TW200523254A - Large conductance calcium-activated k channel opener - Google Patents

Abstract

The present invention provides a large conductance calcium-activated K channel opener comprising a compound of the formula (I): , wherein R1 and R3 are each sulfonamide, carbamoyl, acyl, amino, and the like, m and n are each 0 to 2, R2 and R4 are each cyano, nitro, hydroxyl, an alkoxy, a halogen, or an alkyl, Ring A is benzene or a heterocyclic ring, Ring B is benzene, a heterocyclic ring, a cycloalkane etc, and Ring Q is pyrazole or isoxazole, or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

200523254 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a potassium channel opener activated by high-conductivity calcium, which can be used for frequent urine (P0lakiuria), urinary mcotinence, asthma (Asthma), chronic obstructive pulmonary disease (COPD), cerebral infarction (cerebral infarction), subarachnoid hemorrhage (subarachnoid hemorrhage) and other symptoms or diseases. [Prior art] Potassium-based cells have the most cations and are important in maintaining physiological homeostasis. Potassium channels exist in almost all spinal cells, and these channels are essential for maintaining hyperpolarized resting membrane potentials. 0 high-conduction activated potassium channel openers (also known as BK channels or maximum potassium channels) are particularly Appears in neurons and smooth muscle cells. Because increased intracellular feed concentration and membrane depolarization activate the largest potassium channels, the largest potassium channels are considered to play a decisive role in regulating electromagnetism-dependent calcium influx. Increased intracellular calcium concentration can mediate many processes, such as the release of neurotransmitters, contraction of smooth muscle, cell growth and death. In fact, the opening of the largest potassium channel can cause strong membrane hyperpolarization and thus inhibit these calcium-induced reactions. Therefore, by inhibiting the physiological responses of the mediators of different depolarizations, the substance with the activity to open the maximum potassium channel can be used for treatments such as cerebral infarction, subarachnoid hemorrhage, and frequent urination. ), Urinary incineration 316408 5 200523254 (urinary in Cotinin) and other diseases. It has been reported that drugs that open BK channels have the ability to inhibit electrical contraction of airways induced by guinea pigs. (L Pharmac () 1 Εχρbird, (Retrospective) 'vol. 286: pp. 952-958). Therefore, it can be effectively treated, for example, asthma, COPD and so on. At the same time, it has been suggested that medicines that can open the bk channel can be used as medicines for treating sexual dysfunctions such as erectile dysfunction (World Patent No. 00/34244). Various reports have been made on high-conductance calcium-activated potassium channel openers. For example, a pyrrole derivative (for example, World Patent Case No. 96M0634), a furan derivative (for example, Japanese Patent Case JP2000-351773-Α 唬), a nitrogen-containing 5-membered ring derivative, in which the nitrogen starts with Phenyl or phenylfluorenyl (e.g., World Patent No. 98 / 〇4135), diphenyltriazole derivatives (e.g., J. Med. Chem, 2000, Vol. 45, Nos. 2942 to 2952), and so on. On the other hand, cyclooxygenase inhibitors such as Celecoxib, Valdecoxib, etc. have been used as therapeutic agents for inflammation related diseases such as chronic wind arthritis, etc. However, There have been no reports on the use of these compounds for high-conductance calcium-activated potassium channel openers (for example, Japanese Patent Nos. JP09-9506635-A and JP09-500372-A). Furthermore, as for related compounds, it has been known that Dbitazole derivatives can be used as neurotensin receptor antagonists and cyclooxygenase inhibitors (for example, 'Japanese Patent No. jP11_5〇4624_A, JP63_〇22〇8 〇_a, j ·

Am · Chem · Soc · ’1997, vol. 119, pp. 4882 to 4886, 6 316408 200523254, and J. Med. Chem., 1997, vol. 40, pp. 1347 to 1365). [Summary of the Invention] The object of the present invention is to provide a compound having potassium channel opening activity with excellent high-conduction calcium activation, and which can be used to treat diseases such as frequent urination, urinary incontinence, asthma, COPD, cerebral infarction, subepidermal hemorrhage and the like. The inventors of the present case have conducted intensive research to solve this problem. As a result, they have found that the following compounds have excellent high conduction_activated_channel opening activity to complete the present invention.

In other words, brother S, the present invention is as follows: · Enter the "Biography" tongue opener, which contains the chemical formula ⑴

(I)

The ring surface of the ring filaments; the B ring is a stupid, heterocyclic ring, naphthene or Q yuan is selected from the group of the formula: ^-… 3

R: may be the same or different from each other, and: is a group selected from the group consisting of: 316408 7 200523254

R5 and R6 may be the same or different from each other, and each is (1) hydrogen, (2) optionally substituted alkynyl, (3) substituted cyclic alkyl, which may be substituted with aryl Fused, (4) optionally substituted aryl groups, (5) optionally substituted heterocyclic groups, or (6) alkoxycarbonyl groups, or fluorene 5 and R6 may be combined to form optionally substituted Heterocyclic ring, the heterocyclic ring system is bonded to the atom bonded to R5 and R6; R7 is 0) hydrogen, (2) a substituted alkyl group as required, and (3) a substituted cycloalkane as required. The cycloalkyl group may be substituted with an aryl group, an aryl group, or an aryl group; R is hydrogen, an alkoxy group, a hydroxyl group, a cyano group, or an optionally substituted alkyl group; repair m and n may be Same or different from each other, and 夂 ό Α Λ… V ,, — 1

u aη, or R1 and R2 may be mutually bonded, alkoxymethyl, but if m is Η, and if n is 2, they may be combined to form a ring A and two R4 may be… ^ ^ A group selected from the group consisting of: 316408 8 200523254

Or R3 and R4

r5 ,, / S

R5, R5-N (B Φ combined with the B ring to form a group selected from the following chemical formula

N group; R5

R5 \

P is an integer from 1 to 3 · R13 (1) As needed Substituted alkynyl '(2) nitrogen, (3) chlorine, fluorene halogen, = substituted amine, (6) alkenyl, (7) optionally substituted amine terbium-pentyl (8) 1 oxygen Carbonyl, (9) retyl, (10) heterocyclic group, (1) L) hydroxyl, or (12) alkoxy. And 2. The high-conduction 弼 activated potassium channel opener as in item 1 above, wherein the substituents of the optionally substituted alkyl group of R5, R6, and R7 are 1 to 7 independently selected fumes and / or 1 to 3 groups selected from: 9 316408 200523254 rB, nx, R9: 0 R8:% 〆. , R9 1 R9 0 1 ti RB, N, NX, H, 〇II R8, C \ 1 〇R, 〇 乂, R10, / N R'1 · r8, ctn \ ιί. 〇n ^ Re, 〇, crN , II, 〇〇2 R8, S, n / R9 'V :, R9 〇2 轳 02 rB / N, n, S \ · H R12-0 ^ re, s, N = C— if necessary, substituted Cyclic group and optionally substituted aryl groups, wherein R8 and R9 may be the same or different from each other, and each is a fluorene nitrogen, a fluorene alkyl group, or a hydroxy group may be substituted by aryl groups or Need to be substituted by a substituted cyclic group, (3) hydroxyalkyl, pinaneoxyalkyl, pinane lactyl, (6) substituted heterocyclic group or optionally substituted aromatic group The radical 'or ⑻ can combine R8 and R9 to form a substituted heterocyclic ring, which is bonded to the atom to which R9 is bonded; Ri0 is the same as or different from each other, and each is ⑴ hydrogen The alkynyl group can be replaced by an aryl group that is optionally substituted or a heterocyclic group that is substituted by f as necessary: to replace the '(3) fluorenyl group, (like an oxalyl group, a fluorenyl group, fluorene Hydrazone, hydrazone or (8) optionally substituted heterocyclic group Base circle; R, Department of ⑴wind '(2) 垸 group' Qian group can be substituted by aryl A :: see as needed :, 'disubstituted heterocyclic group, ⑺hydroxyalkyl group, (:), Urethane (5) Substituted heterocyclic group as needed.

2 :: High-conductivity calcium-activated potassium channel opener of item 1, where B% is benzene, heterocyclic ring, ring-burned or ring-diluted, and W is selected from the group of the following formula ... 316408 10 200523254

R3 is a group selected from the group consisting of:

r5, (AR and R, f, R5-〇- r5 〇2 〇2 XH RVS ,, R5 into R6 R7, r6 R5 system (1) hydrogen '(2) alkyl group' The alkyl group can be from 1 to 7 Independently selected halogen and / or 1 to 3 groups selected from:

R ~ 〇, N ^ c— 〇2 r8, n, s〆 〇2

, Optionally substituted heterocyclic groups and optionally substituted aryl groups, (3) optionally substituted cycloalkyl groups, the cycloalkyl group may be fused with an aryl group, (4) optionally substituted Aryl 'or (5) optionally substituted heterocyclic group · R6 is hydrogen, alkyl or alkoxycarbonyl, or R5 and R6 can be combined to form a substituted heterocyclic ring as required, the The heterocyclic ring system is bonded to the atom bonded to R5 and R6; R7 is hydrogen, alkyl or alkoxycarbonyl; 316408 200523254 R8 and R9 may be the same or different from each other, and each is a tritium group, a trityl group, the group The radical may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group plus =, ⑶ via a radical, (4) an oxygen radical, (5) if necessary = a heterogeneous radical of $ The ring group '(6) is optionally substituted aryl, or (?) May combine R8 and R9 to form a optionally substituted heterocyclic ring, and the heterocyclic ring system is bonded to R8 and R9. Atoms of the bond are bonded; R10 and R11 may be the same or different from each other, and are each a hydrogen atom, a halogeno group, and the alkyl group may be substituted by an aryl group or a substituted aryl group if necessary. Net aromatic group be substituted, (3) the burning group, (4) burning burning oxygen group, (5) (iv) burn Jiaji ⑹ yl wide, depending ⑻ ⑺ wire g for a wire instead heterocyclic group; soil

Rl2, fluorene hydrogen, (2) alkyl, which may be substituted by an aryl group substituted as necessary or a heterocyclic group to be substituted, (3) a hydroxyalkyl group, (4) Alkoxyalkyl or (5) optionally substituted heterocyclic groups; m and η may be the same or different from each other, and each is a puppet or] •, and R and R may be the same or different from each other, and each is Keto, cyano, nitryl, mesityl, alkoxy, halogen or optionally substituted alkyl. 4. The high-conducting calcium-activated potassium channel opener as described in item 1 above, wherein B% is (1) benzene or (2) selected from thiophene, pyridine, pyrimidine, pyridine, benzothiophene, 2,3 --- Hydrogen, D, D, 2,3-dihydrobenzofuran, and ′, benzodioxane heterocyclic ring or (3) cyclohexene; R is a group selected from the following chemical formula: 316408 12 200523254

R5, J, R6 RX R5 / 〇, Nj \ R6 9 ί r5 / C, nX, R6

〇2 Q

It R5, S, NX \ R6 R6

RV r6r7 02 〇 2 n? 2 R5, I \ rS \ R5 / N, N, S \ r5 /, R6 R6 R3 is a group selected from the following formula: R5, i X rs R6 R7 R7 R system (1) hydrogen '(2) Baking group' ::!: The end group may be substituted by i to 7 independently selected halogens and / or 1 or 2 groups selected from: R8, · X r \ R8,0 , Shovel, optionally substituted heterocyclic group 圑 and optionally substituted aryl, optionally substituted cycloalkyl, the cycloalkyl may be fused with an aryl, (sentence substituted aromatic as needed Or (5) optionally substituted heterocyclic group; R6 is hydrogen or an alkyl group, or can be combined to form a heterocyclic ring which can be substituted, and the heterocyclic ring system is bonded to r6 R7 is hydrogen or alkyl; R and R may be the same as each other or their m is self-fluorinated hydrogen, (2) alkynyl, which may be substituted by an aryl group if necessary or substituted without a group if necessary The group is substituted by fluorinated or (4) oxyfluorinated groups; ^ R10 and R11 may be the same formula as each other, 0 々, different times, and each item is U) hydrogen, (2) alkyl, ^ 16408 13

200523254; k group can be substituted by aryl group if necessary or heterocyclic group if necessary, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) optional Substituted heterocyclic group; 1 9 R is (1) chloro '(2) alkyl group, and the alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) oxyalkyl or (5) optionally substituted heterocyclic groups; di and n may be the same or different from each other, and each is 0, 1 or 2; R and R4 May be the same or different from each other, and are each a keto group, a cyano group, a nitro group 3, a methyl group, an alkoxy group, a halogen group, or an alkyl group which may be substituted with a hydroxy group; The radical may be selected from the group consisting of a halogen, a radical, a silk radical to be substituted, a cyano 1 radical, an amino methyl group, a hydrogen atom: a substituted amino group if necessary, and an imine substituted if necessary. Group is substituted with '(3) alkenyl, or (4) heterocyclic group. The potassium channel opener activated by the high-conducting calcium of item 1 in item A, where A is a benzene, thiophene, amidin, or pyrazole;

Rld — a heterocyclic ring of the original di’ane, or (3) cyclohexene R is a group of the formula: · 〇 X s I6 9 R $, R tr, ο ο, R6 r6 ·

H RV 《R6

〇2 R5 / N, S \, H R5, 〇,

316408 14 200523254 R3 is a group selected from the following chemical formula: R5, R6 RV > R6R7 Η R is (1) hydrogen, (2) alkyl, the alkyl can be selected from i to 7 independently And / or 1 or 2 groups selected from:

R12-0 '′ substituted heterocyclic group if necessary and substituted Fangmei if necessary, (3)

A cycloalkyl group fused to an aryl group which may be substituted by a hydroxyl group, or (4) a heterocyclic group; R6 is hydrogen or an alkyl group, or R5 and R6 may be combined to form a heterocyclic ring. The group ring may be substituted by hydroxyalkyl; R7 is hydrogen or alkyl; R, R9, R1, and R11 may be the same or different from each other, and each is (1) a gas, (2) an alkyl group, the alkane The group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) a hydroxyalkyl group, (4) an alkoxyalkyl group, and (5) an optionally substituted heterocyclic group Group, or (6) optionally substituted ± 1 aryl group. R, is (1) 氲 '(2) alkyl group, the alkyl group can be substituted by ^ United States or if necessary Heterocyclic groups are substituted, (3) hydroxyalkyl, (^) less oxyalkyl or (5) optionally substituted heterocyclic groups; m and η may be the same or different from each other, and each is 〇, 1 or 2; R2 and R4 may be the same as or different from each other, and are each a cyano group, a nitramyl group, an i-line, an alkyl group, or an alkoxy group; Group, the alkyl group may be Alkoxy group substituted with alkoxy group, ^ 316408 15 200523254 ytyl methyl group, oxoyl group, amine group which can be substituted by a benzyl group, can be i An imino alkenyl group substituted with a hydroxy group or (4) 4,5-dihydrooxazolyl. 6 · As in any one of the items 1 to 5 above, the value of the activated potassium channel opened by r Ren Zhenzhi.

Rl is a group selected from the following formulas:

Rs μ R6 ο ο \, kg N, n, c \ R5 ^ n ^ R6 〇2 # z〇, N, Sl H, 7 kinds of compounds represented by chemical formula (la) or their classes: / 、 面 永 上Acceptable, N〆R6 R5, N, N, S \ R5 ',' f \ r R1a

(I; wherein the A ring system is heterogeneous or heterocyclic ring is dilute; 4′8% 4 ring, heterocycle, ring, or Q ring system is selected from the group of the formula: R13 \ ^ = \ R13

R is selected from the group consisting of:

R 13 RS; rc \ θΆ R6 ′ Η R5〆. Dagger 6

R5〆, N 0 Λ 316408 16 200523254 R3 is selected from the group of the formula: 〇 〇 R, yC \ r5 / 〇, n / C \ R6, accounting for 6

V Ο R5 person r5, q 』\ R5 \ n /,, R6 R5

R5? 2 R, isrs, R6 R7 R5〇—

RV r6r7

-c = c—

H, r5'S \, R5, N, n, s \ R5〆ό, ν,! 5: f? This is the same or different 'and each is hydrogen, (2) as needed: the factory: ^ 基,' ( 3) A substituted cycloalkyl group may be substituted as required, and the cycloalkyl group may be substituted with iH: (4) optionally " " to be substituted aryl, (5) optionally substituted hetero: group, or (6 Oxygenation, or ⑺ can make R5 and R6 combine to form a bonded atomic combination / ㈣ ring family ring system and the bond with mouth V ^, ticks, ⑺ as needed by the replacement of silk, (3) as needed Substituted spring group, the fluorenyl group can be fused with an aryl group, depending on the need to be substituted aryl '(5) alkoxycarbonyl group; R is a hydrogen sulphonyloxy group n, cyano or optionally substituted The radicals may be the same or different from each other, and each is 0, bt2; R ′ ,, _R may be the same or different from each other, and each is a keto group, a cyano group, a nitro group, an oxo group, a sodium compound, Group, oxo group, optionally substituted aminomethyl group, optionally substituted amine group, or optionally substituted cyano group '; but if ^ 2, two r2 may be _ or different from each other, and If 316408 17 200523254 η is 2, the two can be The same or different; or Rla and R2 may combine to form selected from the group of the formula and Ring A:

Or R and R may be combined to form a group selected from the following formula with the B ring: RR5Jr ^ vb

R13 is (i) a substituted alkyl group as needed, (2) a cyano group (5) a substituted amine group as needed, (6) a dilute group I ', its tincture, 1) a substituted group as needed曱 fe group, (8) alkoxycarbonyl group, (9) carboxyl group, or m) alkoxy group; a group of groups' ⑴ ⑴ but ⑴ does not include the following compounds Q ring system in which A ring and B ring are benzene ) k ^ R13 ^ is a hydroxyl group, a substituted alkoxy group at position 2 or a substituted alkoxy group at position 6 of the R system, and a tertiary R13 (") alkoxycarbonyl or carboxyl group, -1- N- (3-isopropyloxypropyl) -4- (3-fluorenyl-5-phenylsulfanyl) 316408 200523254 sulfonamide, (ill) 4- (1- (4-aminosulfonylbenzene) Group) -3-difluorofluorenyl-1H_pyrazol_5-yl) benzidine, and (1V) 4- [5_ (4-aminobenzyl) -3- (3-hydroxypropyl)- 1Η-pyrazol-1-yl] -N-methylbenzoxoxime. &Amp; \ As the compound of item 7 above or a pharmaceutically acceptable salt thereof, wherein R, R6 and R7 are treated as needed. Substituents of substituted alkyl are from 1 to 7 independently selected functions and / or from 3 to 3 groups selected from:

A substituted heterocyclic group and an optionally substituted aryl group, where R8 and R9 may be the same or different from each other, and each is a tritium gas, and the fluorenyl group may be substituted by the required Or, if necessary, substituted, the heterocyclic group is substituted with '(3) prostitutes, reels, and oxo groups' (6) optionally substituted heterocyclic groups or as needed: The aryl group 'or fluorene can combine R and R9 to form a substituted% group ring as required, and the heterocyclic ring system is bound to an atom bonded to RV by 82. ^ R " may be the same or different from each other, and are each a hydrogen atom, a halogeno group, which may be substituted by an optionally substituted aryl group or a substituted heterocyclic group 316408 19 200523254 group ( 3) fluorenyl, (4) oxo, (5) -yl, pentane% fluorenyl, (7) alkoxycarbonyl or (8) substituted heterocyclic group if necessary; R system (1) Hydrogen '(2) alkyl, which can be substituted by optionally substituted aryl or optionally substituted heterocyclic groups, (3m alkyl, alkoxyalkyl, (5) A substituted heterocyclic group is required. 9. The compound as described in item 7 above or a pharmaceutically acceptable salt thereof, wherein the B ring is a benzene, a heterocyclic ring or a naphthene;

Rla is a group selected from the following chemical formula:

R5 c r 〆, nx, accounted for 6 R3 is a group selected from the following chemical formula: 〇2 Vr5, S, N, C \ R6 η V ΗΓ 〇 rc, r5-〇, n-c \ r5 ′, nA R6 R6 H R5,

R5, // c \ r6, r7

R is (1) hydrogen '(2) alkyl, which may be substituted by i to 7 independently selected halogens and / or 1 to 3 groups selected from:

A substituted heterocyclic group and an optionally substituted aryl group, if necessary, a substituted cycloalkyl group, the cycloalkyl group may be fused with an aryl group, (6 substituted aryl groups if necessary Or (5) optionally substituted heterocyclic group; and R tick or alkyl, or R5 and R6 can be combined to form optionally substituted 7 heterocyclic ring, the heterocyclic ring system Combined with the atom bonded to R6, R is hydrogen, alkyl or alkoxycarbonyl; 3164408 20 200523254 R8 and R9 may be the same or different from each other, and each is (1) 氲, (2) alkyl The alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) a hydroxyalkyl group, (4) an alkoxyalkyl group, and (5) an optionally substituted group. Heterocyclic group, (6) optionally substituted aryl group, or (?) Can combine R8 and R9 to form optionally substituted heterocyclic ring, the heterocyclic ring system and R8 and R9 The bonded atoms are bonded; R10 and R11 may be the same or different from each other, and each is a tritium gas, a pyrenyl group, and the alkyl group may be substituted by an aryl group or a substituted group if necessary. Heterocyclic group is substituted, (3) fluorenyl group, fluorenyl group, fluorenyl group, fluorenyl group '(7) alkoxy group or 杂环 substituted heterocyclic group if necessary; R 仏⑴Hydrogen '(2 into a group, the alkynyl group may be substituted by an optionally substituted aromatic group or a substituted heterocyclic group s, and the fluorenyloxyalkoxyalkyl group or (5) may be substituted as required Heterocyclic group; m and η may be the same or different from each other, and R and R4 may be the same or different from each other, and each is a g group, a cyano group,

Radical, hydroxy, alkoxy, halogen or optionally substituted alkyl. 1: The compound according to item 7 above or a pharmaceutically acceptable di-, dipyridine, benzothiophene, -benzodioxane heterocyclic B ring system (1) benzene or (2) selected from thiophene , Pyridine, melamine 2,3-dihydroindole, 2,3-dihydrobenzofuran, and ethnic soils;

Rl 3 is a group selected from the formula: 316408 200523254 R6

丨 R5 ^

R3 is a group selected from the group consisting of:

R6 * R6 1 R6 R5, / R, C〆NF \ R6, R6 R7 R5 (1) hydrogen '(2) alkyl group The alkyl group can be selected from i to 7 independently selected halogens and / or 1 Or 2 groups selected from:

Lu's optionally substituted heterocyclic group and optionally substituted aryl group, (3) optionally substituted cycloalkyl group, the cycloalkyl group can be fused with aryl group, (4) optionally A substituted aryl group, or (5) a substituted heterocyclic group if necessary; R6 is hydrogen or an alkyl group, or R5 and R6 may be combined to form a heterocyclic ring which may be substituted by a hydroxyalkyl group, the heterocyclic ring The family ring system is bonded to the atom bonded by R5 and R6; R7 is hydrogen or alkyl; _ R and R9 may be the same or different from each other, and each is (丨) hydrogen, (2) alkyl, and the alkyl may be borrowed by Substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) a hydroxyalkyl group or (4) an alkoxyalkyl group; R10 and R11 may be the same or different from each other, and each is ( 1) hydrogen, (2) alkyl, which may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group. If necessary = substituted heterocyclic group; R is (1) hydrogen, (2) alkyl group, which can be substituted by aromatic Fangmei 316408 22 200523254 = if necessary, and substituted by heterocyclic group group Instead, ⑺㈣ group, (4) oxygen alkyl or (5) the optionally substituted heterocyclic group; m and η may be the same or different from each other, and are each. R2 and R4 may be the same or different from each other, and each is a fluorenyl group, an aryl group, a nitrocarbyl group, an alkoxy group, a sulfonium group, or an alkynyl group which may be substituted by a group; 'The alkynyl group can be selected from halogen, alkynyl, and optionally, substituted alkoxy, cyano, aryl, optionally substituted amine, and optionally substituted imine, (A group, or a fluorene heterocyclic group. 11. The compound according to item 7 above or a pharmaceutically acceptable salt thereof, wherein the A ring is benzene, thiophene, Dlidine, or sialamine; pyrimidine, pyridine, The benzothiophene B ring system (1) benzene, (2) a heterocyclic ring selected from thiophene, pyridine, and 1,4-benzodialkylene;

Rla is selected from the group of the following chemical formula: R5 ,, N〆, occupying 6 R6 ~, R5 ', ii R3 is selected from the group of the following chemical formula: R5, Λ R5, R5 ,, R6 r6r7, RV "Η R5 Is (1) hydrogen, (2) alkyl, which may be substituted by i to 7 independently selected halogen and / or 1 or 2 groups selected from: R9, optionally substituted Heterocyclic group and optionally substituted aryl group, (?) 316408 23 200523254 cycloalkyl group fused with aryl group which may be substituted by hydroxyl group, or ρ6 ^ #, ^ ^ wood 隹% group group; R Is lice or alkyl, or can be combined with R6 and the heterocyclic ring may be substituted by hydroxyalkyl;% of the force, the R7 is hydrogen or alkyl; and Γ: are the same or different from each other, and Each of them is hydrogen,), and it can be replaced by an aryl group or a heterocyclic group substituted as necessary, (3) a calcined group, (4) Ί a substituted heterocyclic group as required Group, or if necessary, substituted with a clay base, R12 series, '(2) silk', the calcining group can be substituted by a substituted ^^ = heterocyclic group to be substituted Replace, (3) after burning Radicals, elementary radicals or (5) optionally substituted heterocyclic groups; 'and η may be the same or different from each other, and each is 0,] *]; ^ and H4 may be the same or different from each other, and Each is a cyano group, a hydroxy group, a hydroxy group, a halogen, an alkyl group, or an alkoxy group; and a W-based fluorinated hydrogen (2) alkyl group, which alkyl group may be selected from Halo and phenyl radicals substituted with alkoxy, aryl, weenyl, amino, «, alkoxy, amines which can be substituted with phenyl, = selected from alkoxy 烧The imidyl group is substituted with a radical of a radical, ⑶ fine or (4) 4,5-dihydrooxazol-2-yl. a. A drug comprising the compound according to any one of items 7 to n above or a pharmaceutically acceptable salt thereof. 3. The drug as described in the above 12 J member, wherein the drug is a potassium channel opener activated by a high conduction mom. 14. · High-conductivity activated potassium as in any one of items 1 to 5 and 13 above 316408 24 200523254 Channel opener 'wherein it is suitable for ^., Achuan ¥ Calcium-activated potassium channel opener is frequent urination Loss of indication, qi σ when fighting, η a brother or prevention and / or treatment of COPD. 15. A chemical formula ⑴ Mu l: a compound or a pharmaceutically acceptable salt thereof R1

(I) in which the A ring or heterocyclic ring is a ring benzene or a cycloolefin; the Q ring is selected from the group of the following formula ...) k ^ R13, a heterocyclic ring,

Ri and R3 may be the same as each other or not

R 13 is the same, and each is a group selected from:

r5 and R6 may be the same or different from each other and are each (1) hydrogen, (2) 316408 25 200523254 substituted alkyl as needed, (3) cycloalkyl substituted as needed, the cycloalkyl may be different from aryl Fused '(4) optionally substituted aryl, (5) optionally substituted heterocyclic group, or (6) alkoxycarbonyl, or (7) R5 and R6 can be combined to form a A substituted heterocyclic ring is required. The heterocyclic ring system is combined with an atom bonded to R6. R system (1) hydrogen '(2) substituted alkyl group as needed, (3) Substituted cycloalkyl, which can be fused with aryl, (4) substituted aryl as needed, (5) alkoxycarbonyl; R14 is hydrogen or cyano or as needed M and η may be the same or different from each other, and each is 0, 1 or 2; • R2 and R4 may be the same or different from each other 'and each is a keto, cyano, acyl, carboxyl, alkoxy, halogen, Carboxyl group, oxo group, optionally substituted amine group, optionally substituted amine group, or optionally substituted alkynyl group; but if S is 2 ′, two R 2 may be the same or different from each other, and Moreover, if η is 2 ′, two R4s may be internally separated, R may be different from each other, or R2 and R2 may be combined with the A ring to form a group selected from the following chemical formula;

Or R3 and R4 may be combined to form a group selected from the following chemical formula with the 6 ring 316408 200523254

P is an integer from 1 to 3; and R13 is (1) an optionally substituted alkyl group, (2) a cyano group, (3) hydrogen, (4) a halogen, (5) an optionally substituted amino group, ( 6) Alkenyl, (7) optionally substituted amido, '(8) oxo', (9) retyl, (10) heterocyclic group, (η) hydroxy, or (12) Alkoxy; but does not include the following compounds, in which the A ring is stupid; B ring is benzene, pyridine or naphthene; Q ring

Where R13 is fluorene, alkyl, or haloalkyl; R1 is sulfonamido or alkanesulfonyl; 3 R is hydrogen, alkyl, or alkoxy; and if 1η is 1, R2 is hydrogen; or m is. And if n is 1, R4 is hydrogen, alkoxy or alkyl; or n is 0. 16. The compound or the pharmaceutically acceptable salt thereof as described in item 15 above, wherein the substituents of the optionally substituted alkyl group of R6 and R7 are halogens and / or 1 to 7 independently selected by them 3 groups selected from the following: 316408 27 200523254 200523254 9 f Ο Re Li c, r8, n, n々R9, HO R8, C,

Jji H R12〆0, R8 into ... · NSC—

O RV, optionally substituted heterocyclic group and optionally substituted aryl,

Wherein R8 and R9 may be the same or different from each other, and each is a chlorochloro group. The M may be substituted by a filamentary mystery or an = cyclic group as needed. ) Burning the base, depending on whether the f group is substituted with a material group or the aryl group through which it needs to pass, or R8 and R9 can be combined to form a heterocyclic ring which is optionally substituted, the heterocyclic ring Is bound to the atom to which R9 is bonded. Ri and R may be the same or different from each other 'and are each a nitrogen atom, a halogen atom, the

The alkynyl group can be substituted by a substituted aryl group or a heterocyclic heterocyclic group as required. (3) via an alkynyl group, _oxy alkynyl group, (5) a fluorenyl group, and arsenite 2 Group, ⑺ alkoxy group or ⑻ depends on the heterocyclic group to be substituted; R, system ⑴ hydrogen '(2 into a group' The silk can be substituted by an aromatic group or a substituted hetero group if necessary. Cyclic group is substituted, (3) M group, (dialkoxyalkyl '(5) substituted heterocyclic group if necessary. 17. A potassium channel opener activated by a high-conductivity office, such as The compound represented by formula (I) in item h or 16 above, or a pharmaceutically acceptable hydrazone, '. K is a high-conductivity word of any one of the items in above item 316408 28 200523254 channel opener, Neither R1 or R3 is hydrogen. 19. The compound of item 15 or 16 above or a pharmaceutically acceptable salt thereof, wherein neither R1 or R3 is hydrogen. 20. A kind of high-conductivity calcium activated Potassium channel opener, containing the compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof as an active ingredient: R1b

/, The A ring and the B ring may be the same as or different from each other, and are each benzene, pyridine, cyclohexane, or cyclohexene; Rlb is a group selected from the following chemical formula: RVx r " Vx. RVr,

H RSrs,, r5, 0, n, sI accounted for 6 and other symbols have the same meaning as defined above; but P is preferably the meta or para to which it is bonded, and more preferably the The para 'and XA1 rings are each preferably benzene or less. 1. A potassium channel opener with high conduction anesthesia, comprising the compound represented by the following formula or a pharmaceutically acceptable compound thereof: R1b

316408 29 200523254 where each symbol has the same meaning as defined above; but R1 b is preferably bonded to the meta or para position of the A! Ring, more preferably to the para position of the A1 ring, and Αι The ring and β1 ring are each preferably benzene or pyridine. Ο Ο,%. • A high-conductance calcium-activated potassium channel opener, containing the compound of the following chemical formula or a pharmaceutically acceptable salt thereof as an active ingredient:

R

t! Each: The numbers have the same meaning as defined above; ^ 疋 ^ #parents are bound to eight! The meta or para position of the ring is more preferably bonded to the para position of the ^ ring, and the Al ring and the jealous ring are each preferably benzene or hydrazone. -Gateway; calcium activated potassium channel opener, containing the following chemical compounds or their pharmaceutically acceptable salts as active ingredients: R1b

Let θ plb / 定义 have the same meaning as defined above; ren 疋 hamb is preferably bound to the para position of the A1 ring, and Al is tender or para position, and more preferably 24. salts: 24.- Each of the following chemical species is preferably benzene or D specific bite. Two pounds of compound or its pharmaceutically acceptable 316408 30 200523254

Each symbol has the same meaning as defined above; but 疋 R R6NCO- is preferably bonded to the meta or para position of the Aι ring, more preferably to the para position of the A1 ring, and the V ring and the Each of the rings is preferably or 口. ^ Spring 25. A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof: &

Each of the symbols has the same meaning as defined above; but R5R6NCO- is preferably bound to eight! The meta or para position of the ring is more preferably bonded to the para position of the A1 ring, and each of the Ai ring and the Bl ring is preferably benzene or bite. 26.—A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof: and 316408 31 200523254.

Wherein each symbol has the same official meaning as defined above. I M: 5R6N ^ 0; ^ ^ ^ ^ A1 ^ ^ ^ or ^ at the para position of A%, and the A1 ring and the β1 ring are each preferably benzene

27. A compound represented by the following chemical formula or a salt thereof: a Pharmaceutically acceptable 〇

Each of these symbols has the same meaning as defined above; but R5R6NCO- is preferably the meta or para to which it is bonded, more preferably: the para to the A 丨 ring and the A1 ring and the Bi ring Respectively or pyridine. 28. Black poplar A, as in any one of items 20 to 23 above, a new fluorene opener that is activated only by calcium conduction of Y, wherein R3 is a group selected from the following chemical formula:

R5, Η 316408 32 200523254 29. The compound according to any one of items 24 to 27 above or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of the following 圑:

R6

R5, Η 30. The high-conductivity active deactivating opener as described in any one of items 20 to 23 above, wherein R5 is an alkyl group which can be selected from 丨 to 7 independently selected halogens and / or 1 To 3 groups selected from:

And optionally substituted heterocyclic groups. 31. The compound according to any one of items 24 to 27 above or a pharmaceutically acceptable salt thereof, wherein it can be selected from one to seven independently selected halogens and / or one to three selected from The following groups:

And optionally substituted heterocyclic groups. 32. A compound represented by the following chemical formula or a pharmaceutically acceptable compound thereof

Each symbol has the same meaning as defined in the "member" above; 316408 33 200523254 However, the A1 ring is preferably benzene or D than the bit, and the q ring is preferably

3 3 · The compound according to item 32 above or a pharmaceutically acceptable salt thereof, wherein the A1 ring is benzene or pyridine. 3 4 · The compound according to item 32 or 33 above or a pharmaceutically acceptable salt thereof, wherein R1 ring is hydrogen or methyl, m is 0, R4 is methyl, and n is 35. The calcium channel-activated potassium channel opener includes a compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof as an active ingredient:

Each symbol has the same meaning as defined above; however, the A1 ring is preferably stupid or pyridine, and the Q ring is preferably

Pharmaceutically acceptable

36. A compound represented by the following chemical formula or its relatively salts: I 316408 34 200523254 R12

Where q and r are each a unitary number from 1 to 6, and g # is a positive number and the other symbols have the same meaning as defined above;

However, the [R120 (CH2) q] [RU〇 (CH2) r] CHN (R6) c0_ group is preferably bonded to the meta or para position of the A1 ring, and more preferably to the ring In the para position, the two R12 may be the same or different from each other, and the Al ring and the β1 ring are each benzene or pyridine. ° 37. — A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof:

Wherein each symbol has the same meaning as defined above; but the [Rl2〇 (CH2) q] (Rl2〇) CH (CH2) rN (R6) C0- group is preferably bound between the A1 rings The para or para position is more preferably bonded to the para position of the Al ring. The two R12 may be the same or different from each other, and the Al ring and the β1 ring are each preferably benzene or pyridine. t 316408 200523254 38 · —Salts with the following chemical formulas:

Where s and t are each an integer from 0 to 6, ruler and R are each hydrogen or alkyl, and the other symbols have the same meaning as defined above. "But R120 (CH2) tC (R) (R, The (CH2) sN (R6) c0- group is preferably bonded to the meta or para position of the A1 ring, and more preferably to the para position, two R12 may be the same or different from each other, and Al Each of the ring and the β1 ring is preferably benzene or D ratio.

39. A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof: X

Each symbol has the same meaning as defined above; however, the R9R8NCO (CH2) qN (R6) CO- group is preferably bonded to the meta or para position of the ^ ring, and more preferably to the Aι ring And the Al ring and the B ring are each preferably benzene or D ratio σ. 316408 36 200523254 Pharmaceutically acceptable 40. — A compound represented by the following chemical formula or a salt thereof:

However, r9〇cON (r8) (CH2) hetero 6) ⑶- group is preferably a bond, meta- or para-fertilization of soil, more preferably bonded to the para-position of the A1 ring, and is more The rings are each preferably stupid or pyrite. Each symbol has the same meaning as defined above.

In A1 A1 ring 41 · A salt represented by the chemical formula:

Wherein Het is optionally substituted heterocyclic groups which have the same meaning as the above definitions; but, he is a member of Het (CH2) qN (R6) C0- group which is preferably bound to a1 or para is more preferably bonded to the A! ring, and f is preferably benzene or pyridine. Ring 々 42.-A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof: 316408 37 200523254:

Bonded to the A1 ring and the A1 ring and

Each symbol has the same meaning as defined above, but the HetN (R8) (CH2) qN (R6) C0- group is preferably in the meta or para position, and is more preferably bonded to the Al ring pair. Position, the B ring is preferably benzene or D ratio. 43 · —Salts of the formula:

_ Where z is an alkyl group, a halogen or an optionally substituted amine group, and the other symbols have the same meaning as defined above; but R1 is preferably ^ bonded to the meta or para position of the A1 ring, more It is preferably bonded to the para position of the A1 ring, and each of the A1 ring and the Bi ring is preferably benzene or pyridine. 44. The compound according to item 43 above or a pharmaceutically acceptable salt thereof, wherein R1 is a group selected from the following chemical formula: ′, 316408 38 200523254

Each symbol has the same meaning as defined above.

A compound represented by the following chemical formula (U) or a pharmaceutically acceptable salt thereof:

R1

13 (M) wherein Rle is selected from the group consisting of:

—S— R1 R5 5, Bar ^ A: R6 R7 r5-c = c- 0 〇 /, N ^ \ ^, accounting for 6 R5〆% Η RW F ^ 6 R7 human isrl r5 / 〇, n <, R6 or more The compound with the same meaning as defined in the chemical formula (η) or its pharmacy 316408 39 200523254 D1d

Where Rld is selected from the group of the formula: R5〆0, N〆 R6

〇 A Ύί

R6 R7 ii -C = C— R5 / C, NX, R6 f〇2 r5-N, N, S, Η 〇2 R5z〇, lsTS \, R6, 〇2 ^ R5 / S, NX, • / R14 N r5, n people, R6, R6 R7 and other symbols have the same meaning as defined above. 47. A compound represented by the following chemical formula (1-3) or a pharmaceutically acceptable salt thereof:

(R4) n

F (R2) R: wherein Rle is a group selected from the following formula: 40 316408 200523254 Ν R6 ί ^ 〇, ίΤ R6 Ν R6 〇

R Y RsIi R5 " V .RV ° VA!

f 02 r5 / N, n / S, H, 14 _ 〇 2 〇n,, r w and other symbols have the same meaning as defined above. 48 · —A compound represented by the following chemical formula (1-4) or a pharmaceutically acceptable salt thereof: R 1f

(W) r5 \ 〇 R5 ^ 0 R5 / 〇, N, C, y, 5Η RVN, C〆 r6 l6, p R5〆. , Σ 〇2 〇 RVSY r5—s— RV & ‘R7» Ϊ R6 〇2 ^ 〇2 A 〇2 R5 / S, R5〆1% ’, R5〆0, /,, H, k6

14 ν n U2 ii U, and V, r1c '., Rr and other symbols have the same meaning as defined above. 4 9. Jfrj p », • The compound of any one of items 45 to 48 above or a pharmaceutically acceptable salt thereof 316408 41 200523254 X, wherein R5, Han6 or R7 optionally substituted alkyl 1 to 7 independently selected halogens and / or 3 to 3 groups selected from F are substituted: Λ

R8 NTC \ R9 R9 Rs, N, N

〇2 accounts for 9, Λ

R12〆0 ,, Re, s, · N = C— a substituted heterocyclic group as necessary, and an optionally substituted aryl group; wherein each symbol has the same meaning as defined above. 50 A high-conductance calcium-activated potassium channel opener, where the chemical formula r or a pharmaceutically acceptable salt thereof is shown as ==

R6 f ^ 7 R6

R

Wherein Rlg is selected from the group of the following formula: and the other symbols have the same meaning as defined above. D 帛 5 High-conductivity 1 $ activated feed channel opener of item G, 1 in κ is transported from the group of the following formula ... /, τ 316408 42 200523254 r12〆. "Office r9, Γ R 12 / 〇,

Het ^ l · H each symbol has the phase as defined above: 52. A compound represented by the chemical formula τ is acceptable above 52. Salts:

Wherein R g is selected from the group of the following formula: R5 / S / R5 32 R6 ☆, Γγ γ, and the other meanings have the same meaning as defined above. 53. The compound of the above item 52 or a pharmaceutically acceptable salt thereof, wherein R in i is selected from the group of the following chemical formula: "

Each symbol has the same meaning as defined above. 43 316408 200523254 54. A high-conductance calcium-activated potassium channel opener, containing the compound represented by the following formula or its pharmaceutically acceptable salt as an active ingredient: R1! 1

Wherein Rlh is selected from the group of the formula: R5, R6 R5〆0,

R 丨 5 / and other symbols have the same meaning as defined above. The high-conductance calcium-activated potassium channel opener as in item 54 above, wherein R is a group selected from the following formula:

R 12

R 12, 〇 D 12 ^ 〇

Each symbol has the same meaning as defined above. 56. A drug comprising the compound 3 of any one of items 15, 16, 19, 24 to 27, 29 132 to 34, 36 to 49, 52, and 53 above, and 3 pharmaceutically acceptable salts. : 7. The drug according to the above item »56, wherein the drug is a highly conductive two activation: _ channel opener. : 8: If the high-conducting calcium-activated potassium channel opener of item 57 above, t = high-conducting calcium-activated potassium channel opener is used for the prevention of frequent urination, urinary loss, asthma or COPD and / or deal with. In the following, a 316408 44 200523254 group represented by a representative symbol in this specification will be explained. Examples of the "alkyl" and "alkoxyalkyl" and "alkylsulfonyl" include straight-chain or branched Cl-C6 alkyl groups, preferably straight-chain or branched CrC4 alkyl groups, More specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, pentyl, hexyl, and the like. "Hydroxyalkyl" can be exemplified by a straight or branched C6 alkyl group substituted by a hydroxyl group, preferably a straight or branched Ci_C4 alkyl group, more specifically hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxybutyl, hydroxybutyl, etc. Examples of the alkoxy group among "alkoxy" and "alkoxyalkyl" and "alkoxycarbonyl" Such as a straight or branched Ci_C6 silk group, preferably a straight or branched CVC4 alkyloxy group, more specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, tertiary butoxy, pentyloxy, ethoxy and the like. "Functional elements" include fluorine, chlorine, bromine and iodine. Examples of the "alkyl" group include straight-chain or branched C1_Q alkyl groups. Compared with: straight-chain or branched Cl-C4 alkyl groups, more specifically, methyl-, ethyl-, and acetyl groups , Butanyl, pentamyl, hexamyl and so on. "Cycloyl" can be exemplified by a cvcj group substituted with 1 ^, preferably a CrC4 alkyl group, and moreover, 齅 ^ /, limb tick, dichloromethyl, fluoromethyl, dimethyl, Trifluoromethyl, 2,22-dichloro, ^^, acetone, 3 'lactyl, 3-fluoropropyl, 4-lactyl, 4-fluorobutyl and the like. Examples of "dental oxy" include Ci_c6 ^ oxy substituted with halo, CA oxy, and more specifically methoxy, dichlorofluorenyl, 316408 45 200523254 methanoxy, difluoromethyl Oxy, trifluorofluorenyloxy, 2,2,2-trifluoroethoxy, king fluoroethoxy, 3-chloropropoxy, 3-fluoropropoxy, gas-butoxy, 4-fluorobutoxy Base and so on. The "alkenyl" may be exemplified by a linear or branched CrC6 alkenyl group, preferably a linear or branched C ^ C: 4 alkenyl group, more specifically vinyl, allyl, and methyl-2-propenyl , 3-butenyl, 2-pentenyl, honhexenyl, and the like. "Aryl" may be exemplified by monocyclic, bicyclic or tricyclic c6-14 aryl, preferably Cm aryl, more specifically phenyl, naphthyl, phenanthryl, anthracenyl and the like. Particularly preferred are phenyl and Zeki. ► `` Aralkyl '' can be exemplified by linear or branched

Ci-C0 alkyl, preferably straight or branched C "C4 alkyl, more specifically benzyl, 2-phenethyl, phenethyl, 3-phenylpropyl and the like. "Cyclo" may be exemplified by c ^ c: 8 cycloalkyl, preferably C3-C6 cyclo $, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The "cycloalkyl group fused with an aryl group" includes, for example, a -C8 cycloalkyl group, preferably a C3-C6 cycloalkyl group, which is fused with an aryl group (preferably a phenyl group). Specific examples include hydrogenated benzyl and tetralin compounds. "Cyclopenthrene" and "Cycloalkyl fused to an aryl group" may contain substituents such as mesyl, yttrium, Ci_c4 alkyl, Ci_c4oxy, etc., preferably mesyl. Specific examples of the substituted cycloalkyl group which is fused with an aryl group include a 2-alkylene group and the like. The "heterocyclic group" includes, for example, a monocyclic or bicyclic 5 to heterocyclic group which may be partially or completely saturated. The heterocyclic group contains i to 4 selected from nitrogen, oxygen, and sulfur. Heteroatom. The monocyclic or bicyclic heterocyclic group which may be partially or completely saturated may be substituted with a keto group. 316408 46 200523254 ㈣Γί heterocyclic group is preferably enumerated as may be partially or completely ^ to 7 shell heterocyclic group, the heterocyclic group contains! To 4 'Murapine 1 and sulfur heterogen +, and specifically, such as addiction. Sigma bases, pyrrolyls, pyrazolyl groups —a # 土 — [kilopyryl, pyrimidinyl, pyrimidinyl, tetramethyl, hydrazine, hexahydrophenyl Group, pyridoxyl, morpholinyl, tetrahydronanyl, tetrahydrofuranyl, imidazolidinyl, oxazolyl and the like. The bicyclic heterocyclic group is preferably exemplified by a bicyclic heterocyclic group fused with two of the same or different monocyclic heterocyclic groups above, or the above monocyclic heterocyclic group A bicyclic heterocyclic group fused with benzene, and specifically exemplified by dihydroindolyl, tetrahydroquinolyl, and the like. Examples of the "heterocyclic ring" of the A ring and the B ring include monocyclic or bicyclic 5 to 1GM heterocyclic rings which can be partially or completely saturated, and the heterocyclic ring contains 1 to 4 selected from nitrogen , Oxygen and sulfur heteroatoms. Specific examples of the heterocyclic ring include thiophene, sulfan, D-bile, bis-sial, thia-sial, taste-sal, sulfonium, 1,2,4-sulfone. Sit, U, 4_ drink dioxin, π specific bite, 定 定, 哄, coax ,: plowing, hexahydropyridine, hexahydropyridine, tetrahydropyridine, dihydropyridine, pyrrolidine, orthopyridine, four Hydrogen Π pentene, hexahydro D homopendme morphine, homopyrine, tetrahydropyran, benzo [b] thiophene, benzo [b] furan, indole, 2,3-dihydro Indole, 2,3-dihydrobenzyl [b] furan, M_benzodioxane, / quinoline, 1,5-benzodioxetine, pyridoxazole, pyridimidazole, benzo Isoxazole, benzothiazole, pyridothiophene, and benzimidazole. Of these, Z is roaring bite, pyridine, pyrimidine, dagen, thiazole, pyrazole, pyrrole, thiophene, and indole, and particularly preferred are pyridine, thiophene, and pyrazole. Examples of the "cycloalkane" of the B ring include C3_Cs naphthenes, preferably C3_C6 316408 47 200523254, and more specifically cyclopropane, and cyclobutane is preferably cyclopropane. j pentane,% hexane, etc. Examples of the "cycloolefin" of the β ring include A-cycloolefin, and more specifically cyclopropene, cyclobutane, and cyclohexene.戍% hexene and so on. "Ring" and ", a heterocyclic group formed by the bonding of the atoms bonded by Wif j" Han is composed of R and R9 and the atom to which they are bonded. > Examples include pyrrolidine, concrete, and other specific materials.疋, hexa, morpholine, thiomorpholine, heterocyclic cyclic materials, 柿 柿 烷 alkane lactyl, (iv) can be glutamate soil (U1) _ group, ⑺ alkane A Sheng ~ Benji Xun Temple Add a substituted alkoxy group, == take diamine ... Substituted amine group, and: two :) can be r group, benzyl and so on: add L: f element; Cycloalkynyl, etc., R's moonyl, (5) dilute group; fluorene can be substituted for oxy, meridian, etc. by adding a substituted imine group; fluorene can be substituted by amine, aromatic silk, etc. (8% oxoyl; (9) heterocyclic group; etc .. Preferred examples of substituted heterocyclic ring substituents include those substituted with ?? Three 5- or 6-membered monocyclic heterocyclic groups selected from the heteroatoms of nitrogen, oxygen, and sulfur. Akashi is said to be preferably methyl and 316408 48 200523254, sigma. R5, R6, and R7 Preferred examples of the substituted aryl group include a hydroxy-substituted alkyl group. A specific example of the substituted aryl group is a 2-hydroxyfluorenylphenyl group. A substituted alkyl group of R, R6, and R7 The substituents can be listed as Halogen and / or 1 to 3 groups selected from the following formulas: • (A) (B) (C) (D) [) R9 R9 〇2 τ. R8n ′ ,, 1 .. (I) (F ) (G) (H) B 〇2 V,. A (J) 〇2 R8 people, ^ 〇2 rB / N, nzS, (K) H (L) R12-0, 9 R8 people · N = C— (M) (N) (〇) RVr,. Rvi (E) (P) optionally substituted heterocyclic group and (Q) optionally substituted aryl 'wherein each symbol has the meaning as defined above Same meaning. Among the above, (A), (F), (Η), σ), (M), (〇), Lu (P), and (Q) are preferred, and (A), (F), (Η), (μ), (P), and (Q). The heterocyclic group as the substituent of the substituted alkyl group of R, R, R, or Het is preferably pyridyl, pyrazolyl, pyridyl, pyrimidinyl, tetrazolyl or thiazolyl. The heterocyclic group may be substituted with an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, or the like, and is preferably substituted with a fluorenyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, or the like. Examples of the substituent of the substituted aryl group of R8, R9, R1G, R11, and R12 include a halogen, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, and the like. 316408 49 200523254 Heterocyclic groups of R 11 R, R, and R12 are preferably exemplified by cynosyl, pyrazolyl, pyridyl, orthothiazolyl, tetrazolyl, or tetrahydropiperyl Thio. The heterocyclic group may be an alkyl group, a southern alkyl group, a hydroxyl group, an alkoxy group, and the like, and a heterocyclic group related to RH ^ Rn is particularly preferable. Regarding the heterocyclic group of R, a base or a tetrahydrowarnan group is particularly preferred. Regarding heterocyclic groups of R, 4,5-dihydrooxazole is particularly preferred. Examples of R or R's substituted aminoformyl group and substituted amino group include, for example, halogen, hydroxy, alkoxy, amine, or mono- or dialkylamino. Examples of the substituent of the substituted alkyl group of R4 and R4 include alkyl group, alkyl group, halogen group, and the like. Examples of the substituted alkyl group include hydroxyamidobis 2-hydroxyethyl, methylamidomethyl, trifluoromethyl, and the like. Examples of the substituted group of the substituted alkyl group of R13 include (1) halogen, hydroxyl, (3) haloalkoxy, (4) alkoxy which may be substituted with halogen, alkoxy, phenyl, etc., (5) Amino groups substituted with alkyl, hydroxyl, etc., (6) cyano, (7) alkoxycarbonyl, (8) carboxyl, (9) can be substituted with alkyl, phenyl, etc. Substituted amine groups, and (10) imino groups which may be substituted with alkoxy, hydroxyl, and the like.乂 丨) halogen, (2) hydroxyl, (4) alkoxy substituted with halogen, alkoxy, phenyl, etc., (6) cyano, (8) carboxyl, (9) alkoxy And amine groups substituted with alkyl, phenyl, and the like, and (10) imino groups substituted with alkoxy, hydroxyl, and the like. The substituted amine group of R13 may be an alkyl group, a phenyl group, or the like. The substituent of the substituted aminoamino group of R13 may be an alkyl group or the like. The substituted group of the substituted alkyl group of R may be a cyano group, a halogen group, a vial group, 316408 50 200523254 alkoxy group, and the like. The substituted amine group of z may be an alkyl group or the like. Examples of the pharmaceutically acceptable salts of the present invention may include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, and acetate, fumarate, Organic acid salts such as oxalate, citrate, formate, slate g double salt, tosylate or maleate. Examples of the compound containing an acidic group such as a carboxyl group include alkali-containing salts (for example, alkali metal salts such as sodium and potassium salts, alkali salts such as calcium salts: metal salts, triethylamine salts, and the like). Organic base salts or amine salts such as lysates, etc. tHS 1 λ The compound of the present invention or a pharmaceutically acceptable salt thereof includes solvates such as its 4 salts and hydrates.

: In the compound of the present invention, asymmetric carbons may exist) = isomers, and the compound (1) of the present invention may include any isomers and mixtures. In addition, cis-form and trans-form may exist. In the case where the synthetic compound of the present invention has a double bond or a cycloalkanediyl moiety, an unsaturated bond such as a carbonyl group may exist in the compound of the present invention. Master Mutation Book: The compound (1) of the second invention may contain any of these compounds. The compound of the invention may be prepared by the following method. Furthermore, unless otherwise specified, the following methods will be used

316408 51 200523254 Explained as pyrazole or isoxazole of the Q ring. However, if other corresponding starting materials are used, the following compounds can also be prepared in a similar manner. Mouth

Related Reaction Method The reaction related to R1 can be performed similarly to the phase with R3.

Method 1: Compounds in which the Q ring is pyrazole and R13 is an optionally substituted alkyl, alkenyl, or heterocyclic group can be prepared by the following method: 2 (III)

13a (R2), > -R13a + (R2) (I-a) νηνη2 (V)

13a (VI) where R13a #, optionally substituted alkyl, # group or heterocyclic group, trans "is methoxy and alkoxy such as ethoxy or imidazole, and other symbols have The same meaning as defined above. According to J. Am. Chem. Soc., Vol. 72, 2948 to 2952 316408 52 200523254, 1950's method, the reaction between compounds (II) and (III) can be in A It is carried out in the presence of bases such as sodium lindenate, sodium ethoxide, and sodium hydride. The compound (IV) and the compound (V) or a salt thereof (for example, hydrochloride) are used in a cereal (for example, hydrazone) Alcohol, ethanol, isopropanol, ethylene glycol, DMF, DMS (acetic acid, water, or mixtures thereof) at room temperature to the reflux temperature of the solvent for 1 to 24 hours to obtain compounds (I-a) and (VI ). The resulting reaction mixture is subjected to recrystallization or chromatography to isolate the compound (I_a).

Method 2: Compound (I-a) can also be prepared by the following method:

R1

(VII) > 13a

In the formula, R is a methyl group, an ethyl group, and other alkyl groups; X is a halogen or an optionally substituted alkylsulfonyloxy group (preferably trifluorosulfanylsulfonyloxy group); and γ is a B (0H ) 2, -B (〇Ra) 2 or -Sn (Ra) 3, where Ra is an alkyl group; and other symbols have the same meaning as defined above. The reaction between the compounds (VII) and (V) can be performed in a similar manner to the reaction between the compounds (IV) and (V) in Method 1 316408 53 200523254. Measure ^ Conversion of compound (VIII) to compound (vm) by a conventional method using a halogenating agent (for example, phosphorus oxychloride and oxybromide breaking ο or a stigmatizing agent (for example, three gas sintered lithoflavin needle) -a), and then in the presence of a palladium catalyst, the compound (VIII-a) is reacted with the compound to obtain a compound (〖_ &). Regarding the palladium catalyst, it can be used moderately, for example, (triphenylene Phosphine) palladium (〇), bis (triphenylene) palladium (π) and palladium acetate (η) and other zero or divalent palladium catalysts. When using y-based -B (〇Η) 2 or -B (OR In the case of the compound (IX) of (2), a base is preferably added in the reaction. For the base, an inorganic base such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal phosphate, or an alkali metal fluoride, or Organic bases such as triethylamine. Any solvent can be used as long as the solvent does not negatively affect the reaction. Examples of this solvent include DME, THF, dioxane, DMF, dimethylacetamide, toluene, benzene And mixtures thereof. The reaction is generally carried out at 60 to 150 ° C, suitably 80 to 120.0, and generally carried out at i to 24 hours. Method 3: Q pyrazole ring system and laugh-based group R13 or halogen compounds can be prepared by the following method: 316 408 54 200 523 254

In the formula, p is a third butoxycarbonyl group or a benzyloxycarbonyl group, and each symbol has the same meaning as defined above. The compound (I_b) is mixed with a nitriding agent (for example, diphenylphosphoryl azide) at j0 ° C to 15 (TC, in an alcohol (for example, tertiary butanol and benzyl alcohol) and a base (for example, three In the presence of ethylamine and diisopropylethylamine), react in a solvent (for example, ethyl acetate, ethylene glycol, dimethyl alcohol, DMF, DMSO, and di-t-qinrutan) for 30 minutes to 10 hours The compound (I_c) is obtained. In this method, an activator (for example, gas ethyl carbonate, ethyl gas carbonate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, and phenyl chlorocarbonate), and Nitrided steel undergoes an azide reaction. The compound (I-c) is treated with an acid (for example, or according to a conventional method, (IC,). Hydrogen acid and tetrafluoroacetic acid), and catalytic hydrogenation is performed so that the compound can be prepared.

Use of nitrosate, sodium acid, linoleic acid, organic dietary compounds such as' isopentane in solvents (e.g., water, acetic acid, hydrochloric acid, hydrobromic acid, nitric acid 316408 55 200523254, or mixtures thereof) Nitrile) and the like to convert the compound (I_C,) into a diazo compound, and then the diazo compound and a nucleophile (for example, lithophonic acid, chloric acid to vaporize cuprous hydrogen / stearic acid-cuprous bromide) , Moth, moth potassium and moth sodium) react to obtain compound Gd). The reaction is generally between -2 ° C to 100 ° C: (and proceeded) and is generally performed for 10 minutes to 10 hours. Method 4: Q soil is saliva and R13 is aminoamino, cyano, or as needed Compounds having a methyl group substituted with aralinyl can be prepared according to the methods described in j. Med. Chem., Vol. 40, pages 1347 to 1365, 1997 and Japanese Patent No. 09-506350. Method 5 : The compound (Ie) in which the Q ring is isoamylazole and R13 is an optionally substituted alkyl, alkenyl or heterocyclic group can be prepared by the following method:

56 316408 200523254 Each symbol in the formula has the same meaning as defined above. Compound (X) is reacted with sea-based amine or a salt thereof (e.g., hydrochloride) in a solvent (e.g., water, methanol, ethanol, or a mixture thereof) to prepare compound (XI). The reaction is generally performed at a temperature from 0 ° C to the reflux temperature of the solvent. Fortunately, the temperature is from room temperature to 50 ° C, and the reaction is generally performed for i to 24 hours. In the case of using amines, it is better to perform the reaction in the case of nitrogen carbonate (for example, nitrogen carbonate). Let compound (XI) and compound (XII-a), (χ: _ such as, and, in, and ㈣ 钟) reacts in the presence of the compound (xm) to obtain the compound (xm). This is all in the _ delay until the ice block cools Wen Qi ^ 丄 main 24 hours. In a solvent (for example, methanol, 7 ^ in, φ, # Ethyl%, benzene, methylbenzene, xylene and chloroform (xm) to obtain the compound (Ie). ^^ and p-toluene acid) treatment chemical refluxing temperature is performed, and-two to the solution method 6: Compound (M) can also be prepared by the following method

316408 57 200523254 Each symbol in the formula has the same meaning as defined above. The reaction between the compound (XIV) prepared according to Chem · Commun ·, pages 1558 to 59, 2001, and the compound can be similar to the reaction between the compound (VIII-a) and the compound (IX) in Method 2 The method is performed to obtain a compound (If). Method 7: Compound (I) can be prepared by the following methods: R1,

, Γ

H 'A HalY ^ \ > LX (r2, R3-f B (R4) n (XIV-a) (XlV-b) where each symbol has the same meaning as defined above. By the conventional method, the halogenation is used. Agents (for example, bromine, chlorine, iodine, and N-bromosuccinimide ammonium compound (XIV_a) to give compound (xiv_b). The reaction between compound (xw-b) and compound (XIV_a) can be similar to compound ( Vllll-a) and compound (IX) are carried out by a method.

The Rl-s〇2N (r5) (r6) compound can be prepared by the following method 316408 58 200523254

Each symbol in the formula has the same meaning as defined above. In ~ J (for example, chloroform and dichloromethane), the cooling temperature of ice cubes = the reflux temperature of the agent, preferably at room temperature, treated with M acid Compound (Ig) 'i is obtained from 1 to 48 hours to obtain compound (χνυ.) If necessary, in the presence of a base (for example,' triethylamine), or an excess of compound (XVII) is used to make the characters Γγντ, t 仏The compound (XVI) and the compound (XVI) react with the compound (XVII) at a temperature from the β part of the ice cube to room temperature for 1 to 24 hours, and the compound (Ih) is obtained. Method 9: R1-NH, The compound can be prepared by Method 6: 7 times wrong by the following

(H) (xvni) Each symbol in the formula has the same meaning as defined above and above. Acid, aerobic, in the presence or absence of solvents (such as' acetic acid, acetic acid, 316408 59 200523254 monochloride, carbon monosulfide, ethyl chloride or mixtures thereof), using nitric acid, mixed acids Compound (I-g) is treated with acetamyl nitrate, etc. to obtain compound (XVIII). The reaction is generally at -20. 〇 to 100. 〇, and generally 30 minutes to 12 hours. Compound (XVIII) in a solvent (for example, water, methanol, ethanol, butane, THF, di-D, etc., ethyl acetate, acetic acid, dioxin,

Or a mixture thereof) to obtain compound (1)). The reduction reaction can be carried out using sodium pentoxide, lithium borohydride, and lithium aluminum hydride, or using a metal (for example, iron, zinc, and :), or by using a transition metal (for example, -carbon, onset of oxidation, Raney = ney And their catalytic hydrogenation. In the case of catalytic nitriding, the hydrogen source can be formic acid, formic acid, M_cyclohexane, etc. This is usually performed at -2 (TCi 15th generation, And it usually takes 30 minutes to 48 hours. Method 10: The compound can be obtained by the method

Rl is -NHCOR5 or -NHS〇2R5 y or is prepared by the following method: 316408 60 200523254

R3-f B) (R4) n (1-1) Each symbol in the spring style has the same meaning as defined above. The N-halidation or N-stone yellowing of compound (I-i) can be carried out in a solvent under the presence of presence. Examples of the solvent include THF, dioxane, diethyl ether, ethylene glycol dioxane, benzene, dioxane, dioxane, chloroform, toluene, dioxane, DMF, DMSO, water, and Its mixture. Examples of the base include potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide oxidation, diethyl version, -isopropylethylamine, 1,8-diaza-one spring [5 · 4.0] undecane-7-ene (DBU), pyridine and 4-dimethylaminopyridine. The reaction is generally carried out at -80 ° C to 150 ° C, and it is generally carried out for% shovels for 48 hours. Knife Method 11: Preparation: R1 -COOR5 or -CONW compounds can be prepared by the following method 316408 61 200523254

Each symbol in the formula has the same meaning as defined above. The compound (XIX) is reacted with a cyanating agent (for example, sodium cyanide and acetonitrile, such as acetonitrile, D coffee, DMF, or a combination thereof), and the reaction is obtained within 24 hours. Compound (XX). Compound (X): It is prepared by using catalyst-free catalysts such as diphenylphosphine peak and zinc cyanide and cyanating agent.… Using thallium (for example, hydrochloric acid and sulfuric acid) or test (for example, sodium hydroxide and Lice potassium oxide) causes the compound (XX) to be hydrolyzed in a solvent (for example, water, methanol, ethanol, propanol, tertiary butanol, ethylene glycol, diethylene glycol or a mixture thereof) to the compound (1,) The reaction is generally carried out in the 0 to 15 generations, and is generally carried out for 30 minutes to 48 hours. Alternatively, the compound (Im) can also be prepared by Method 6 or 7 316408 62 200523254.: = Where it exists Next, at _2 ... to room temperature, react "vn) or compound (χχι) 3. Tiller (-〇) or compound (In). Use test (for example, sodium hydroxide (E.g., water, methanol, ethanol, diisocyanate)

Hydrogenation in ethylene glycol (ethylene glycol or a mixture thereof) to obtain a compound (1_0) in which R5 and R are hydrogen. (2) in the presence of a condensing agent (for example, u_dicyclohexylcarbodiimide, 丨 _ethyl (diaminoamidopropyl) carbodiimide, carbonyldiimidazole, and diethyl cyanophosphate) In the case, if necessary, the compound (I_m) is condensed with the compound (XVH) or the compound (XXI) in a solvent (for example, DMF, THF, and dioxane) to obtain the compound (1-0) or the compound (I -n). The reaction is generally carried out in the range of 30 to 24 hours. If necessary, the reaction using the blending agent can also be performed in the presence of hydroxybenzotriazole, N-hydroxysuccinimide, and the like. (3) The compound (I-m) is converted into a carbonate (a mixed acid anhydride of gaseous ethyl carbonate, gaseous ethyl carbonate, etc.). Then, in the presence of a base (for example, triethylamine and pyridine), the carbonate is compounded with the compound (χνπ) or the compound (χχι) in an appropriate solvent (for example, THF, toluene, nitrobenzene or a mixture thereof). In a solvent), the compound (1-0) or the compound (1-1-η) is obtained by condensation at room temperature to the reflux temperature of the solvent for 1 to 24 hours. 316408 63 200523254 Method 12:

R-, 0-R5 or -S-R5 compounds can be prepared by the following methods:

Each symbol in the formula has the same meaning as defined above. Compound (Ip) or compound (I_r) and compound (χχπ) in an appropriate solvent (for example, water, DMS0, DMF, toluene, THF, or a mixed solvent thereof) in a base (for example, sodium hydroxide and hydrogenation) Sodium) is reacted in the presence of 2 ° C to the reflux temperature of the solvent for i to 24 hours to obtain the compound or compound (Is). Method 13: Compounds of R1-series-SorR5 can be prepared by Method 6 or 7, or by the following method: 64 316408 200523254

Oxidation

Where =: has the same meaning as defined above.

(Ml) (I'S) and oxidants (for example, m-chloroperbenzoic acid and chrysophyllum spp.) In a suitable formula (such as acetic acid, dioxin, chloroform, dichlorofane or mixtures thereof). The reaction time is 30 minutes to 2 to obtain the compound (It). ^ Method 14: R1 system-S02N (R6) OR5 or -CON (R6) OR5 compound or Ri system-so2nhn (r5) (r6) or -CONHN ( The compound of R5) (R6) can be prepared by the following method: 65 316408 200523254

or

〇

(xxm) 〇

In the formula, Hal is halogen such as chlorine and bromine, and other symbols have the same meaning as defined above. 66 316408 200523254, the compound D (XVI-a) or the compound (χχν) and the compound (χχιΐϊ) in a suitable solvent (for example, water, ethyl acetate, DMF, dms〇, chloroform, chloroform, THF or Mixture), in the presence of a base (for example, triethylamine, sodium bicarbonate, and potassium carboxylate), react with ice cube to the reflux temperature of the solvent for 1 to 24 hours to obtain compound (I_u) or compound (i_w ). Compound (xvi-a) or compound (xxV) is reacted with compound (xχιV) in a manner similar to the above to obtain compound (ι_ν) or compound (I-X). Method 15: R-COR5 compounds can be prepared by the following methods:

Grignard reaction of compound (Iy) from compound to compound (Iy) in a solvent (eg, THF, diethyl ether, ethylene glycol difluorene, benzene, fluorene, diphenylbenzene, and dioxane) at -20 to 10 (rc) The compound (XXV) is obtained after 1 hour. The compound (XXVII) and an oxidant [for example, chromic acid-sulfuric acid, chromium (VI) -sulfuric acid-acetone (Jones reagent), chromium oxide (VI) _pyridine complex (Collins reagent ), Dichromates (for example, sodium dichromate and potassium dichromate sulfur 316408 67 200523254 acid, pyridinium chlorochromate (PCC), manganese dioxide, DMSO-electrophilic activating reagent (for example, dicyclohexyl Carbodiimide, acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, trifluoroacetic anhydride, grass gas, and autogen), sodium hypochlorite, potassium hypooxygenate, and sodium hypobromite], in -20 ° C to 100 ° C, react for 30 minutes to 24 hours to obtain compound (i_z). &Quot; Method 16: R1 system-NHS〇2N (R5) (R6) compounds prepared by the following method can be borrowed Prepared by:

Η Η

(XXVIII) R6 Η R6 I R5 / N, So2Hal

Each symbol in the formula has the same meaning as defined above. Compound (M,) is reacted with compound (XXVIII) in a similar manner to the method to obtain compound (I-aa,). '11 Method 17: The R1-OCON (R5) (R6) compound * can be prepared by the following method: 316408 68 200523254

(XXIX) R6 I R5 / N, CoHal R6

Each symbol in the formula has the same meaning as defined above. The formula of 11 allows compound (I-p) to react with compound (XXIX) in a similar manner to give compound (I-bb). Method 18: The following method is used to prepare compounds of R1 series-C (R7) = C (R5) (R6):

In the same sense, the compound (χχχ) is used to perform the compound (χχχ) on the compound (χχχ) to perform a wmig reaction for 30 minutes to 24 hours to obtain the compound (I_cc). Examples of solvents used in this reaction include water, methanol, ethanol, Tertiary butanol, thf, diethyl ether, ethylene glycol dioxane, DMF, OMSO'benzene, toluene, dioxobenzene, dioxane, dichloromethane, aerosol, digas ethane, and propionitrile For 316408 69 200523254 Sodium ethoxide, potassium tert-butoxide, butyllithium, hexamethyldisilazide, and DBU. Examples of compounds to be substituted alkyl This test includes sodium methoxide, Sodium hydride, potassium hydride, diisopropylamine bell :): menstruation, diethylamine, diisopropylethylamine, method 19: Q ring isosteazole and Rn as needed (I-dd) can be borrowed Prepared by:

In the formula, Y1 is -B (ORa) 2 or _Sn (〇Ra) 3, wherein Ra is an alkyl group, and Rhenium is a substituted alkyl group as required, and other symbols have the same meaning as defined above. ^ Using a halogenating agent (for example, gas, N-gas succinimide, and sodium hypochlorite), the compound (XXXI_a) is halogenated by a conventional method to obtain the compound (XXxi_b; >) ° Compound (XXXI-b) and Compound (XXXXX) in a solvent (for example, diethyl ether, diisopropyl ether, THF, dioxane, acetone, ethyl acetate, dioxin, h, 1,2-dichloroethane, tetracarbonated carbon, benzene, Benzene, Benzene, 316408 70 200523254 DMSO, methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, water or mixtures thereof, in a base (for example, sodium bicarbonate, bicarbonate Potassium, sodium carbonate, potassium carbonate, calcium carbonate, pyridine, and triethylamine) are reacted in the presence of compound (XXXIII). The reaction is generally carried out at -20.0 to 15 (rc performed 'preferably at 0 C to 100 C 'and it is generally carried out for 1 to 24 hours. Alternatively, the compound (XXXIII) can also be prepared by subjecting the compound (XXXIII) according to the method described in Acta chemica Scandinavica, vol. 48, pp. 01 to 07, 1994 ( χχχΐ-a) is prepared by reacting with! | chemical agents and compounds (χχχΙΙ), without Compound (χχχΐ-ΐ3) is isolated. The last compound (XXXXXII) is reacted in a manner similar to the reaction between compound (VIII-a) and compound (IX) in method 2 to obtain compound (I-dd Method 20: Q ring system is Dfazole, R1 is coon (R5) (R6), R2 is hydrogen, and a ring compound is pyrroline, tetrahydropyridine or tetrahydroazepine (1 < Magic can be prepared by the following method: 316408 200523254

In the formula, P1 is an amine protecting group such as Boc, χ is 0 or 1, and y is 1 or 2, and other symbols have the same meanings as defined above. In a suitable solvent (for example, THF, dioxane, dimethyl ether, and DME), by treating with a base (for example, butyllithium and lithium diisopropylamide), the temperature is -78 ° C to room temperature. The compound (XXXIV) is converted into a lithium compound, and then the lithium compound is reacted with the compound (XXXIV) for 1 to 24 hours to obtain the compound (XXXVI). The compound (XXXVI) is reacted with an acid [for example, trimethylsilyl polyphosphate (PPSE) ] Reaction, or the compound (XXXVI) is converted into a halide or a sulfonate, treated with a base (for example, pyridine and DBU) and deprotected to obtain the compound (XXXVII). This reaction can be performed in an appropriate solvent (for example, dioxane, aeroform, THF, dioxane and the like, DMF, and DMSO) at a temperature from 0 ° C to the reflux temperature of the solvent for 1 to 24 hours. The final compound (XXXVII) and triphosgene (triphosgene) 72 316408 200523254 and HN (R5) (r6) in appropriate solvents (for example, dichloromethane, chloroform, THF, dioxane, DMF, and DMSO) The compound (I-ee) is obtained by reacting for 1 to 24 hours at a temperature from ice cooling to room temperature. This reaction can also use (R5) (R6) NCOHal or (R5) (R6) NCO and a base (e.g., pyridine and triethylamine) instead of triphosgene and HN (R5) (R6). Alternatively, the hydroxyl group of the finally obtained compound (XXXVI) can be converted into OC (= S) SMe, and then tributyltin hydride and a radical initiator (for example, 2,2'-azobisisobutyronitrile (AIBN )) The final compound is processed to obtain a compound of A ring system D bilo bite, hexahydro D bite, or hexahydropipiperidine. Method 21: Compounds of the R1 series -CON (R6) COR5 or -C0N (R6) S02R5 can be prepared by the following methods:

73 316408 200523254 r5-c〇?

Each symbol in the formula has the same meaning as defined above. Reacting compound (I-ff) with compound (χχχνπι) or compound (χχχχχ) in the presence of a base such as 'sodium bicarbonate, potassium carbonate, triethylamine and pyridine' at -20 ° C to room temperature 30 minutes to 24 hours to obtain the compound (I-gg) or (I-hh). Method 22: A compound in which the Q ring is isoxazole and R13 is a halogen-substituted alkyl group can be prepared by the following method: 316408 74 200523254 • CH〇 (R2). R 卞 (R4) n (XLI)

(XL)

TMS-R (XLIII) 13c

co-r13c h2n〇h hci

D1

In the formula, r13c is a halogen-substituted alkyl group, and Alk is an alkyl group, and other symbols have the same meanings as defined above. This reaction can be performed according to the method described in Drug Development Research Volume 51, pages 273 to 286 (2000). ^ Make compound (XL) and compound (XLI) in a suitable solvent (for example, benzene, toluene, dibenzobenzene, acetic anhydride), and a base (for example, triethylamine, diisopropylethylamine, and D [ In the case where t is present, the compound (XUI-a) is obtained by reacting at the reflux temperature of the solvent for 1 to 48 hours. The compound (XLII-a) is converted according to a method using an alcohol (for example, methanol), and The compound is compounded with hydrazone in a suitable solvent 316408 75 200523254 j (for example: DME and THF) in the presence of a catalyst (for example, rhenium fluoride) in the range of 0.00 to 100. 〇 Reaction for 1 to 24 hours. Then, add an appropriate acid (for example, hydrochloric acid and sulfuric acid) to it to allow the reaction to proceed for 24 to 24 hours to obtain compound (xlIV). Compound (XLIV) and hydroxylamine hydrochloric acid The salt is in a suitable solvent (methanol, ethanol, isopropanol), in the presence of a base (for example, sodium acetate, triethylamine, sodium carbohydrate, and sodium bisulfate) at the reflux temperature of the solvent Reaction for 1 to 24 hours to obtain compound (XLV). ≫ Using a halogenating agent (for example, _ Potassium iodide) and sodium bicarbonate in a suitable solvent (for example, THF, dioxan, dioxan, water, and mixtures thereof), and the compound (xlv) is blocked at the reflux temperature of the solvent under the conditions of light shielding. % Reaction for 1 to 24 hours to obtain the compound (I-: ί). Method 23: Compounds of #group or oxooxy group can be obtained according to Synthesis, 1989, pages 275 to 279, and Tetrahedron Lett., 1984, Volume 25, prepared on pages 4587 to 4590. Method 24: ⑴ If used as a towel in the above method, the compound of the present invention or the starting compound contains a functional group (for example, a meridian, an amine, a cycline, etc. ), The functional group can be protected by a protective group used in the synthesis of organic chemistry to perform the reaction, and then the protective group can be removed to obtain the desired compound. The protective group via the group can be tetrahydropiperanyl, TMS, etc. The protective group of the amine group can be 316408 76 200523254, the basic group, etc. The protective group of the slow group can be a methyl group and an ethyl group, such as a benzene group, a stupid methyl group, etc. =) Ruoguang's method above Among the 'revealed compounds or starting compounds 3 are An amine group can be protected if necessary, so hydrazone can be reacted with an alkyl halide in the presence of a base (such as sodium hydride, diethylamine, sodium carbonate, and potassium carbonate) (where the alkyl group is equivalent to R5 or R6 may be reacted "as necessary", or (ii) a dialkyl azodicarboxylate and triphenylphosphine p-ol (wherein the alkyl portion is equivalent to "5" If necessary, the alkyl group is taken), and the Mltsunobu reaction is performed, and if necessary, the deprotection is performed to obtain a compound containing an amino group which is mono- or di-substituted by an optional alkyl group. 1) If in the above method, the compound of the present invention or the starting compound can be similar to the method of converting the compound (Li) to the compound (Ik) in the method 1 丨, and react with the blue The amine group is converted into the corresponding amidine. (4) If the compound of the present invention or the starting compound contains a carboxyl group in the above method, it can be reacted with amine in a manner similar to the method of converting compound (Im) to compound (1-0) in method 12 to This carboxyl group is converted into a corresponding aminoformamyl group. (5) If in the above method, the compound of the present invention or the starting compound contains a double bond, the double bond can be made by a catalyst hydrogenation using a transition metal (platinum, palladium, rhodium, ruthenium or nickel) catalyst Converted to the corresponding single bond. (6) If in the above method, the compound of the present invention or the starting compound 3 has an ester group, the ester group can be converted by hydrolysis using a base (for example, sodium hydroxide and potassium hydroxide) of 316408 77 200523254 Into the corresponding carboxyl group. (7) In the above method, if the compound of the present invention or the starting compound contains an aminomethyl group, the aminomethylthio group can be converted into a corresponding dietary compound by a reaction using trifluoroacetic anhydride. (8) In the above method, if the compound of the present invention or the starting compound contains a carboxyl group, the carboxyl group can be converted into 4,5 by reacting with 2-haloethylamine in the presence of a condensing agent. -Dihydrooxazole_2_yl. ⑼If in the above method, the compound of the present invention or the starting compound

Containing Jing 'can convert the silk into the corresponding halogen by Hunan halogenated finance. Alternatively, if the above method is used, the compound of the present invention or the starting compound contains a halogen, and the halogen can be treated with alcohol to convert the halogen to a corresponding oxyl group. (10) If in the above method, &, n & nD, enter the right # _ ^ said the month of the compound or the starting compound Moqi A #. For example, lithium aluminum hydride, sodium borohydride and stone pent weathering bell ; And diborane). Use it to convert 5 Hais into a corresponding

Phase, oxidation as ::: = (12) If in the above method "★" New button, or traitor. Contains carbonyl hydrazone, which can be used in the presence of the compound of the invention or the initiation, by the amination: the reductive amination reaction of the several groups or metaphors: (: if the above Method "Early: Generation or double-substituted fiber. Tanaka, the compound of the present invention or the starting compound 3) 6408 78 200523254 contains a carbonyl group or an aldehyde, which can be reacted with several groups or bis-compounds to make the ( 14) If apricots contain sulfamethoxamine in the above method, you can use the test (for example, the Sulfonamide (the treatment of sulfonamides (::::: sulfonium) converts the sulfonamides into relative compounds (e.g., sodium and potassium salts). In the Ershi method, the compound of the present invention or the starting compound is hunted in alcohol. (E.g., methanol and ethanol), in a test (e.g., in the case of reaction with sericylamine to convert hydrazone to the corresponding oxime. In the above method, the compound of the present invention or the starting compound = halogen 'By using a flavoring agent (same as the method mentioned in the method.) The halogen is converted into the corresponding cyano group in the above method. In the above method, the compound of the present invention or the starting compound each has an element. According to Tetrahed, 2G41 to 2 () 75, 2002 The method described in the above-mentioned method converts this element into the corresponding amine. If in the above method, the compound of the present invention or the starting compound 1 has a pitted rimyl group, it can be used by using N-methyl succinimide. Make the compound, sigma, and N-butanediimide, and then react the butadisyl compound with the amine compound to convert the oxidized oxygen group to the corresponding; silk silk brewing group. Or, The N-succinimide can be treated with a reducing agent (for example, sodium borohydride) to convert the N-succinimide into a corresponding hydroxyamidino group. (19) If in the above method, The compound of the present invention or the starting compound 316408 79 200523254 s has benzylamine 'can be converted to the corresponding amine according to Synthesis, 1985, pages 770 to ⑺. In the preparation method above: Various compounds or intermediates can be prepared by conventional methods such as column chromatography and recrystallization. Examples of recrystallized solvents include alcohols such as T-alcohol, ethanol, and 2-propanol. Examples include diethyl solvents, solvents such as ethyl acetate, vinegar solvents, and aromatic solvents such as toluene. , C, and _ solvents, such as hexachloride, water and mixtures thereof. According to conventional methods, the compounds of the present invention can also be converted into pharmaceutically acceptable salts, and then the pharmaceutically acceptable salts Recrystallization, etc. The compound VII of the present invention or a pharmaceutically acceptable salt thereof can be prepared as a pharmaceutical composition containing a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. Carriers include, for example, diluents, binders (for example, syrup, gum arabic, animal gum, sorbitol, gum powder, and polyvinyl group), excipients (for example, lactose, sugar, starch, dish) Potassium acid, sorbitol and glycerol), lubricants (e.g., hard rock, talc, polyethylene glycol, and stone dioxide), disintegrants (e.g., distarch), and wetting agents (e.g., laurel Sodium alkyl sulfate). 7) The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally 'and used as an appropriate pharmaceutical formulation. Guan Rui Pharmaceutical preparations suitable for oral administration include solid preparations such as lozenges, particles, gums, and powders, or liquids such as liquids, suspensions, and emulsions. Regarding pharmaceutical preparations suitable for administration without sigma, they can be listed as suppositories, using 316408 80 200523254 injection or injectable by injecting distilled water, physiological saline, glucose water soluble 316408 80 200523254. The dosage of the compound (1) or a pharmaceutically acceptable salt thereof of the present invention may vary depending on the mode of administration, the age, weight and physical condition of the patient, the type or privacy of the disease, and may generally be about 1 to milligram / Kg / day, more preferably about 0.1 to 30 mg / kg / day.

The compound (1) of the present invention or a pharmaceutically acceptable salt thereof has excellent potassium channel opening activity of conductive cyclization, and can cause cell membrane electricity: hyperpolarization 'and can be used for prevention, remission, and / or Treatments, such as hypertension, premature birth, irritable bowel, chronic heart failure, laryngitis, myocardial infarction, cerebral infarction, arachnid hemorrhage, cerebral vascular leanness, cerebral hypoxia, peripheral hemorrhagic disease, anxiety, Male baldness, erectile dysfunction, diabetes, diabetes, peripheral neuropathy, other diabetic complications, infertility, urethral stones and their concurrent pain, frequent urination, urinary incontinence, nocturnal enuresis, asthma, chronic obstructive pulmonary disease (COPD), asthma or COPD-associated cough I, stroke, cerebral anemia, traumatic encephalopathy, and so on. [Embodiment] Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. The abbreviations used in the examples and reference examples each have the following meanings: ^ THF: Tetrahydropyran DMF: N, N-diamidinofluorenamine DMSO: Difluorenylsulfenyl DME: 1,2-bis Ethoxyethane 316408 200523254

Me: methyl Et: ethyl t-Bu: third butyl TMS: trimethylsilyl Tf: trifluoromethanesulfonyl Boc: third butoxycarbonyl Bn: benzyl Ph: phenyl 1

4,4,4-trifluoro-; u (4-methylphenyl) butane 1,% dione (23.0 mg Imol) and 3-methylphenylhydrazine hydrochloride A solution of (174 mg, 11 molasses) in ethanol (5 liters) was refluxed under heating for hours. After the reaction mixture was cooled, the residue was purified under reduced pressure by silica gel column chromatography (hexane ·· ethyl acetate = 9 ° C. • ”9〇 · 10) to obtain (3_methylphenyl) _5_ (Kouwuwu # yl) -3- (difluoromethyl) -fluorene-II than saliva (298 mg, 94%) in powder form. Table MS · 317 [M + H] +, APCI (MeOH) Examples 2 to 7 6408 82 200523254 The reaction and treatment were performed in a manner similar to Example 1 to prepare the following compounds. Table 1

cf3 Example Rx Physical property constant, etc. 2 MS: 328 [M + H] +, APCI (MeOH) 3 〇MS: 408 [M + H] +, APCI (MeOH) 4 MS: 345 [MH]-? ESI ( MeOH) 5 MS: 317 [M + H] +, APCI (MeOH) 6 MS: 345 [MH]-, ESI (MeOH) 7, N MS: 383 [M + H] +, APCI (MeOH) 83 316408 200523254 Example 8

10% palladium-carbon (250 mg) was added to 5- (4-methylphenyl) _1- (4-nitrophenyl) -3- (difluorofluorenyl) -111-bipyrrole (2.40 g, 6.91 mmol) in a solution of 1 d (50 mg) and ethanol (50 ml), and the mixture was stirred in a hydrogen hydride ring at room temperature for 2 hours. The insoluble matter was separated by filtration and washed with THF, and then, the filtrate and the washing solution were combined and reduced under a reduced pressure condition to obtain {4- [5- (4-methylphenyl) _3- as a solid. (Trifluorofluorenyl MH-nazol-1-yl] phenyl} -amine (214 g, 98/0). MS: 318 [M + H] +, APCI (MeOH) Example 9

Propane gas (0.030 ml, 0.35 mmol) was added dropwise {[5 (4-fluorenylbenzyl) _3_ (trifluorofluorenyl) _hd to α-syl] phenyl} amine} ( 101 mg, 0.32 mmol) and triethylamine (0.066 ml, ο. "Mmol) in a solution of dichloromethane (5 ml), and the mixture was stirred at room temperature for 3 days. The diluted Hydrogen acid was added to the reaction mixture, and 4 mixtures were taken out using gas imitation. The extract was washed with brine and passed through sodium sulfate, and the solvent was removed under reduced pressure. The residue was passed through silicone Tube 316408 84 200523254 ^ Chromatography (acetic acid acetate: hexane = 90%: 10%> 80%: 20%) was purified to obtain n- {4_ [5_ (4_fluorenylphenyl) as a powder ) _3_ (trifluoromethyl) _ih_sialo-1-yl] benzyl} propanamine (92 mg, 77%). MS · 374 [M + H] ·, APCI (MeOH) Example 10 or less The compound was prepared by back-treatment in a manner similar to that of Example 9. ϋ 矣 矣?

In a chamber dish, add dimethylaminopyridine (0.22 g, 1.82 mmol) and triethylamine (3.80 pen liters, 9 7 2 gu 4K 27.3 pen ears) to 4- [5- (4 -Fluorenylphenyl) _3fluorenyl) -1fluorene Its ######## of the main stilbamine (6.93 g, 18.2 mmol) in a solution of two 316408 85 200523254 gas methane (70 ml). A solution of di-tert-butyl dicarbonate (4.76 g '21.8 mmol) in dichloromethane (70 ml) was added dropwise at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and added thereto with ethyl acetate and 20% aqueous oxalic acid solution, and the organic layer was separated. The organic layer was washed twice with water and washed with brine, dried over sodium sulfate and shrunk under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 3 · 1) to obtain a powdery ({4_ [5_ (4_methylphenyl) _3_ (trifluoromethyl) Propyl) -1H-salyl_1-yl] phenyl} sulfofluorenyl) aminobutyric acid tert-butyl ester (7.46 Luchunk, 87 ° / 〇). MS. 499 [M + NH4] + 5 APCI (io mM-AcONH4 / MeOH) Example 12 The following compounds were prepared by reacting and treating similarly to Example u. Table 3 Examples Chemical structure Physical property constants, etc. 〇 、, 〇〇 boyVi / Ch3 CH3 MS: 524/526 [M + NH4] +? A PCI (10mM-AcONH4 / Me OH) Example 13 86 316408 200523254

At room temperature, bell carbonate (949 g of '6.87 mmol) was added to {4- [5- (4-fluorenylphenyl) -3- (trifluorofluorenyl) -1 hydrazone-pyrazole small] benzene Butyl} sulfofluorenyl) aminobutyric acid tert-butyl ester (661 mg, 1.37 mmol) in DMF (3 ml). At room temperature, tert-butyl bromoacetate (321 mg, 1.65 mmol) was added. Mol) was added thereto, and the mixture was stirred for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the extract was washed with water and brine. Dry over sodium sulfate and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 12: 1) to obtain N- (third butoxycarbonyl) _N _ ({4- [5- (4_ 甲Phenyl) -3- (trifluorofluorenyl) phenylphenylsulfonyl) glycine tert-butylamine (441 mg, 54%).

Ms · 613 [M + NH4] + 5 APCI (10 mM-AcONH4 / MeOH) The compounds described in Examples 14 to 21 were prepared by reacting and treating similarly to Example 13. 316408 87 200523254 Table 4 Examples Chemical structure Physical property constants, etc. MS: 579 [M + H] +, 14 Boc \ J APCI (10mM-Ac〇 NH4 / Me〇H) P h3c

88 316408 200523254

table

Example Rx Physical property constant, etc. 15 MS: 560 [M + NH4] +, APCI (10 mM-AcONH4 / MeOH) 16 MS: 506 [M + H] +, APCI (10 mM-AcONH4 / MeOH) 17 MS: 509 [M + H] +, APCI (10mM-AcONH4 / MeOH) 18 MS: 574 [M + NH4] 'APCI (10mM-AcONH4 / MeOH) 19? H3 h3c ^ x MS: 474 [M + NH4] '' APCI (10mM-AcONH4 / MeOH) 20 MS: 490 [M + NH4] +, APCI (10mM-AcONH4 / MeOH) 21 H3C \ MS: 446 [M + NH4] +, APCI (10mM-AcONH4 / MeOH) Implementation Example 22

Triphenylphosphine (131 mg, 0.50 mmol) and 2- (2-pyrimidinyloxy) ethanol (70 mg, 0.50 mmol) were added to {4- [5- (4-fluorenylbenzene 89) at room temperature. 316408 200523254 earth) (fluoromethyl) -1 like fluorene small group] phenyl} arsenite tributyl ester (200 g, 〇42 true T s Yile Maojian · 42 Bi Mo Er) in thf ( Solution in 3 ml) and diethyl azodicarboxylate (87 mg, 0.50 mmol =) was slowly added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel "main chromatography (hexane: ethyl acetate 290: 10◊U) to give a liquid ({4_ [5_ (4_fluorenylphenyltrifluoromethane) ) 1H-S-I-yl] phenyl [mu] saflavinyl) [2 Decamidinyloxy) ethyl] third butyl carbamate (128 mg, 51%). MS. 604 [M + H] ^ APCI (100 mM-AcONH4 / MeOH) Examples 2 The compounds below 3 to 2 8 were prepared by reacting and treating in a similar manner to Example 22.

316408 90 200523254

9] 316408 200523254

Make (H- [5- (4-methylphenyl) _3_ (trifluorofluorenyl) _1H_pyrazolyl] phenyl} continyl) [2decadyl-2-yloxy) ethyl ] Aminobutyric acid tertiary butyl acetate (mg 0.25 millimoles) was dissolved in trigas acetic acid (3 ml). = The mixture was stirred at room temperature for 2 days and poured into a saturated aqueous solution of sodium bicarbonate. The quinone was extracted with ethyl acetate and the extract was washed with brine and then concentrated under reduced pressure. The residue was purified by silica gel column 316408 92 200523254 chromatography (hexane: ethyl acetate di 80: 20-> 〇: purified by cutting to obtain 4- [5- (4-methylphenyl) as a liquid ;)-3- (trifluoromethyl;) _ 1Η-pyrazolyl] -N- [2 _ (^ σdefinite-2 * -yloxy) ethyl] benzite xanthamine (31 mg, 25%) MS: 504 [M + H] +, APCI (MeOH) The compounds of Examples 30 to 42 were prepared by reacting and treating similarly to Example 29.

93 316408 200523254

Table 7 (continued) Examples Chemical structure Physical property constants and the like 33 / ^ cf3 h3c MS: 479 [M + H] +, APCI (MeOH) 34 H0 \ 〇 ^^ CF3. γ h3c MS: 438 [M-Η], ESI (MeOH) 35 H3C H > = n 〇MS: 357 [M + H] +? APCI (MeOH) 36 cr ^ cv 0 ^ ° MS: 437 [M + H] +, APCI (MeOH) 37 H UnU 3 gx> MS: 420 [M + H] +, APCI (MeOH)

94 316408 200523254 Table 7 (continued) Examples of chemical structure, physical constants, etc. 38 MS: 406 [M + H] +, APCI (MeOH) 39 〇 MS: 409 [M + H] +, APCI (MeOH) 40 MS: 373 [M + H] +? APCI (MeOH) 41 / —N w / y ^ NH〇-y HJ o MS: 357 [MH] ;, ESI (MeOH) 42 MS: 371 [M-H] _? ESI (MeOH) 95 316408 200523254 Example 43

^ Using ({415 GA 4-methylphenyl) -3- (trifluoromethyl) -1 fluorene-pyrazol-1-yl] benzyl)% fluorenyl) amino phosphonium tert-butyl ester (130 Mg, 0.27 mmol) Φ and aminoethyl chlorohydrochloride (58 mg, 0.40 Mol), reacted in a manner similar to that of Example 13 to obtain a crude product, [2_ ( Dimethylamine ^) ethyl *] ({4- [5- (4-fluorenylphenyl) fluorene (trifluorofluorenyl) n-small group] benzyl} sulfonyl) carbamic acid third butyl ester . The prepared crude product was not separated: the reaction was then carried out in a manner similar to that of Example 28, and the reaction /% of the product was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and purified by column chromatography (aqueous imitation: methanol = 50: 1). The obtained product / combination was dissolved in an alkane solution such as hydrochloric acid-dioxane, diethyl ether was added thereto, and the 5 substances were removed. The precipitated solid was collected by filtration to obtain N- [2β (diamido) ethyl] -4-[> (4-methylphenyl) -3- (trifluoromethyl; pyridine) as a solid. Azol-1-yl] benzenesulfonamide hydrochloride (98 mg, MS 453 [M + H] + ^ APCI (10 mM-AcONH4 / MeOH) Example 44 316408 96 200523254 (i)

Me

Add gas sulfonic acid (4.36 ml, 65 5 quinoxaline and w • Mao Mao) at room temperature to add fluorenylphenyl) small phenyl_3_ (trifluorofluorenyl HH | i (0.99 g, 3 yuan ★ ear) in a solution in chloroform (5.0 ml) and make this mixed _ ^ 莫

hour. The reaction mixture was poured into ice cubes and water and the organic layer was washed with water with chloroform 4 and concentrated. The residue was purified by a tritium tube: a method (hexane: ethyl acetate = 100: 80: 20) to obtain two: 2-amidino-5- [l-phenyl-3- (di ϋ 甲 其, 彳 υ πΐχ ϊ 4 L 丞 (j (―random methyl) _1H_pyrazolyl gas (1.17 g, 890 / 〇). Shellfish & MS: 401/403 [M + H ] +, APCI (Me〇H) (2)

NH 3

30% ammonia water (2 ml) was added to 2-methyl, -5 phenyl-3- (trifluoromethyl) _1H_D than sal_5_yl] benzene gas (rigid 0.25 μmol) in THF (5.0 mL). The mixture was stirred at the same temperature for 4 hours, and the reaction mixture was poured into ethyl acetate / water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure of 316408 97 200523254. The residue was purified by silica gel tube decantation to produce ethyl acetate (90: 10 ◊ 0: 100) and purified to give: final form: methyl-5- [l-phenyl-3- ( Dill methyl) -1H-sialyl-5-yl] benzenesulfonamide (86 mg, 90%). MS: 382 [M + H] +, APCI (MeOH) Example 45 The following compounds were prepared by reacting and treating the compound of Example 1 in a manner similar to (1) and (2) of Example 44.

Table 8 Examples of chemical structure, physical property constants, etc. 45 ΝΗ2 Λ CF3 MS: 396 [M + H] +, APCI (MeOH) Example 46 The following compounds were used in a similar manner to Example 44 (2). The compound of 44 (1) is prepared by reaction and treatment. 316408 98 200523254 Example 4 7

Table 9

Example ----— Physical property constants, etc. 46 AH, j > CP3 H◦ ~ h3c MS: 426 [M + H] +, ESI will be 5- [5 _ ('methylphenyl) at J8 ° C ) _3- (trifluoromethyl) _lH_pyrazole-1 · yl] -1,2-benzisothiazole_3 (2H) -one dioxide (160 mg, 1 mole) was added to the tick clock Ming (53.2 mg, 1 # millimolar) in suspension in thf (3 liters). The reaction mixture was allowed to warm to room temperature, and then the mixture was stirred for 4 hours. Ice cubes, a 1% aqueous solution of hydrogen acid and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure for one month. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7〇 ·· 30 > 50:50) to obtain 2_ (hydroxymethyl) _4_ [5airanyl group as a solid Benzoyl) -3- (trifluorofluorenylpyrazole small group) benzenesulfonamide (77 mg, 0%) MS: 412 [M + H] +, APCI (MeOH) 316408 99 200523254 Example 48

Grass straw chlorine (23 mg, 0.18 mmol) and one drop of DMF were added to N ({4 [5 (4-fluorenylphenyl) _3_ (trifluoromethyl ηαβ-phenylyl) phenyl) stone shellfish Fluorenyl) glycine (60 μg, 0.14 mmol) in Fe solution in dichloromethane (2 mL) and the mixture was stirred for 3 hours. The reaction mixture was reduced [ Concentrated under conditions such that the residue was dissolved in thF (2 ml)

Next, the mixture was added to a 50 / fluorene-methylamine aqueous solution (2 ml) / ethyl acetate (2 ml) with stirring under the conditions of the ice cold part. The mixture was stirred at the same temperature for 2 hours' and poured into ethyl acetate / water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-> 100) to obtain n, n_dimethyl-2-({4- [5- (4-fluorenylphenyl) _3_ (trifluoromethyl) _1H_afc sialyl] phenyl} sulfosyl) acetamidine (55 mg, 86%). MS: 467 [M + H] +, APCI (MeOH) Example 49 The following compounds were prepared by reacting and treating the compound of Example 4 in a manner similar to that of Example 48. 316408 100 200523254 table

The compounds of Examples 50 to 57 were prepared by reacting φ and treating in a manner similar to Example 48.

101 316408 200523254 Table 11 Chemical structure

Physical constants, etc. MS: 404 [M + H] +, APCI (MeOH) MS: 390 [M + H] 'APCI (MeOH) MS: 346 [M + H; T, APCI (MeOH) MS: 418 [M + H; T, ESI MS: 388 [M + H] ESI 102 316408 200523254 Table 11 (continued) Physical property constants of the chemical structure of the example 55 h3c Eight h3c ^-MS: 390 [M + H] 'ESI 56 h3c — --- MS: 371 (M + H) 'APCI (MeOH)' 57 h3c MS: 447 [M + H] +? APCI (MeOH) '. Example 5 8

Methyl methyl carbonate (16 mg, 0.14 mmol) was added to methylaminoethyl) -4- [5- (4-methylphenyl) -3- (trifluoromethylsialyl-butyl) benzylsulfonate Amidamine (52.0 mg, 0.12 mmol) in a solution of pyridine (2 ml), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was taken by Purified by gel column chromatography (Hexane ·· acetic acid 316408 103 200523254 ethane-80 · 20-> 0 · 100) and purified to obtain methyl- {2-[({4- [5- (4-Methylphenyl) -3- (trifluoromethyl) pyrazolyl] benzyl} arthazinyl) amino] ethyl} aminocarbamate (50.4 mg, 86.0 / 〇) MS: 497 [M + H] +, APCI (Me0H) Example 59

Group) -3- (difluorofluorenyl) -1 fluorenyl-D-pyrazol-1-yl] phenyl) luteinyl) aminosulfonic acid second butyl ester (87.8 g, 0.14 mmol) The reaction was performed in a manner similar to Example 28. The crude product obtained was not separated, and then the reaction was carried out in a manner similar to Example $ 8 using chlorocarbon 酉 曱 曱 Sa (16 oz.'0 · 14 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20.0: 100) to give { 2 _ [({4- [5- (4- Fluorenylphenyl) -3 _ (-difluoromethyl) -1H-d ratio. Small group] phenyl} stone yellow phenyl group) amine] ethyl} Ethyl sulfamate (33.5 mg, 50%). MS: 481 [M + H, ESI (MeOH) Example 60 (1) 316408 104 200523254

Trifluoromethanesulfonic anhydride (15 · 5 ml, 92.1 mmol) was added dropwise to 4- [5hydroxy-3- (trifluoromethyl) _1Η_pyrazolyl] benzene under -20 ° C argon atmosphere. Sulfonamide (23.6 mg, 76.7 mmol) and 2,6-di-tert-butyl-4-methylpyridine (24.6 mg, 119.9 mmol) in dioxane (750 ml) suspension. The mixture was warmed to zero. Then, the mixture was stirred at the same temperature for 30 minutes, and then the reaction mixture was poured into a saturated aqueous solution of sodium rhenium carbonate under ice-cooled conditions. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to approximately 200 ml under reduced pressure. Shen Dianwu was collected by filtration and washed with dioxane to obtain fluorene 4- (aminesulfonyl) phenyl] -3- (trifluorofluorenyl) -1 fluorenyl-5-yltrifluoro as a solid. Decanter sulfonate (23.6 mg, 70%). Melting point: 114 to 11 5 (2)

-Aminosulfenyl) phenyl] -3- (trifluorofluorenyl) -1Η-pyrazole-5_yltrimethylene methyl ester (220 mg, 0.50 mmol), 1, 4-Benzodioxane boronic acid (108 mg, 250 mmol), potassium carbonate (346 mg, 2.5 mmol) and dichlorobis (triphenylphosphine) palladium (70 mg, 0.10 mmol) Ear) was suspended in 0,5,316,408,2005,23,254,4-dioxane (3 ml), and the suspension was refluxed under heating for 6 hours. The suspension was poured into ethyl acetate / water, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Shixi gel column chromatography (hexane: ethyl acetate: 10% 25 · 75) and recirculating HpLC to obtain 4_ [5_ (2,3_ hydrogen 1, 4 Benzo-Sulfuryl) _3_ (trifluoromethyl) -Nizole · Buyl] sulfenazamide (103 mg, 48%). " MS: 426 [M + H] +, APCI (MeOH) ❿Example 61 (1)

HCI

H2N h2no2s

HN — ^ S〇2NH2

Me02C ^ Y ^ c〇2Me 〇

Heat dimethyl 1,3-acetonedicarboxylate (13.8 g, 79.0 mmol) and 4-monosulfamidinophenylhydrazine hydrochloride (Π · όg, 79.0 mmol) while heating Stir at Cπ for 2 hours. After the reaction mixture was cooled, a saturated aqueous solution of sodium bicarbonate was added thereto and the mixture was washed with THF-ethyl acetate. 10/0 hydrogen acid was added to the aqueous layer to adjust ρΗ to 4, and the mixture was extracted with THF-ethyl acetate. The mixture was twice. The extract was dried over magnesium sulfate and concentrated under reduced pressure. Diethyl ether-ethyl acetate was added, and the residue was mixed with the mixture. Then, the solid obtained by passing through the collector was charged to {1_ [4_ (aminesulfonyl) phenyl] _5_oxy_ 4,5_dihydro-1H? Pyzol-3-yl} fluorenyl acetate (12.85 g, 52%). 316408 106 200523254 MS: 312 [M + H] +, APCI (MeOH) (2) The following compounds were prepared by reacting and treating in a manner similar to (1) of Example 60. Table 12 Examples Chemical structure

61 (2) Chang Lou Zhang, etc. NMR (CDC13): 3.75 (2H5 s). 3.76 (3H, s), 4.91 (2H, s), 6.43 (1H, s) 5 7 · 76 ( 2H, d, 'J = 9.0Hz), 8.06 (2H, d J = 9.0Hz), (3) The following compounds were prepared by reacting and treating in a manner similar to (2) in Example 60. . W Example Physical property constants, etc. 61 (3) ρ 0》 s, nh2 MS: 386 [M + H] + 5 APCI (MeOH) Example 62 The following compounds are similar to those of Example 60 (丨) It is prepared by reacting and treating in the manner of (2). The prepared compound is converted into a sodium salt according to a conventional method. 107 316408 200523254 Table 14

Examples Chemical structure, physical property constants, etc. 62 (1) Cl MS: 333/335 [M + H] +? APCI (MeOH) 62 (2) Os ^ rr0Na Cl MS: 317/319 [M-Na]% ESI Lu The compounds of Examples 63 to 66 were prepared by reacting and treating in a manner similar to (2) of Example 60.

] 〇8 316408 200523254

Table 15

cf3 Example Rx Physical property constant, etc. 63 MS: 407 [M + H] + 3 APCI (MeOH) 64 ch3 MS: 416 [M + H] +, APCI (MeOH) 65 H3C; N_fA h3c ν = ^ MS: 412 [M + H] +, APCI (MeOH) ch3 66 MS: 410 [M + H] +, APCI (MeOH) Example 67 (1) The following compounds were prepared in a manner similar to (1) of Example 60 Prepared by reaction and treatment. Table 16 Examples Chemical structure Physical property constants etc. 67 (1) αN. ° 1 MS: 371 [M + H] +, APCI (MeOH)

109 316408 200523254 (2) Compounds below

〇 u

Η It is prepared by the reaction and treatment of Song like in the examples. The method of (2) of 60 is entered in the embodiment r ~ Table 17 / = \ ~ ——— Physical property constants and so on ~ — 67 (2) QN—N ~~ ^ ---__ MS: 355 [M-Na] · , ESI (MeOH) -----—__ Example 68

Sodium cyanoborohydride (186 mg, 2.95 mmol) was added to 4- [5- (lH-D bow 丨 D-do-5-yl) _3_ (trifluoromethyl) _m_0 than sialoyl] benzene at room temperature. Razinamine (300 mg, 0.74 mmol) in acetic acid (4 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was tested with a saturated aqueous solution of sodium bicarbonate under ice-cooled conditions, and then extracted with ethyl acetate. Then, it was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-> 25:75) to obtain 4_ [5_ (2,3_dihydro_ih-ind) as a powder. Indole-5-yl) -3- (trifluoromethane HH_pyrazolyl) benzenesulfonamide (155 mg, 51%) MS: 409 [M + H] + ^ APCI (MeOH) 316408 110 200523254

Example 6 9 CN

> * Add sodium cyanoborohydride (32 mg, penmor) to 4- [5- (2,3-dihydro-1H_indole-5-yl) -3_ ( Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (102 mg, 0.25 millimolar) in a solution of gadolinol (3 t liter), then, using 1% aqueous hydrogen acid solution was used to adjust the pH of the mixture to 4 and a formalin solution (3, 1 ml) was added thereto = after stirring the reaction mixture at room temperature overnight, under reduced pressure; indifferent. The residue was made sensible with 30/0 ammonia and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex ·· ethyl acetate 10 25: 75) to obtain:-[4- (5- (1-methyl-2,3-dihydro_1H, No. 5-yl) hydrazone (trimethylmethanyl) _azol-1-yl] benzenesulfonamide (98 mg, 90%). MS ·· 437 [M + H] +, APCI (MeOH) Example 70

316408 111 200523254 2N sodium hydroxide solution (12.8 ml, 25.6 mmol) was added to Π- [4- (aminosulfonyl) phenylmethylphenylacetic acid acetic acid 0.30 g, 8 56 millimoles) in a solution of methanol (33 mL) and the mixture was refluxed under heating for 30 minutes. After the reaction mixture was dried, the mixture was concentrated under reduced pressure and 10% hydrochloric acid was added thereto and extracted with ethyl acetate. #Rinsing the organic layer with brine ', dried over magnesium sulfate, and shrunk under reduced pressure. After adding hexane to the residue and stirring the mixture, the mixture was concentrated under reduced pressure to obtain [1- [4- (amine petrolyl) phenyl] 5 (4-methyl) in powder form. Phenyl) -1H-pyrazolyl] acetic acid (28 g, $.

MS: 370 [M + Η] ·, ESI Example 71 The following compounds were prepared by similar processes and treatments as in Example. '70 way to carry out anti

316408 112 200523254 H2N〇2S ^^

(CF3CO) 2〇

In the ancient a ... wide ... factory, trifluoroacetic anhydride (143 mg, 0.868 mol) was added dropwise to 2_π_ [4_ (amine base 1 mg, ... mo 1.36 mol) ) In suspension in chloroform (4 liters), the mixture was allowed to stand overnight at room temperature. The reaction mixture was added and the mixture was stirred for 30 minutes and the organic layer was washed with acetic acid and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to an analytical method (aeroform: methanol = 30 ·! ≫ 9η · ^ 4-Γ3 Ψ w,. 1}, and obtained a powdery [(乱 (基) -5- ( 4-methylphenyl) -1H "than wow mg, 17%). L-based] benzyl lutein amine (20 MS: 351 [U-ny, ES1 (MeOH) Example 73

丞 jbenzyl] -5- (4-methylphenyl ester (55-7 g, 0.15 mol) in THF (15 liters) = -3- ammonium acid makes the mixture under heating conditions After refluxing, the mixture was cooled down, and the Π3 316408 200523254 reaction mixture was cooled with ice, and 10% hydrochloric acid was slowly added thereto. After the mixture was stirred, ethyl acetate (500 ml) was added. And water (500 ml) were added thereto and the mixture was divided into portions. The organic layer was washed 'dried through sodium sulfate' with brine and concentrated under reduced pressure. To the residue was added methanol-diethyl ether-hexane The mixture was stirred. The obtained crystals were collected by filtration. The crystals were washed with diethyl ether and hexane and dried to give 4- [3- (hydroxyfluorenyl) -5- (4-fluorenyl) as crystals. Phenyl > 1-pyridyl-1-yl] benzenesulfonamide (42.8 g, 83%). Melting point · 173 to 174 ° C • MS: 344 [M + H] +, APCI (MeOH)

Example 74 h2n〇2s

Sulfuryl chloride (0.33 ml, 4.52 mmol) was added to a solution of 4 phenylphenyl) _1Tau + phenyl] benzamine_g, _hair j) in THF (20ml) And the mixture was refluxed for 1 hour under the same conditions. After the reaction mixture was cooled and concentrated under the conditions of ^, the residue was separated by gel column chromatography = imitation. Methanol = 50: to obtain 4 gas (a 316408 114 200523254 group) in powder form- 5- (4-fluorenylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (242 mg, 38%) and 4- [3-[(4-Gabutoxy) -5- ( 4-methylphenyl) methyl] HD to σ sitting group] benzathionine (457 mg, 60%). 4- [3- (chlorofluorenyl) -5- (4-methylphenyl) -lHHl-yl] benzoflavinamine MS: 362/364 [M + H] +, APCI (MeOH) 4- [ 3-[(4-Gasbutoxy) methyl] _5- (4-methylphenyl) _1H_yrazol- ^ yl] benzoxanthinamine MS: 434/436 [M + H] +, APCI (MeOH) Example 75

Add sodium hydride (60%, 30 mg, 0.75 mmol) to 4_ [3_ (gasmethyl) -5- (4-methylphenyl) _1H-pyrazol-yl] benzenesulfonamide (9 0 mg = 0.25 millimoles) and phenylalcohol (81 mg, 0.75 millimoles) in THF (3 milliliter), and the mixture was refluxed under heating overnight. After the reaction mixture was cooled, 10% hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 3: 2 紬 1 · 1) was purified to obtain 4- [3-[(benzyloxy) methyl] _5 as a liquid. Methylphenyl) _1H_ than fluoren-1-yl] benzenesulfonamide (37 mg, 33%). MS: 434 [M + H] + ^ APCI (MeOH) 316408 115 200523254 Example 7 6 The following compounds were prepared by reacting or treating in a manner similar to that of Example 75 (a). ,

Example 7 7 h2no2s

h2n,

Br HBr

/, / Soil, j-rn-Ut, Fengxiang, Lane: carboxylic acid in the dagger (357 mg 'U millimolar), 2-bromomethylamine hydrobromide (287 mg' 1.40 mmol), N-Cyclobenzotrifluorene (203 mg,)% mmol, triethylamine (0.42 ml, 3.00 mmol), and 1-ethyl-3- (3, -dioxanyl) A solution of propyl propyl) carbodiimide hydrochloride (288 mg, 1.50 mmol) in DMF (5 ml) was stirred overnight at room temperature. Water was added to the reaction mixture and ethyl acetate was used. The mixture was extracted. The extract was washed with brine, dried over sodium sulfate, i, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (gas-form: methanol = 50: 3〇:丨) Purified to give 4- [3_ (4,5_dihydro + 3, azole_2_yl) _5_ (4_methyl316408 116 200523254 phenylphenyl) -1Η-pyrazolyl] benzene as a powder Sulfonamide (170 mg, 45%). MS: 383 [M + H] +, APCI (MeOH) Example 78

CH〇h2no2s make 醯 'a / * Renren I-丄 a: ¾ J | stone to amine (7.0 g, 0.020 mol) and manganese dioxide (35 g, 〇mol mol) in THF (140 The suspension in liters) was heated under the conditions of heating, cooling, and cooling for 1 hour. After the reaction mixture was cooled ', the insoluble matter was removed by filtration and washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to obtain 4- [3_fluorenyl-5_ (4-methylphenyl) trowel (4.8 g '68%) in powder form. Bisyl] benzite xanthamine MS: 340 [M + H] & ^ ^ APCI (MeOH) Example 79

CHO

NC- ^ 〇B Diethyl (cyanomethyl) phosphonic acid (016 ml ancient # potassium butoxide (135 milli $, ancient Zeng, Mao Maoer) and Mao Ke, 1.2 pen Er) added 4, Phenylbenzyl) -1Η "biwasyl] benzenesulfonamide (34 (

% G, 1.00 milligram J 316408 117 200523254 in THF (4 liters) and the mixture was stirred at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced conditions. The residue was purified by silica gel column chromatography (chloroform: formamidine ^ 30 · 130. 丨) to obtain 4- [3-[(E) -2-cyanovinyl] -5- () as a powder. 4-methylphenyl) _1H_pyrazolyl] benzenesulfonamide (316 mg, 87%) OM: 365 [M + ηΓ, APCI (MeOH) 'Example 8 Compounds of 0 and 81 Prepared by reacting or treating similarly to Example 79. Table 20

Example 82 Π8 316408 200523254

CN 丨 Shi, j 丞 benzyl)-1H-Zirconazole, i group] Benzoxanthinamine (250 Cang Xiu, 0 6Q Gu-ττ, 'V υ 毛 哥 υ · 69 pen ears) and 5% palladium _Carbon (500 milliseconds

Suspend the suspension in methanol (mL), and sonicate it at room temperature under a ring of hydrogen. After the insoluble matter was removed by filtration and washed with methanol, the filtrate and the washing solution were combined and the residue of the mixture was concentrated under reduced pressure by column chromatography (aerosol · · methanol = 5 (): i_ > 3〇 :: = to give a powder of fluorene 4_ [3_ (2_cyanoethyl) _5 _ (" ylphenyl) pyrazole-1_yl] benzenesulfonamide (169 mg, 79%). MS: 367 [M + H] +, APCI (MeOH) Example 83

Sodium triethoxyborohydride (223 mg, 10 mmol) was used at room temperature forever ^ 4 (methyl ethyl) · 5_ (4-methylphenyl). Oh salyl] benzene Shekel, 0.50 millimoles) and aniline (0055 ml, 0.600 millimoles = ^ THF (4 liters) and stirred the mixture overnight. An aqueous sodium bicarbonate solution was added to the reaction mixture. It was also extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced conditions. The residue was subjected to silica gel column chromatography (chloroform: a: 316408 119 200523254 = 5 〇m) purified to give a powder ㈣ aniline methyl) -5- (4-methylbenzyl ㈣ 坐 small group] benzophenanthramine (157 mg, 75%) 〇MS ·· 419 [M + H] +, APCI (MeOH) Example 84

Under heating conditions, 4_ [3_methylfluorenyl_5_ (4_methylphenyl) _ih_ sialyl + yl] benzite xanthamine (341 mg, io mmol), O-methyl- A mixture of ammonium hydrochloride 025 mg '丨 .5 mmoles) and sodium carbonate (79 mg, 0 75 = ears) in ethanol (3 $ liters) and water (3 ml) in a heated mixture of two Under reflux for 3 hours. Water was added to the reaction mixture, and the mixture was taken out using a sodium hydroxide solution. Extraction was performed with brine washing, sodium, sodium, η 丄, L ^^, and concentrated under reduced pressure. The residue was purified by silica gel tube ^ main chromatography (gas-form: methanol = 5 ():! _ ≫ 3G: υ to obtain a powder [3 [(E)-(methoxyimino) methyl] -5- (4-methylphenyl) _ιη-, the natural stone amine (trans; 280 mg, 75%) and solid '[[〇 (methoxyimino) methyl] -5- (4-methylphenyl) -11-orbityl] benzylsulfenamide (cis; 93 mg, 25%). 316408 120 200523254 4- [3-[(E)-(methoxyimine) (Methyl) fluorenyl] -5- (4-methylphenyl) -fluorenyl-o-pyrazole-1 -yl] benzoxamine MS: 371 [M + H] +, APCI (MeOH) 4- [3- [(Z)-(Methoxyimino) fluorenylmethylphenyl) _1] 9_pyrazole-1 -yl] phenylamine g MS: 371 [M + H] +, APCI (MeOH)

Example 8 5 The following compounds were reacted in a similar manner to Example 84.

Example 86

Make methyl_3_phenylisoxazole_4_yl] benzenesulfonyl chloride (2⑻ to 乂 HF (3 ml) 'and cool the solution to () -prolinol (182 mg, ι · 80 mmol) was added to 316408 12] 200523254 solution, and the mixture was gradually warmed to room temperature and stirred at room temperature for 6 hours. Ethyl acetate (8 ml) was added thereto, and water (3 ml) was used Then, the mixture was washed with brine (2 ml), and under a reduced pressure> Chen fine. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1-> 1) 1) Purified to give fluorenyl-3 monobenzyl iso-1½zol-4-yl) phenyl] sulfonyl-1-pyrrolidin-2-yl) methanol (232 mg, 97%). MS: 399 [M + ΗΓ, APCI (MeOH) —Examples 87 to 108, and the σσ system under 乂 were prepared by reacting or treating in a manner similar to Example 86.

122 316408 200523254 Table 22 〇, W / 〇

Example RX1 RX2 Physical property constant, etc. 87 h2n, / Η H—— MS: 330 [M + H] +? APCI (MeOH) 88 H3C \ ^ 〇, n / Η H—— MS: 359 [M + H] +, APCI (MeOH) 89 ry H—— MS: 385 [M + H] +, APCI (MeOH) 90 ch3 H—— MS: 368 [M + H] +, APCI (MeOH) 91 〒h3 H0 ^ \ / HH—— MS: 373 [M + H] +, APCI (MeOH) 92 a H—— MS: 397 [M + H] ^ 5 APCI (MeOH) 93 ™ 3 ch3 H—— MS: 371 [M + H] +, APCI (MeOH) 94 ry H—— MS: 462 [M + H1 'APCI (MeOH)

123 316408 200523254

Table 22 (continued) Example RX1 RX2 Physical property constants, etc. 95 Η H—— MS: 403 [M + H] +, APCI (MeOH) 96 ch3 HH—— MS: 373 [M + H] +, APCI (MeOH ) 97 CH3- h〇, ^ n / HH—— MS: 373 [M + H] +, APCI (MeOH) 98? H3 H—— MS: 419 [M + H] +, ESI 99 HO—H—— MS: 399 [M + H] +, ESI 100 HH—— MS: 387 [M + H] +? ESI 101 h3c, H0, ^ N / HH—— MS: 387 [M + H] +, ESI 102 HH —— MS: 385 [M + H] +, ESI 103 HH—— MS: 447 [M + H] +? ESI 104 ζλ. H HO ^ H—— MS: 421 [M + H] 'ESI 105 HO ^ ^^ N〆HH—— MS: 401 [M + H] +, ESI 106 ch3 HH—— MS: 387 [M + H] +, APCI (MeOH) 124 316408 200523254 Table 22 (continued) Example RX1 RX2 Physical properties Constants, etc. 107 h3c, n / 1 ch3 H—— MS: 343 [M + H] + 5 APCI (MeOH) 108 h3c, / 3 NH Br—— MS: 407/409 [M + H] 'APCI (MeOH ) Example 109

HO

Make N-[(lR) -3-hydroxy-1_methylpropyl] -4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzenesulfonyl chloride (100 mg, 0.26 mmol) was dissolved in methanol (3 ml) and sodium alcohol (0.5 M methanol solution, 0.51 ml, 0.25 5 mmol) was dissolved therein at room temperature. After the mixture was stirred for 10 minutes, the reaction mixture was concentrated under reduced pressure. Acetone was added to the residue and the mixture was stirred 'next' to collect the precipitate by filtration to give _N-[(lR) -3-hydroxy-1-methylpropyl] _4_ (5_fluorenyl_ 3-Phenylisoxazol-4-yl) sulfenamide sodium salt (96 mg, 98%). MS: 385 [M_Na]-, ESI (Me0H) Examples 110 to 11 2 The following compounds were prepared. You prepared and reacted or treated in the same manner as in Example 109. 125 316408 200523254 Table 23

Example Rx Physical property constant, etc. 110 ch3 MS: 371 [M-Na] 'ESI (MeOH) 111 ch3 MS: 371 [M-Na]' ESI (MeOH) 112 MS: 373 [M-Na + 2H] 'APCI (MeOH) Example 113 The following compounds were prepared by reacting or treating similarly to Example 70. Table 24

Example Chemical structure Physical property constant, etc. 113 H00C, (^ \ Ϊ MS: 279 [M-H] '5 ESI Example 114 126 316408 200523254

A solution of diamidamine in THF (2M '2.9 ml, 5.80 mmol) was added to N-fluorenylhydrazine {4- [3- (4-bromophenylmethylisoxazolyl) at room temperature. ] Phenyl} sulfofluorenyl) aminotricarboxylic acid tert-butyl ester (450 mg, 114 mmol), tris (diphenylenediacetone) dipalladium (110 mg, 012 mmol), 2-Dicyclohexylphosphinodiamidino) biphenyl (90 mg, 0.23 mmol) and tertiary butoxide (220 mg, 2.29 mmol) in toluene (15 halos) In suspension. The mixture was heated to 80 ° C in a sealed tube and stirred for 20 hours. The suspension was poured into ethyl acetate / water. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 ◊ 50:50) to obtain diamidoamino group as a solid) phenyl > 5-fluorenylisoxazole Sodium sulfonamide (154 mg, 47%). MS: 372 [Μ + Η] +, APCI (Me0H) Example 115 The following compounds were prepared by reacting or treating in a manner similar to Example 1] 4. 127 316408 200523254

The p-toluenesulfonic acid monohydrate (0,18 g, millimolar) Yong 4 ^^ (4- / styrophenyl) _5_fluorenylisopropanol 0_4_yl] benzolite yellow ceramide (3.7 〇g 9 ″ 4 house mole) and ethyl brewed acetone (44 ml, η ″ millimoles) in toluene, house suspension. A condensing sub-assembly equipped with a Dean_s water separator was installed and the mixture was refluxed under heating for Η hours. After the gas mixture was cooled, ethyl acetate (ml) was added to the reaction mixture. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to & gel column chromatography (hexane: ethyl acetate. 2: hydration to obtain a solid 1 = M4 · mophenyl) -4— {4-[(2,5 · dihydrazyl) -in ”ratio. Sitting on a small base) Shi Huangjing ^ Benji} -5-fluorenyl isoxazole (3.11 g, 70%). 316408 128 200523254 MS: 471/473 [M + H] +, APCI (MeOH) Example 117

Add N- (2-methoxyethyl) amidamine (60 mg, os? Millimolar) to 3- (4-bromophenyl) -4- {4-[(2,5-di Methyl-1H-pyrrole- 丨 _yl) sulfofluorenyl] phenyl} -5-fluorenylisoxazole (200 mg, 0.42 mmol), two (40 g, 0.04 mmol), 2-dicyclohexylphosphino-2-(N, N-diamidino) biphenyl (35 mg, 0.99 mmol) and carbonic acid Tritium (280 mg, 0.86 mmol) in a suspension of L4-dioxane (4 ml) and tertiary butanol (2 ml), and the mixture was heated to 100 T under microwave irradiation: And stirred for 5 hours. After the suspension was poured into ethyl acetate / water, the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on a stone tube (hexane: ethyl acetate = 95: 5-> 65:35) to obtain a solid. The solid was dissolved in trifluoroacetic acid (3 ml) and water (0 ml) and the mixture was heated to 6 (rc and stirred for 6 hours. After the reaction mixture was cooled, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen diacetate ( 25 ml) and the mixture was extracted with ethyl acetate (3 × 10 ml). The extract was washed with salt, dried over sodium sulfate, and dried under reduced pressure. The residue was passed through Silica gel column chromatography (hexane: ethyl acetate = 卯: 316408 129 200523254 10-> 30: 70) ^ ^ ^ alcohol (0.5 ml) to a liquid. The liquid at room temperature in 曱To the cold solution in liters, 4N-hydrochloric acid-dioxane solution (20 milliseconds was added and the mixture was stirred for 20 minutes. The reaction mixture was concentrated to give 4- (3- {4- [(2-Methoxyethyl) (methyl) amino] phenyl} _5_Methylisoxazol-4-yl) benzenesulfonamide hydrochloride (92 mg, 54%). MS: 402 [M + H] +, APCI (MeOH) The compounds below Examples 118 and 119 were prepared by reacting or treating similarly to Example 117. Table 2 6 〇 、、 々◦

Example Rx Physical property constant, etc. 118 α. MS: 426 [M + H] +, ch3 APCI (MeOH) 119 h3c j MS: 386 [M + H] +, APCI (MeOH) Example 120 130 316408 200523254

1) BocNH2 --- ►

2) HCI = Sodium phenoxide (115 mg, millimolar) is added to 3_ (heart / stinky base) _5_methyl_4_phenylisoemetic (referred to as mg, 0.64 mole) at room temperature. (Monophenylene amidinoacetone) dipalladium (60 mg, 〇07 — Λ # A 9 wat χτ Mao Binger), 2-dihexyl hexyl W group-2-(N, N-diamidino) group Benzene (50 mg, butyl tertiary butyl acetic acid (115 mg, 0.098 benzyl and urticaria) and M, Moore) in methylbenzyl (5 ml), cardiac fluid The mixture was heated to / 0 ^ under microwave radiation conditions and allowed to bleed for 1 hour. After the suspension was poured into ethyl acetate / water, the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced age. The residue was purified by tritium column chromatography (hexane: vinegar-'θ 5 > 75.25) to obtain a solid. This solid was dissolved in a 4N hydrogen chloride solution (5 ml) and allowed to fall at room temperature. This thing is 16%. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 gross liters), and the mixture was extracted with ethyl acetate (3 x 10 ml). The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95. 5-> 50: 50) to obtain [4_ (5_methyl_'phenylisoxazole- 3-yl) phenyl] amine (116 mg, 73%). MS: 251 [M + H] + > APCI (MeOH) Example 121 316408 131 200523254

Aqueous sodium bicarbonate solution (2M, 1.3 ml, 2.60 mmol) was added to 4-bromofluorenyl-3-phenyliso-azole (200 mg, 0.84 mmol) at room temperature. ), 4-Acetylphenylboronic acid (21 mg, 丨 28 mmol) and digas bis (triphenylphosphine palladium (60 mg, 0.09 mmol)) in a suspension of DME (5 ml) And the mixture was heated to 100 ° C under microwave irradiation and stirred for 2.5 hours. After the suspension was poured into ethyl acetate / water, the organic layer was washed with brine, dried over sodium sulfate, and Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate di 98: 2-> 65 · 3 5) to obtain ^ [心 ^- Methylphenylisoxazole-cardio) phenyl] ethanone (189 mg, 81%). MS: 278 [M + H] +, APCI (MeOH) Examples 122 to 134 • ^ A, 5A were prepared by reacting or treating in a similar manner to Example 121. 132 316408 200523254 Table 27

Example Rx Physical property constant, etc. 122 J c H MS: 252 [M + H] +, APCI (MeOH) 123 c MS: 278 [M + H] 'APCI (MeOH) 124 h2 MS: 251 [M + H] +, APCI (MeOH) 125 LA MS: 281 [M + H] 'APCI (MeOH) 126 / CH3 X MS: 278 [M + H] +, APCI (MeOH)

133 316408 200523254 Table 27 (continued) Example Rx Physical property constant, etc. 127 h3c-nY ^ HC1, MS: 281 [M + H] +5 APCI (MeOH) 128 Η〇η \ MS: 252 [M + H] + , APCI (MeOH) 129 Η H3C ^ / N, 〇X MS: 293 [M + H] +, APCI (MeOH) 130 ί «3 H3C / N \ 0 κ MS: 279 [M + H] +, APCI ( MeOH) 131 D \ MS: 261 [M + H] +, APCI (MeOH) 132 ΗΟ ^ 0 \ MS: 280 [M + H] +, APCI (MeOH) 133 Η00 \ MS: 266 [M + H] + , APCI (MeOH) 134 h3c / 0, 0 MS: 266 [M + H] +, APCI (MeOH) Example 135

Make 4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzoic acid (100 mg, 0.36 mmol) and N-hydroxysuccinimide (72 mg, 0.38 mmol) ) 134 316408 200523254 was dissolved in DMF (3 ml) and 1-ethyl j- (3, -dimethylaminopropyl) carbodiimide hydrochloride (45 mg, 0.39 Millimoles). The reaction mixture was gradually warmed to room temperature and the mixture was stirred at room temperature overnight. Ethyl acetate (100 ml) was added to the mixture and the mixture was washed with a saturated aqueous solution of sodium hydrogen acid acid and water, dried over magnesium sulfate 'and concentrated under reduced pressure. The residue was crystallized from hexane and collected by filtration. The crystals were dissolved in DMF (3 ml) and cooled to -78 ° C. After adding S-propylamino alcohol (30 mg, 0.4 mmol) to the formula, the reaction mixture was gradually warmed to room temperature, and the mixture was stirred at room temperature overnight. Ethyl acetate (20 ml) was added to the reaction mixture and the mixture was washed with a 10% citric acid solution and water and concentrated. The residue was purified by Shiyuki gel column chromatography (hexane: ethyl acetate-95 · 5-> 80 · 20) to obtain solid berberylethyl] 4 (5-methyl —3, benzyl isosalyl) phenylammonium amine (105 mg, 87%) OMMS: 337 [M + H] ^. APCI (MeOH) Examples 136 to 148 or at: = The compound was reacted in a similar manner to Example 135 316408 135 200523254 Table 28 RX1 CH3 Ό RX2 'N Example RX1 RX2 Physical property constants and so on 136 Ph〆MS: 279 [M + H] +, APCI (MeOH) 137 Ph〆MS: 295 [M + H] +, APCI (MeOH) 138 〇Ph〆MS: 337 [M + H] +, APCI (MeOH) 139 〇〇〇 ^^ n Human H 〇Ph〆MS: 323 [ M + H] +, APCI (MeOH) 140 Ph〆MS: 380 [M + H] +, ESI 141 Ph〆MS: 337 [M + H] +, APCI (MeOH) 142 Ph〆MS: 336 [M + H] 'APCI (MeOH) 143 H3C CH j H〇 ^ nA H 0 \ Ph〆MS: 351 [M + H] +, APCI (MeOH)

136 316408 200523254 Table 28 (continued) Example RX1 RX2 Physical constants and so on 144 HO— Ph ^ MS: 399 [M + H] +, APCI (MeOH) 145 .OH Ph〆MS: 363 [M + H] +, APCI (MeOH) 146 H〇 ”Ph〆MS: 367 [M + H] +, APCI (MeOH) 147 〇0 Ph〆MS: 351 [M + H] +, APCI (MeOH) 148 σ HCl MS: 280 [ M + H] +, APCI (MeOH) Example 149

Under the conditions of microwave irradiation, 3- (4-bromophenyl) -5-fluorenyl-4-phenylisoxazole (5.00 g, 15.9 mmol), zinc cyanide (1.88 g, 16.0 mmol) Ear) and a suspension of (triphenylphosphine) palladium (1.85 g, 1.60 mmol) in DMF (80 ml) were heated to 175 ° C and stirred for 5 minutes. After the suspension was poured into 137 316408 200523254 and washed with brine, the organic layer was washed with brine, then passed through sulfuric acid to dry, and concentrated under reduced pressure. The residue was purified by Shi Xisheng's official column chromatography (hexane: ethyl acetate = 6: " 4_ (5_fluorenyl_4_phenyliso, 3_yl) ^^ MS: 261 [M + H] +, APCI (Me〇H) Example 150

Make 4- (5-fluorenyl-4-phenylisosialyl-3-yl) benzyl (200 g, 7 7 mmol) and osmium oxide powder (2.40 g, 42.8 mmol) Ear) Suspension in propanol (50 liters) was refluxed under heated conditions for 14 hours. After the reaction mixture was cooled, it was concentrated under reduced pressure. After waiting for the addition of chloric acid, the mixture was extracted with ethyl acetate. Ricoh The organic layer was washed with brine, dried over sodium sulfate, and dried under reduced pressure.

Concentrated under pieces. The residue was purified by silica gel column chromatography (gas-form: methanol = 10: 1) to obtain 4- (5-fluorenyl-4-benzylisofluorenylfazolyl) benzenesulfonic acid ( 2.01 g, 94%). Soil MS: 278 [M-ΗΓ, ESI (MeOH) Example 151 316408 138 200523254

^ 4- (5-Methyl-3-benzylisoisozol-4-yl) phenol (150 mg, 0.60 mmol, acetone hydrolysate in DMF (3 ml) and 60% hydrogenation at room temperature Sodium (27 gram, 0.88 mole) was added thereto. After 10 minutes, ^ ethoxy) tetrahydrorupran (137 mg, ⑽mmol) was added to the mixture at room temperature. And the m complex was given overnight. Ethyl acetate (ml) was added to the reaction mixture, and the mixture was washed with water, followed by addition through sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10—> 70:30) to obtain an oily substance. Of the compound 5 -methyl_3 -phenyl 1 {4 examples of tetrahydrol-pyran-2-yloxy) ethoxy] phenyl} isoxazole (141 mg, 62%). MS: 380 [M + H] +, APCI (MeOH) Example 152

CFXOoH ΙΗ〇 ^^ 〇

I dissolved 5_fluorenylphenyl-4_fluorene- [2- (tetrahydro-2'-piperanyloxymeta] oxy ^ benzyl} iso, mg mg, 0.37 mmol) in vinegar (4 house L) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was purified after concentration under reduced pressure 316408 139 200523254. The residue was purified by Shiyuki column chromatography (hexane: ethyl acetate,: 10_ > 0: 100) to obtain: 2- [4- (5-fluorenyl_3_phenylisoxazol_4_yl) phenoxy] ethanol (52 mg, 47%) in the final form. MS: 296 [M + H] + 5 APCI (MeOH) Example 153

舲 Potassium hydroxide powder (197 mg, 3.50 mmol) was added with 2-methoxy-4- (5-fluorenyl-3-benzylisoxazol-4-yl) benzoxonitrile (109 mg, 0.377 mmol) was dissolved in tertiary butanol (40 liters), and the mixture was refluxed for 5 hours under a heated preparation. After the reaction mixture was cooled, brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried through sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 爿: 2) to obtain 2-methoxyl as a solid moon bean | (5_methylphenylisoamidine) _4 _Yl) benzamidine (273 mg, 73%). MS: 309 [M + H] +, APCI (MeOH) Example 154 The following compounds were prepared by reacting or treating similarly to Example 153. 316408 140 200523254 Table 29

Pyridinium chloride (270 mg, 2.34 mmol) was added to methoxy: 4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzidine (45 mg, Ι46 4 mol) and the mixture was heated at 190 ° C for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Shi Yusheng column chromatography (hexane: ethyl acetate = 1: 1) to obtain 2-hydroxy_4_ (5_methyl-3_phenylisoxazolyl) as a solid. ) Benzamidine (34.9 mg, 81%). MS: 293 [M-H]., ESI (MeOH) Example 156 316408 141 200523254

Stir 5_ ^ ^ r Benzo-4- (4 4 5 5-tetramethyl-1,3,2-—U-boron-2-yl) isotropic wow (_, Wanzhu) under heating (605 grams, 2 12 moles), 4-bromo-2-foxybenzonitrile (300, Li, Gu + Maoxi 1.4151mol), Ibarium acetate (3 1 · 7 gram '142 mol)), 2-ϊ four mouth Gan Maoguan juice J 2 —-hexylphosphino-2,-(N Ν-dimethylamino) biphenyl (111 mg, 〇283 Suspension of mol, Mao Wudou) and linoleic acid (910 mg, 4.245 mmol) in toluene (7.0 ml) when the suspension was 24 +. The suspension of sodium sulfate was dried 'and under reduced pressure It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: υ) to give 2-methoxy-4- (5-methyl-3-phenyl) as a solid. Isoquinazol-4-yl) benzonitrile (188 mg, 46%). After the floating solution was poured into ethyl acetate / water and the organic layer was washed with brine, passed through MS: 291 [M + H] +, APCI ( MeOH) Example 157 The following compounds were prepared by reacting or treating in a manner similar to that of Example 1. 56. 142 316408 200523254 Table 3 0 Example Chemical structure Physical property constant, etc. 157 CN MS: 291 [M + H] + APCI (MeOH) ’Example 158

-N- [4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzyl] glycinate (138 mg, 0.39 mmol) was dissolved in methanol (1 ml ) And 1N aqueous sodium hydroxide solution (945 μl) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and a 10% hydrolic acid solution-ethyl acetate was added thereto. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the crude product (M, M%, methyl_3_phenyliso (_4_yl) benzyl) ] Aminoacetic acid. Without isolating the obtained crude product, luteinic acid chloride I :) was the second, and the mixture was refluxed for 2 hours. Using dichloromethane (2 f and dilute the reaction mixture. To this was added dropwise a solution of 3-dichloromethane (59 g of 〇79 mol) and triethylamine (80 mg, 7979 hexane). And the mixture was mixed with the reaction mixture and the residue was purified to obtain N-[(3-hydroxypropylamino) carbonylmethyl] -4- (5-methyl as a powder 316408 143 200523254. -3-phenyliso_azol-4-yl) benzamidine (56 mg, 36%). MS ·· 394 [M + H] +, APCI (Me0H) Example 159 h2n〇2s "^

CO〇H

——J \, jxx jl-u ^-j)-carboxylic acid (2.14 g, 6 mmol), diphenylphosphonium azide (155 ml, 7 2 mmol) and triethylamine (1.00 Ml, 7.2 mmol) in tert-butanol (30 ml) and M-dioxane (30 ml) under reflux for 16 hours under heating. After the reaction mixture was cooled with ice, ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (gas-form: methanol = 50: i _ > 20: _ to give a solid aminesulfonylphenyl group) -3- (a third butyloxyethylamino group) ) _5_ (4-based) -1H-pyrazole (569 mg, 22%). Somoto MS: 429 [M + HrJ APCI (10 mM.AcONH4 / MeOH) Example 160

nh〇316408 144 200523254 Add trifluoroacetic acid (2 ml) to i- (4-Aminosulfonylphenyl) -3 — (third butoxycarbonylamino) -5- (4-fluorenylphenyl) _111 -Pyrazole (510 mg, 1.19 mmol) in aerosol (5 ml) and stir the mixture. Ethyl acetate and a saturated aqueous solution of sodium osmium carbonate were added to the reaction mixture. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitated solid was collected by filtration to obtain 3-amino-1- (4-aminesulfonylphenylfluorenylphenyl) -1Η-koubiwa (295 Mg, 75%). MS: 329 [M + H] +, APCI (MeOH) Example 161

〇2 millimoles). Sodium chromate (17 mg) cooled in ice cubes, water (2 ml) and 48% aqueous hydrogen bromide solution (1 ml) were added to 3-amino-1- (4- (aminesulfonylphenyl) _5_ (4_methylphenyl) _11 {_pyrazole (66 mg ^ Shudu Xi cooled in ice cube ΠΓ # 4 * .1 * La .1 /.

0.2 笪, 〇 *, 士: Renjiu, Π, --.... and the mixture was granted for 10 minutes. Add a solution of copper bromide (43 mg, 0.3 mmol, ml) in the chamber, and at 80 ° C; add ethyl acetate and water to the reaction mixture, wash with water, dry through sodium sulfate, and protect the residue The substance was purified by silica gel column chromatography (chloroform 3) 6408] 45 200523254 to 1- (4-aminosulfonylphenyl) -3-bromo-5- (4-fluorenylbenzyl)- 1H-orbizole (33 mg, 39%). MS: 392 [M + H] +, APCI (Me0H) Example 162 (1)

Make 2 · (4-bromobenzyl) _1-pyridin-3-ylethanone (8.0 g, 27.5 mmol), hydroxylamine hydrochloride (2.00 g, 28.8 mmol), and carbonic acid A suspension of sodium bicarbonate (2.45 g, 29.2 mmol) in ethanol (70 ml) and water (10 ml) was stirred at 60 C for 3 hours. After removing the solvent by concentration under reduced pressure, ethyl acetate / water was added to the residue. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ·· ethyl acetate = 1: to obtain 2- (4-bromophenylethyl ketone) as a powder (7 ·% g, 94%). MS: 291/293 [M + H] +, APCI (MeOH) (2)

Diisopropanolamine was used to dissolve 2- (4_ > styrophenyl) pyridinyl ethyl ketone (40 g) in THF (40 ml) and at -60. 〇 2M di 316408 146 200523254 solution (heptane / THF / ethylbenzene solution) (15.1 ml, 30.2 mmol) was added dropwise thereto. After the addition, the reaction mixture was warmed to -30 ° C and acetic anhydride (1.55 ml, 16.4 mmol) was added thereto at one time. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was poured into ethyl acetate / water. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ·· ethyl acetate = 1: 1) to obtain 4- (4_bromophenyl) _5_ (methyl_3-methyl) 疋- 3-yl-4,5-dihydroisoharmonic. Seated-5-ol (2.54 g, 56%). MS: 333/335 [M + H] +, APCI (MeOH) • (3)

4- (4-Bromophenyl) _5_methyl_3_pyridine_3_yl_4,5_monolactone, az-5-ol (2.5 g, 7.6 mmol) and monohydrated pair_ A suspension of toluenesulfonic acid (ι · 7 g, 9. mmol) in methanol (25 ml) was heated under heated conditions for 24 hours. After the cold part, the reaction mixture was concentrated under reduced pressure, and ethyl acetate / saturated sodium hydrogen carbonate solution was added thereto. The phases were separated, 'washed with brine', dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 3.0 to obtain 3 liquid 4_phenyl groups) _5_methylriponazole-3-yl] [1 pyridine (1.9 g, 78/0). MS: 315/317 [M + H] +5 APCI (Me〇H) (4) 316408 147 200523254

In a manner similar to Example 149, the compound system prepared by [5_fluorenyl_3- (3-pyridyl) isoxazole above (3) was reacted and treated to prepare 4-4-yl] benzonitrile. . MS · 262 [M + H] +, APCI (Me〇H) (5)

The compound prepared in the above (4) was reacted and treated in a manner similar to that of Example 49, and was reacted and treated in a manner similar to that of Example 15 to prepare 4- [4] in the form of hydrochloride. 5-methyldUDttpyridyl) isoxazol-4-yl] benzoic acid. MS: 279 [M-H] + ^ ESI (MeOH)

The following compounds were prepared by reacting and treating in a manner similar to the above examples or according to a generally used conventional method. 148 316408 200523254 Table 31 Examples of chemical structure, physical constants, etc. 163 h3c MS: 426 [M + H] +, APCI (MeOH) 164 η4'Ό ^ Γ " 3 H3C-N \ ch3 MS: 411 [M + H] 'APCI (MeOH) 165 P h3c MS: 424 [M + H] +, APCI (MeOH) 166 〇MS: 327 [MH] · ESI (MeOH) 167 ci MS: 424 [M + H] +, APCI (MeOH )

149 316408 200523254

Table 31 (continued)

Example 173 The following compounds were prepared in a similar manner to Example 72 by reaction 150 316408 200523254 or treatment. Table 32 Examples Chemical structure Physical properties ~~ Η2θΌ ^ ν ^ N ~ ------ 173 MS: 337 [M-H]-? P ESI (MeOH) h3c Example 174

Compounds are described in Journal of Medicinal Chemistry, vol. 40, pp. 1347 to 1365 (1997).

φ The compounds of Examples I75 and Π6 and below are those of Example 122 of oxazole and prepared in a manner analogous to the reaction or treatment using 4-bromo-5-methyl-3-phenyl. 151 316408 200523254 Table 34 Examples of chemistry, 纟 ~ physical property constants, etc. 175 〇 〇 〇 °° MS: 308 [M + H] +? APCI (MeOH) 176 MS: 351 [M + H] +, APCI (10mM- AcONH4 / MeOH) Example 177

(Boc) 20

" " ^ BocHN

[3- (5-fluorenyl-3-benzylisoxazolyl) phenyl] amine (500 mg, 2.00 mmol) was dissolved in n-oxane (5 ml) and the Di-tert-butyl carbonate was added thereto, and the mixture was stirred at 9 (rc for 6 hours. The reaction mixture was cooled to room temperature and 10% aqueous citric acid solution was added), and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5 ·· 1 a 3: 丨) to obtain [3- (5-methyl-3-phenylisoxazole) as a solid. 4- (4-yl) phenyl] aminophosphonium tert-butyl ester (553 mg, 82%). MS: 351 [M + H] +, APCI (10 mM-AcONH4 / MeOH) 316408 152 200523254 Example 178 The following compounds were made to react or treat the compound prepared in Example 177 in a manner similar to Example 151 While prepared. Table 35 Examples of chemical structure, physical property constants, etc. 178 CX jCX T2 Boc P MS: 493 [M + H] +, APCI (10mM-AcON H4 / Me〇H) The compounds of Examples 179 and 180 were implemented The compounds prepared in Examples 176 and 178 were prepared by reacting or treating similarly to Example 29. Table 3 6 Examples Chemical structure Physical property constants, etc. 179 MS: 309 [M + H] +, APCI (MeOH) 180 H! N ^ 0 / 〇 MS: 287 [M + H] +, APCI (MeOH)

The following compounds of Examples 181 to 184 were prepared by reacting or treating the compound prepared in Example 44 (1) in a manner similar to that in Example 44 (2) of 153 316408 200523254. Table 37

Example Rx Physical property constant, etc. 181 Η〇η ^ Λ ch3 MS: 454 [M + H] 'ESI 182 h3c, c / ^ N, MS: 440 [M + H] +? ESI 183 Η A ~ N, h3c 0 MS: 454 [M + H] 'ESI 184 H HO 1 ch3 MS: 440 [M + H] +, ESI Examples 185 to 187 The compounds below are similar to those using 5-fluorenyl-3-phenyl- 4- (4,4,5,5-tetrafluorenyl-1,3,2-difluorenylborane-2-yl) isoxazole was prepared by reaction or treatment in the manner of Example 156. 154 316408 200523254 Table 38

Example Rx Physical property constant, etc. 185 MS: 295/297 [M + H] 'APCI (MeOH) 186 HX MS: 275 [M + H] +, APCI (MeOH) 187 η3ο ° Υ ^ MS: 300 [M + H] +, APCI (MeOH) The compounds of Examples 188 and 189 were prepared by reacting or treating the compounds prepared in Examples 156 and 185 in a manner similar to that of Example 150. Table 39

• 〇)

HO

Example Rx Physical property constants, etc. 188 Me0-MS: 308 [MH]-? ESI 189 Cl- MS: 312/314 [MH]-, ESI Examples 190 and 191 155 316408 200523254 186 order compound or treatment prepared While prepared. The following compounds were reacted in the same manner as in Example 15: 3 and Example 15: Table 40

The mouthpieces below Examples 192 to 222 were prepared by reacting or treating in a similar manner to Example 48. ,

156 316408 200523254

157 316408 200523254

Table 41 (continued) Example chemical structure physical property constants, etc. 195 MS: 379 [M + H] +, APCI (MeOH) 196 MS: 379 [M + H] 'APCI (MeOH) 197' 0 h3c MS: 434 [ M + H] +, APCI (MeOH) 198 〇0 h3c MS: 418 [M + H] +, APCI (MeOH) 199 Cl _ CH, MS: 401/403 [M + H] +, APCI (MeOH )

158 316408 200523254

Table 41 (Continuous example chemical structure physical property constants, etc. 200 CIV h3c ° ^ H d MS: 426/428 [M + H] +, APCI (MeOH) 201 Civ h3c V < W:? N VN H2N " ~ ^ H / ==== (0 Q MS: 370/372 [M + H] +, APCI (MeOH) 202 H); w; 〇 > = N 'CH30 ^ MS: 367 [M + H]' APCI (MeOH ) 203 CH, H. ~ MS: 329 [M + H] +, APCI (MeOH) 204 〇 ~ CH, MS: 350 [M + H] +, APCI (MeOH) 205 MS: 381 [M + H] + , APCI (MeOH)

159 316408 200523254

Table 41 (continued) Examples of chemical structure, physical constants, etc. 206 9V CH, MS: 350 [M + H] +, APCI (MeOH) 207 9V ~ CH, MS: 324 [M + H] f? APCI (MeOH) 208 o ch3 0 MS: 338 [M + H] +, APCI (MeOH) 209 0 CH3 MS: 338 [M + H] + 5 APCI (MeOH) 210 〇 'CH, CH3 MS: 338 [M + H] + ? APCI (MeOH) 211 q ch, CH3 0 MS: 338 [M + H] +? APCI (MeOH)

160 316408 200523254

Table 41 (continued) Examples of chemical structure, physical constants, etc. 212 9v CH, HOMS: 338 [M + H] + 5 APCI (MeOH) 213 HC 9 \ CH «MS: 350 [M + H] +, APCI (MeOH) 214 H2N ^^ MS: 350 [M + H] +, APCI (MeOH) 215 H〇 ^ > = N MS: 365 [M + H] +, APCI (MeOH) 216 MS: 377 [MH ]-, ESI 217 MS: 363 [M + H] + 5 ESI

161 316408 200523254

Table 41 (continued) Examples of chemical structure, physical property constants, etc. 218 MS: 384 [M + H] +, ESI 219 9 ~ CH, MS: 353 [M + H] +, ESI 220 OH less = N Ο MS: 337 [M + H] +, ESI 221 _ a — ο 9η3 H ,. Q MS: 434 [M + H] +, APCI (MeOH) 222 0 CH3 Η2Ν Ο MS: 378 [M + H] +? APCI (MeOH)

The compounds of Examples 223 and 224 are prepared by reacting or treating the compounds prepared in Examples 187 and 194 in a manner similar to Example 70. 316408 162 200523254 Table 42

(3R) -3 _ {[((4_ (5_Methyl_3_phenylisoisoxazolyl) phenylfluorenyl) amino] fluorenyl butyrate (952 mg, 2.52 mmol)) 1N aqueous sodium argon oxide solution (3 mL, 3.0 mmol) was added to an alcohol (5 mL) at 0 C, and the mixture was stirred at room temperature for 2 hours. Make the reaction mixture

After concentration 'water (60 ml) was added to the towel and the mixture was washed with diethylamine. The pH of the aqueous layer was adjusted to 3 with 10% hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried through sulfur steel, and concentrated under reduced pressure. Put the calendar (3 ml) into the money, and then in 〇WN- butylated diimine (29 mg 2.52 mol) and ethyl ethyl 3-(3, a ^ monomethylaminopropyl) carbon dimer Imine chlorate (482 mg, 2.52 mmol) was added. Divide the mixture one by one 316408 163 200523254, reach to the shirt and search overnight at room temperature. Ethyl acetate (1 ml) was added, f, middle f, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and water. The residue was converted to I using hexane B and filtered to obtain N-{(lR) -3-[(2,5-dioxolyl) oxy] Small methyl orthopropyl} -4- (5-fluorenyl-3_phenyl isothiophile. Sit-4-yl) benzylamine, mg, 75%). MS: 462 [Μ + ΗΓ, APCI (MeOH) Example 226 The reaction of Example 225 was performed as follows. The following compounds were prepared by analogy or treatment.

Make N _ {(111 ^ 3 _ [(2,5-dioxopyrrolidin-1-yl) oxy] -1-fluorenyl-3- 164 316408 200523254 oxopropyl 4- (5-methyl-3- Phenylisoxazole_4_yl) benzamide (丨 ⑻mg, 0.22 mmol) was dissolved in THF (5 ml) and 30/0 ammonia water (1 ml) was cooled under ice-cooling. ) Added to it. The mixture was stirred at room temperature overnight, the reaction mixture was poured into ethyl acetate / water. The organic layer was washed with brine, dried over sodium sulfate, and under reduced pressure; the concentrated residue was passed through a silica gel column Chromatography (hexane ·· ethyl acetate = 75: 25 _ > 〇: 100) was purified to obtain n _ [(1r) _3_amino · 4-yl_3-oxopropyl]- 4- (5-methyl-3-phenylisoxazol-4-yl) benzidine (875 mg, 75%). MS: 364 [M + H] +, APCI (Me0H) Example The compounds below 228 to 230 were prepared by reacting or treating in a manner similar to that of Example 227.

] 65 316408 200523254

Synthesis Example 231

Table 44 Examples of chemical structure, physical property constants, etc. 228 CH, 〇〇 ^ ° MS: 364 [M + H] +, APCI (MeOH) 229 MS: 408 [M + H] +, APCI (MeOH) 230 MS: 422 [M + H] +, APCI (MeOH) makes N-{(lR) -3-[(2,5-dioxopyrrolidin-1-yl) oxy] -1-fluorenyl-3-oxopropane } -4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzidine (100 mg, 0.22 mmol) was dissolved in THF (5 ml) and the solution was removed at 0 ° C. Sodium borohydride (16 mg, 0.42 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride (2 ml) was added to the reaction 166 316408 200523254 mixture at 0 ° C and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-> 1: 1) to obtain N-[(lR) -3-hydroxy-1-fluorenyl as a solid. Propyl] -4- (5-fluorenyl-3-phenylisoxazol-4-yl) benzamide (75 mg, 99%). MS ·· 351 [M + H] +, APCI (MeOH) Example 232 The following compounds were prepared by reacting or treating in a manner similar to that of Example 23 1. Table 45 Examples of chemical structure, physical property constants, etc. 232 Η ^-X3 MS: 351 [M + H] +, APCI (MeOH) Example 233 The following compounds were reacted in a manner similar to (2) of Example 44 Or prepared. 167 316408 200523254 Table 46

Examples Chemical structure physical property constants, etc. 233 (^ 1 h3c ^^ MS: 440 [M + H] 'ESI Examples 234 to 248 The following compounds were prepared by reacting or treating similarly to Example 48. 168 316408 200523254

Table 47 Examples of chemical structure, physical property constants, etc. 234 h3c MS: 357 [M + H] +, APCI (MeOH) 235 PH ηο ^ 〇JL Ρ (ΧΝ MS: 367 [M + H] +, APCI (MeOH) 236 MS: 363 [M-H] 'ESI 237 Η2N ^ η ο MS: 350 [M + H] +, APCI 238 9ν / CH, 0 MS: 337 [M + H] +, APCI 239. Β MS: 364 [ M + H] +, APCI

169 316408 200523254

Table 47 (continued)

Examples Chemical structure, physical property constants, etc. 240 MS: 309 [M + H] + 5 APCI 241 〇y__ CH, hc, Q MS: 384 [M + H] +5 APCI 242 〇 ~ CH, MS: 370 [M + H] +, APCI 243 K1 0 CH, hci o MS: 356 [M + H] +? APCI 244 πLet MS: 353 [M + H] +? APCI 245, ACirr σ 'MS: 377 [M-Η] , ESI 170 316408 200523254 Table 47 (continued)

Examples Chemical structure physical property constants, etc. 246 ~ CH, HCI V / MS: 370 [M + H] +, APCI 247 9 \ CH, H3C HCI MS: 385 [M + H] +, APCI 248 HCI MS: 350 [ M + H] +, APCI Example 249 The following compounds were prepared by reacting or treating similarly to Example 121. Table 48 Examples Chemical structure Physical property constants, etc. 249 Let: MS: 261 [M + H] +, APCI (MeOH)

Example 250 (1) 171 316408 200523254

Bromine (6.0 ml, H7 "mmol) was added to a solution of 3-phenylisoxazole (84 mg, 5.787 mmol) in acetic acid (15.0 ml), and the mixture was heated at 9 (TC) The mixture was stirred for 96 hours. The reaction mixture was cooled and poured into a saturated aqueous solution of sodium bicarbonate and the mixture was taken with ethyl acetate. The organic layer was washed with a saturated aqueous solution of 15% sodium thiosulfate followed by brine, and dried over sodium sulfate. , And under reduced pressure, / chen fine. The residue was purified by Shixi gel column chromatography (hexane: ethyl acetate = 100: 0-> 90: 10) to obtain a solid 4-bromo_3-phenylisoxazole (1290 mg, 99%).

MS: 224/226 [M + H] +, APCI (2) The following compounds were prepared by reacting or treating similarly to Example 121 using 4-bromo-3-phenylisoxazole. Table 49

Examples Chemical structure, physical property constants, etc. 250 (2) HO Q MS: 264 [M-H] -5 ESI The compounds of Examples 251 and 252 were prepared by reacting or treating in a similar manner to that of Examples 135. 172 316408 200523254 Table 50

The compounds of Examples 253 and 254 are prepared by reacting or treating in a manner similar to that of Example 150.

The compounds of Examples 255 and 256 and below were prepared by reacting or treating in a manner similar to that of Example 151. 173 316408 200523254 Table 52

Examples Chemical structure Physical property constants, etc. 255 MS: 310 [M + H] +, APCI (MeOH) 256 MS: 427 [M + NH4] + 5 APCI

Example 257 The following compounds were prepared by reacting or treating in a manner similar to that of Example 152. Table 53

Examples Chemical structure Physical property constants, etc. 257 Γ3 0 MS: 326 [M + H] + 5 APCI

Example 258 The following compounds were prepared by reacting or treating in a manner similar to that of Example 153. 174 316408 200523254 Table 54

The compounds of Examples 259 and 260 were prepared by reacting or treating in a similar manner to that of Example 156.

Example 261 The following compounds were prepared by reacting or treating in a manner similar to that of Example 158. 175 316408 200523254 Table 56

Examples Chemical structure, physical property constants, etc. 261 HO 〇 ^ > > = N 〇MS: 380 [M + H] +, APCI Example 262 The following compounds are reacted or treated in a manner similar to that of Example 162. preparation.

Table 57

Examples Chemical structure, physical property constants, etc. 262 Bxvr crN, N MS: 329/33 1 [M + H] + 5 APCI Example 263 The following compounds were reacted in a manner similar to (4) of Example 1 62 or Prepared by processing. Table 58

176 316408 200523254 Examples 264 to 266 The following compounds were prepared by reacting or treating similarly to Example 48. Table 59

Examples Chemical structure Physical property constants, etc. 264 MS: 339 [M + H] +? APCI 265 Η2N ο MS: 336 [M + H] +, APCI 266 9 \ CH, MS: 399 [M + H] +? APCI

The compounds of Examples 267 and 268 were prepared by reacting or treating in a manner similar to that of Example 150. 177 316408 200523254 Table 60

The compounds of Examples 269 to 271 were prepared by reacting or treating in a manner similar to that of Examples 153.

178 316408 200523254 Table 61

Examples Chemical structure physical property constants, etc. 269 〇 2VΛΌο;-^ ν, ° WN MS: 308 [M + H] 'APCI 270 〇H2N ^ OucH3 〇 ^ ° MS: 280 [M + H] +, APCI 271 〇H3Cy ^ CH3 ^ Vp Ci N MS: 308 [M + H] + 5 APCI The compounds of Examples 272 and 273 were prepared by a reaction or treatment similar to that of Example 156. 179 316408 200523254 Table 62

Example 274 The following compounds were prepared by reacting or treating in a manner similar to (5) of Example 162. Table 63

The compounds of Examples 275 to 289 were prepared by reacting or treating in a similar manner to Example 48. 180 316408 200523254 Table 64 RXl RX3

RX2 Example RX1 RX2 RX3 Physical constants and so on 275 Ph Me MS: 387/389 [M + H] +, APCI 276 ch3 o Ph Me MS: 351 [M + H] 'APCI 277 H know Ph Me MS: 280 [ M + H] 'APCI 278 0 HCI Ph Me MS: 280 [M + H]' APCI 279? H3 u 〇3-pyridyl Me MS: 381 [M + H] +, APCI 280 〇HO eight Y ^ N people ^ Ηη H 3 -pyridyl Me MS: 354 [M + H] +, APCI 281 〇HO eight V ^ N human 〆 ^ & H 3 -pyridyl Me MS: 354 [M + H] 'APCI 282 3-pyridyl Me MS: 351 [M + H] +, APCI 283 Λα 3-pyridyl Me MS: 401 [M + H] +, APCI 181 316408 200523254 Table 64 (continued)

Example RX1 RX2 RX3 Physical property constants, etc. 284 HO. 3-pyridyl Et MS: 368 [M + H] +, APCI 285 2-Port ratio σ-base Me MS: 324 [M + H] 'APCI 286 HO. 2 -Pyridyl Me MS: 354 [M + H] +, APCI 287 3-pyridyl Et MS: 338 [M + H] +, ESI 288 〇 3Η pyridyl Et MS: 368 [M + H] + , ESI 289 3-pyridyl Et MS: 400 [M + H] +, ESI Example 290 The following compounds were prepared by reacting or treating in a manner similar to Example 70. 182 316408 200523254 Table 65

(1)

2-pyndinecarbohydroxymoyi chloride (500 mg, 3 19 mmol) and tributyl (1-propyn-1-yl) under ice-cooled conditions A solution of tin (1.94 ml, 6.38 mmol) in THF (10 liters) was added dropwise with triethylamine (1 ml, 7 u mmol) for 15 minutes. After the mixture was allowed to stand overnight and the temperature was returned to warm, the reaction mixture was concentrated and diluted with hexane. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane) to obtain 2- [5-fluorenyl-4- (tributyltinyl) iso-azole_3_yl] ol as an oily substance. Pyridine (554 mg, 39%). MS: 447/449/451 [M + H] +, APCI (MeOH) (2) 316408 183 200523254

Make 2- [5-methyl-4- (tributyltinyl) isoxazol-3-yl] pyridine (100 mg '0.223 mol), 4-bromobenzonitrile (61 mg, 0.325 mmol) ), Di (dibenzylphosphine) concubine (30 mg, 0.026 mmol) and copper ethene (5 g, 0.026 mol) in dioxane (3 ml) under heating conditions

Under reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of potassium fluoride was added thereto, and the mixture was stirred at room temperature for 2 hours. After removing the precipitate by filtration, the filtrate was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane ·· ethyl acetate = 95 : 5 65 · 35) and purified to obtain 2_ [5_methyl_4_ (4_aminophenyl) isosulfone as a powder. Sit-3-yl] pyridine (48 mg, 83%). MS: 262 [M + H] +, APCI (MeOH) Examples 292 and 293 (The dimer is prepared by reaction or treatment in a manner similar to (1) and ⑺ in Example 291.) 316408 184 200523254 Table 66

The compounds of Examples 294 to 299 were prepared by reacting or treating in a similar manner to Example 48.

185 316408 200523254 Table 67

Example Rx Physical property constant, etc. 294 h9n hK, 〇 \ MS: 365 [M + H] +, ESI 295 H3C, η VN \ MS: 324 [M + H] +, ESI 296 H3c / 〇Η H3cj0 \ MS: 366 [M + H] +, ESI 297 Ί H MS: 395 [M + H] +? ESI 298 H, C MS: 352 [M + H] +, ESI 299 H3C, Η h3c \ MS: 365 [M + H] +, ESI Under dry ice-acetone cooling, a 1.6N n-butyllithium hexane solution (21 ml, 33 mmol) was added to 4-bromo-5-fluorenyl-3-phenylisoxazole (7.14 g, 0.30 mmol) in THF (100 ml). In the same

Example 300 (1)

186 316408 200523254 «Teach this mixture to 30 people) Hydropyridin-4-one (6.8 g, 34.3) Warm to room temperature. After 30 minutes, add the third butoxycarbonyl six 3 4 · 3 millimoles). The reaction was mixed to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetonitrile -2 · 1). The obtained residue was crystallized from diethyl ether-hexane to obtain 4-hydroxy-4- (5 -Methyl-3_phenylisoxazol-4-yl) hexahydropyridine q-carboxylic acid tert-butyl ester (5.83 g, 54%). MS: 359 [M + H] +, APCI (MeOH) (2)

4-Hydroxy-4- (5-fluorenyl-3-phenylisoxazol-4-yl) hexahydropyridine q-carboxylic acid third butyl ester was dissolved in PPSE dichlorobenzene solution (40 ml) and The mixture was heated at 140 C overnight. After cooling, the reaction mixture was poured into water 'neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) and waited for 4- (5 -fluorenyl-3-phenylisoisoππ_4_yl) -1,2,3,6- Tetrahydro D ratio. (193 mg, 16%). MS · 241 [M + H] +, Preparation of APCI (MeOH) PPSE dichlorobenzene solution: Di (trimethylsilyl) ether (0.5 liter) and o-dichlorobenzene (1 liter) 316408 187 200523254 this mouthpiece was heated to 15 (rc) and phosphorus pentoxide (2 g) was divided into several portions. The mixture was allowed to stand at the same temperature for W minutes, and the prepared solution was cooled to room temperature to obtain ppsE Dichlorobenzene solution. (3)

Lu ^ Add 2 methoxyethylamine microliters (0.42 mol) to a solution of triphosgene (41.2 mg, 0.14 mmol) in dichloromethane under ice-cooled conditions and then add three Ethylamine (120 μl, 0.84 mmol), and the mixture was stirred at the same temperature for 15 minutes. 4_ (5_methyl_3_benzyl iso% azole-4-yl) -1,2,3,6-tetrahydropyridine (95 mg, 0.39 mmol) was added thereto and the mixture was stirred at room temperature Mix for 2 days. The reaction mixture was purified by a silica gel column chromatography (gas-form: methanol = 100: 0-> 97 ·· 3) to obtain N- (2-methoxyethyl) _4_ (5-methylphenyliso Oxazole-cardiacyl) -3,6-dihydropyridine_1 (211) -formamidine (121 mg, 91%). MS: 342 [M + H] + ^ APCI (MeOH) Example 3 01 188 316408 200523254

(1) Make 4-bromophenylacetic acid (ΐ5.0 g, 7.0 mmol), nicotinic acid: (7.47 Xin Luke '7.0 mmol) and triethylamine (9.7 liter' 7.0 mmol) Ear) was dissolved in acetic anhydride (60 ml) and the mixture was refluxed under heating for 20 hours. The mixture was cooled to 110 ° C, and water (30 ml) was gradually added thereto while stirring. After 30 minutes, the reaction mixture was allowed to cool to the chamber ✓ JDL 'and the crystals of Shen Dian were collected by passing through it' was washed with water and diethyl ether and dried to obtain (2E) -2- (4-bromo Phenyl) -3-pyridine-3-triacrylic acid (11.1 g, 52%). _ MS: 302/304 [Μ-ΗΓ, ESI (MeOH)% (2) sulfolium (29 ml '4.0 halo) is added dropwise to methanol (150 ml) at -10 ° C, And the mixture was stirred for 20 minutes. (2e)-(4-Bromobenzyl) -3-D is compared. After the addition of stilbyl-3-yl acrylic acid (11.0 g, 3.6 mmol), the mixture was gradually warmed to room temperature, and then, was allowed to stand for 7 hours at 7 (rc.) Under reduced pressure. In addition to methanol, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and 316408 189 200523254 under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: ◊ 1 · 1) to obtain (2E) _2_ (4_bromophenylbuthyl 3-pyridyl fluorenyl acrylate) as a liquid ( 8.78 g, 76%). MS · 318/320 [M + H] +, APCI (MeOH) (3) at temperature (2E) -2- (4-bromophenyl) _3-pyridin-3-yl A solution of fluorenyl acrylate (14.14 g, 44.4 mmol) and europium fluoride (70 mg, 0.046 mmol) in DME (100 ml) was added (trifluoromethane) trimethylsilyl beta · 23 tail rises, 55.7 millimoles). !! After hours, 4N hydrochloric acid (1000 liters) was added thereto and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate water> mineral liquid was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to quantitatively obtain a crude liquid. The product (3E) 3- (4, odorant phenyl) -13} trifluoro_4_pyridobutyryl_3_dilute_2one. MS: 356/358 [M + H] ^ APCI (MeOH) (4) make (3E) -3- (4-benzyltnu fluoropyridinyl 1-butyr-3-enone (15.0 g, 42.1 g) Moore), Hydroxylamine Hydrochloride (3.22 g, 46.3 Lumamore) and Sodium Acetate (3.80 g, M · 3 mmol) in absolute ethanol (Thor :: The mixture was refluxed for 1 hour under heating. After the mixture was cooled down and concentrated under reduced pressure, ethyl acetate was added thereto, the organic layer was washed with brine, dried over sodium sulfate, and The residue was purified by silica gel column chromatography (hexane: acetic acid 9 · 1◊1 · 丨) to obtain a powder; H4-bromobenzene) Hi-difluoro -4- (¾Amine) cyprodin-3-ylbutanone (8.80 g, 316408 190 200523254 MS: 389/391 [M + H] +, APCI (Me〇H) (5) make 3 -(4-bromophenyl) -l5U_trifluoro (hydroxylamino) pyridylbutan-2-one (8.80 g, 22.6 mmol), iodine (5 74 g, 22.6 mmol), potassium iodide ( 315 g, 2% mmol) and sodium bicarbonate (19.0 g, 226 mmol) in THF (200 ml) and water (100 mmol The mixture in the mixed solvent was refluxed for 7 hours under light-shielding conditions, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and ethyl acetate was added thereto. The mixture was washed with brine. , Dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Shixi gel column chromatography (hexane ·· ethyl acetate = 9 ·· 1 1: υ to obtain an oily substance 3- [4- (4-bromophenyl) -5 ((trifluorofluorenyl) isoisalanyl] yl] succinium, 73%). MS: 369/371 APCI (MeOH) Example 302

Iso-5- (trifluoromethyl) isophilic. Sitting ice-based] benzene? .G, 5.08 t mole) refluxed under 6N hydrogen acid (10 N for 4 days. The mixture was allowed to cool and concentrated under the known conditions to obtain a powdery 4_ [3- ) Isochrysyl-4-yl] benzoic acid hydrazone (1.71 g, 9 ^ — (Di MS: 333 [M-Η] · 5 ESI (MeOH) ° 316408 191 200523254 Example 303

(i) 2-Methoxy nicotinaldehyde oxime (i.35 mg, smolole), tributyl (1-propyne small group) tin (2 97 ml, 9.76 mmol) under ice-cooled conditions Mol), potassium bicarbonate (1780 mg, 17 74 mmol) and a suspension of water (one drop) in ethyl acetate (10 liters) were added with N-gassuccinic acid imine (1320 * g ' 9.76 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was released using ethyl acetate, and the test was performed by condensing the insoluble matter with fresh hydrazone and concentrating the filtrate under reduced pressure. Residue by Shi Ximu column chromatography (Hexane: ethyl acetate g | = 5 (): i%: ⑽: to give an oily ❺ 2-methoxy_3 Office 曱 _ 4 (three Dingxiji) Yikoujunjun-3-yl] Hou, Ding (182.0 mg, 43%). _ MS: 477/479/481 [M + H] +, APCI (MeOH) ⑺> 2 foxy _3. [5-fluorenyl_4- (tributyltinyl) isosalanyl] oh bite (Ancient 3 is Aike 'ms millimol), cardiac bromobenzamide mg, 〇6⑻ ⑻mol And digas bis (triphenylphosphine) palladium (11) (42 mg, 0.060 mmol) in No. & (61 liters)> The valley liquid was refluxed under heating conditions overnight. The reaction mixture was cooled And acetic acid was released from ethyl acetate. Fluoride was added to it and the mixture was stirred at room temperature for% minutes. Shen Dianwu was removed by filtration and the filtrate was washed with brine, dried over sodium sulfate 316408 192 200523254 and dried. And concentrated under reduced pressure conditions>. The residue was purified by silica gel general analysis (ethyl acetate: methanol H ridges column layer 1-> 93 · 7) to obtain

4- [3- (2-Methoxyl ratio. Dyn-3-yl) -5-methylisoisomer = sulfonamide (64 mg, 35%). Soil "-this T MS: 310 [M + Hr, APCl (MeOH) Examples 304 to 341 The following compounds were prepared by reacting and treating in a manner similar to the above-mentioned examples using relative starting compounds . , -Has

316408 193 200523254

Example A ring R1 304 305 〇- 306 307 〇 " 308 < 〇 ^-309 310 311 312 313 O '" 314 〇- 315 Q- -N -N -N

4-CON (CH2CH2OH) 2 4-CONH (CH2) 2〇 ^ N =) NR = λ 4-CONH (CH2) 2CKv) 4-CONH (CH2) 2CH3 4-CONH (CH2) 2- ^ 4- CONMe2 5 -CONHC (Me) 2CH2OH 5-CONH (CH2) 2〇H OH 5-CONHCH2CHCH3 (R) OH 4-CONHCH2CHCH3 (R) OH

OH 4-CONHCH2CHCH2〇H (R2 m R3 R4 n R13 X MS: rrVz 3-CI 1 H-0 Me CH 401/403 [M + H] +, APCI-0 H-0 Me CH 401 [M + H] +, APCI-0 H-0 Et N 416 [M + H] +, ESI-0 H-0 Et N [M + H] +, ESI-0 H-0 Et N 399 [M + H] +, ESI -0 H-0 Et N 322 [M + H] +, APC!-0 H-0 Me CH 352 [M + H] + fESI-0 H-0 Me CH 324 [M + H] +, ESI-0 H-0 Me CH 338 [M + H] +, ESI-0 H-0 H CH 323 [M + H] +, ESI-0 H-0 H CH 339 [_] +, ESI-0 H-0 H CH [M + H] +, ESI see 194 316408 200523254 R1

317 4CONH2 318 Vy 4-CONHCH2CHOH (S) 319 4 ^ 0NH (CH2) 2 ^ p) 320 4-CONH (CH2) 2〇H 321 4 ^ 0NH (CH2) 2- ^) 322 4 »CONH (CH2) 3p 323 ^ CONHCH2CH (OH) CF3 324 4CONHCH2CH (OH) CH2〇Me-0 H 325 ^ 4-CON H2 326 4-CONHCH2CONH2 327 < Q ~ H 328 HN ^ H

-0 4-CH3-0 Me CH -0 4 ^ H3 · 0 Me CH -0 4-CH3-0 Me CH -0 4-CH3-0 Me CH

-0 H -0 H -0 H

-0 H -0 H 4-CN1 H -0 H

293 [M + Hl + .APCI 351 [M + H] +, APCI 398 [M + H] +, APCI 337 [M + HJ + .APCI 384 [M + HJ + .APCI ^ QQ [M + HI + 丨 ESI 391 [M + H + + HJ + .APCI 357 [M + HJ + .APCI 297 [M + HJ + .APCI 354 [M + H] +, APC! 316 [M + H] +, APCI

329 4-CONHCH2CH (OH) CH2〇Me-0 H

-0 Me N • 0 Me N -0 Me CH -0 Me CH 4-F 1 Me CH 4-F 1 Me CH -0 CF3 N -0 Me CH (commercially available) -0 Me N 368 [M + HJ +, APα 195 316408 200523254 R1

333 4-CONHOMe 309 0 Me CH [m + h] +, APCI

OH -0 -0 -0 -0 -0 -0 -0 -0 -0 ΦΟΝ1 H H 5-Me

0 CF3 N 0 Me N ο- 334 ^ CONHCH2CHCH2OH (S) 335 4-CONH2 336 < Q > ~ 4-CONH2 337 4-CONH2

338 4-COOH 339 4-CCX) Me

340 4 «COOH 341 & H 408 [_] +, APCl 294 [M + H1 + .APCI ～ 309

2-OMe-〇 Me CH [_] + 丨 APCI 309 2rOMe-〇 Me CH [M + H] + APci m 292

4, Me-0 Me CH [jvmj-ESI

~ 30B

4, Me-0 Me CH | m + H] +, APCI 296

H 4-F 1 Me CH ^ nj-ESI 279 H 4-F 1 Me CH [M + H] + Apci Example 3 4 2

H〇, / ^ NH2 H〇, 〇 Cl

Make 2-Gas-4- (5-pyridyl-3-phenyliso_ ° -4-yl) benzoic acid (78 316 408 196 200523254 g '0.25 mmol), (s) -l -Amino-2-propanol (0.039 ml, 0.49 mmol), N-hydroxybenzotriazole (40 mg, 0.30 mmol), and ethyl-3- (3'-di A mixture of methylaminopropyl) carbodiimide hydrochloride (100 mg, 0.52 mol) in DMF (2 ml) was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7 · 3 1 · 〇) to obtain 2_ 气 _ 义 [(2 ^ _2_hydroxypropyl) -4_ ( 5-Amino-3-benzylisoxazol-4-yl) benzimidamine (mg,, 91%).

MS: 371/373 [M + H] +, APCI Example 343

The mixture was extracted artificially. -Benzoisoxazol-4-yl) benzamide (30 mg, in a solution in [dichloromethane (2 ml). The reaction was mixed for a day, and the diluted ammonia was added thereto. Wash with brine using chlorine The extract was dried over sodium sulfate, 316408] 97 200523254 The residue was purified by nh stone tube column: 5) to obtain -N- (morpholine-2-ylmethyl) benzidine as caramel. And concentrated under reduced pressure. Analytical method (chloroform: methanol = 100: 95 4- (5-methyl-3-phenylisoshuwa-4) yl) amine (13 mg, 53%). MS. 378 [M + H] +, APCI Example 344

Me

Br. 7V ^.

NH OH (1) Bromine (49.4 g, 309 * 11, + λ c Fanchuan y Maoming) was added to methyl isoxazoscarbamate at room temperature (30 g, 206 m 箪 u u, ,,, Hairy bucket) in solution in lice imitation (103 liters) and reflux the mixture; 3 hours. ^ w; ^ 2 彳 纟 d τ ~ σP, the reaction mixture was poured into a saturated aqueous solution of potassium bicarbonate-a saturated aqueous solution of sodium thiosulfate and extracted twice with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate 'and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 4-bromo-5-fluorenylisoxazole-3-carboxylic acid ethyl ester (27 3 g) as a solid. , 60%). MS: 220/222 [M + H] + > APCI (MeOH) (2) Sodium hydroxide aqueous solution (4N, 2050 316408 198 200523254 liters under ice-cooled conditions) , 8 1.8 House Mor)) added 4_ Mo_5_methyl Yushugu ^ " Methyl tetrazole-3-carboxylate (15.01. $ Wu Er) in? Alcohol (150 ml) The solution, and the mixture was stirred at room temperature for 2 hours. Rhenium chlorochlorate (2 to 8 U: mol) was added and the mixture was concentrated under reduced pressure. Make the residue> ethyl acetate in sodium acetate, pass through sodium sulphate, Du Shao T, Qu Bu H Gu Wen Wen Yi ^, and the bar under reduced pressure ==. The residue was triturated twice to obtain 4-bromo-5-methylisoxazole "· carboxylic acid (121 g, 86%) as a solid. MS: 160/162 [M-C02-H]-^ ESI (Me〇H)

(3) Add grass gas (616 mg, 4% millimolar) at room temperature to 4- Mo Qiao _ = word saliva-3 province acid (ganglia mg, 2.43 millimolar) and get yang: '0.243 f Mol) in suspension in chloroform (10 ml) and disturbed = mixture for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in aerosol (5 ml), and then cooled under ice conditions: the mixture was added with 3-amino-4,4-hydroxyl D ratio to bite gas chlorate (533 milliliter t3.64 millimolar Ear) and roaring bite (960 mg '12 "millimoles) in suspension in chloroform (5 pen liters).扰 Stir the mixture at room temperature for 2 hours. Add water = extract the mixture twice with ethyl acetate. The combined organic layers were filtered through sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 4-bromo-N_ (4-hydroxypyridine-Hongyl) -5-methyliso mouthylazole-3-amidine as a solid (574 mg, 79 / 〇). . MS ·· 298/300 [M + H] +, APCI (MeOH) ⑷4H (4-hydroxypyridin-3-yl) -5-methylisoD isoxazole_3_formamidine ^ 72, g , I.92 μmol) and polyphosphoric acid (5.72 g) were stirred at 50 ° C. for 1 hour. After cooling, the reaction mixture was diluted with water. The test was performed with 316408 199 200523254 with a 15/0 aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and filtered under reduced pressure. The residue was purified by silica gel column chromatography (aerosol · ethyl acetate: 1) to obtain 2- (4-bromo_5_methylisoxazole_3_yl) as a solid. Oxazole [4,5-c] pyridine (331 mg, 61〇 / 〇). MS: 280/282 [M + H] +, APCI (MeOH) (5) make 2- (4- Mo-5- Methyl isothiophene_3, π, 3] Ausal [4,5_c] d ratio was reacted and treated in a manner similar to Example 121 to obtain 4_ [5_methyl-3-([1,3] Aesophyllum [4,5_small specific bite_2_yl) isoisialyl_cardiyl] benzidine, amine. MS: 321 [M + H] +, APCI Example 345

Me

OH

⑴ Make 4 prepared 5_methylisosialyl_3_acid acid react in a manner similar to the use of 3-amino_2 and carry out rhyme 4_ and process to 4- innocent ^ Pure_3 都 5_ Methyl iso-sat_3 • benzylamine. · Instigation 4 · Secret Roar. Set _3_ base) _ base heterophilia. Glycine (512 mg, ⑺mmole) and galacrylidine flow overnight; after that, ′, the reaction mixture was poured into water and 15% sodium hydroxide water was used; The organic layer was washed with brine. The 316408 200 200523254 was dried over sodium sulfate and concentrated under reduced phase conditions. Residual silica gel column chromatography (hexane ·· ethyl acetate di 93: 7 ◊ 17 · 3 was processed to obtain 2_ (4_ 漠 _5_methylisotropic salivary_. 3) Erjun [5,4-b] pyridine (101 mg, 21%). 5 J%

MS ·· 280/282, APCI (3) makes 2- (4-bromomethylisosialphtalol_3_yl} [1,3] peptone [5,4_b] similar to that of Example (3) The reaction is carried out in a manner that can be used to obtain 4- [5-methyl-3-([1,3] shu saliva [5,4initiation_2_yl) heterophilia. Sitting_4 A

Lamine. Soil J

MS: 321 [M + H] +, APCI Example 346

Let's prepare 5-Azoylisoxazole! Acids are similar to those using acetamidine

The reaction was carried out in the manner of (3) of Example 344 and treated to obtain N, _acetoxy-4- > odor-5-amisinoisoosialocarbohydrazine. (2) Add triethylamine (586 mg, $ • Nemomol) to N & yl-4-bromo-5_fluorenylisoxazole-3-carbohydrazine under ice-cooled conditions (506 mg '1.931 mmol) and 2-chloro-u-dimethyl criperline (-Cong) (490 mg, 290 mmol) in aerosol (15 ml) In solution. The mixture was stirred at room temperature overnight and refluxed for 5 hours. After cooling 316408 201 200523254, water was added and the mixture was extracted with aerosol, and concentrated under reduced pressure. The residue was dissolved in 2-organic layer (mL) and the mixture was refluxed overnight. The residue was converted to a solid by analytical method (hexane: ethyl acetate = 9: 1 ◊ 4 · & column layer 2 (4, fu 5 Jiaqili "I α #), '" 2- (4-bromo-5-fluorenyl iso% azole-3-yl) -5-methyl g, 13%). , 3,4-% diazole (62 mM MS: 244/246 [M + H] +, APCI (MeOH) (3) makes 2- (4-bromo-5-methylisoisomerate. Sit_3 _ 基) _5_methyl ", 3l Wow was reacted and treated in a manner similar to Example m to obtain

Methyl-3- (5-fluorenyl], 3,4-arabinyl-2-yl) isomeryl benzoyl] benzyl. MS: 285 [M + H] +, APCI Example 347

In this case, 3- (chlorofluorenyl) -5_ (5-methyl_3-phenyliso harmonicawa-4yl) -1,2,4-fluorenediazole (100 mg, 0.1%) 36 mmol) in DMF (2 ml) was added sodium acetate (44 mg, 0.54 mmol), and the mixture was stirred at 6 (rc for 3 hours. After the mixture was cooled, water was added thereto, And the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate di 10). : 丨) Purified to give [5- (5-methyl-3-benzylisoxazolyl) -acetate as a solid 316408 202 200523254 azole-3-yl] methyl ester (87 · 4 mg , 81%). MS ·· 300 [M + H] +, APCI (Me0H) Example 348

Add a solution of [5- (5-methyl-3-phenylisoxazolyl-sulfosail-3-yl] methyl acetate (86.2 mg '0.29 mmol) in methanol at room temperature ( 0.5 ml) and then potassium carbonate (199 mg, ι 44 mmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and passed through sulfuric acid Sodium was dried, and concentrated under pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate y: i: 丨) to obtain ^ dimeric [5- (5- Fluorenyl-3-phenylisoH and other azole-4-yl) -1,2,4-dioxazol ~ 3 merudyl alcohol (67.8 mg, 91%). MS ·· 258 [M + H] +, APCI (MeOH) Example 3 4 9

h2n

316408 203 200523254 p- [5- (5-fluorenyl-3-phenylisoxazol-4-yl) ^, 2 4_-bis at room temperature. Sat-3-yl] fluorenol (67.8 mg, 0.% mmol) in acetone, Tim Li I in water (1 ml), 2,2,6,6-tetramethylhexahydro D specific bite- 1-oxygen free beauty (41 ng '0.26 mol) and sodium bicarbonate (50 mg) in water, followed by potassium odorant (3.6 mg, 0.03 mmol). The solution was allowed to cool to zero. And an aqueous solution of sodium hypoxia (0.9 ml, 0.58 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was poured into 10% hydrogen acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane. Grass-fed chlorine (〇26 ml, 0.29 mmol) and DMF (0.015 ml) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, poured into 30% aqueous ammonia (2 ml), and extracted with a gas-form. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ·· ethyl acetate = 5: 1-> 1: 1) to obtain 5_ (5_methyl-3-phenylisopentawa) as a solid. 4-yl) -1,2,4-D, etc. diazol-3-carboxamide (33.1 mg, φ 47%) OMMS: 271 [M + H] +. APCI (MeOH) Example 3 50 The following compounds were prepared in a similar manner to Example 344 or 345 using the corresponding starting material compounds. 204 316408 200523254

Examples 351 to 419 The following compounds were prepared by reacting and treating in a manner similar to the examples mentioned above using the corresponding starting compounds.

351 4-Me-0 304 [M + H] +, APCI

352 3-S〇2NH (CH2) 2CH3 4-Me 1 425 [M + H] +, ESI

205 316408 200523254

Example R1 R2 m R3 R13 XY MS: m / z 353 -CONHCH2CH (OH) CH3 (R)-0 H Me CH CH 337 [M + H] +, ESI 354 -CONH (CH2) 2〇CH3-0 H Me CH CH 337 [M + H] +, APCI 355 -conhch2-y ° ^ | Bn 0 H Me CH CH 468 [M + HKAPCI 356 -COOH F 1 H Me CH CH 296 [MH]-, ESI 357 -CONHOH -0 H Me CH N 296 [M + H] +, APCI 358 -CONH (CH2) 2C〇NH2-0 Me Me CH CH 364 [M + H] +, APCI 359 -CONHCH2CH (OH) CH3 (S)- 0 H Et N CH 352 [M + H] +, ESI

206 316408 200523254

360 -conh2-0 361 HCI -conh2-0 362 HCI -conh2-0 363 -conh2-0 364 -conh2-0 365 -conh2-0 366 HCI -conh2-0 367 HCI-conh2-0 368 -COOEt-0 369 -c〇nh2-0 370 -CONHa-0 371 -CONH2-0 OH 〇-CH O CH H

294 [M + H] +, APCI 367/369 [M + H] +, APCI 311 [M Ten H] +, APCI

Q- H 3-F 1 H -0 H -0 5-OMe -0 4-OMe -0 3-F1

297 [M + HJ + APCI 243 [M + H] +, APCI 337 [M + H] +, APCI 310 [M + H] +, APCI 310 [M + H] Ten, APCI

326 [M + H] +, APCI

H -5-Me -4-Me-

281 0 [M + H] +, APCI 294 0 [M + H] +, APCI 0

294 [M + H] +, APCI 207 316408 200523254

Example 372 373 374 375 376 377 378 378 379 380 381 382 Salt _ -CONH2 < X) NH2conh2 -CONH2 -CONH2 -CONH2 -CONH2 -CONH2 -CONH2 -CONH2 -CONH2

-0 -0 -0 -0 -0 -0 -0 -ο -ο -ο

H -0 H 5-F 1 H -0 6-OMe -0 H 3-F 1 H -0 H 5-F 1 H -0 H -0 1-Me -0

330 [Μ + Η] +, ΑΡΙΙ 298 [M + H] +, APCI 282 [M + H] +, APCI 311 [M + H] + fAPCI 299 [M + H] +, APCI 331 [M + H] +, APCI 299 [M + H] +, APCI 338 [M + H] + fAP〇l 337 [M + H] +, APCI 284 [M + H] +, APCI 208 316408 200523254

Implementation R1 R2 m MS: m / z 383 Η 4-Br 1 368/370 [M + H] +, APCI 384 -CN-0 347 [M + H + MeOH] +, APCf 385 -COOH-0 332 [MH ]-, ESI

Example salt R1 X MS: nVz 386 -CONHCH2CH (OH) CH2OH (S) CH 407 [M + H] Ten, APCI 387 -CONHCH (CH2OH) 2 CH 407 [M + H1 +, APCI 388 HCI -CX) NH (CH2) 4CONH2 N 433 [M + H] +, APCI 389 HCI -CONH (CH2) 3CONH2 N 419 [M + H] + fAPCI 390 HCI conh (ch2) 2c〇nh2 N 405 [M + H] +, APCI 391 -conh2 CH 333 [M + H] +, APCI

209 316408 200523254 Example Salt R1

392 393 394 395 396 397 398 399 400 401 402 403 404 -C〇NH (CH2) 2〇H -Cl 1 CH HCI -CONH (CH2) 2 ^ Q) -Cl 1 CH -CONH (CH2) 2 nQ ^ COOEt -〇CH -C〇NHCH2 -CONH (CH2) 2- ^ Q)

0 CH 0 CH

Me -CONHCH2C (CH3) 2〇H • c〇nh (ch2 > 3- ^ -CONHCH2 cf3 -CONH (CH2) 2-n3nh if 〇-CONH (CH2) 2hQ ^ CONH2 -CONHCH2CH (OH) CH3 (R)- COOH -conhch2-^ /-ch3

0 CH 0 CH 0 CH 0 CH 0 CH 0 N 0 CH 0 CH

R4 n MS: m / z 357/359 • 0 APC! 418/420 " 0 [M + H] +, APCI 456 '0 [M + H] +, ESI 438 0 [M + H] +, ESI n 398 _ 0 [M + H] +, ESI .351 0 [M + H] +, ESI 398 " 0 [M + H] +, ESI a 438 -0 [M + H] + fESI 391 -0 [M + H] +, APCI n 427 0 [M + H] +, APCI 338 • 0 [M + H] +, APCI F 1 296 h 1 [MH]-, ESI 403 F 1 [M + H] +, ESI 210 316408 200523254

Example R1 R2 m X R4 n MS: nVz Guang \ Γ- WO -CONHCH2CH (OH) CH2OH (S)-0 CH F 1 371 [M + H] +, AP〇i 406 -CONHCH2CH (OH) CH3 (R )-0 CH F 1 355 [M + H] +, APCI 407 -conhch (ch3) ch2〇h (R) 0 CH F 1 355 [M + H] +, APCI 408 -C〇NHCH (CH3) CH2OH ( s)-0 CH F 1 355 [M + H] +, APCI 409 -CONH (CH2) 2CONH2-0 CH F 1 368 [M + H] +, ESI 410 -conhch2c〇nh2-0 CH F 1 354 [M + H] +, ESI 411 -conhch2ch (〇h) ch2oh (R) F 1 CH-0 371 [M + H] +, APCI 412 -CONHCH2CH (OH) CH2〇H (S) F 1 CH-0 371 [ M + H] +, AP〇i 413 -CONHCH2CH (〇H) CH3 (S) F 1 CH-0 355 [M + H1 +, APCI 414 -conhch2ch (oh) ch3 (R) F 1 CH-0 355 [M + H] +, AP〇l 415 -CONHCH (CH2OH) 2 F 1 CH-0 371 [M + H] +, APCI 416 -CON (CH3) 2 F 1 CH-0 325 [M + H] +, APCI 417 -CON (CH2CH2OH) 2 F 1 CH-0 385 [M + H] +, APCI 211 316408 200523254

> m〇 π μ δρτ.ι j ίι I ^ w I

419 -COOMe F 1 CH 312 [M + H] +, APCI

212 316408 200523254

213 316408 200523254 〇

Number B ring R3 R4

29 H 2-F 30 H λ r * or 31 -ο 2-Me-32 〇3-Me-33 H 5-CI 34 H-35 6-Me-36 6-OMe-37 5-Me-38 5- OMe-39 < y H • 40 H-0 0 1 ο ο Ο Ο Ο Ο 214 41 42 43 44 45 46 47 48 R1 5-CONH2 2-CONH2 5-CONH2 4- CONH2 5- CONH2 4- S02NH2 5- S02NH2 5-S02NH2 Ο

49 Ν CF3 50 CH OH 51 CH OMe 316408 200523254

R1 X R3 52 -CONHCH2CH (OH) CH2OH CH Me 53 -CONHCH2CH (OH) CH2OH N Me 54 -C0NHCH2CH (0H) CH20H N OMe 55 -CONHCH2CH (OH) CH3 CH Me 56 -CONHCH2CH (OH) CH3 N Me 57 -CONHCH2CH (OH) CH3 N OMe 58 -CONH (CH2) 2〇H CH Me 59 -CONH (CH2) 2OH N Me 60 -conh (ch2) 2〇h N OMe

Number R1 X R3 R4 n R13 61 -conhch (ch2oh) 2 CH H 4-F 1 cf3 62 -conhch (ch2oh) 2 CH Me-0 cf3 63 -CONHCH (CH2〇H) 2 CH Me 0 Me 64 -C0NHCH2CH ( 0H) CH20H CH H 4-CI 1 Me 65 -CONHCH2CH (OH) CH2〇H CH H 4-F 1 H 66 -conhch2ch (oh) ch2oh NH-0 H 67 -C0NHCH2CH (0H) CH20H CH H 4-CI 1 H 68-conhch2ch (oh) ch2oh CH Me-0 H 69 _conh (ch2) 2oh CH H 4-F 1 Me 70 -CONH (CH2) 2- ^ CH H 4-F 1 Me 71 -C0NHCH2CH (0H) CH20H CH H 4-F 1 Me 72 -CONHCH (CH2〇H) 2 CH H 4-F 1 Me

215 316408 200523254 Experimental Example 1 For the relaxation effect of isolated rabbit bladder contraction induced by potassium, male NZW rabbits (weight: 2.0-35 kg) isolated the bladder sub-soaked in ice-cooled Krebs bicarbonate solution (In mM: Naa of 118, KC of 4.7, CaCl2 of 2.55, MgS04 of! 18, Kg2PO4 of 1.18, NaHC0 of 24 · 88 and glucose in U). After removing the mucosal layer, cut the bladder into long strips (5 mm long, 3 to 4 mm

The specimen was set in a tissue bath containing 10 ml of Krebs solution. The tissue bath was maintained at 3rc and filled with 95% oxygen / 5% dioxygen to form a rolled body. So 'stretch the specimen with an initial tension of 20 ± 10 grams and measure the isometric tension change with a force-displacement transducer. By changing the organ solution to a high · K + (30 mM) Krebs solution (with blessings as the army: Naa of u, κα of 4.7, 2 plus 55, howling of i8, and κη2ρ of the worker. 4, 24 · 8δ NaHC03 and dextrose) to pre-shrink ㈡.

After obtaining a stable tension, the compound was added to the tissue bath cumulatively (10 to 10 M). The effect of a plurality of compounds was expressed in such a manner that the maximum relaxation percentage produced by the 10-4 M poppy test was taken as 1GG%. Calculate 50 relaxation concentration (IC5G) and compare the compounds of the present invention: (μM) with A, B and C, less than, less than, and less than in Table 68 below. These ranges are shown below. $ ΜΜ > C > 1 μΜ > b > 0.5 μΜ > a 316408 216 200523254 Table 68

Test compound IC5Q value Example 30 C—Example 45 C Example 46 C Example 51 C Example 5 9 C Example 115 A Example 124 C Example 136 A Example 141 A Example 14 6 C _ Example 152 B Example 155 C Example 2 0 7 B Experimental Example 2 Inhibition effect of rhythmic bladder contraction induced by substance P in anesthetized rats. These experiments used a weight between 200 and 300 grams. See Sprague-Dawley female rats (9-12 weeks old). After anesthesia with carbamate (subcutaneously administered at a dose of 1.2 g / kg), a catheter was placed between the right and left thigh veins. One of the intravenous catheters was used to administer the compound, and the other catheter was used to inject the substance p (0.33 μg / kg / min). A catheter can also be inserted into the ureter for catheterization. The carotid artery was inserted with a polyethylene catheter to continuously monitor the arterial blood pressure and heart rate. For the purpose of continuous injection, a urethral bladder catheter is inserted into the bladder through the urethra and fixed near the urethral opening with a suture. Connect one end of the catheter to the pressure transducer 2] 7 316408 200523254 to measure the force in the bladder. The other end of the catheter is used to infuse saline into the bladder. After waiting for the blood pressure and heart rate shirt and after bladder urination, the intracystic pressure was measured by slowly filling the bladder with about 0.6 ml of physiological saline. After about 10 minutes, intravenous injection (p = kg / min) was started to stabilize the reflex effect of urination. Compounds were not administered until the bladder had contracted for more than 15 minutes. Make all. The materials were dissolved or suspended in a physiological medium containing 0.5% Tween 80 to facilitate intravenous administration (0 mm / kg). Dosing experimental = Observing the frequency of Langeric contraction and intravesical pressure for 35 minutes. Fruit: The compounds of the present invention reduce the frequency of rhythmic contractions of the bladder. The stomach changes the magnitude of the contractions. At the same time, we measured the rhythmic contraction frequency: the time (min. 2) of the 0.25 mg / kg compound that was widely administered. The inhibitory time of the compound of the present invention (min.% M) is shown in Table 69 below. Table 69 Formula 3 Test Compound 100% Inhibition 7 ^ ¥ 7 Example 59 5J ~ Example 93 9.1 '~ Example 124 — 8 ^ 2' ^ Consecutive Example 13 5 ^ Γ7Τ8 ~~~~ Example 142 ^ Ϊ7Τ3 ~ 'Example 171 ^ Ϊ2Τ8 ~-_ Example 207 ^ ΠΤ9 ~ ^ ~~ At the same time, lbenoioxln was pre-administered to selectively pass 316408 218 200523254 activated potassium channel blocker (0 · 15 mg / m, intravenous administration), can reduce the inhibitory effect of the compound of the present invention on rhythmic bladder contraction. This result implies that the potassium channel of the present invention can be provided by the potassium channel activated by high-conduction hydrazone. Bladder cystic muscle relaxant activity. The high-potassium potassium phase-releasing activity will make X-month chemical & materials effective in preventing and treating frequent urination and urine (industrial availability). The active ingredient compound of the present invention or its pharmaceutically acceptable Potassium channel opening activity and accepts:, :: = potential hyperpolarization ', so that the compound or its pharmacologically useful, members can be used to prevent, slow and / or treat frequent asthma, chronic obstructive pulmonary disease (COPD), etc. & incontinence, milk

316408 219

Claims (1)

200523254, clarify the scope of patents ... -A kind of channel-activated_channel_opener containing a chemical compound or a pharmaceutically acceptable salt thereof as an active ingredient x (1) ring system benzene or heterocyclic ring; Bit system stupid, heterocyclic ring Ring, Q ring system selected from the group of the following formula J〇 ^ R13 Group R13: 0 R13 R1 and R3 may be the same or different from each other, and each is an optional group:% (group 02 R5, S, n / d5〇2 R, N, S, N〆R5—0— r5-s— r5, A RV ^ A R6, R6 R7,, ^, R6 R7 r5 ψψ Η Ί t > 〇 t) 〇2 r5-S, i ^ 02 r5 / N, n, S \ H 〇2 R5 force, (\ TS \, 〇6 R and R6 may be the same or different from each other, and each is (1) hydrogen, ( 2) a substituted alkyl group as required, (3) a substituted cycloalkyl group as required, the cycloalkyl group 3164408 220 200523254 can be fused with an aryl group, (4) a substituted aryl group as needed, ( 5) optionally substituted heterocyclic group 圑, or (6) alkoxycarbonyl group, or (7) R5 and R6 may be combined to form optionally substituted heterocyclic ring, the heterocyclic ring system is The atoms bonded by R5 and R6 are combined; R7 is fluorene hydrogen, (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, and the cycloalkyl group may be fused with an aryl group, ( 4) optionally substituted aryl, (5) alkoxycarbonyl; R14 is hydrogen, alkoxy, hydroxyl, cyano or optionally substituted alkyl; m and η may be the same or different from each other, and each is 〇, i or 2; R2 And R4 may be the same as or different from each other, and are each a keto group, a cyano group, a nitro group, a hydroxyl group, an alkoxy group, a nanyl group, a carboxyl group, an alkoxycarbonyl group, a silken group substituted if necessary, and a substituted group if necessary. Silk or substituted alkyl as needed; but if 4 2, two r2 may be the same or different from each other, and if n is 2 ′, two R4 may be the same or different from each other; A group selected from the group consisting of: The group of the following chemical formula or R and R can be combined to form an electoral ring; 316408 22] 200523254 p is an integer from 1 to 3; and Rl3 is (1) ^ requires a substituted alkyl group, (2) cyano group, (3) hydrogen, (4) nansin, and optionally substituted amine 'pinene Base, (7) as required Instead of aminomethylamyl, (8) alkoxycarbonyl, (9) carboxyl, (10) heterocyclic group '(11) vial, or (12) alkyloxy. 2. If the scope of the patent application (1) of the highly conductive tritiated potassium channel opener 'wherein' R5, R6 and r7, the substituted group of the optionally substituted alkyl group is 1 to 7 independently selected function elements And / or 1 to 3 groups selected from: rvI 9 '0 R8〆0, 〆, P, R9 0 R8, N, N human Η · RJ, 1 0 r8, 0 R1V accounts for 11 · Ry夂 人 &, R9 r8,0, ctn ,, 6 02 R8 people N 〆 account for 9, r8, n, 02 R ~ S, 丨 f 〇2 R8 > i, N / S ,, H R12, 0, , R8 ^ S, N = C— a substituted heterocyclic group and an optionally substituted aryl group, where R8 and R9 may be the same or different from each other, and are each hydrogen, (2) an alkyl group, The alkyl group may be substituted by a substituted aryl group or a heterocyclic group substituted by 316408 222 200523254 if necessary, (3) a carbamoyl group, a fluorenyl group, a fluorenyl group, Optionally substituted heterocyclic groups or optionally substituted aryl groups, or R8 # D R9 can be combined to form optionally substituted heterocyclic rings, the heterocyclic ring system and the ruler 8 is bonded with the atom to which it is bonded W and R " may be the same as or different from each other, and are each a tick, a saccharyl group, and the silk may be substituted by a substituted silk or a substituted heterocyclic group as necessary, (3) a fluorene group , Fluorenyloxyalkyl, (5) sulfonyl, sulfonylsulfuryl, fluorenyloxy or a heterocyclic group that is substituted as required; Ru-based fluorene, (2) fluorene, which The alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) via an alkyl group, (4) an oxygen group, and optionally a heterocyclic group which is slowly substituted. Group. 3. As for the high pass thorium-activated potassium channel opener of the scope of application for patent, wherein the ring B is a benzene, a heterocyclic ring, a ring, or a ring dilute 'R1 is a group selected from the following formula ... r5 , N on R5〆. , X, R5〆1% X, ΗV 〇2 V r5, c, nX \ F ^ S, NX, R6, know r5 ", RSA RY r5, V R7 d2 R5,? R, irs, R6? 〇2 ^ 〇2 R5 / N, N into ρ ^ 〇, N ″, Η, R is a group selected from the following chemical formula: 316408 223 200523254 R5, 〇 Ⅱ II R5 people R6 R5, 〇2 〇2 R5 / S \ RV R6R7 R5 series (1) hydrogen, (2) alkyl group, the alkyl group can be selected from 1 to 7 independently selected functions and / or 1 to 3 groups selected from the following Substitute: p9 〇9 NSC- R8 II, R, S, N, · R8zN, S / · 〇2 〇2 Heterocyclic group substituted if necessary and aryl group substituted if necessary, (3) A substituted cycloalkyl group, if necessary, which may be fused with an aryl group, (4) a substituted aryl group, if required, or (5) a heterocyclic group, which may be substituted as required; R is hydrogen , Fluorenyl or oxo, or may combine r5 and r6 to form an optionally substituted heterocyclic ring, the heterocyclic ring system is bonded to the atom bonded to ... and R6; R7 is hydrogen, Alkyl or alkoxycarbonyl; R8 and R9 may be the same as or different from each other, and each is a fluorene nitrogen or a fluorenyl group, and the alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) ㈣ Group, (4) silk group, optionally substituted heterocyclic group, (6) optionally substituted aryl group, or ⑺ may combine R8 and R9 to form optionally substituted heterocyclic group Ring, the heterocyclic ring system is bonded to the atom bonded to R8 and R9; R and R may be the same or different from each other, and each is (丨) hydrogen, (2) alkyl = alkyl group may be determined by f Substituted aryl or optionally substituted heterocyclic group to be substituted, (3) fluorenyl 'fluorenyl, 316408 224 200523254 alkylsulfonyl, (6) alkylsulfonyl, (7) alkyl Oxycarbonyl or (8) optionally substituted heterocyclic groups; R is (1) 氲 '(2) alkyl, which may be substituted by optionally substituted aryl or optionally substituted hetero The cyclic group is substituted, (3) a hydroxyalkyl group, (4) an alkoxyalkyl group, or (5) a heterocyclic group substituted as necessary; and η may be the same or different from each other, and each is on 1 or 2; and R and R4 may be the same or different from each other, and are each a keto group, a cyano group, a nitro group, a hydroxy group, an alkoxy group, a halogen group, or an optionally substituted alkyl group. 4. The high-conducting calcium-activated potassium channel opening substance I of item 丨 of the patent application, wherein the B ring system (1) benzene or (2) is selected from thiophene, pyridine, pyrimidine, pyridine, benzo D volume Heterocyclic ring of phen, 2,3-dihydroindole, 2,3-dihydrobenzofuran, and heart benzodioxane or (3) cyclohexene; R1 is a group selected from the following chemical formula Group: -〇0 R6 0 Ά r5 ~ R5zfij, NZ occupies 6, r6, Η R6? I? 〇2 i? R5 / C, n / C \ r5 ^ S-m-C \ ^, R & RV-1 0—, 4V, H R5 \ f 02 〇2 R5 / N, Nj \ R5 / 〇, ^ S \ H, ^ R3 is selected from the group of the following chemical formula RVx · RY Rx V " h R is (1) hydrogen, (2) alkyl, this The alkyl group may be substituted by i to 7 independently selected halogens of 316408 225 200523254 and / or 1 or 2 groups selected from: R and Y are optionally substituted heterocyclic groups and optionally substituted aryl groups, (3) substituted cycloalkyl groups as required, which may be fused with aryl groups, and optionally Substituted aryl group, or (5) optionally substituted heterocyclic group; R6 is hydrogen or alkyl, or R5 and R6 can be combined to form a hydroxyalkyl group A substituted heterocyclic ring, which is bonded to the atom bonded to R5 and R6; is hydrogen or alkyl; R and R9 may be the same or different from each other, and each is (1) hydrogen, (2) Alkyl, «Hydroxyalkyl may be substituted by optionally substituted aryl or optionally substituted hetero, group groups, (3) hydroxyalkyl or (4) alkoxyalkyl; R and R11 may Are the same or different from each other, and are each (1) hydrogen, (2) alkyl, and the alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, a fluorenyl group, (4) Sixian or (5) Heterocyclic group substituted if necessary; t is fluorene hydrogen, (2) Carbo group, which can be substituted by earth as needed or = The cyclic group is substituted, either through a radical () or IU, or (5) optionally substituted heterocyclic group; two and 11: the same or different from each other 'and each is 0 ,! Or 2 ;: each of R may be the same or different from each other, and each is a network group, a nitrogen-based soil, a radical, a alkoxy group, a fluorene group, or a alkynyl group which may be substituted by a group; 316408 226 200523254 and R 3 series (1 ) Hydrogen, (2) alkyl, the alkyl may be selected from halogen, hydroxy, optionally substituted alkoxy, cyano, carboxyl, aminoformyloxycarbonyl, optionally substituted amino And optionally substituted by a substituted imine Z '(3) a dilute group, or (4) a heterocyclic group. 5. The high-conducting calcium-activated potassium channel opener according to item 1 of the scope of patent application, wherein the A ring system is benzene, thiophene, pyridine, or pyrazole; the B ring system (1) benzene '(2) is selected from thiophene, uding, 嗔 σding, Hjj well, benzothiophene, 2,3-dihydroindole and 1,4-benzodioxane heterocyclic ring, (3) cyclohexene; 〆R1 is selected From the group of the following chemical formula: 6 ο, ιΑ R5 i2 R6 r5, c \ R5—〇-H R5, 俨 02 〇2, ie R5 / N, | \ TS, R5 / 〇, fsrS, R * H . .6 R is a group selected from the following formula: R5, H R5 is (1) hydrogen, (2) alkyl, which may be substituted by i to 7 independently selected halogens and / or 1 or 2 groups selected from:) 10 R8, human R1 ... ^ 9, R11 R9 316408 227 200523254 Depending on the substituted heterocyclic group and the optionally substituted aryl and aryl fused ring ring, the aryl group can be taken from the tank) ( 4) Heterocyclic group; gas = system hydrogen or alkyl group, or can be combined with ^ to form a heterocyclic ring, heterocyclic ring can be replaced by hydroxyalkyl; r7 hydrogen or alkyl; P :, R9, R1 °, and RU may be the same or different from each other 'and each is a tick, and the scorch group may be substituted by an aromatic group which is substituted as necessary or a heterocyclic group which is substituted by depending on the type Substituted, (3) via an alkyl group, optionally substituted heterocyclic groups, or optionally substituted aryl groups; Ί system (1) hydrogen (2):!: The group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, such as a light-emitting group, an oxygen group, or an optionally substituted heterocyclic group; 'and η Can be the same as each other Or different, and each is 0, i, or 2; R 2 and R 4 may be the same or different from each other, and are each a cyano group, a nitro group, a halogen group, a halogen group, or a halogen group; and R is a hydrogen atom, ( 2) An alkyl group, which may be substituted by a halogen group, a hydroxyl group, or an alkyl group substituted by a group selected from a halogen group and a phenyl group, a cyano group, an alkyl group, an aminomethyl group, or an alkyl group. Oxoyl, amines which may be substituted by phenyl groups, and imine groups which may be substituted by groups selected from alkoxy groups and alkyl groups, (3) almond or (4) 4,5- Dihydrofluorene and other salivary 2-yl groups. 5 · If the scope of patent application is the first! High potassium soil activated potassium channel opener according to any one of items 5, to 316408 228 200523254 R1 is a group selected from the following chemical formula: 5R \ 〆6 NIR one one 〆6, N RIN 5 RH 〆6 NIR / 〇5 R OMC 〇2 A compound represented by the chemical formula (la) or a pharmaceutically acceptable salt thereof: D 1a (la) wherein A ring is benzene or heterocyclic ring or cycloolefin; Q ring is selected from the group of the following formula: B ring is benzene, heterocyclic ring, ring ring, NT, N, -R 13 R 13 R 13 Rla is a group selected from the following formula: ο o R6 ρ r5, n, c \ r5 / 〇, n, c \ R6 '6R3 is a group selected from the following formula:, N Η 〇〇ι, 〆R6 r5 / C, n, C, r5, s, n R6 _ _ R6 〇_ c ίΤ ΓΓ I II II II R, NX \ r5 / 〇, NX, r5 / N, NX \ R5 乂, NX \ p ^ 6, p ^ 6, Η ι p ^ 6 〇〇〇 R6 14 RJ, r5, J \ R5y, f on r5, r5, n ^ r NX, N〆R6 R7 229 316408 200523254 〇2 R5-S, fs R6 ° -s- ¥ RV R6 R7 Λ R5—〇 一 R ' 〇2, ° vs, R6, R and R6 may be the same or different from each other, and each is (1) hydrogen, (2) a substituted alkyl group as required, and (3) a substituted cycloalkyl group as required, the cycloalkane May be fused with an aryl group, (4) an optionally substituted aryl group, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl group, or (7) R5 and R ° combines to form a substituted heterocyclic ring, which is bonded to the atom bonded to R5 and R6; R system (1) hydrogen '(2) optionally substituted alkyl (3) If necessary, a substituted ring filament may be fused with an aryl group, and if necessary, a substituted aryl group ('5) alkoxycarbonyl group is required; scale hydrogen, alkoxy, hydroxyl, cyanide Or optionally substituted alkyl; 'and η may be the same or different from each other, and each is 40, u]; R, and R may be the same or different from each other, and each is keto, cyano, sulfo ,, Ethyl, alkoxy, halide, tertyl, oxo, as needed · Substituted amino methyl alcohol group, depending on f to be substituted amino group or optionally substituted alkyl group, but if m is 2, two r2 may be the same or different from each other and if n is 2, two R4 may be the same or different from each other; or Rla and R may be combined to form a group selected from the following chemical formula with the A ring ... 316408 230 200523254 or R and R can be combined to form an American group with the B ring selected from the following chemical formulas: p is an integer from 1 to 3; and (1) an optionally substituted alkyl group, (2) a cyano group, (3) hydrogen, (a sentence element, (5) an optionally substituted amine group, (6 ) Alkenyl, (7) optionally substituted aminoamino, (8) alkoxycarbonyl, (9) carboxyl, (10) heterocyclic group, (11) hydroxyl, or (12) alkoxy But 疋 ⑴ does not include the following compounds, in which A ring and b ring are benzene; Q ring system ^ R is a hydroxyl group, an alkoxy group or a cycloalkoxy group substituted at the 2 position, R4 is a fluorenyl group substituted at a 6 position, and R13 is an alkoxycarbonyl or carboxyl group, (ϋ) Ν · (3, isopropyl Oxypropyl) winter (3_fluorenyl_5_phenyl-1H-pyrazole small group) benzamidine, 4_ (1acyl 4-aminosulfonylphenyl) _3_difluoromethyl group) Methyl fc amine, and (1V) 4- [5, (4-aminobenzyl) -3- (3-hydroxypropylpyrazole_1-yl-methyl 231 316408 200523254 methylbenzyl hydroxamic acid. The compound of item 7 of the patent scope or a pharmaceutically acceptable salt thereof, among which R, R6, and R7 are substituted with an optionally substituted alkyl group of 1 to 7 independently selected halides and / or i to 3 Selected from, t ReX ^ RV ^ 〇2 R8, S, N〆 A9, N = C— R12,0 ,, r8-s \ 8 substituted heterocyclic groups and optionally substituted aryl groups, where R and R9 may be the same or different from each other, and each is a hydrogen atom, (2 ^ group 'The silk can be substituted by aryl groups that are peak substituted as necessary or substituted heterocyclic groups if necessary, ⑺ pure group ⑺ oxygen group, f f depends on W group H) ㈣ = Substituted aryl group, or ⑻ can combine r and r9 to form as needed, a disubstituted heterocyclic ring, the heterocyclic ring system is bonded with the surname of the bond of trans 8 and R9; can be The same or different, and the respective butterfly watts' (2 groups, the fluorene can be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group, (3) by an alkyl group, Alkenyl group '(5) fluorenyl group, fluorenyl group, oxo group, or optionally substituted heterocyclic group' · P series fluorinated hydrogen, fluorenyl group, the alkynyl group 3J6408 232 200523254 can be obtained by A substituted aryl group or a substituted heterocyclic group if necessary, (3) a calcined group, (4) a fluorenyl group, and (5) a substituted heterocyclic group if necessary. 9. as The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the B ring is a benzene, heterocyclic ring or naphthene; > Rla is a group selected from the following chemical formula: R5, γ R5〆 0, person, 6 , N〆, and R3 are selected from the following chemical formula: winter group: 〇2〇R5, S, NX, account for 6 R6, V, Μ, ⑴, hydrogen, sulfonyl, and Weiji can be independently selected by a halogen and / or 1 to 3 groups selected from: R8 \ IsT, R10, X11 R9 di / N, R 12〆. , F R9 NSC— R8, A1, S〆 " ,, Rk 〇2 Heterocyclic group to be substituted and aryl group to be substituted if necessary, (3 Cycloalkyl group to be substituted if necessary The cycloalkyl group may be fused with an aryl group. (4 An optionally substituted aryl group, or an optionally substituted heterocyclic group; * R6 is a gas or an alkyl group, or may be combined with " And optionally substituted heterocyclic ring, the heterocyclic ring system is combined with the bond of ... and M; σ R7 is hydrogen, alkyl or alkoxycarbonyl; R8 and R9 may be the same or different from each other, and Each is fluorene, fluorenyl: 316408 233 200523254 This cyano group may be substituted by an aryl group optionally substituted or a heterocyclic group substituted by f, (3) fluorenyl, fluorenyl (5) A substituted heterocyclic group if necessary, or a substituted aryl group, if necessary, or R8 and R9 may be combined to form a optionally substituted heterocyclic ring, the heterocyclic ring system Bonded to the atom bonded to R8 and R9; R10 and R11 may be the same or different from each other, and each is a fluorene nitrogen, and the fluorenyl group may be substituted by the alkyl group as necessary Aryl or optionally substituted heterocyclic group is substituted with '(3) minus group, (4) silk, ⑺ 酿 基 group eryl, ㈣ ⑻ or ⑻ if necessary substituted heterocyclic The group can be a hydrogen atom ('2'), and the silk can be substituted by an optionally substituted aryl group or a substituted heterocyclic group, if necessary, (5) an alkoxy group. Or (5) optionally substituted heterocyclic group; the working soil m and η may be the same or different from each other, and each V and h are the same or different from each other, and each is @ 同 二 cyan: nitro, search Group, ⑥oxy, oxo or optionally substituted alkyl. 10. The compound or the pharmaceutical L salt thereof according to item 7 in the scope of the patent application, wherein # X 幻 个 B monocyclic system benzene or hydrazone is selected from the group consisting of thiophene, pyridine, pyrimidine, pirphine, phenoline, 2,3-bis Heterocyclic ring of Dind, 2,3-dihydrobenzfuran and 4 alkane; R1 is selected from the group of the following chemical formula: R6 0 R5, N, lsTC \ 316408 234 200523254 R3 is a group selected from the following chemical formula: r5-n ^-r5-n- RV R6 * R6, R6 1 R6R7 R is (1) hydrogen, (2) alkyl group, the alkyl group can be obtained by 1 To 7 independently selected halogens and / or 1 or 2 groups selected from: Optionally substituted heterocyclic groups and optionally substituted aryl groups, (3) A substituted cycloalkyl group, if necessary, which may be fused with an aryl group, (4) a substituted aryl group is required, or (5) a substituted heterocyclic group R is hydrogen or an alkane, if necessary Base, or make. Combined with R6 to form a heterocyclic ring which may be substituted by a hydroxyalkyl group, the heterocyclic ring system is bonded to the atom bonded and bonded by R5 and R6; is hydrogen or alkyl; R8 and R9 may be the same or different from each other , And each is (1) hydrogen, (2) alkyl,, and the group may be substituted by an aryl group optionally substituted or a substituted hetero group, ('3) hydroxyalkyl or (4) Alkoxyalkyl; R and R11 may be the same or different from each other, and are each hydrogen, (2) Alkylalkyl may be substituted by an aryl group or a heterocyclic group substituted if necessary Group plus Han '(3) fluorenyl group, (4) silk group or (5) optionally substituted heterocyclic group group; R] 2 series (1) hydrogen, (2) alkyl group, the alkane The group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group 圑, (3) a hydroxyalkyl group, 316408 235 200523254 oxo or (5) an optionally substituted heterocyclic group Groups: "" are the same or different from each other 'and each is 〇2, · the domain ~ times are not 次 and each is a keto, cyano, / Jingtu, Xuan milk group, dentin, or can be obtained through An alkyl group; and R is a hydrogen atom (2), and the alkyl group may be selected from the group consisting of a functional group, an alkyl group, an optionally substituted amidino group, a cyano group, a carboxyl group, and an optionally substituted amine. And an optionally substituted imino group to obtain a heterocyclic group. 11. For example, the compound or a pharmaceutically acceptable salt thereof according to item 7 of the scope of patent application, in which A ring is benzene, thiophene, pyridine σ Ring or oxazole; B ring system (1) benzene, (2) heterocyclic ring selected from thiophene, pyridine, pyrimidine, pyridine, benzothiophene and 1,4-benzodioxane; Rla is selected from Groups of the following chemical formula: r5 η 9 R6 ο R3 is a group selected from the following formula: R5, · A RS R5, / • R6 R7 R ^ l2 R5 is (1) hydrogen, (2) alkyl group, which The alkyl group may be substituted by 1 to 7 independently selected halogens and / or 1 or 2 groups selected from the group consisting of: R8, R9 R8 ^ 8v ^, N,, r12〆., · 316408 236 200523254 A substituted heterocyclic group and a cycloalkyl group fused with an aryl group if necessary, and the aryl group may be a heterocyclic ring R6 system by using a (4) heterocyclic group; hydrogen Alkyl, or R5 and R6 may be combined. The heterocyclic ring may be substituted by hydroxyalkyl; R7 is hydrogen or alkyl; R, R, R, and R11 may be the same or different from each other, and each is hydrogen. Fluorenyl, which may be substituted by an optionally substituted aryl group or an optionally substituted family group, (㈣, (4) oxoalkyl, ⑺ optionally substituted heterocyclic group Or an optionally substituted aryl group; R is (1) hydrogen '(2) alkyl, and the alkyl group may be substituted by an optionally substituted aryl group or an optionally substituted heterocyclic group. Substituted, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) optionally substituted heterocyclic groups; m and η may be the same or different from each other, and each is 0, ι, or 2; R2 And R4 may be the same or different from each other, and are each cyano, nitro, meridian, halogen, alkyl, or alkoxy; and R13 is (1) hydrogen, (2) alkyl, and the alkyl may be selected by Functional group, hydroxy group, alkoxy group which can be substituted by group selected from halogen and phenyl group, cyano group, carboxyl group, aminoformyl group, alkoxycarbonyl group, which can be substituted by phenyl group Group, and may be substituted by a radical selected from imine and alkoxy groups to hydroxyl groups substituted, (3) alkenyl or (4) 4,5-dihydro-oxazol fathoms _2_ group. A medicament, which comprises the compound according to any one of claims 7 to 丨 丨 or a pharmaceutically acceptable salt thereof. 316408 237 12 200523254 u. As for the drug of item 12 of the patent application, wherein the drug is a potassium channel opener activated by high conductance # 5. 14. If a high-pass potassium channel opener according to any one of the items ^ and 13 of the scope of the application for patent, wherein the high-pass live open-source is used for frequent urination, prevention and treatment of disease And / or processing. , Asthma or chronic obstructive pulmonary disease 238 316408 200523254 VII. Designated Representative Picture · There are no plans in this case (1) The designated representative picture in this case is the (...) picture. (2) Brief description of the component symbols in this representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 4 316408