlled delivery to the human body. This agent can be prepared by dissolving or dispersing the compound in a suitable carrier. Absorption Enhancement 刎 can also be used to push compounds through the skin. This rate can be controlled by providing a rate-controlling film or dispersing compound in a polymer matrix or gel. The compounds of the present invention can also be administered in the form of microfat granules. Such as those skilled in the art. , Microlipids-generally derived from phospholipids or other lipid substances. Microlipids can be formed from a single or a layer of hydrated liquid crystals that can be dispersed in an aqueous medium. __ -128 The paper mill is suitable ^ iiiI? TCNS) A4 size ⑽ x297mm) — — — llllllfl — ^ 1111111 ^ f --- IIIIII (Please read the precautions on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 44248 5 A7 P ---------- B7 V. Description of Invention (126) Any non-toxic physiologically acceptable and metabolizable lipid can be used. In the form of microfat granules, the composition I may contain a stabilizer, a preservative, an excipient and the like in addition to the compound of the present invention. The preferred lipids are natural and synthetic squamous lipids and squamaline choline (imprintin), which can be used separately or in combination. The method of forming microfat particles is known to those skilled in the art. See, for example, Prescou, Cell Biological Methods, Volume XIV, N.Y. College Press, New York (1976), page 33, and so on. The "medicine-acceptable cations" used in the present application are "positive-charged inorganic or organic ions generally considered suitable for human consumption. Examples of pharmaceutically acceptable cations are hydrogen, alkali metals (lithium 'sodium and potassium), magnesium, calcium, Ferrous, ferrous, ammonium, and alkane according to the 'dual regulation 1' according to trialkylammonium, tetraalkylammonium, diethanolammonium, and choline. The cations ~ T are exchanged by known methods such as the ion exchange method. Used in this paper'_ Pharmaceutically acceptable salts, esters, and amidines &quot; Re-acidified salts, amino acid addition salts, zwitterions, esters, and amidoamines of the compounds of Formula I-VIII are used within the scope of the present invention's reasonable judgment Human and lower animal tissues are in contact without toxicity, irritation, allergic reactions, etc., and are within a reasonable benefit / danger ratio and are beneficial to the intended use. The "pharmaceutically acceptable salt" used in this article indicates that this technology is learned Known salts. For example, SM Berge et al. Details the pharmaceutically acceptable salts in Medical Science Journal, 66: 1-19 (〖977). The pharmaceutically acceptable non-toxic acid addition salts are with inorganic acids such as hydrochloric acid and hydrogen stream. Acid, phosphoric acid, sulfuric acid and peroxyacid or organic Such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid salt, or formed by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include Nitrate, bisulfate, boron 129- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) "--------- Clothing -------- Order- -------- Line-(Please read the notes on the back before filling out this page) 44248 5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 V. Invention Description (127) Acid salt, formate, Butyrate, valerate, 3-phenylpropionate, camphor, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate , Succinate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphor sulfonate, methane sulfonate, 2-acetylsulfonate, glucose Acid salt, glucoheptanoate, lactobionate, glycerol phosphate, pectate, lauryl sulfate, etc., metal salts such as sodium, potassium, magnesium or calcium or amine salts such as ammonium Triethylamine salts and the like, which can be prepared according to conventional methods. As used herein, "pharmaceutically acceptable esters" means-esters of the compound of the present invention which are hydrolysable in vivo and which are easily broken in the human body leaving the original compound or its salt. The pharmaceutically acceptable non-toxic esters of the present invention include Cm alkyl esters and Cs_7 cycloalkyl esters, and C] _4 alkyl esters are preferred. Esters of the compounds can be prepared according to conventional methods. "Pharmaceutically acceptable amidine" as used herein means a non-toxic amidine of the present invention derived from ammonium, primary Cm alkylamine, and secondary Ct. 0 dialkylamine. In the case of secondary amines, the amine may also contain A nitrogen atom may be a 5- or 6-membered heterocyclic ring. Derived from ammonium, Cw alkyl primary ammonium & Ci_2 dialkyl secondary ammonium amine is preferred. The amidines of the compound of formula VIII may be based on conventional methods Preparation. Preferably, the present invention &gt; amidine also includes amino acids and peptide derivatives of the compounds of formula I-VIII. &Quot; A pharmaceutically acceptable prodrug &quot; or &quot; prodrug &quot; as used herein is indicated in Reasonable medical judgment Fan® is suitable for prodrugs of the compounds of the present invention in contact with the human body and lower animal tissues = non-toxic, stimulating 'allergic reactions, etc., and within a reasonable benefit / danger ratio, and beneficial to the intended use. The prodrug of the invention can be quickly transformed into the above formula in vivo by hydrolysis in blood, for example -130- This paper size is applicable to China Garden Store Standard (CNS) A4 (210 X 297 mm) (Please read the back (Please fill in this page before taking note) I -------- Order --------- · 442485 A7 printed by the production bureau member JL Consumer Cooperative ____B7_____ V. Description of the invention (128) A full discussion of compound α can be found in T. Higuchi and V. Stella's A · c.S. Conference series as a prodrug of the delivery system, Vol. Edward B. Roche's edited drug-designed biotransformable vector, American Medical Association and Paramount Press (1987). "Prodrug esters" as used herein means any of several forms that can be hydrolyzed under physiological conditions Examples of esters. Examples of prodrug esters include pentamyloxymethyl, ethynylmethyl, phthalofluorenyl, indanyl, and methoxymethyl, and those skilled in the art. Other examples of prodrug esters See the aforementioned reference (T. Higuchi and V. Stella &quot; as a prodrug of the delivery system.-A local formulation of a compound of the invention includes powders, sprays, ointments and inhalants. The active compounds are combined with aseptic conditions Pharmaceutically acceptable carriers are mixed with any required preservatives, buffers or propellants if needed. Ophthalmic formulations, ointments, powders and solutions are also within the scope of the invention. Activity of the pharmaceutical composition of the invention The exact dosage can be changed to obtain the amount of active compound effective to achieve the desired therapeutic effect on the specific patient, the composition and mode of administration. The selected dose will depend on the activity of the specific compound, the route of administration, the severity of the condition to be treated, and the treatment to be treated The patient's condition and previous medical history will depend. However, the starting dose of the compound is lower than the dose to achieve the desired therapeutic effect and gradually increasing the dose until the desired effect is achieved. The present invention includes formulae I-VIII A pharmaceutically active metabolite formed by the biological conversion of a compound in the body. As used herein, a pharmaceutically active metabolite refers to a compound formed by the biological transformation of a compound of formula in vivo. The invention includes compounds of the formula [_VIII] and metabolites thereof. Biotransformation is detailed in GOOdman and -131-This paper size is applicable to China National Standard (CNS) A4 specification (2) 0 X 297 g g) ---.----------. ^ -------- Order -------- *-&lt; Please read the Zhuyin on the back first? Please fill in this page again for matters) 4424 8 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _____B7__ V. Description of Invention (129)

Gilman's Therapeutic Pharmacy Basis, 7th Edition, which is incorporated herein by reference. The compounds of the present invention, including but not limited to those defined in the examples, have potassium channel opening activity in mammals, especially humans. As for channel opening agents, the compounds of the present invention are useful for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and Stroke and other diseases. The ability of the compound of the present invention to treat asthma, epilepsy, hypertension, Raynaud's syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorder, urinary incontinence, functional bowel disorder, neurodegeneration and stroke can be based on The following method proves: D.E_ Nurse et al., Br j Ur〇l vol. 68, pages 27-31 (1991); BB · Howe et al., J. Pharmac〇1:

Exp. Ther., Vol. 274, pp. 884-890 (1995); K. LawSon, Pharmacol. Ther., Vol. 70, pp. 39-63 (1996); DR Gehlert et al., Neuro-Psychopharmacol &amp; pSyChiat ·, Vol. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research Nine, Vol. 28, pp. 95-127 (1993); J. E. Freedman et al., Neuroscience 2 vols. 145-152 (1996); and D. Spanswick et al., Vol. 3 90, 52 pp. 25 (1997, November 4). The aqueous liquid composition of the present invention is particularly useful for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke, etc. disease. When used in the above or other treatments, a therapeutically effective amount of a compound of the present invention may be used in a pure state, or a pharmaceutically acceptable salt, ester, and amidine-132 may be present. 297 public cage) --------------- --------- Order · -------- ~ ί Please read the notes on the back before filling in this Page) 44248 5 A7 ---------------- B7____ 5. In the invention description (130) or prodrug state, these derivatives can be used. Alternatively, the compound may be administered in a pharmaceutical composition containing a desired compound in combination with one or more pharmaceutically acceptable excipients. A "therapeutically effective amount" of a compound of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment. It should be understood, however, that it can be determined by participating physicians within a range of sound medical judgments. The specific therapeutically effective dose for any particular patient will depend on a variety of factors, including the condition to be treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; Dosing time, route of administration, and excretion rate of the specific compound used; treatment period; drugs that are combined or administered with the specific compound used, and similar factors known in the art. For example, it is also known in the art that the starting dose of the compound is lower than the dose that achieves the desired therapeutic effect and that the dose is gradually increased until the desired effect is achieved. The total daily dose of a compound of the present invention administered to humans or lower animals may range from about 0.003 to 10 mg / kg / day. For oral purposes, a more preferred dose ranges from about 0.01 to about 5 mg / kg / day. If desired, the effective daily dose may be divided into several times for purposes of administration; therefore, single-dose compositions may contain such amounts or constitute submultiples of the E1 dose. --------— In ^!-II Order · -------- Line (Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Bureau Employee Consumer Cooperatives 33 This paper size applies to China National Standard (CNS) A4 (210 x 297mm)

Claims (1)

4 42 Add S858478 Patent Application A8 Chinese Patent Application Amendment Amendment (March 90) Printed by the Shell Corps Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs *. Patent Application Scope 1. A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein η is 0 or 1; m is 1 or 2; m + η is not 3; A is NR, 0, or S; A 'is NR3, 0, S, or CR4R5; D is C (0); D 'is C (0), S (0) or S (0) 2; R〗 is a phenyl group substituted with 1 or 2 of the following substituents: dentin, no 2 CN, CF 3 and OH 'substituted by nitro, sedenyl, or benzo P cedadiazole R2 and R3 are hydrogen, alkyl or phenyl-Ci.4 alkyl; R4, R5, 116 and 117 are hydrogen or C]- 4 alkyl; and when EΓ is S (0) or S (0) 2, then A1 is CR4R5. 2. The compound according to item 1 of the scope of patent application, wherein a is NR2. 3. The compound according to item 1 of the scope of patent application, wherein a is 0. 4. The compound according to item 1 of the scope of patent application, wherein A is s. 5. The compound according to item 1 of the scope of patent application has the formula I v: ---------- installation ------ order ------ line (please read the precautions on the back first) (Fill in this page again.) This paper is a Chinese standard (CNS) A4 ^ (210X297 mm) 44248 5 A8 B8 C8 D8. Scope of patent application Fibre, fat, or pharmaceutically acceptable salts of shellfish consumption by the Central Bureau of Standards, Ministry of Economic Affairs, where A is: NR2, 0, or S; A 'is NR3, 〇, S, or CR4R5; R, is Phenyl substituted with the following substituents: _ prime, N02, CN, CF3 and OH, thienyl substituted with nitro, or benzopyridadiazole; R2 and R3 are hydrogen '(: monoalkyl or phenyl -(^-4 alkyl; R4, R5, Chi 6 and R7 are hydrogen or C t -4 alkyl. 6. Compound according to item 5 of the scope of patent application, where A is NR] and A1 is NR3. 7 A compound according to item 5 of the patent application, where A is NR2; A is NR3; R6 is hydrogen; and R7 is hydrogen. 8. The compound according to item 5 of the patent application is 5- (3-bromo- 4-fluorophenyl) -2,3,5,8,9,10-hexahydropyrido [3,4-1)] [1,7] pyridin-4,6 (111,711) -dione 9_ Compound according to item 5 of the scope of patent application, where A is NR2; and -2-pack -------- order ------- line (please read the note-^ on the back before filling (This page) This paper uses China National Kneading Rate (CNS) from specifications (2 丨 〇 &lt; 297 public envy) 44248 5 AS BS C8 D8 Central Standard of the Ministry of Economic Affairs Printed by Behr Consumer Cooperative 6. The scope of patent application A is 0. 10. The compound according to item 5 of the patent application park, where A is NR2; and A 'is S. 11. According to item 5 of the scope of patent application. Compounds in which A is 0; and A in NR3. 12. Compounds according to item 5 of the scope of the patent application, where A is 0; A 'is NR3; R6 is hydrogen; and r7 is hydrogen. 13. According to the scope of patent application The compound of item 12 is 5- (3-bromo-4-fluorophenyl) -5,8,9,10-tetrahydro-111-piperano [; 3,4_1)] [1,7] Pyridine-4,6 (11711) -dihydrazone. 14. The compound according to item 5 of the patent application, wherein A is 0; and A is 0. 15. The compound according to item 5 of the scope of patent application, wherein A is 0; A1 is 0; R6 is hydrogen; and K · 7 is hydrogen. 16. The compound according to item 15 of the scope of patent application is selected from the following group -3- --------- ^ ------ ΪΤ ------ line (please read the back first Please pay attention to this page and fill in this page again) This paper standard applies the China National Standard (CNS) Α4 grid (2 丨 0Χ2ί &gt; 7 mm) 4 4248 b 8 8 8 8 Group of patent applications: 5- (3-bromo-4-fluorophenyl) -5,10-dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine -4,6 (7H, 9H) -dione; 5- (4-Ga-3-nitrophenyl) -5,10-dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 5- (3-cyanophenyl) -5,10-dihydro-1Η, 3Η-dipiperano [3,4 -b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 5- (4-fluoro-3- "phenyl) -5,10-dihydrodipiperano [3, 4-b: 4,3-e] -pyridine-4,6 (7H, 9H) -dione; 5- (5-bromo-2-hydroxyphenyl) -5,10-dihydro-1H, 3H- Dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 5- [4-fluoro-3- (trifluoromethyl) phenyl]- 5,10-dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 5- (3,4- Dichlorophenyl) -5,10-dihydro -1Η, 3Η-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 5- (2,1,3-benzohumidazole -5-yl) -5,10-dihydro-1H, 3H-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H) -dione; 4- (5-nitro-2-fluorenyl) -5,10-dihydro-1Η, 3Η-dipiperano [3,4-b: 4,3-e] pyridine-4,6 (7H, 9H ) -Dione; and 5 (5-nitro-3-b-sedenyl) -5,10-dimuridine [3,4-b: 4,3-e] pyridine-4,6 ( 7H, 9H) -dione. 17. The compound according to item 5 of the scope of patent application, where A is 0; and A 'is S. -4-(Please read the precautions on the back before filling this page]. The size of the paper is applicable to the Chinese National Standard (CNS) A4 scale (210X297 mm) 4 4248 5 A8 B8 C8 m々, the scope of patent application 18. According to the compound in the scope of patent application No. 5, where A is 0; A1 Is S; R6 is hydrogen; and R7 is hydrogen. 19. The compound according to item 18 of the scope of patent application is 5- (3-bromo-4-fluorophenyl) -5,10-dihydro-1H, 3H-piperano [3,4-b] pyrim Urano [4,3-e] pyridine-4,6 (7Η, 9Ή) -dione. 20. The compound according to item 5 of the patent application park, wherein A is S; and A is NR3. 21. The compound according to item 5 of the patent application, wherein A is S; and A is 0. 22. The compound according to item 5 of the patent application, wherein A is S; and A is S. 23. The compound according to item 1 of the patent application park has formula V: ---------- meal ------. Π ------ line (please read the back Please fill in this page again for attention) Printed by the staff of the Central Government Bureau of the Ministry of Economic Affairs Or its pharmaceutically acceptable salt, in which the size of this paper method is in accordance with the Chinese National Standard (CNS) A4 (210X297 mm). It is printed by the Male Workers Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 442485 A8 58 C8 D8 The scope of patent application A is NR2, 0 or S; A is NR3, 0, S or CR4R5; R is phenyl substituted by 1 or 2 of the following substituents: halogen, N02, CN, CF3 and OH, nitrate A substituted fluorenyl group, or benzopyrimidazole; R2 and R3 are hydrogen, C]. 4 alkyl or phenyl-Ch # alkyl; R4, K5, R6 and K7 are murine or C 1 _ 4 bases. 24. The compound according to item 23 of the scope of patent application, wherein A is NR2_; and A is NR3. 25. The compound according to item 23 of the scope of patent application, wherein A is NR2; and A 1 is 0. 26. The compound according to item 23 of the scope of patent application, where A is NR2; A is 0; R6 is hydrogen; and K · 7 is star 13 27. The compound according to item 26 of scope of patent application is selected from The following groups: 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-1)] [1,7] benzopyridine-.1,8 (3Η , 4Η) -dione; (+)-9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] [l, 7] pyridine- 1,8 (3H, 4H) -dione; and (-)-9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] [l , 7] 荇 -6-This paper size adopts Chinese National Standards (CNS &gt; A4 grid (210X297 mm) --------- ^ ------ ΐτ ------ .ii (Please read the notes on the back before filling out this page) 4 424 8 5 A8 B8 C8 D8 printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs, and the scope of patent application -1, 8 (3H, 4H) -Dione. 28. Compound according to item 23 of the patent application, where A is NR2; and A1 is S. 29. Compound according to item 23 of the patent application, where A is NR2; and A, CR4R5 30. The compound according to item 23 of the scope of patent application, wherein A is N R-2 A 'is CR4R5; R4 is a star, R5 is hydrogen; R &gt; 6 is wind, and r7 is hydrogen. 31. The compound according to item 30 of the patent application park is selected from the following group: (-)- 5- (3-bromo-4-fluorophenyl) -2,3,5,7,8,9-hexahydro-1H-cyclopentane [b] [l, 7] pyridine-4,6- Diketone; (+)-5- (3-bromo-4-fluorophenyl) -2,3,5,7,8,9-hexahydro-1H-cyclopentane 0] [1,7] 葚Pyridin-4,6-dione; (+)-5- (3-chloro-4-fluorophenyl) -2,3,5,7,8,9-hexahydro-1H-cyclopentane [ ] [1,7] Benzidine-4,6-dione; and (-)-5- (3-chloro-4-fluorophenyl) -2,3,5,7,8,9-hexahydro- 1H-cyclopentane [1?] [1,7] pyrimidine-4,6-dione. (Please read the notes on the back before filling this page.) This paper uses the Chinese National Standards (CNS) ) ^^ grid (210X297 mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4424 8 ο Α8 Β8 C8 D8 六 、 Application for a patent scope 32. According to the compounds in the scope of patent application No. 23, where A is 0 ; And A 'is NR3. 33. The compound according to item 23 of the scope of patent application, where A is 0; A 'is NR3; is chlorine, and R7 is hydrogen: 34. The compound according to item 33 of scope of the patent application is selected from the following group: Group: 9- (3-bromo-4-fluorophenyl) -2-methyl-2,3,5,9-tetrahydropiperano [3,4-13] pyrrolo [3,4-e] Pyridine-1,8 (4H, 7H) -dione; and 9- (3-bromo-4-fluorophenyl) -2,3,5,9-tetrahydropiperano [3,4-1)] Pyrrolop [3,4-e] pyridine-1,8 (4H, 7H) -dione. 35. The compound according to item 23 of the patent application park, wherein A is 0; and A 'is 0. 36. The compound according to item 23 of the patent application park, wherein A is 0; A 'is 0; is hydrogen; and R7 is hydrogen. 37. The compounds according to item 36 of the scope of patent application are selected from the following groups: -8- This paper size applies the Chinese National Standard (CNS) A4 Washing (210X297 mm) --------- 1 ------ 1T ------ M (Please read the notes on the back before filling this page) 4 4 8 5 Α8 Β8 C8 The Ministry of Economic Affairs ordered the Central Government Bureau to print 9- (3-bromo · 4-fluorophenyl) _5,9_dihydro · 3 氢 _furanΗ [3,4_b] pyrrolo [4 3 e] pyridine- 1,8 (4H, 7H) -dione; '(9R) -9- (3-bromo · 4-fluorophenyl) _5,9_dihydro_3H-furo [3,4_b] pyrolo [ 4,3-e] pyridine-1,8 (4H, 7H) -dione; and (9S) -9- (3-bromo-4-fluorophenyl) -5,9-dihydro-3H-furo [3,4-b] pyrrolo [4,3-e] pyridine-1,8 (4H, 7H) -dione. 38 'The compound according to item 23 of the scope of patent application, wherein A is 0; _ and A are S. 39. The compound according to item 23 of the scope of patent application, wherein A is 0; and A- is CR4R5. 40. The compound according to item 23 of the scope of patent application, wherein A is 0; A is CR4CR5; R4 is ammonia, R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen. 41. The compound according to item 40 of the scope of patent application is selected from the following group: 5- (3-bromo-4-fluorophenyl) -5,7,8,9-tetrahydrocyclopane [b ] Pyrano [4,3-e] pyridine-4,6 (1H, 3H) -dione; and 5 · (4-chloro-3-nitrophenyl) -5,7,859-tetrahydrocyclopentane [B] Piperane paper standard uses China National Standards Corporation (CNS) Α4 size (210 × 2 mm) η First read and read Note I Binding of the Central Bureau of Standardization of the Ministry of Economic Affairs and Consumer Cooperatives 44248 5 A8 B8 C8 D8 6. Application scope of patent [4,3-e] pyridine-4,6 (1H, 3H) -dione. 42. The compound according to item 23 of the scope of patent application, wherein A is S; and A 'is NR3. 43. The compound according to item 23 of the scope of patent application, wherein A is S; and A 'is 0. 44. The compound according to item 23 of the scope of patent application, wherein A is S; and A1 is S. 45. The compound according to item 23 of the scope of patent application, wherein A is S; and A is CR4R5. 46. The compound according to item 23 of the scope of patent application, wherein A is S; A_ is CR4R5; R4 is hydrogen; / is ammonia; R6 is hydrogen; and R7 is wind. 47. The compound according to item 46 of the scope of patent application is 5- (3-bromo-4-fluorophenyl) -5,7,8,9 · tetrahydrocyclopentane [b] pyrano [4, 3-e] pyridine 4,6 (1H, 3H) -dione. 48. The compound according to item 1 of the scope of patent application, has the formula VI: -10- This paper size is easy to use in poor countries (CNS) A4 size (210X297 mm) binding. Thread (please read the precautions on the back first) (Fill in this page again) 44248 6 A8 B8 C8 D8 7. Scope of patent application Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs, or a pharmaceutically acceptable salt thereof, where: A is NR2, 0, or S; A 'is NR3, 〇, S, or CR4R5; Ri is replaced by 1 or 2 of the following -Substituted phenyl: halogen, N02, CN, CF3 and OH, thienyl substituted by nitro, or benzopyrimidazole; R2 and R3 are hydrogen, (4_4 alkyl or phenyl-Ci.4 R4, κ · 5, Κ · 6, and R7 are wind or C 4 bases. 49. Compounds according to item 48 of the patent application, where A is NR2; and A is NR3. 50. According to the application The compound of the 48th scope of the patent, where A is NR2; and A 'is 0. 51. The compound of the 48th scope of the patent application, where A is NR_2; and A' is S. 52. According to the scope of patent application The compound of item 48, in which A is NR2; and A1 is CR4R5. -11---------- ^ ------ 1T ------ r line (please read first Note on the back of the page, please fill in this page again.) The paper size is used in the poor countries (CNS &gt; A4 size (210X297 mm)) Printed by the Shell Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 442485 A8 B8 C8 D8 Patent Fangu 53. The compound according to item 48 of the scope of patent application, where A is NR], A1 is CK> 4R5; R4 is hydrogen; K · 5 is R6 is hydrogen; and R7 is hydrogen. 54. According to the fifth scope of patent application The compound of item 3 is selected from the group: 5- (3-bromo-4-fluorophenyl) -2,3,5,8,9,10-hexahydrobenzo | ^] [1,7] Phenidine-4,6 (1H, 7H) -dione; 5- (3-bromo-4-fluorophenyl) -2-methyl_2 ′, 5,8,9,10-hexahydrobenzo [ 13] [1,7] Pyridine-4,6 (1H, 7H) -dione; (-)-5- (3-bromo-4-fluorophenyl) _2,3,5,8,9,10 -Hexahydrobenzo [bn], 7] pyridine-4,6 (1H, 7H) -dione; and (+)-5- (3-bromo-4-fluorophenyl) -2,3,5 , 8,9,10-hexahydrobenzo [1 »] [〗, 7] Hysteria _ 4,6 (1H, 7H) -dione. 55. The compound according to item 48 of the scope of patent application, where A Is 0; and A 'is NR3. Β 56 · Compounds according to item 48 of the scope of patent application, where A is 0; A is NR3; Rs is hydrogen; and -12- This paper size applies to Chinese national standards ( CNS) grid (210x297 male thin) 11 II 11 n I ^, / (Please read the precautions on the back before filling out this page) Central Standards Bureau of the Ministry of Economic Affairs Printed 442 4 B 9 A8 B8 C8 __ -__ 2! ____, the scope of patented ^ is hydrogen. 57. The compound according to item 56 of the applied patent garden is selected from the group: 10- (3-Ga-4-fluorophenyl) -3,4,6,1〇_Tetrahydro_2Η_pipe Furo [3,4-b] [l, 6] Phenidine-1,9 (5H, 8H) -dione; 10 ″ (3,4-dichlorophenyl) -3,4,6,1 〇-tetrahydropiperano [3,4-b] [1,6] pyridine-1,9 (5H, 8H) -dione; 10_ [4 · Ga-_3- (trifluoromethyl) phenyl ] · 3,4,6,10-tetrahydro-2H-piperano [3,4-b] [l, 6] pyrimidine-1,9 (5Η, 8Η) -dione; 10- (4- GA-3-nitrophenyl) -3,4,6,10-tetrahydro-211-piperano [3,4 讣] [1,6] naphthyridine-1,9 (5Η, 8Η)- Dione; 10- (3,4-dibromophenyl) -3,4,6,10-tetra-1_2 only-slightly benzo [3,4-1 »] [1,6] pyridine-1,9 (5Η, 8Η) -dione; 10- (5-nitro-3-pyrimyl) -3,4,6,1〇_tetrahydro-2ί_piperano [3,4-b] [l , 6] Phenidine-1,9 (5H, 8H) -dione; and 10- (3-bromo-4-fluorophenyl) -3,4,6,10-tetrahydro-2H-pirano [ 3,4_b] [l, 6] Phenidine-1,9 (5H, 8H) -dione. 58. The compound according to item 48 of the patent application park 'where A is 0; and A f is 0 ° 59 A compound according to item 48 of the scope of patent application, where A is 0; and A 'is S. 60. The compound according to item 48 of the scope of patent application, in which -13- this paper size uses the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) ~ ------ --- 1 ------ iT ------, line (Please read the notes on the back before filling this page) 42485 A8 B8 C8 D8 t. The scope of patent application A is 0; and A ′ is CR4R5. 61. The compound according to item 48 of the scope of patent application, where A is 0; A ′ is CR4R5; ruler 6 is rat, and R7 is nitrogen. 62. A compound according to item 48 of the scope of patent application, where A is 0; A 'is CR4R5; R * 4 is wind, R &gt; 5 is chlorine; K · 6 is nitrogen, and R7 is nitrogen. 63. According to the scope of patent application The compound of item 62 is 5- (3-bromo-4-fluorophenyl) -5,8,9,10-tetrahydro-1H-piperano [3,4-b] pyridin-4, 6 (3H, 7H) -diketone. 64. The compound according to item 48 of the scope of patent application, wherein A is 0; A 'is CR4R5; R4 is methyl; R5 is methyl; is or, and R7 is nitrogen . -14- The standard of this paper is Chinese National Standard (CNS) Α4 grid (210 × 297 mm) --------- t -------? Τ ------ line ( Please read the precautions on the back before filling this page) Printed by the Men's Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 442485 A8 BS C8 D8 3-bromo-4-fluorophenyl) -7,7-dimethyl-5,8,9,10-tetrahydro-1H-piperano [3,4-b] 4 phthaloline-4,6 (3H , 7H) -dione. 66. The compound according to item 64 of the application, wherein A is S; and A1 is NR3. 67. The compound according to item 48 of the scope of patent application, wherein A is S; and A 'is ◦. 68. The compound according to item 48 of the scope of patent application, wherein A is S; and A1 is S. 69. The compound according to item 48 of the application, wherein A is S; and A 'is CR4R5. 70. The compound according to item 48 of the scope of patent application, wherein A is S; A is CR4R5; R4 is wind, bottom, R6 is nitrogen, and R7 is wind. 71. The compound according to item 70 of the scope of patent application is 5- (3-bromo-4-fluorophenyl) -5,8,9,10 · tetrahydro · 1Η · thyrano [3,4-b] Xanthroline · 4,6 (3Η, 7Η) · 2-15- This paper is applicable to the standard of the middle and poor countries (CNS) A4 specification (210 × 297 mm) --------- ^ ----- -^ ------ 0 (Please read the notes on the back before filling out this page) Λ8 BS C8 D8 Among them, eight are NR: where 'is 9- (3-bromo-4-fluorobenzene, the scope of patent application is based on The compound of the patent application No. 1 has the formula νπ: R, Rs or a pharmaceutically acceptable salt thereof, wherein A is NR2, 0 or s; Ri is a phenyl substituted with 1 or 2 of the following substituents: halogen, NO2, CN, CF3, and OH; Fluorenyl, or benzopyrimidazole; R2 and R3 are fluorene, c] -4 alkyl or phenyl-Cid alkyl; R4 'R5, R6 and fluorene or C ^ .4 alkyl. 73. Compound according to item 72 of the scope of patent application, * 7 &gt; · According to compound at item 72 of scope of patent application, A is NR2; is hydrogen; I is hydrogen; I is gas; and is hydrogen "75 The compound group according to the scope of the application for patent No. 74) -2,3,5,6,7,9-hexahydro Only) _ Ketone U_ ~ • Emulsions. 'According to the 72th application scope of the patent application, where a is 0-16 home kneading rate (CNm4 ^ (210 predicate reading)! III »II 11.. (This page) Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 44248 5 A8 B8 C8 ______ D8 VI. Patent Application Range 77. The compounds according to item 72 of the patent application range, where A is 0; R4 is hydrogen; R5 Is hydrogen; I is hydrogen; and K · 7 is hydrogen. 7S. The compound according to item 77 of the scope of patent application is selected from the following group-group: 9- (3-bromo.4-fluorophenyl) -2, 3,5,9-tetrahydro_411_piperano [3,4_b] pyreno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide; (+)-9 -(3-brook, 4-fluorophenyl) -2,3,5,9-ρ hydrogen-4H-piperano [3,4-b] pyreno [2,3-e] pyridine-8 ( 7H) -one 1,1-dioxo; (-)-9- (3-bromo-4-fluorophenyl) -2,3 ,; 5,9_tetrahydro-4H-pirano [ 3,4-b] pyrimido [2,3-e] pyridine-8 (7H) -one 1,1-dioxide; 9- (3-cyanophenyl) -2,3,5,9 -Tetrahydro-4H-pyrano [3,4-b] pyreno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide; (+) _ 9- (3_ Aminophenyl) -2,3 , 5,9_tetralactam-4H-pyrano [3,4-b] &gt; * S · pheno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide; (-)-9- (3-cyanophenyl) -2,3,5,9-tetrahydro-4H-piperano [3,4-b] pyreno [2,3-e] pyridine- 8 (7H) -one 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -2,3,5,9-tetrafluorene-4H-anhydro [3,4- b] thiophene [2,3-e] pyridine-8 (7H) -one 1,1-dioxide; (+)-9- (4-gas-3 · nitrophenyl) -2, 3,5,9-tetrahydro_4H-weirano [3,4-b] pyrimido [2,3-e] pyridine-8 (7H) -one M-dioxide; -17- paper Standards: Chinese National Standard (CNS) 8-4 (2Ι0 × 29? Mm) --------- ^ ------ 1T ------ line (please read the first Please fill in this page again for attention) Printed by the Central Government Bureau of the Ministry of Economic Affairs and Consumer Cooperatives A8 B8 C8 D8 6. Scope of patent application (-)-9- (4-chloro_3_nitrophenyl) _2,3, 5,9_tetrahydro-4Η_piperano [3, xin ^ pheno [2,3-e] pyridine_8 (7H) _one 1, 丨 _dioxide; (+)-9- ( 4-fluoroiodophenyl) -2,3,5,9-tetrahydro-4H-piperano [3,4-b] pheno [2,3-e] pyridine_8 (7H) _one 1 ; 1_dioxide; and (+ 9- (4-fluoro-3-erphenyl) -2,3,5,9-tetrahydro-4H -Piperano [3,4-b] pyreno [2,3-e] pyridine-8 (7H) -one 1,1-dioxide. 79. The compound according to item 72 of the scope of patent application, wherein a is s. 80. The compound according to the scope of application for item i has the formula νιπ: Or a pharmaceutically acceptable salt thereof, wherein A is NR2, 0, or S; Ri is a phenyl substituted with 1 or 2 of the following substituents: halogen, no2, CN, CF3, and OH 'substituted with nitro's P Cephenyl, or two tons of benzoP; R2 and R3 are hydrogen, Cm alkyl, or phenyl-Cm alkyl; R4, Rs, 6 and R7 are hydrogen or C 1.4 amyl. 81. The compound according to item 80 of the scope of patent application, wherein A is N R2. 82. The compound according to item 80 of the scope of application for patents, where A is NR2; R4 is nitrogen and R5 is martial arts, -18- This paper is applicable to the countries with difficulties in China (CNS> 8 4 standard (210 X 297) Xian) ^ 1T line (please read the note f on the back before filling in this page) 4 42 4 8 5 A8 BB C8 D8 Air stupid 9 (5H), where A is 0, among which 6, the country that applied for patent R6 is hydrogen; And R7 is hydrogen. 83_ The compound according to item 82 of the scope of the patent application is _〇_ (3_bromofluorene) -3,4,6,7,8,10-hexahydro_2H-n [3; .2-b] [1,7] Botan, ketone 1,1-dioxide. 84. Compound according to item 80 of the scope of patent application 85. Compound A according to item 80 of the scope of patent application Is 0;. R4 is nitrogen, is nitrogen, R6 is hydrogen; and R »7 is nitrogen. 86. The compound according to item 85 of the scope of the application for patent, which is 丨 〇_ (3_ 漠 *) -3,4 , 6,10-tetrahydro_2H, 5H_piperano [3,4 b] thyrano [2 3'-padimidine-9 (8H) -one 1,1_dioxide ^ 'e] nt 87. The compound according to Item 80 of the patent application park, where A is s. 88.-A kind of compound for the treatment of asthma, epilepsy, hypertension, Raynaud's sign Group, headache, pain, eating disorder, functional intestinal disorder, neurodegenerative j partial wind, urinary incontinence, and male or female dysfunction medical composition, including 2 therapeutically effective amount of the compound accepted according to the scope of the patent application Active ingredients and pharmaceutically acceptable carriers. The pharmaceutical composition according to the scope of the patent application "item is used to treat urinary incontinence. 90 90. The pharmaceutical composition according to the scope of patent application 88 is used to treat males 19-present Paper scale (use 8 TCNS in China) Α4 wash grid (2 丨 0X29 * 7mm) ---------- Installation ------ Order ------ Paper "Please Ask the note $ on the back of the mackerel first and then copy the ears) Printed by the Male Workers Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 4.2 48 5 A8 B8 C8 D8 6. Applicants for patent dysfunction and premature ejaculation 91. According to the scope of patent application The pharmaceutical composition according to item 88 is for treating females who have orgasm deficiency, insufficient clitoral erection, vaginal congestion, difficulty in sexual intercourse, and vaginal cramps. 92.-Compound of formula IX: ΝΗ, IX. Wherein Α is selected from 0 , S, and NR2, wherein R2 is hydrogen, Ci-4 alkyl, or phenyl-C 2.4 alkyl (Please read the notes on the back before filling this page). Packing. Order printed by the Central Laboratories of the Ministry of Economic Affairs, the Shellfish Consumer Cooperatives «. -20- This paper size applies to China National Standards (CNS) A4 Xiege (2 丨 0X297mm) 4 42 increase S858478 patent application A8 Chinese amendments to the scope of the patent application (March 90) Seal printed by the Bayou Consumers Cooperative of the Central Bureau of Plant Planning, the Ministry of Economic Affairs *. Scope of patent application 1. A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein η is 0 or 1; m is 1 or 2; m + η is not 3; A is NR, 0, or S; A 'is NR3, 0, S, or CR4R5; D is C (0); D 'is C (0), S (0) or S (0) 2; R〗 is a phenyl group substituted with 1 or 2 of the following substituents: dentin, no 2 CN, CF 3 and OH 'substituted by nitro, sedenyl, or benzo P cedadiazole R2 and R3 are hydrogen, alkyl or phenyl-Ci.4 alkyl; R4, R5, 116 and 117 are hydrogen or C]- 4 alkyl; and when EΓ is S (0) or S (0) 2, then A1 is CR4R5. 2. The compound according to item 1 of the scope of patent application, wherein a is NR2. 3. The compound according to item 1 of the scope of patent application, wherein a is 0. 4. The compound according to item 1 of the scope of patent application, wherein A is s. 5. The compound according to item 1 of the scope of patent application, has the formula I v: (Fill in this page again.) This paper is a Chinese standard (CNS) A4 ^ (210X297 mm)