TWI304809B - Prodrugs of 4-phenyl-pyridine derivatives - Google Patents

Description

1304809

Wherein R is hydrogen, lower carbon alkyl, lower alkoxy, self-nuclear, or trifluoromethyl; R1 is hydrogen or south; or R and R1 together with the ring carbon to which they are attached is _CH= CH-CH=CH-; R2 and R2 are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy, or cyano, or 'R2 and R2 may together be -CH=CH-CH=CH - which is optionally substituted with 1 or 2 substituents selected from a lower alkoxy group or a lower alkoxy group; R3, R3_ are independently hydrogen, lower alkyl or cycloalkyl; R4, R4' is independently of each other -(CH2)mOR6 or lower alkyl; or R4 and R4' together with the N-atom to which they are attached form a cyclic third amine-based binding

line

-4- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304809 A7 B7 V. Description of invention (

R5 is argon, hydroxy, lower alkyl, lower alkoxy, -(CH2)mOH, -COOR3, -CON(R3)2, -N(R3)CO-lower alkyl, or -C(0 ) R3 ;

R6 is hydrogen, lower alkyl or phenyl; X is -C(0)N(R6)-, -N(R6)C(0)-, -(CH2)mO-, or -CKCHJf;

η is 0, 1, 2, 3 or 4; and m is 1, 2 or 3; and its pharmaceutically acceptable acid addition salt. It has been found that these N-oxides of the invention have in vitro activity at the NK1 receptor and/or can be used as a prodrug of a compound of the formula -

It is an antagonist of the neurokinin 1 (NK-1, bulk P) receptor. However, prodrugs have the advantage of physical properties such as parenteral application of water solubility enhanced by parenteral drugs or their enhanced absorption from the digestive tract, or their enhanced drug stability for long-term storage. The compound of formula 11 has limited water solubility and is not capable of rapid perfusion. It has therefore been found that derivatives of the compounds of formula II are advantageous for the suitability of these compounds for parenteral and submuscular applications. The N-oxides of the compounds of formula I have proven to meet all the requirements of good prodrugs. -5-

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Line 1304809 A7 B7 V. Description of the invention ( ) In most cases, the prodrug is a pharmacologically inactive derivative of the parent drug molecule, which requires spontaneous or enzymatic conversion in the body to release the active drug, and its parent drug Molecules have improved transport properties. It has been demonstrated that the optimal structural and physicochemical properties of the desired therapeutic response at the target site do not necessarily present the optimal molecular form and nature for delivery to the final site of action. Typically, only a small portion of the administered dose reaches the target area, and because most of the reagents also interact with non-target locations, ineffective delivery causes undesirable side effects. The difference in the characteristics of such transport and in situ effects of many drug molecules is the underlying cause of the bioreversible chemical derivatization of drugs, that is, the formation of prodrugs is a means of frequently improving the overall efficiency of the drug. Prodrugs are designed to overcome the medical and/or medical thermodynamic problems associated with the parenteral molecule that limits the clinical utility of the drug. In recent years, many types of bioreversible derivatives have been developed for the purpose of designing prodrugs. The use of vinegar as a carboxyl- or trans-based functional drug is the most popular. Others are known as peptides of Drugs of the Future, 1991, 16(5), 443-458, prodrug derivatives such as 4-imidazolidone, or N-oxides, for example, as described in U.S. Patent 5,691,336 . As stated previously, the compound of formula 11 is an antagonist of the neurokinin receptor. The central and peripheral effects of mammalian tachykinin P have been combined with many inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease, as well as conduction vomiting and regulation of central nervous system (CNS) diseases. Such as Parkinson's disease (Neurosci. Res 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640- 1645) -6 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304809 A7 B7 V. Description of invention (Kallikrein receptor antagonist in pain, headache (especially migraine), · Alzheimer's disease, multiple sclerosis, morphine absorption attenuation, cardiovascular changes, edema (such as edema caused by burns), chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperactivity, and other respiratory diseases ( Evidence for the use of allergic rhinitis, intestinal inflammatory diseases (including ulcerative colitis and Crohn's disease), eye damage and eye irritation can be found in "Reeeptoi" and Tachykinin Receptor Antagonists&quot ;, J. Autcjn. Pharmacol., 13, 23-93, 1993. In addition, neurokinins are being developed for the treatment of many physiological diseases that are conjugated to tachykinins (either episome p) excess or imbalance. 1 receptor antagonist. The body P has included diseases of the central nervous system, such as anxiety, depression, and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798 patents). Neurokinin-1 The body antagonist can be used to treat sports injuries and treat induced vomiting. In addition, the selective neurokinin-1 receptor has been described in The New England Journal of Medicine, Vol. 340, No. 3, 190-195, 1999. Antagonists reduce vomiting of cisplatin rust. The use of neurokinin-1 receptor antagonists to treat specific forms of urinary incontinence is described in Neuropeptides, 32(1), 1-49, (1998) and Eur. J. .

Pharmacol., 383 (3), 297-303, (1999). Further, U.S. Patent No. 5,972,938 describes a method of treating psychophysiological or physical and mental disorders by administering a tachykinin receptor (e.g., NK-1 receptor) antagonist. The object of the present invention is a compound of the formula I and a pharmaceutically acceptable salt thereof, the above compound -7 - the paper scale Guanjia Lai) Α4_Γι(^ 297) binding

Line 1304809 A7 " —--------___ B7 V. Description of the invention (^ j --- a '-------- Preparation 1 containing their pharmaceutical agents and their manufacture, and above The use of a compound for controlling a disease (especially a disease of the aforementioned kind) or a manufacturing agent. | Zhu, ... the best indication of the present invention. It is shown to include a disease of the central nervous system, for example, by administering an NK] receptor Antagonists treat or prevent specific depressions. 3 Major depressive episodes have been defined as most of the day and almost every time there is a loss of interest or joy for all or nearly all of the activities for at least two weeks. The following terms used in the description of the general nouns of this specification are used independently or in combination. The term "lower alkyl" as used herein means a straight or branched alkyl group having 1 to 7 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Preferably, the lower carbon group is a group having from 1 to 4 carbon atoms. Lower alkoxy" denotes a group wherein the alkyl residue is as defined above and which is bonded via an oxygen atom. The term "halogen" means gas, iodine, fluorine or bromine. The noun "cycloalkyl" means a saturated carbocyclic group containing 3 to 0 carbon atoms. The noun "cyclic third amine means, for example, pyrrole Acridine_][_yl, piperidine-yl-yl, piperidinyl-1, morpholine-4-yl, or i,i-dioxythiomorpholine-based. Preferably, wherein X is - A compound of C(0)N(R6), wherein the counter 6 is a methyl group, for example, the following compound: 4-{5-[(3,5-fluorenyltrifluoromethylbenzyl)-decylamine formazan Base]_4_o-tolyl ρ than precipitate-2-yl}. _4 -oxy brigade "• Well-1-Resistance third vinegar, 1304809 A7 B7 V. Description of invention ( ) 5·-[(3, 5-贰Trifluoromethylindolyl)-methylamine-mercapto]-4'-o-tolyl-1-oxy-3,4,5,6-tetrahydro-2Η-[1,2·] Ethyl bispyridyl-4-carboxylate, (RS)-6-[3-(ethinylmethylamino)-oxapyrrolidin-1-yl]-indole-(3,; 5-fluorene Methylbenzyl)-indole-methyl-4-o-toluene nicotinamide, Ν-(3,5-fluorenyltrifluoromethylbenzyl)-indole-methyl-6-(4-oxomorpholine -4-yl)-4-o-phenyl hydrazine, N-(3,5-fluorenyltrifluoromethyl)-6-(1,1-dioxo-1 and 6-4-oxo base Thiomorpholine 4-yl)-N-methyl-4-o-tolylbenzamide, N-(3,5-fluorenyltrifluoromethylsulfonyl)-6-(4-carbazyl- 1·oxypiped-1-yl)-N-methyl-4-o-tolylbenzamide, N-methyl-N-(2-methylben-1·ylindenyl)-6 - ( 4-oxyl"lin-4-yl)_ 4-o-tolyl-indoleamine, N-methyl-6-(4-oxymorpholin-4-yl)-N-indol-1-yl Methyl-4-o-phenylphenyl nicotinamide, N-(2-methoxyindol-1-ylmethyl)-N-methyl-6-(4-oxymorpholin-4-yl) -4-o-phenyl hydrazine, N - (2-methoxyindolyl)-N-methyl-6-(4-oxo-p-lin-4-yl)-4-o-tolyl Nicotinamide, N-(5-chloro-2-methoxybenzyl)-N-indolyl-6-(4-oxoxylin-4-yl)-4-o-tolylbenzamide , N-(2-Chloro-5-methoxyindenyl)-N-methyl-6-morpholin-4-yl-4-o-toluene based on the test-fixation amine 'N-methyl-6-(4- Oxymorpholin-4-yl)-N-pentafluorophenylmethyl-4-o-tolylbenzamide, -9- This paper scale applies to Chinese national standards (CNS> A4 specification (210X 297 public) 1304809 A7 _ __ _B7__ V. Description of the invention (7) N-methyl-6-(4-oxyl? 4-yl)-N-indole-2_ylmethyl-4-o-toluene based on the test amine, N-[2-decyloxy-5_(5-trifluorodecyltetrasyl-1-yl) ^基]-Ν-Methyl-6-(4-oxomorpholine_4_yl)_4_o-tolylbenzamide, >^-(1,4-dimethoxyindole-2_ Methyl)_;^-mercapto-6-(4-oxoxylin-4-yl)-4-o-tolylbenzamide, or 5'-[(3,5-fluorene trifluoromethyl)芊 ) ) _ _ _ _ _ _ _ _ _ _ _ carboxylic acid. More preferred are compounds wherein X is -N(R6)-CO-, wherein R6 is hydrogen or methyl. An example of such a compound is: 2-(3,5-fluorenyltrifluoromethylphenyl)-:^-methyl-:^-[6-(4-oxymorpholin-4-yl)-4-yl曱Phenylpyridine·3_yl; μisobutylamine, 2-(3,5-fluorenyltrifluoromethylphenyl)_Ν-[4-(2-chlorophenyl-6-(4-oxy)?淋-4-yl)pyridine-3-yl]-N-methylisobutylamine, 2-(3,5-fluorenyltrifluoromethylphenyl)_N-[6-(4-oxomorpholine- 4-yl)-4-o-tolypyridin-3-yl]-isobutylamine, 2-(3,5-fluorenyltrifluorophenyl)-indole-[4.-(2-chlorophenyl) )-1-oxy-3,4,5,6-tetrahydro-211-[1,2,]bipyridin-5,-yl]-1^-methylisobutylamine, 2-(3, 5-贰Trifluoromethylphenyl)-N-(6-oxydimethylamino-4-o-tolypyridin-3-yl)-N-methylisobutylamine, 2-(3,5 -贰Trifluoromethylphenyl)-N-[4-(2-phenylphenyl)-6-oxydimethylaminopyridin-3-yl]-isobutylamine, -10 - paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1304809 A7 B7

8 V. Description of the invention (2_(3,5-fluorenyltrifluorophenyl)-Nl-(4.hydroxy-1-oxy-n-tolyl-3,4,5,6-tetrahydro-2-indole-[ 1,2,]-bipyridine-51-yl)-indole-methylisobutylamine, 2-(3,5-fluorenyltrifluorophenyl)-indole-{6-[(2-hydroxyethyl) ))-1-oxymethylamino]-4-o-tolypyridin-3-ylindole-N-mercaptoisobutylamine, (尺)-2-(3,5-fluorenetrifluoromethylbenzene -1^-[6-(3-hydroxy-1-oxypyhadin-1-yl)-4-o-tolypyridin-3-yl]-N-methylisobutylamine, 2- (3,5·贰trifluoromethylphenyl)-N-methyl-N-[6-(4-oxymorpholinyl)-4-o-tolypyridin-3-yl]-acetamide, 2_(3,5-fluorenylmethoxyphenyl)-:^-methyl-:^-[6-(4-oxymorpholin-4-yl)-4-o-tolylpyridine „3_yl]- Acetamide, or 2-(3-fluoro-5-trifluoromethylphenyl)-N-methyl-N-[6-(4-oxomorpholin-4-yl)-4-o-tolyl Pyridin-3-ylethylamine, the compound of the formula I and pharmaceutically acceptable salts thereof can be prepared by methods known in the art, for example, by the following method, which comprises a) a compound of the formula

Oxidation with a suitable oxidizing agent to produce a compound of the formula: This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇 X 297 mm) !304809 A7

Wherein the substituent has the meaning indicated above, and, for example, it is required to convert the obtained compound into a pharmaceutically acceptable acid addition salt. This step, for example, can be prepared as follows: under ice cooling, 1 mM of a suitable oxidizing agent (such as 3-chloroperbenzoic acid) in 5 liters of a suitable solvent (such as a gas sloping slope) The solution was added to a solution of 1 mM of the compound of formula II in 50 ml of a suitable solvent (e.g., methane). (d) Track the degree of reaction at a suitable time (typically 1 hour to 24 hours) and by thin layer I. In the case where the product formation is too slow, the reaction mixture can be stirred at room temperature. The product can be isolated by flash chromatography at 15% to 85% yield. Further purification of the crystalline product can be accomplished by recrystallization from a suitable solvent. For this conversion, other oxidizing agents can be used in place of 3-hydroxyperonic acid. Such oxidizing agents are well known to those skilled in the art, such as dimethyldioxirane in propylamine, hydrogen peroxide in acetic acid, or potassium peroxymonosulfate in a suitable solvent (e.g., water). Salt formation is carried out at room temperature by a method well known to those skilled in the art. Not only salts of inorganic acids but also salts of organic acids can be considered. Hydrogen hydrochloric acid, hydrobromide, sulfate, nitrate, citrate, acetate, cis -12-

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This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) 1304809 A7 B7 V. Description of invention (1C) Butenedioate, succinate, methanesulfonate, p-toluenesulfonate Wait for an example of this salt. The preparation of the compound of formula I is illustrated in more detail below with reference to Figures 1-8. The starting materials are known compounds and can be prepared according to methods known in the art, for example, in accordance with the method described in EP 99103504.9. In the sketch, use the following shorthand:

PivCl Trimethylacetamidine Chloride THF Tetrahydrofuran TMEDA Ν,Ν,Ν',Ν1-Tetramethylethylenediamine DIPEA Ν-Ethyldiisopropylamine KHMDS Hexamethyldiphenylphosphonium nitride-13 - This paper size applies China National Standard (CNS) Α4 Specifications (210Χ 297 mm) 1304809 A7 B7 V. Description of Invention (11 Thumbnail 1

The definition of the substituent is as shown above -14 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304809 A7 B7 V. Description of the invention (12 Sketch 2

XIV HIM R5· XI!

THF

sO

〇

H, /Pd-C xm

PivC!/NEt3

〇

2. I2.-78°C sJ0

0

XV

B(〇Hj2 > Pd[P(Ph)z]4

80 ° C

Vl

XVI

The definition of the substituent is as shown above. -15 -

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304809 A7B7 V. Description of invention (13 Thumbnail 3

1. BuLiATMEDA THF. -78. 〇>-35*0 2

I2 THF, -78X

NIH

X

The definition of (R2)n Z = C1, Br, I or 0S(0)2C6H4CH3 and other substituents is as shown above. 16

This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1304809 A7 B7 V. Invention description (14 sketch 4

SOCL

XXVII

Oxidizer (R1)n

R

**V OINIR

The definition of the -4 substituent is as shown above. -17-This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1304809 A7

The paper size is applicable to the Chinese National Standard (CMS) A4 (21〇x 297 mm) 1304809 A7

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304809 A7

This paper scale applies to China's B standard (CNS) A4 specification (210x 297 mm) 1304809 A7 B7 V. Description of invention (18 sketch 8

(R2)n

XXXIII

The definition of the substituent is as shown above. As stated previously, the compound of formula I and its medicinal use may be used as a prodrug of a parent compound of formula II which exhibits the pharmacological properties of a valuable hydrazine. These compounds are antagonists of the neurokinin HNK-1, a bulk P) receptor. -21 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304809 A7 B7 -|Q ~ — V. Description of invention ( ) In addition, some N-oxides of formula I are for NK-1 The receptor has a good affinity. For some preferred compounds, pKi値 is in the range of 8.3 to 8.7. The compound was investigated according to the test shown below. Binding assay (in vitro) Human ΝΚι receptors were evaluated in human NKi receptor-infected CHO cells for the affinity of the test compound for the NK! receptor (using the Semliki virus expression system) and with [3H] bulk P (final concentration 0.6 nM) ) radiation mark. Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%), leupeptin (8 μg/ml), MnCl2 (3 mM), and phosphonium powder (2 ju Μ). The binding assay included 250 microliters of film suspension (1.25 X 105 cells/test tube), 0.125 microliters of buffer for the replacement agent, and 125 microliters of [3H] bulk P. The substitution curve is determined by the concentration of at least 7 compounds. The test tube was pre-soaked with ΡΕΙ (0.3%) for 60 minutes, and washed with 2×2 ml of GF/C filter in HEPES buffer (50 mM, pH 7.4), and then incubated at room temperature for 60 minutes. The activity of the radiation remaining on the filter is measured by scintillation counting. All tests were repeated three times in at least 2 separation experiments. The compound of formula I can be used as evidence of a prodrug of its parent compound of formula 11 in accordance with the following description. N-oxide prodrugs are converted to the corresponding parent compound and due to the reduction mechanism, and there is some evidence from the literature that the reaction similar to living organisms is probably catalyzed by hemoglobin, thus obtaining the stability of the study in plasma and blood. The decision. The presence of an oxidizing agent in the working solution should help prevent N-oxide reduction. Conversion in plasma: 10 μl of prodrug in 100 μg/ml DMSO solution-22- This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1304809 A7 B7 - — V. Description of invention ( ) 1 ml of plasma was used to reach a final concentration of 1 μg/ml. The cultivation was carried out at 37 ° C and 8 equal portions were obtained at different time points over 30 minutes. These aliquots were treated with 3 volumes of cold MeOH containing H2 02 (final concentration 10% Wv) and centrifuged at 3500 g for 20 minutes at 10 °C. The supernatant was directly used to obtain LC-MS-MS (HPLC on reverse phase column X- Terra MS C18 3.5 y 2.1 x 30 mm Waters using polar gradient MeOH/capric acid acetate 1% 20/80/ MeOH; time of conduct: 3.0 minutes; injection volume: 10 μl: flow rate: 0.2 μl/min, and MS/MS detection on a PE Sciex API-2000 MS/MS spectrometer; ion source: Turbospray; ionization mode: ESP + ) determines the drug content. Conversion in fresh blood: The same procedure is used for stability studies in the blood, although care must be taken after treatment with Η 2 Ο 2 . Sample stability (plasma and blood): First prepare the final matrix (treated in 3 volumes of cold MeOH containing 2〇2-10% ν/ν, and centrifuged at 3500 g for 10 minutes in 10 liters of plasma or blood), then The cells were cultured in 2 tubes at 37 ° C; the prodrugs or drugs were then cultured and finally determined by LC-MS-MS as previously described. It has been found that the method used to stop the reaction in the plasma and blood is reliable enough to carry out the study, at least immediately after the analysis. The half-life period of prodrugs converted into drugs in plasma is reported in the table below (it is important to find that plasma sample cavitation is true for t丨/ 2値): -23- This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210X 297 mm)

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Line 1304809 A7 ______B7 V. Description of invention (21) tl/7 (hours) Sample number Dog plasma Human plasma Mouse plasma 1 18 8 4 2 18 12 5 16 16 6 2 Stability in the blood 'very low' (ti/2&lt ; 30 minutes) and η cannot be measured. Accurate. However, the conclusion is that there is no major species difference in the safety of the blood, and the prodrug is converted into the desired drug in high yield (>90%). According to the test, the compound of the formula I can be used as a prodrug of the formula π parent compound. The compound of the formula I and its medicinal use can be used as a pharmaceutical, for example, in the form of a pharmaceutical preparation. The pharmaceutical preparation can be administered orally as a tablet, a coated tablet, a sugar bond, a hard and silicone capsule, a solution, an emulsified or a suspension. However, the administration can also be effected by enteral administration in the form of a suppository or parenteral administration in the form of an injection solution. For the manufacture of tablets, coated tablets, troches, and hard gelatin capsules, the compounds and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or phased excipients using acid addition salts. Lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof can be used as such a miscellaneous substance, for example, an ingot of a medicinal ingot or a sugar (8) hard gelatin capsule is used for a soft gelatin capsule. The agent is, for example, oil, sample, fat, semi-solid, and liquid polyol. > Suitable excipients for making solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like. -24- Paper Scale Standards® National Standard (CNS) A4»(21G><297 mm) ' "~~~ __一 1304809

Suitable excipients for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. Further, the pharmaceutical preparation may contain a preservative, a solubilizer, a stabilizer, a wetting agent, a sweetener, a coloring agent, a flavoring agent, a salt buffer of different osmotic pressure, a masking agent, or an antioxidant. It may also contain other therapeutic valuable substances. The dose can be varied within a wide range of P degrees, and of course in individual cases should be individual requirements. Generally, in the case of oral administration, a daily dose of about 10 to 1000 mg of the compound of formula I per person should be appropriate, although the upper limit may be exceeded if necessary. The following examples describe the invention without limitation. All temperatures are expressed in degrees Celsius = formulas starting with a compound of formula II are generally described in the description. This oxidation step is always the final step in obtaining the ruthenium-oxide of the compound of formula I. A detailed description of this last step is specifically described in Examples 1, 2 and 13 below. The oxidation of the remaining compounds 3 to 12 and 14 to 29 - is generally described in the above description. Example 1 2-(3,5-Indolyltrifluoromethylphenyl)-:^-methyl-]^-"6-(4-oxoxy-ylidene-4-yl)-4-o-tolylpyridine- 3-kib-isobutylamine amide a) 4 - (5 - schochyl-2-ether-to-bite) 口Linlin Add 27 ml (3 15 mM) morpholine to 20 g-25 in 10 minutes - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304809 A7 B7 23 ------- V. Description of invention ( ) (1263⁄4 mol) 2 -chloro-5-nitro P is more than a solution of 150 ml of tetrahydroquinone chew. The reaction mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed by venting and the residue was redissolved in ethyl acetate (200 mL). The organic phase was washed with EtOAc (EtOAc m. Melting point 142 _ 143 Ό. ))) 2,2-di-decyl-N-(6-norlin-4-yl-p-precipitate-3-yl)-propanamine 2.5 g of 10% palladium on activated carbon was added to 27.3 g (126 Millol) a solution of 4-(5-nitro-2-pyridyl)-morphine in 600 ml of methanol. The reaction mixture was hydrogenated (room temperature to about 45 ° C, 1 bar) until a theoretical amount of hydrogen was consumed (about 3 hours). The catalyst was filtered and washed twice with 100 ml portions of methanol. The hollowed-out filtrate produced 22.6 grams of a purple oil which, according to thin layer chromatography analysis, comprised about 95% of the desired aniline derivative. This crude product was dissolved in a mixture of 240 ml of tetrahydrofuran and 6 ml of diethyl ether. After cooling to 0 ° C, 26 ml (189 mmol) of triethylamine was added in one portion. Stirring was continued while 23 g (189 mmol) of trimethylacetamidine was added dropwise over a period of 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for one hour. The solvent was then removed by venting and the residue was suspended in 2 mL of a 1N solution of sodium bicarbonate. The product was extracted 3 times with 200 mL portions of di-methane, dried (MgSO4) and evaporated. The solid residue was recrystallized from ethyl acetate / hexanes to afford 28.6 g (yield: 86%). MS m/e (%): 264 (M+H+, 100). c) N-(4-iodo-6-morpholin-4-ylpyridine-3-11-2, 2-dimethylpyramine 28.4 g (108 mmol) 2,2-dimethyl-N -(6-Molin-4-yl-rhodin-3-yl)-propanamide and 49 ml (324 mmol) N,N,N,,N,-tetramethyl -26- This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304809 A7 B7 V. Description of the invention (24 Ethylenediamine in argon under 60 〇 ml of tetrahydrofuran in an ice bath to •78 ° C. In 1 Within a few hours, add 202 ml (324 mmol) of 1.6 N solution of n-butyllithium to hexane. Warm the reaction mixture to a maximum of _35 overnight. After cooling again to _78 Torr, add dropwise in 15 minutes. 37 g (146 mmol) of iodine dissolved in 60 ml of tetrahydrofuran solution. The dry ice bath was replaced with an ice bath, and when the temperature of the reaction mixture reached 〇.〇, 90 birds were added within 1 minute ( 363 millimoles) a solution of sodium thiosulfate pentahydrate in 250 ml of water. Then add 1000 ml of diethyl ether and separate the organic layer. The aqueous layer is extracted with 500 ml of di-methane and the combined organic layer is dried (MgSO4). And evaporation. 15.6 g (37%) of the title compound was obtained as a light brown oil which crystallised upon standing at room temperature MS m/e (%): 389 (Μ+, 71),358 (25),3〇4 (43 ), 57 (1〇〇). 丄^^-dimethyl-anthracene-(6-morpholin-4-yl-4-o-tolylpyrazin-3-, _propanamide 3,50 g ( 9.0 mmoler) Ν-(4-Iodo-6-morphin-4-ylpyridin-3-yl)-2,2-dimethylpropanamide, 35 ml of toluene, 18 ml of sodium hydrogen citrate 2Ν Solution, a mixture of 312 mg (0.27 mmol) of ruthenium (triphenylphosphine) ruthenium (〇), and ι·34 g (9.9 mmol) of o-phenylphenylboronic acid were heated at 8 ° C for 12 hours under argon. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layer was washed with 50 mL of brine, dried (MgSO4) and evaporated. The title compound is white foam. MS m/e (%): 354 (M+H+,100) 〇e)6 -11 11 Lin-4-yl-4-o-phenylene p-precipitate-3- Keamine•27- This paper scale adopts Chinese National Standard (CNS) A4 specification (210 X297 mm)

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1304809 A7 B7 V. Description of the invention (2.93 g (8.28 mmol) of 2,2-dimercapto-N(6-morpholine-4-yl-4-o-tolylpyridin-3-yl)-propanamide A suspension of 8 ml of hydrochloric acid in 3N and 5 ml of 1-propanol was heated to 9 〇 _95 < χ: overnight. The reaction mixture was cooled to room temperature, washed with 3 parts of 20 ml of diethyl ether and diatom The filtrate was diluted with 20 ml of water and adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with 4 parts of 1 mL of di-methane. Wash with 50 ml of brine, dry (magnesium sulfate) and evaporated to give 2 - 31 g (yield) of title compound as white foam. MS m/e (%): 269 (M+,1 〇〇) 〇HH - (令-么琳- 4 base-4 - o-methyl stupid said cold _ 3 • base) _ amine 2.24 g (8.3 m mole) 6-morpholine _4 · base _4_ o-tolylpyridine _3_ylamine in 17 ml The solution of trimethyl orthoformate and 3 drops of trifluoroacetic acid was heated at 13 〇 π for 2 hours. The reaction mixture was evaporated and dried for 3 hrs. The residual oil was dissolved in 5 ml of tetrahydrofuran and 63 〇 mg was added dropwise under ice cooling. (166 millimeters The ear was hydrogenated in 20 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour and then cooled to hydrazine. (: and acidified by addition of 28% hydrogen acid solution (ρΗ1-2). After stirring for 5 minutes, add 28% sodium hydroxide solution to reach pH 10. The solution was filtered through celite, evaporated and purified by flash chromatography to yield 1.56 g (66%) of the title compound as white foam. MS m/e (%) : 283 (Μ+,1〇〇) 〇,,贰tetrafluoromethylphenyl VN-A J6-morpholine·4_某_4_碑tolyl ρ than -3-yl)-isobutyl hydrazine Neck 1.46 g (5.153⁄4 mol) methyl _(6-nor- _4_yl-4-o-tolyl tr-pyridyl-3-yl)-amine with 1.32 ml (7.73 mmol)>|- Ethyldipropylamine is applicable to China National Standard (CNS) A4 specification (210X 297 mm) on 15 to 28-paper scale.

Line 1304809 A7 B7 V. Description of the invention (The solution of chlorinated methane was cooled in an ice bath, and 18 g (5.67 mmol) of 2-(3,5-fluorene tetrafluoromethylphenyl)_2 was added dropwise. _Methylpropionyl chloride. The reaction mixture was warmed to 35-40 X: 3 hours, cooled again to room temperature and stirred with 25 mL of saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted. The combined organic layer was dried (MgSO4) and evaporated. EtOAcjjjjjjjjj -N-曱基-Ν-Γ6-Μ-氦苴汁4_基)_4_ 曱 曱 基 p 比 比 _ 3 3 _ _ 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 - gas benzoic acid (about 7 〇%) in a solution of 35 ml - chloromethanone, 5.0 g (8.84 mmol) of 2 (3,5-fluorene tetrafluoromethylphenyl)_N-methyl 4_ ( A solution of 6-morpholine_4_yl_4_decylpyridin-3-yl)-isobutylamine in 50 ml of dichloromethane. After stirring for 1 hour at 〇 °C, 2.6 g (25.7 mmol) of triethylamine was slowly added. The reaction mixture was concentrated to a total volume of 1 mL and the residue was purified by flash chromatography. The crude material was suspended in 20 mL of diethyl ether. The melting point is 149_丨5丨 (partial decomposition). MS m/e(%): 582(M+H+,100) 〇Example 2 2 -_ίϋτ··Oxytrifluoromethylphenyl)-N-indole 4-(2-phenylphenyl)-6-(4 - oxalyl-4-yl)-»> than -3-yl 1-yl-methyl-isobutyl amide in accordance with the procedure of Example 1 above, in step d) replaced with 2-chlorophenylboronic acid o-Phenylboronic acid' is available in comparable yields to the title compound such as White -29- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ·; Binding

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crystallization. 141141-143 °C (partial decomposition), MS m/e(%): 602(M+H+,1〇〇),624 (M+Na+,10) Example 3 Ιι,ί3,5·武三U-Phenyloxymorpholine•龃里phenylpyridin-3-yl-1-isobutylpyrene glare The steps of steps a) to g) were prepared according to the above Example 1, to obtain a parent compound such as white in a comparable yield. powder. Step f) is omitted. MS m / e (%): 552 (M + H +, 1 〇〇) n </ RTI> </ RTI> </ RTI> <RTIgt; Example 4 i_l(3,5·Wu-difluoromethylphenyl)-N-"4'-(2-(phenylene)-1-yl)-K5'6-tetrahydro-2Η-Π, 2Ί double Pyridine-51-a 1-N-methylisobutylamine The steps of steps &amp; ??? to §) were prepared according to the above Example 1, using piazinyl substituted morpholine in step 及 and 2-phenylphenyl in step d) Boric acid is substituted for o-tolylboronic acid to give a parent compound such as a white powder in a comparable yield. MS m/e (%): 583 (M+, 20), 296 (78), 255 (100). N-oxide was obtained according to step h) of Example 1. Example 5 ^(., (3,5-Wu-difluoromethylphenyl)-N-(6-oxydimethylamino-4'-o-tolyl acridine-3-yl)-N-methyliso Butanamine The steps of steps &amp; g to g) were prepared according to the above Example 1, using dimethylamine hydrochloride in place of morpholine in step a) to give the parent compound as a white solid in a comparable yield. Mp 174-175eC. MS m/e (0/〇): 524 (M+H+, 100). • 30· This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

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Line 1304809 A7 B7 --7^2δ ----------:- V. Description of the invention ( ) According to step h) of Example 1, an N-oxide is obtained. Example 6 -Phenylphenyl)-N · f 4 - tchlorophenyl)_ 6 _ M dimethylaminopyridin-3-yl 1-isobutyl decylamine Prepared steps a) to g) according to Example 1 above In the step &amp;), the dimethylamine hydrochloride is used in place of the phenanthrene and in the step d), the 2-phenylphenylboronic acid is substituted for the o-tolylboronic acid to give a parent compound such as a white solid in a comparable yield. Melting point 162-163 ° C 〇 MS m/e (%): 544 (M+H+, 100) Ν Ν-oxide was obtained according to step h) of Example 1. Example 7 2-(3,5-fluorenetrifluoro-methylphenyl)-Nl-(4 dihydroxy q-aryl-4, indolyl-3,4,5,6 di g-f,-2H-[ l,2,l-bipyridinemethanthinamine according to the above-mentioned Example 1 to prepare the steps of steps 〇 to g), in step a) using 4-ion-based lyophilized, Lin, in comparable yield A parent compound such as a white foam is obtained. MS m/e (%): 580 (M+H+, 100). The N-oxide was obtained according to step h) of Example 1. Example 8 2li.3,5·贰Trifluoromethyl.碁Phenyl hydroxy ethoxylate A certain amine 1-4-o-tolyl^bit-3-yl}-N-methylisobutylamine according to the above Example 1 The steps of preparing steps a) to g), in step a) using N-methylethanolamine in place of morpholine, in a comparable yield to the parent compound such as -31 - the paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm) 1304809 A7 B7 —---- V. Description of the invention (white foam. MS m/e (%): 554 (M+H+, 1〇〇). Obtained according to step h) of Example 1. N-oxide. Example 9 (with -2-(3.5-fluorene trifluoromethane) ^^-"6-(3-hydroxy-1-indole-salt-pyridin-1-yl)-4-o-tolylpyridine-3 -Based 1-N-methylisobutylamine The steps of steps a) to g) were prepared according to the above Example 1, and (R)-3-hydroxypyrrolidine was used in place of morpholine in step a). The rate gives the parent compound such as white foam. MS m/e (0/〇): 566 (M+H+, 1 〇〇) Ν Ν-oxide was obtained according to step h) of Example 1. Example 1 0 St. II (3 '_j. 武二氟.methylphenyl)_Ν_methyl·Ν-『6-(4-ethoxy??_2diyl)-4-o-tolyl ρ -3-yl 1-acetic acid amine 185 mg (1.14 mmol) 1,1'-carbonyl diimidine was added to 3 mg (1.1 mmol) of 3,5-fluorene (trifluoromethyl)-benzene A solution of the base acetic acid in 7 ml of N,N-dimethylformamide, and the solution was stirred at room temperature for 3 minutes. After the addition of 283 mg (1 mmol) of methyl-(6-morpholine-4-yl-4-o-tolyl-3-yl)-amine (as described in step f of Example 1), The reaction mixture was heated at 9 ° C overnight. After cooling to room temperature, the solvent was removed in vacuo and the residue was taken up in ethyl acetate (30 mL). The organic phase was washed with water (2 χ 3 mL), brine, dried (MgSO4) and evaporated. Rapid chromatography yields 5〇6 mg (94%\ of the parent compound such as light brown foam. MS m/e(〇/0) ♦· 538(Μ+Η+,1〇〇) 〇 -32- 1304809

The N-oxide was obtained according to step h) of Example 1. Example 1 1 ill 3,5 - rabbit methoxyphenyl dimethyl _ N _ "6 _ ( 4 - gas morpholine _ 4 _ _ o-methyl phenyl pyridine - 1 - r. Add 244 mg (1.5 mmol) & carbonyl diimidazole to 226 mg (1.153⁄4 mol) of 3,5-dimethoxyphenylacetic acid in 7 ml of N,N-dimethyl: decylamine solution And the solution was stirred at room temperature for 3 minutes. Add 283 gram (1 mmol) of methyl-(6-morpholine-4-yl-4-o-tolylpyridine-3-yl)amine (as in the example) After the preparation of step f), the reaction mixture was heated at 7 Torr for 7 hours. After cooling to room temperature, the solvent was removed by venting and the residue was redissolved in ethyl acetate (30 mL). Wash with salt water, dry (magnesium sulfate) and evaporate. Rapid chromatography yields 347 mg (75%) of a parent compound such as a white blister. MS m/e (%): 462 (Μ+Η+,1〇〇 The N-oxide was obtained according to step h) of Example 1.

Example 1 2 U 3 _Fluor-5 - Two Jade! Phenyl) N-fluorenyl-N-"6-(4-hydropyrazine-4.indole-4)-o-tolylpyridinium _ 3 - 卜, 醢 将 will be 195 mg (1.2 耄 Mo) 1} 1, carbonyl dimizone added 266 mg (1.2 mmol) of 3-fluoro-5-trifluorodecylphenylacetic acid in 7 ml of N,N-dimethylformamide solution, and the solution was in the chamber Stir for 3 minutes. After the addition of 2833⁄4 g (13⁄4 mol) of methyl (6-morpholin-4-yl-4-o-tolylpyridyl)-amine (as described in step f of Example 1), the reaction mixture was at 9 Torr. Β〇 plus..., 6 hours. After cooling to room temperature, remove the solvent and remove the residue; check again -33-

1304809 Α7 Β7 5, invention description ( τι

In 30 ml of ethyl acetate. The organic phase was washed with water (2 χ 3 mL), brine, dried (MgSO4) and evaporated. Flash chromatography yielded 432 mg (88%) of a parent compound such as a pale yellow foam. MS m / e (%): 488 (M + H +, 1 〇〇) N N-oxide was obtained according to step h) of Example 1. Example 1 3 今-{ 5 『(?., a 5 · 武-trifluoromethylbenzylmethylamine aryl) _4_ ortyrylpyridin-2-yl b-4-oxypiped-1- Carboxylic acid tert-butyl gl_6-gas-N-methyl-4-o-tolyl sulphur i 醢 neck in 〇 ° C 50 ml (50 millimoles) o-tolyl magnesium gas salt in tetrahydrofuran 1M solution A solution of 3.41 g (20.0 mmol) of 6-chloro-N-methyl in a solution of the base amine in 80 ml of tetrahydrofuran was added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. Cool to 〇.〇, then add 5.7 ml (100 mmol) of acetic acid and 51 g (22 mmol) of 2,3-milk-5,6-dicyano-1,4-benzene After the addition of %, the reaction mixture was warmed to room temperature and stirred for 15 minutes. Add 30 ml of 2N aqueous solution of sodium hydroxide followed by 1 liter of ethyl acetate and 200 ml. The mixture was separated and the organic layer was washed with 4 portions of 250 mL sodium hydroxide in 2N aqueous solution. The combined aqueous layer was extracted with 3 portions of 500 ml of ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium sulphate and Drying over sodium sulfate. Concentration gave 5.44 g of a brown-brown oil. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -93 ° C. b) 4-(5-Methylamine-methylmethyl-4-o-phenylpyridin-2-yl)-piperazine-1-1 34 This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1304809

Stem tert-butyl ester 8.31 g (31.9 mmol) of 6_gas_N_methyl-4-o-tolyl oxime amine, 6.53 g (35.0 mmol)! _T-butoxycarbonylpipe, well, 167 ml (95.6 mmol)]^-ethyldiisopropylamine, and a catalytic amount of 4_(:^,;^_dimethylamino)-pyridinium mixture Heat to reflux overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane and washed with 2 parts of aqueous hydrazine chloride solution. Drying over sodium sulfate and concentration gave 107 g of crude material. The flash column chromatography provided 6.28 g (48.0%) of the title compound as a white solid. MS m/e(%): 411 (Μ+Η+,1〇〇). £L4-{5-丨(3,5-贰-trifluoromethyl芊)_methylaminemethanyl·!·4_粼甲甲基峨2-2-丨-g泉11 Well-1 -Restoric acid tert-butyl ester 20 ml of hexamethylene nitrogen arsenide in tetrahydrofuran oxime solution (20 mmol) was added to 6.28 g (15.3 mmol) of 4-(5-methyl) at 0 °C. Aminomethylmercapto-4 -o-tolylpyridin-2-yl)-bred-i_co-acid tert-butyl ester in 250 ml of tetrahydrofuran. After 30 minutes, 2 · 81 ml (15.3 mmol) of 3,5-wu (trifluoromethyl)benzyl bromide was added dropwise. The reaction mixture was warmed to room temperature overnight. An aqueous solution of water and sodium hydroxide was added, followed by extraction with 3 portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The flash column chromatography yielded 6.89 g (70.8%) of the parent compound as a white solid. MS m/e(%): 637 (Μ+Η+, 100). The ruthenium-oxide was obtained according to step h) of Example 1. Example 1 4 5'-"(3,5-fluorenyltrifluoromethylindolyl)-methylamine-mercaptol-1-4'-o-methyl-l-oxyl-3,4,5,6- Tetrahydro-2!1-"1,2'1 bispyridyl-4- oxime ethyl ester-35-

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Line-book paper size Common Chinese National Standard (CNS) Specification (210 X 297 mm) 1304809 A7 B7 Preparation of 4-{5-[3,5-fluorenetrifluoromethylhydrazino)methylamine thiol according to the above a step of -4-o-tolylpyridin-2-yl}-pitrin-dicarboxylic acid tert-butyl ester (Example 13), in step b), using ethyl inipicic acid to replace the third butoxycarbonyl group Pipelined and used in step c) 5, methylamine-mercapto-4, o-tolyl-3,4,5,6-tetrahydro-211-[1,2']bispyridyl-4-carboxylic acid Ethyl ester replaces 4_(5-methylamine-methylindolyl-4-o-phenylphenylpyridine-2-yl)-piperidine-butyl carboxylic acid, and the parent compound such as white is obtained in a comparable yield. solid. MS m / e (%): 608 (M + H +, 100) N N-oxide was obtained according to step h) of Example 1. Example 1 5 (RS)-6-[3-(Acetylmethylamino)-1_oxygen 17 butylate 5_ 贰trifluoromethylbenzyl)-N-methyl-4-o-methyl 4 醯 Preparation of 4-{5-[(3,5-fluorenyltrifluoromethylbenzyl)-methylamine-methyl hydrazino]-4-o-tolyl p than benzyl-2-yl}- Step of 1-carboxylic acid tert-butyl ester (Example 13), using (RS)-3-(ethenylmethylaminopyrrolidine in place of 1-t-butoxycarbonylpiperidin in step b) and in step c) using (rs)_6_[3_(ethyl arylmethylamino)-»»Bihabit-1-yl]-N-mercapto-4-o-toluene based on a slit amine to replace 4-(5-methyl The amine mecoyl-4-o-toluene-yl-u-bit _ 2 -yl)- ν» oleo-1-carboxylic acid tert-butyl ester gives a parent compound such as a pale yellow solid in a comparable yield. MS m/e (%): 593 (M+H+, 100). The N-oxide was obtained according to step h) of Example 1. Example 1 6 N-(3,5-Wutrifluoromethylbenzyl)-N-methyl-6-Γ4-oxoline-4-yl-36- 1 permanent paper scale i Buckle 1^8) A4 size (210X297 mm) 1304809 A7 B7 ~ ------— ——-—............... — V. Invention description ( ) 4 - o-toluene, a nicotinamide monohydrate, a) 6-gas-N-methylnicotamine, 230 ml (3.16 mol) of sulfonium chloride in 〇 ° C, 5 gram (317 mmol) Ear) 2-Chlorine for acid testing. After the mixture was heated under reflux for 2 hours, the steaming hall was used to remove excess thiocyanate. The oily brown residue was dissolved in 25 ml of methylene chloride. The solution was treated with methylamine gas at 0 ° C until the exothermic reaction was no longer observed. The resulting suspension was diluted with 1000 ml of dichloromethane/water. Separate the layer and the water layer is extracted with 3 damages; The combined organic layers were dried with sulphuric acid, and concentrated to give 53.2 g (98%) of the title compound as pale yellow solid. MS m/e (%): 171 (M+H% 15). 1) 6-gas-N-methyl-4-o-methyl-p-butanyl j-indene glare 50 ml (50 mmol) of o-tolyl magnesium chloride in 1 M solution of tetrahydrofuran was added dropwise at 3.degree. Gram (20.0 mmol) 6_Chloro_]^-Methylpropanol was taken as a solution of decylamine in 80 mL of tetrahydrofuran. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was again cooled to 〇.c, followed by dropwise addition of 5.7 ml (100 mmol) of acetic acid and 51 g (22 mmol-er) of 2,3-dichloro-5,6-dicyano-1,4 - Benzene g in 18 ml of tetrahydropyran solution. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 5 min. Add 30 ml of 2N aqueous solution of sodium hydroxide and then! Diluted with liters of ethyl acetate and 200 ml of water. The layers were separated and the organic layer was washed with 4 portions of 25 mL aqueous sodium hydroxide. The combined aqueous layers were extracted with 3 parts of 5 mL of ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium sulphate and dried over sodium sulfate. Concentration gave 5.44 g of a brown-red oil. Flash column chromatography provided 2.15 g (41.3%) of the title compound as a pale yellow solid. Melting point 91· -37- The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304809 A7 B7 V. Description of invention (9 3 〇C. MS m/e(%): 260 (M+, 11) c) N-methyl-6-?"lin·4_yl-4-o-toluene based on the amines to be charged 1.00 g (3.84 mmol) of 6-chloro-indole-methyl-4-o-toluene Baseline smoked guanamine, 0.37 ml (4.22 mmol) morpholine, 2.0 ml (12 mmol) Ν-ethyl diisopropylamine, and catalytic amount of 4 - (Ν, Ν-dimethylamino) The mixture of pyridine was heated to 100 ° C overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane and washed with 2 portions of water. The combined aqueous layer was extracted with 3 portions of methane, dried over sodium sulfate and concentrated to yield 1.23. Crude product. Rapid column chromatography provided 1.11 g (92.9%) of the title compound as a white solid. melting point 156158 V. MS m/e (%): 311 (M+, 64) d) N-( 3,5-Wu Di gas methyl fluorenyl)-n-methyl-6-, Lin-4··yl-4 _o-tolylnicotinium amide at 1. C will be 1.123⁄4 liters of methylene nitrogen Dreaming fresh in tetrahydromethane Μ solution (1.12 millimoles) added 0.27 grams (0.87 millimoles) N -Methyl-6-oxa-4-yl-4-o-indole phenyl in a solution of saponin in 15 ml of tetrahydrofuran. After 30 minutes, 0.16 ml (0.87 mmol) was added dropwise. 5, 武(三气methyl), bromine, and the reaction mixture was warmed to room temperature overnight, then quenched with water and then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The title compound was obtained as a white solid. MS m/e (%): 538 (M+H+, 100) e) N-(3,5-indoletrifluoromethylmethyl)- N-methyl-6-(4- gas group V4-o-tolylbenzamide-38- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1304809 A7 B7 V. Description of the invention (0.17 g of 3-chloropertoic acid (70%, 〇.71 mmol) was added to 0.40 g (0.74 mmol) of N-(3,5-贰 at 0 °C Trifluoromethylbenzyl)-N •methyl_6·Mallin-4-yl-4-o-tolyl was finally detected in 4 ml of dichloromethane. The reaction mixture was reacted after 4 hours. It is diluted with dichloromethane and washed with 3 parts of saturated aqueous solution of sodium bicarbonate. The combined aqueous layer is extracted with dimethyl hydrazine. The combined organic % liquid is washed with a saturated aqueous solution of gasified sodium, dried and concentrated with sodium sulfate. Column chromatography yielded the title compound as a white solid. MS m/e (%): 534 (M+H+, 100) s s s s s s s s s s s s s s s s s The melting point is 1丨j 7 . Example 1 7 K3,5-fluorenyltrifluoromethylbenzyldioxy-1 Α θ-4 - gas thiopurine _.&lt;»lin-4-yl)-oxime-methyl-4-neo-methyl Stupid based on guanamine? )...Ν - ( 3..,5 - 武二气methyl 贵基)_Ν -Methyl-6-thiophenoline-4 -yl-4- 4-toluene The indoleamine was prepared as described above for the preparation of 4-{5-[(3,5-fluorenyltrifluoromethylbenzyl)-methylaminemethylhydrazino]-4-o-p-phenylpyridin-2-yl}-piperazine- The step of carboxylic acid tert-butyl ester 'in step b) uses thio- phenazine instead of ι_t-butoxycarbonyl brigade _ and in step c) uses N-methyl-6-thio- lt ;#-4 -yl-4-o-tolyl-smoke-smoke-substituted amine 4-(5-methylaminocarbamimidyl-4-o-tolylpyridine-2-yl)_piperidine-1-carboxylic acid Butyl ester 'the title compound is obtained as a white solid in a comparable yield. MS m/e (0/〇): 554 (M+H+, 100). -39- This paper size applies to China National Standard (CNS) A4 specification (210X297 public) ·! Binding

Line 1304809 A7 B7 V. INSTRUCTIONS ( ) Ι111τ(3,5-贰Trifluoromethylindolyl)-N-methyl-6-oxime-oxo-1 Α ΙζΜΛ. and 咏-4-yl)-4-粼 笨 基 烟 烟 在 689 689 689 689 mg (1.12 mmol) Oxone® was added to 1.24 g (2.24 houser) N-(3,5-fluorenyltrifluoromethylbenzyl)-N-A at 0 C Base-6-thiomorpholin-4-yl-4-o-tolyl-indoleamine (step a) in 25 ml of methanol. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1.5 hr. It was quenched with 5 ml of a 40% aqueous solution of sodium hydrogen sulfite and then 6 ml of a 1 N solution of sodium hydroxide was added to adjust the pH to 7-8. The mixture was diluted with 50 ml of water and extracted with 3 portions of 150 ml of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated to give 1.20 g of crude material. Flash chromatography provided 1.02 g (79.9%) of the title compound as white solid. MS m/e (%): 570 (M+H+, 100). gJ_N-(3,5-fluorenyltrifluoromethylbenzyl)-6-(1,1-dioxo-1Α6-4-oxo_thio-indolyl-4-yl)-N-methyl-4 - o-toluene based on the mannitol according to the above procedure (step b), using N-(3,5-fluorene trifluoromethyl fluorenyl N-methyl-6-(1-oxo-1 λ 4-thio- phen -4 -yl)-4-o-phenylene substituted for N-(3,5-fluorenyltrifluoromethylbenzyl)-N-indolyl-6-thiomorpholin-4-yl-4- The o-toluene is obtained as a base compound such as a white solid in a comparable yield based on the base amine. MS m/e (%): 586 (M+H+, 100). Obtaining N-oxide according to step h) of Example 1. . Example 1 8 &gt;^-(3,5-fluorenyltrifluoromethylsulfonyl)-6-(4-methylindol-1-#葚戚耕_^ base)-N-methyl-4-o-toluene Base smoked guanamine-40-

This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1304809 A7 B7 V. Inventive Note (0.071 ml (0.56 mmol) trimethyl chlorohydrazine is added dropwise to 0.089 at room temperature. ML (1.1 mmol) of N,N-dimethylformamide and 38 mg (〇·56 mmol) of a mixture of imiban 3 The reaction mixture was cooled to 〇 ° C, and 〇.1 gram ( 0_19 millimolar) 1^-(3,5-fluorenyltrifluoromethylhydrazino)_^^methyl-6-嗓_-1-1-yl-4·o-toluene is based on the amine-based amine. The ice water bath is removed. The mixture was stirred overnight. The reaction was quenched with aq. EtOAc EtOAc EtOAc. The title compound was obtained according to the step h) of Example 1 (m.m. Example 1 9 I-Methyl-N-(2-methylindole-1-ylmethylhydrazine~-4_^U 4-o-indolyl-sodium nicotinamide a) N-methyl-6-? Lin-4-yl-4-o-toluene is prepared according to the above method based on the above preparation of 4-{5-(3,5-fluorenyltrifluoromethylbenzyl)methylaminecarbamyl]-4-o-toluene The step of the base ρ is more than the 2-butylic acid - the third vinegar (Example 1 3, step b), using the lining to replace the 1 _ third butoxycarbonyl brigade π well, The title compound, such as a white solid, is obtained in a comparable yield. MS m/e(%): 311 (Μ+, 63). b) Ν-Methyl- Ν-(2-methylindole-1-ylmethyl)·6 - _4-yl-4-lin toluene based on the detection of guanidine according to the above preparation Ν-(3,5-贰Trifluoromethylbenzyl)-Ν-methyl-6-morpholin-4-yl-4-o-phenylene benzene oxime oxime step (Example 16, step d), using -41 - This paper scale applies China National Standard (CNS) A4 specification (210X 297 mm)

Install m\ k 1304809 A7 B7 ___;__ —-—- ^ V. Description of the invention ( ) 1-chloromethyl-2-methylindole substituted 3,5-fluorene trifluoromethyl quilted chlorine, comparable The yield gave a parent compound such as a white solid. MS m / e (%): 466 (M + H +, 100) N N-oxide was obtained according to step h) of Example 1. Example 2 0 N-methyl-6 - (4-butyryl)-lin-4-yl)-N-yl-1-ylmethyl-4-o-mercapto-nicotinamide Prepared N-methyl as described above Step of -N-(2-methylindole-1-ylmethyl)-6-oxalin-4-yl-4-o-tolylbenzamide (Example 19), using 1-chloro in step b) The methyl hydrazine is substituted for 1-chloromethyl-2-methyl hydrazine to give a parent compound such as a colorless viscous oil in a comparable yield. MS m/e (%): 452 (M+H+, 100) ??? N-oxide was obtained according to step h) of Example 1. Example 2 1 Ν-(2-methoxyindol-1-ylmethyl)-fluorenyl-mercapto-6-(4-oxymorpholin-4-yl)-4-o-tolylnimidamide according to The above procedure for preparing N-methyl-N-(2-methylindole-1-ylmethyl)-6-morphin-4-yl-4-o-tolylbenzamide (Example 19), in step b The use of indole-4-supply-2-ylmethoxy-1-yl oxime ester in place of chloromethyl-2-methylbenzene gives a parent compound such as a colorless viscous oil in a comparable yield. MS m / e (%): 482 (M + HT, 100) N N-oxide was obtained according to step h) of Example 1. Example 2 2 N-(2-methoxyindenyl)-N-methyl-6-(4-oxoxyindol-4-yl)-4-o-methyl-42- This paper scale applies to Chinese national standards (CNS) A4 specification (210X297 public)~~; 1304809

The procedure for preparing N-methyl-N-(2-methylmethylmethyl)-6-morpholine-4-yl-4-indole benzamide according to the above (Example 19) Substituting b-chloromethyl-2-methylindole with 2-methoxybenzyl hydrazine in step b) gives a parent compound such as a colorless viscous oil in a comparable yield. MS m/e (%): 432 (M+H+, 1 〇〇) N An N-oxide was obtained according to step h) of Example 1. Example 2 3 - _ Oxo- 2 - methoxy aryl) ζΆ Ψ Μ Μ ~ ~ ~ 6 - ( 4 - gas capryron 2 4 _ yl) _ 4 - o- phenyl phenyl final amine can be prepared according to the above Ν - methyl The step of Ν-(2-methylphenylmethyl)_6_morpholine_4_yl_4_o-tolylbenzamide (Example 19), using 5-chloro-2-methoxy in the step The benzinium chloride is substituted for chloromethyl-2-methylbenzene to give a parent compound such as a white solid in a comparable yield. MS m / e (%): 466 (M + H +, 100) N N-oxide was obtained according to step h) of Example 1. Example 2 4 N-(m-Methoxybenzyl)-n-methyl-6-morpholine-m-methylmethyl nicotinic acid N-mercapto-N-(2-methylhydrazine) was prepared as described above. -I-methyl)_6_morpholine_4_yl-4-o-tolylbenzamide step (Example 19), in step 躁^ using 2-nitro-5-methoxybenzyl hydrazine instead of ι _Chloromethyl-2-methylsulfate gives a parent compound such as a white solid in a comparable yield. MS m/e (〇/〇): 466 (M+H+, 100). -43 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1304809 A7 B7 V. Description of the Invention ( ) According to the step 1 of Example 1, the N-oxide is obtained. Example 2 5 E·!·Methyl-6-(4-oxoline-4-yl)-N-pentafluorophenylmethyl-4-o-methylbenzamide as described above. Base-N-(2-methylmercaptomethyl)_6-morpholine-4-yl-4-o-toluene based on the step of detecting the amine (Example 19), using 2, 3, 4 in step b), The 5,6-pentafluorobenzylhydrazine bromide is substituted for 1-chloromethyl-2-methylhydrazine to give a parent compound such as a white solid in a comparable yield. MS m / e (%): 492 (M + H +, 100) N N-oxide was obtained according to step h) of Example 1. Example 2 6 N -Methyl-6-(4-oxymorphin-4-yl-ylmethyl-4-o-methylidene nicotinamide. Preparation of N-methyl-N-(2-A) according to the above Step by step according to the step (b), in step b), 2-chloromethyl hydrazine is used in place of 1-chloro Methyl-2-methylindole, a parent compound such as a white solid is obtained in a comparable yield. MS m/e (%): 452 (M+H+, 100). The ruthenium oxide was obtained according to the step h) of Example 1. Example 2 7 Ν-"2-methoxy-5-(5-trifluoromethyl 1tetrazole: !_ylmercaptoin in-methyl -6-(4-oxomorpholin-4-yl)-4 -Indole-toluene nicotinamide according to the above preparation of N-mercapto-N-(2-methyl-S-1-ylindenyl)-6-morphine-4-yl-4-o-toluene based on the detection of guanamine Step (Example 19), in step b) make the -44- paper scale applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304809 A7 B7 V. Description of the invention (with indole-4-sulfonic acid [ 2-decyloxy-5-(5-trifluoromethyltetrazole-i-yl)-phenyl]-methylacetate substituted 1-chloroindol-2-methyl, obtained in comparable yield The parent compound is as a white solid. MS m/e (%): 568 (M+H+, 100). N.s. Methyl-6-(4-oxo-oxime-4-yl)-4_-o-phenylene is used in the preparation of N-methyl-N-(2-methylmercaptomethyl)-6. Step of porphyrin-4-yl-4-o-tolylbenzamide (Example 19), substituting 2-chloromethyl-1,4-dimethylhydrazine for i•gasmethyl_2_ in step b) The base compound, such as a colorless viscous oil, is obtained in a comparable yield. MS m/e (〇 /〇) : 512 (M+H+,1〇〇) N Obtain N-oxide according to step h) of Example 1. Example 2 9 5..··-_Ι·(·2·, ϋ二气methyl+基)_Methylamine, 甲甲基基甲笑甚_ .....^4,,:.3 JL, 5,6 _ 四气-2_ Η -『1,2,1 臀旁々-4 _ Grandpa 200 mg (0.333⁄4 mol) 5'-[(3,5-trifluoromethylbenzyl)-methylamine fluorenyl]-4'-o-tolyl-3,4,5,6 A mixture of tetrahydro-2-indolyl-[1,2,]bispyridyl-4-ylcarboxylate (Example 14), 1 mL of aq. After washing with 2 parts of ethyl acetate, the aqueous layer was acidified to pH 4 with aqueous 1N aqueous acid, extracted with di-methane, dried over sodium sulfate and flash column chromatography to afford 81 mg (42%) of compound Such as white solid. -45- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Binding

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A7 B7 43 V. INSTRUCTIONS ( ) MS m/e(%): 580 (M+H+,100) N An N-oxide is obtained according to step h) of Example 1. Example A Ingots of the following compositions were prepared in the usual manner: mg/pillage prodrug 5 lactose 45 corn starch 15 microcrystalline cellulose 34 magnesium stearate 1 tablet weight 100 Example B Capsules of the following compositions were prepared in mg/capsules Medicine 10 Lactose 155 Corn Starch 30 Talc 5 Capsule Filling Weight 200 First, the active substance, lactose, and corn are mixed in a mixer and then in a pulverizer; The mixture is returned to the mixer, talc is added and thoroughly mixed. The mixture is filled into hard gelatin capsules by mechanical means. -46 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) ·; 1304809 A7 B7 V. Description of invention (

Example C A suppository of the following composition was made: mg/suppository prodrug 15 suppository material 1285 total 1300 suppository material was melted in a glass or cylinder, thoroughly mixed and cooled to 45 °C. At this point the finely divided active is added and stirred until it is completely dispersed. The mixture is poured into a suppository mold of appropriate size, allowed to stand for cooling, and then the suppository is removed from the mold and individually packaged in wax paper or metal foil. -47- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)

Claims (1)

A8 B8 C8 D8 1304|(10)115966 Patent Application Chinese Patent Application Renewal (August 97) Patent Application 1. A compound of formula I Wherein R is hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoromethyl; R1 is hydrogen or i; or R and R together with the ring carbon to which they are attached is _ch=CH- CH=CH-; R and R2 are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy, or i|L; or R and R2 together may be _CH = CH-CH = CH-, It is optionally substituted with 1 or 2 substituents selected from lower alkyl or lower alkoxy; R3, R3' are each independently hydrogen, lower alkyl or cycloalkyl; R4, R4' are each other Independently being -(CH^OR6 or lower alkyl; or R4 and R4' together with the N-atom to which they are attached form a cyclic third amine group R5 is hydrogen, hydroxy, lower alkyl, lower alkoxy, 72054-970813.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 09 804 3 AB CD VI. Application for Patent Park _(CH2)m0H, -C00R3, -CON(R3)2, -n(r3)co-lower alkyl, or _C(0)R3; R6 is hydrogen, lower alkyl or phenyl; X is -C(0)N(R6)-, -N(R 6)C(0)-, -(CH2)m0-, or -0(CH2)m-; η is 0, 1, 2, 3 or 4 And m is 1, 2 or 3; and its pharmaceutically acceptable acid addition salt. 2. A compound of formula I according to claim 1 wherein X is -C(0)N(R6)- and R6 is a fluorenyl group. 3. A compound of formula I according to claim 2, which is 4-{5-[(3,5-fluorenyltrifluoromethyl)-nonylaminoindolyl]-4-o-indole p is more than -2 -yl} - 4 -milyl-shouting -1 - retinoic acid second butyl S曰' 5'-[(3,5-fluorenylfluorenyl)-decylamine hydrazine ]]-4·-o-indolyl-1-oxy-3,4,5,6-tetrahydro-2 Η-[1,2']bipyridyl-4-carboxylic acid acetyl ester, (RS)- 6-[3-(ethylhydrazinylamino)-:!-oxapyridinium-1-yl]-indole-(3,5-fluorenyltrifluoromethylbenzyl)-indole-indenyl-4 -o-toluene smouldering amine ' Ν-(3,5-fluorenyltrifluoromethylbenzyl)-fluorenyl-fluorenyl-6-(4-oxymorpholin-4-yl)-4-o-indolephenyl Nicotinamide, N-(3,5-trifluorotrifluorobenzyl)-6-(1,1-dioxo-1 λ 6-4-oxythiomorpholin-4-yl)-indole - mercapto-4 - o-phenyl fluorene oxime amine Ν-(3,5-fluorenyltrifluoromethyl fluorenyl)-6-(4-methylmercapto-1 oxy odor 11 well-1 - Base)-N-mercapto-4-o-phenylphenyl nicotine decylamine '72054-970813.DOC -2- Ben paper strength: scale applicable Chinese national standard (CNS) A4 specification (210X297 dongdong) 1304809 as C8 D8 six Patent application scope N-mercapto-N-(2-indolyl-1-ylindole -6-(4-oxomorpholin-4-yl)-4-o-phenylphenyl nicotinamide, 'N-mercapto-6-(4-oxymorpholin-4-yl)- N-Indol-1-ylindenyl-4-o-phenylphenyl nicotinamide, N-(2-decyloxyindol-1-ylindenyl)-N-indenyl-6-(4-oxyl Morpholine-4 -yl)-4-o-phenylphenylnicotinium amide, N-(2-oxooxybenzyl) "N-methyl-6-(4-oxomorpholin-4-yl) -4-o-toluene based on basic decylamine, N-(5-chloro-2-indolyloxybenzyl)-N-indolyl-6-(4-oxomorpholin-4-yl)-4-o-fluorene Phenyl nicotinamide, N-(2- gas-5-decyloxybenzyl)-N-indolyl-6-morpholin-4-yl-4-o-phenylphenyl nicotinamide, N- Mercapto-6-(4-oxomorpholin-4-yl)-N-pentafluorophenylindol-4-o-tolylbenzamide, N-mercapto-6-(4-oxyl?啉-4-yl)-N-naphthalen-2-ylindenyl-4-o-phenylphenyl nicotine decylamine, N-[2-methoxy-(5-(trifluoro)-tetrazolium-1 -yl)-benzyl]-N-mercapto-6(4-oxymorpholin-4-yl)-4-o-phenylphenyl nicotinamide, N-(l,4-dimethoxynaphthalene) -2-ylmethyl)-N-mercapto-6-(4-oxomorpholine-4-yl)-4-o-phenylphenyl nicotinamide, or 5·-[ (3,5-fluorenyltrifluoromethyl)-decylamine fluorenyl]-41-o-tolyl-1-oxy-3,4,5,6-tetrahydro-211-1:1, 21] Bipyridyl-4-carboxylic acid. 4. A compound of formula I according to claim 1 of the scope of the patent, wherein X is - 72054-970813.DOC -3 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304809 - C8 D8 The patent application garden N(R6)C(0)- and R6 are hydrogen or methyl. 5. A compound of formula I according to claim 4, which is a compound of formula 4, which is 2-(3,5-indolyltrifluoromethylphenyl)-N-indenyl-N-[6-(4-oxymorpholine- 4-(yl)-4-o-phenylphenylpyridin-3-yl]-isobutylamine, 2-(3,5-fluorenyltrifluoromethylphenyl)-N-[4-(2-chlorophenyl) -6-(4-oxomorpholine-4-yl)pyridin-3-yl]-N-mercaptoisobutylamine, 2-(3,5-fluorenyltrifluorophenyl)-&gt;^ -[6-(4-oxymorpholin-4-yl)-4-o-p-phenylpyridin-3-yl]-isobutylamine, 2-(3,5-fluorenyltrifluorophenyl) -N-[4i-(2-chlorophenyl)-1-oxy-3,4,5,6-tetrahydro-2H-[l,2']bipyridine-5'-yl]-N-oxime Isobutylamine, 2-(3,5-fluorenyltrifluoromethylphenyl)-N-(6-oxydiamidino-4-indolylphenylpyridin-3-yl)-N-indole Isobutylamine, 2-(3,5-indolyltrifluoromethylphenyl)-N-[4-(2-chlorophenyl)-6-oxydiamidinopyridine-3-yl]- Isobutamide, 2-(3,5-fluorenyltrifluorophenyl)-:^-1-(4-hydroxy-1-oxy-4'-o-tolyl-3,4,5,6 -tetrahydro-211-[1,2']-bipyridine-5|-yl)-&gt; 1-mercaptoisobutylamine, 2-(3,5-fluorenyltrifluorophenyl)-N -{6-[(2-hydroxyethyl)-1-oxynonylamino] -4 - o-Phenylpyridin-3-yl}-N-mercaptoisobutylamine, (R)-2-(3,5-indolyltrifluoromethylphenyl)-N-[6-(3 -hydroxy-1-oxypyrrolidin-1 -yl)-4-o-phenylphenylpyridin-3-yl]-N-mercaptoisobutylamine, 2-(3,5-fluorenetrifluoromethylbenzene Base)-N-mercapto-N-[6-(4-ethoxy?72054-970813.DOC -4- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A8 B8 C8 D8 , application for patent Fanyuan 1304809 leaching + base)-4: material phenyl seal _3_ cup ethoxylated amine, 2-(3,5-decyloxyphenyl ketone 4 m .. T base _N_[6_ (4_ oxymorpholine _ group)_4_o-tolyl oxime"-yl]-ethylamine, or gas _5_trimethylphenylmethylmethyloxyphyllin-4-yl)+ Phenylphenyl (tetra)_3_yl]-acetic acid amine. • A pharmaceutical agent for the treatment of N 1C -1 receptors against the 丨丨 丨丨 ^ ^ M φ ^ ^ agent-related diseases, which contains a pharmaceutically acceptable agent according to the scope of claims 1-5. Slave! Compounds and medicines I According to the method of the compound of formula 1 of claim 1, the method includes Oxidized with a suitable oxidizing agent to produce a compound of the formula The significance of the indications in which the substituents have the scope of application for patents 72054-970813.DOC. -3 - This paper scale applies to the towel ® ® home standard (CNS) eight 4 specifications (210X297 mm) &quot; 8. According to the patent application scope __5 | i Μ ^ member of any of the formula I compounds, according to claim 7 of the scope of patents 9. According to the scope of the patent application &quot; to prepare. For example, any compound of formula I, which is used in the treatment of NK] receptor antagonist-related diseases. 10. According to the scope of the patent application No. 1-5, the dog is manufactured with one or more boxes of τ as a compound of the formula I, which uses the phase S1 ^ 5 to treat the NK-1 receptor antagonist-related diseases. . VIII 11 according to the scope of the patent application 丨 is the compound of the formula ～ 7JT 〇 which is defined as the scope of the patent application. 72054-970813.DOC This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public Chu)