TW200410938A - Aryloxyphenyl and arylsulfanylphenyl derivatives - Google Patents

Abstract

The invention provides compounds of the formula, Wherein the substituents are as defined in the application. The compounds are valuable glycine transport inhibitors.

Description

200410938 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to a novel compound of a glycine transporter inhibitor, and itself is effective in treating diseases of the central nervous system. [Prior Art] Background of the Invention Gluten is the main stimulating amino acid in the mammalian central nervous system (CNS) and acts through two types of receptors, namely, ionic and metabolic receptors. Ionic glutamate receptors can be divided into three subtypes based on their affinity for agonists to these receptors. In short, N-methyl-D-aspartic acid (NMDA), (7 ?, Phen-2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) and kainic acid (or kainic acid) receptors. NMDA receptor Contains binding sites for regulatory compounds (eg, glycine and polyamines). Glycine binds to its receptor to enhance activation of the NMDA receptor. For the treatment of schizophrenia and other diseases that bind to NMDA receptor dysfunction Such NMDA receptor activation may be a potential target. Activation can be accomplished by inhibitors of the glycine transporter. Molecular colonization has shown the existence of two types of glycine transporters: GlyT-1 and GlyT-2, where GlyT-1 can be further subdivided into GlyT-la, GlyT-lb, and GlyT-c. NMDA receptors are blocked by compounds such as phencyclidine, which can induce schizophrenia-like State of mental illness. Similarly, NMDA antagonists (eg, ketamine) can induce similar symptoms Negative and cognitive symptoms of schizophrenia. This shows that NMDA receptor dysfunction is involved in the pathophysiology of schizophrenia. NMDA receptors have been associated with many diseases, such as pain (Yaksh, Pah 37: 1 1 1-123 ( 1989)), cramps, myoclonus, and epilepsy (Trueong et al., Movement Disorders 3: 77-87 (1988)), learning, and memory (Rison 533-552 (1995)). Glycine transporter antagonists or inhibitors Agents are generally believed to be highly beneficial for the treatment of schizophrenia (Javitt, WO 97/20533). Glycine delivery antagonists or inhibitors are effective in treating both the positive and negative symptoms of schizophrenia and other psychiatric disorders, and are effective To improve cognition in conditions with weakened cognitive processes, such as Alzheimer's disease; multiple vascular infarction dementia; AIDS dementia; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis Or diseases in which the brain is damaged by internal or external effects, such as head trauma or stroke. Similarly, spastic diseases such as epilepsy, cramps, or myoclonus can also benefit from Acid transporter antagonists. Clinical trials using glycine have been reported, see Javitt et al., Dm · J · Pwc / n. Wo; 151: 1234-1236 (1994) and Leiderman et al., 5b /. Pac / nWry 39: 213-215 (1996). It is reported that treatment with high doses of glycine can improve the symptoms of schizophrenia. There is still a need for more effective compounds for the treatment of NMDA-bound diseases. The present invention provides compounds having potential inhibitors of glycine transporters. Therefore, they are effective in treating diseases that are combined with NMDA dysfunction. 200410938 [Summary of the Invention] Summary of the Invention The present invention provides a compound of the general formula I: (R4 ) r

Y is N, C, or CH; X is 0 or S; m is 1 or 2; p is 0, 1, 2, 3, or 4; q is 0, 1, or 2; s is 0, 1, 2, or 3; r is 0, 1 or 2; Q represents C, P-OR5 or S = 0, where R5 represents hydrogen or CV6-alkyl j A is OR6, where R6 represents hydrogen, CV6-alkyl, aryl or aryl- CV6-alkyl, where aryl can be substituted with halogen, CF3, OCF3, CN, NO2 or alkyl; AR represents phenyl or heteroaryl; each R4 represents CV6-alkyl, C3_8-cycloalkyl or C3_8-cycloalkyl-Cu · institution; 200410938 The dotted line indicates the bonding as needed; each R1, which can be the same or different, is independently selected from the group consisting of free q-6-alkyl groups, Or two R1 connected to the same carbon atom can form a 3- to 6-membered helical cycloalkyl; each R2, which can be the same or different, is independently selected from free halogen, cyano, nitro, CV6 alk (alk / alkyn) yl, CV6-alk (alk / alkyn) oxy, alk (alk / alkyne) thio, hydroxy, hydroxy-c1-6_alk (alk / alkyne) group, halogen-CV6-alkane (Ene / alkynyl) yl, halo-alk (ene / alkynyl) oxy, C3_8_cycloalk (en) yl, c3_8-cycloalkane Composed of alkenyl-Cu alk (en / alkynyl), fluorenyl, (fluoren-6-alk (en / alkynyl) oxycarbonyl, Cl.6-alk (en / alkynyl) sulfonyl or -NR9R1 () In the group, R9 and Ri. Each independently represents a hydrogen, a Cw alk (en / alkynyl) group, a c3_8_cycloalk (en) yl group, a cycloalk (en) yl-Cw alk (en / alkyn) group, or An aryl group, or R9 and R10 together form a 3- to 7-membered ring, which may include another heteroatom as required; each R3, which is substituted on AR, and may be the same or different, is independently selected free halogen , Cyano, nitro, Cm-alk (ene / alkynyl) group, C1-6-alk (ene / alkyn) oxy group, Cle6-alk (ene / alkyne) thio group, hydroxyl group, hydroxy group-C1-6- Halo (alkyn), halogen_〇γ6-homo (alkyn), halo-Cifane (alkene / alkynyl) oxy, C3.8-cycloalkane (alkene), C3_8-cycloalkane (ene ) Alkyl (alkene / alkynyl), cv6-alk (alkene / alkynyl) sulfonyl, aryl, aryl-Cw-alk (alkene / alkyn) oxy, aryl_Cl_6-alkane (alkene / alkyne) ), ^ (Alk / alkynyl) oxycarbonyl, fluorenyl, -NHCO-Cy alk (alkyn / alkynyl), -CONRuR12, rii and R! 2 are independent and represent hydrogen, CV6-alkane (alkene / alkynyl) group, c3_8-cycloalkane (en) yl group 200410938, C3 · 8-ring compound (suspect) group-Ci · 6-yuan (susceptible / Alkynyl) or aryl, or ru and R12 together with the nitrogen to which they are attached form a 3- to 7-membered ring, which may include another heteroatom as required; or NR13R14, where R13 and R14 are each independently Ci_ 6-Taiwu (dilute / block) group, C3_8-ring courtyard (suspect) group, C3_8-ring courtyard (suspect) a -Ci-6-alkane (alkene / alkyne) group or aryl group, or R13 and R14 The nitrogens they connect together form a 3- to 7-membered ring, which may contain another heteroatom if necessary; or two adjacent R3 substituents together form a ring fused with AR, which is selected from the group consisting of the following Of:

Where W is 0 or S, and R 'and R, are hydrogen or CV6-alkyl; or two adjacent R3 substituents together form a heteroaryl group that contains one or two heteroatoms fused to AR ; Or an acid addition salt thereof. In the case where the integers p, q, r, and s are 0, the substituent is hydrogen. If Y represents C, then a dotted line exists. If Y represents N or CH, the dotted line does not exist. The present invention provides the above-mentioned compound of formula I for use as a medicament. The present invention provides a pharmaceutical composition comprising the compound of formula I described above or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent. 200410938 The present invention provides the use of the compound of formula i above or a pharmaceutically acceptable acid addition salt thereof for the preparation of schizophrenia (including both positive and negative symptoms of schizophrenia) and other mental illnesses. . Compositions of diseases in the group, and preparations for improving cognition in conditions where the cognitive process is weakened, that is, Alzheimer's disease; dementia with multiple vascular infarction; AIDS dementia; Hunting Dayton's disease; Parkinson's disease; amyotrophic lateral sclerosis; or diseases in which the brain is damaged by internal or external effects, such as head trauma or stroke; and spastic diseases, such as epilepsy, cramps Or myoclonus. The present invention provides a method for treating free-schizophrenia (including both positive and negative symptoms of schizophrenia) and other psychiatric diseases in living animals (including humans), and improvement thereof. Cognitive methods in conditions of weakened cognitive processes, namely, Alzheimer's disease; multiple vascular infarct dementia; AIDS dementia; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis Diseases; or diseases in which the brain is damaged by internal or external effects, such as head trauma or stroke; and spastic diseases, such as epilepsy, cramps, or myoclonus' The method includes administering a therapeutically effective amount of the above formula Compound I or a pharmaceutically acceptable acid addition salt thereof. [Embodiment] Detailed description of the invention The preferred embodiment of the invention is that Y is N; the preferred embodiment of the invention is that X is S; the preferred embodiment of the invention is that Q is C; 200410938 of the invention A preferred embodiment is where A is OH; a preferred embodiment of the invention is where p is 1 or 2; a preferred embodiment of the invention is where m is 1; a preferred embodiment of the invention is where q is 0 ; The preferred embodiment of the present invention is wherein r is 0 or 1; the preferred embodiment of the present invention is wherein s is 1 or 2; the preferred embodiment of the present invention is wherein AR is phenyl, thiophene, pyridyl, Pyrimidinyl, thiazolyl, imidazolyl or benzozolyl; the preferred specific examples described above are where R4 is CH3; the preferred specific examples of the present invention are where AR is phenyl; r and q are both 0; p is 1 or 2; s is 1 or 2; r is 0 or l; m is 15R1 is CH3; eight is 011; Q is C; Y is N; and X is S; a better specific example above is each of R3 Is independently selected from halogen, CN6-a-oxyl or Cw-a-based; the more specific example above is where each R3 is independently selected freely

Among the group consisting of Cl, F, OCH3, tertiary-butyl, 2-propyl, or methyl group, a particularly preferred embodiment of the present invention is that the compound of the present invention is one of the following: (+ / -)-{4- [2- (4-methoxy-phenylthio) -phenyl] -trans-2,5-dimethyl-morphazin-1-ylacetic acid; (+ / _) _ {4- [2- (4_chloro_phenylthio) -phenyl] -trans-2,5_dimethyl-piperazin-1-ylbuacetic acid; (+ / _) · {4- [2- (4-Third-butyl-phenylthio) · phenyl] -trans-2,5-dimethyl 12 «Τ * from V'200410938-Methazine-l-yl} -acetic acid; (+/-)-{4- [2- (4-fluoro-phenylthio) -phenyl] -trans-2,5_dimethyl-pyrazine-1_yl} -acetic acid; (+ / -)-{4- [2- (4-% di-butyl-phenylsulfanyl) -phenyl] -2-methyl-naphthyl-1-yl} -acetic acid; (+/-)-{4 -[2_ (4-isopropyl-phenylthio) -phenyl] -2_methyl-pentamidine-1 -some} -acetic acid; (+/-)-2- {4- [2- (4 -Third-butyl-phenylthio) -phenyl] -trans-2,5-dimethyl-morphazin-1-ylpropanoic acid; {4- [5-chloro-2- (4 -Methoxy-phenylthio) -phenyl] -2 (7?)-Methyl-P-sodium-1-yl} -acetic acid; {4- [2- (4-methoxy-phenylthio) ) -Phenyl] -2 (i?), 5 (Phenyl-dimethyl-nazine · 1-kibacetic acid {4- [5-Chloro-2_ (4-methoxy-benzyl) -phenyl] -2,2 -_ * methyl-nano-1_yl-acetic acid; (+ / _) _ { 4- [5-Chloro_2- (4 · trifluoromethyl-phenylthio) · phenyl] -2-methyl-pyrazine-1-ylacetic acid; H- [5-chloro-2- ( 3-methoxy-phenylthio) -phenyl] -2 (7?) · Methyl-tonazin-1-ylacetic acid; (+/-)-{4- [2- (4-phenyl -Phenoxy) _phenyl] -2-methyl-morphazin-1-yl} -acetic acid; (+ / _) _ {4- [2- (4-methyl-phenylthio) -phenyl ] -Trans-2,5-dimethyl-pyrazine-l-yl} -acetic acid; (+/-)-{4- [2- (4-isopropyl-phenylthio) -phenyl] -Trans-2,5-dimethyl- 200410938 mouth oxen-1-ylacetic acid; (+/-)-{4- [2- (2,4-monomethyl-phenylthio) -benzene [] -Trans-2,5-dimethyl-nazine-l-yl} -acetic acid; tert-butyl-phenylthio) _phenyl] _3_methyl-nazine-l-yl} -Propionic acid; {4- [2_ (4_isopropyl-phenylthio) -phenyl] -P sinazine-1-ylacetic acid; (+ / _) · 2_ {4_ [2- (4- Methoxy-phenylthio) phenyl] · 3-methyl · nazine · 1-propionate; or a pharmaceutically acceptable acid addition salt thereof. Definition of substituents = halogen means fluorine, chlorine, bromine or iodine. The noun-alk (en / alkynyl) refers to CV6-alkyl, c2-6-alkenyl, or c2_6-alkynyl. The term C3_8-cycloalkyl (alkenyl) refers to c3_8-cycloalkyl or cycloalkenyl. The term CV6-alkyl refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms inclusive, and includes, but is not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1 -Butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl. Similarly, C2_6-alkenyl and C2_6-alkynyl respectively represent these groups having 2 to 6 carbon atoms, including a double bond and a triple bond, respectively, which include, but are not limited to, vinyl, propenyl , Butenyl, ethynyl, propynyl, and butynyl. The term C3_8-cycloalkyl refers to a monocyclic or bicyclic 200410938 ring carbocyclic ring having 3 to 8 carbon atoms, which includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The term C3.8-cycloalkenyl refers to a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms and including a double bond. In the term C3.8-cycloalk (en) yl-CV6-alk (en / alkynyl), C3-8-cycloalk (en) yl and CV6-alk (en / alkynyl) are as defined above. Nomenclature cv6-alkane (alkene / alkyne) oxy, CV6-alkane (alkene / alkyne) thio, hydroxy-Cw-alk (alkene / alkyne) yl, halogen-Cw-alk (alkene / alkynyl) yl, halogen-c ^ -Alk (en / alkynyl) oxy, Cw-alk (en / alkynyl) sulfonyl, and the like refer to the group in which Cw-alk (en / alkynyl) group is as defined above. As used herein, the term Cm-alk (ene / alkynyl) oxycarbonyl refers to a group of the formula Cw alk (alkyn / alkynyl) _o-co-, where the cv6-alk (alkene / alkynyl) group is as described above definition. As used herein, the term fluorenyl is cynyl, C1-6_alk (en / alkynyl) carbonyl, arylcarbonyl, aryl-Cw-alk (en / alkynyl) carbonyl, c3.8-cycloalkane ( Alkenyl) carbonyl or C3-8-cycloalk (en) yl-(: ^-alk (en / alkynyl) yl-carbonyl. The term used herein "3_ to 7_ members containing another heteroatom as needed "Ring" refers to a ring system, for example, 1-morpholinyl, menidinyl, azepine, 1-pyrazinyl, 1-homosazinyl, 1-imidazolyl, pyrrolyl, or pyrazolyl, all of which Both can be further substituted by alkyl groups. The term heteroaryl can represent a 5-membered monocyclic ring, for example, thiazole, 1,3,2-[% thiazole, 1,3,2_diazole, 3 //- 1,2,3_di_wow, 1,3,2-dithiamidine, 1,2,3-1% monoamidine, 1,2,3-dione dimile, triazole, different employment 200410938 azole, employment Azole, isothiazole, thiazole, 1 //-imidazole, 1 //-pyrazole, 1 //-pyrrole, furan or thiophene, and 6-membered monocyclic ring, for example, I, 2, 3, 3-thiazine, 1 , 2, renthiazine, 1,2,5-hydrazine, 1,4,2-hydrazine, 1,4,3-azathiazine, 1,2,3-diazine, 1, 2,4_diblazine, 4 // _ 1,3,2_dibenzine, 1,4,2- Hydrazine, 2i / -1, 5,2-dioxazine, 1,2,3_ dithiazine, 1,2,4_ dithiazine, 4 oxazine 1,3,2_dithiazine, 1, 4, 2-di warmazine, 2 ug-1,5,2 · dithiazine, 2 bawel 1,2,3-fluorenediazine, 2 pay -1,2,4 · didiazine, 2 ug-1, 2 , 5-pyridine diazine, 2i / -l, 2,6-pyridine diazine, 2 dan-1,3,4-pyridine diazine, 2 / 1,1,2,3 · thiadiazine, 2 dan- 1,2,4-thiadiazine, 2 / fl, 2,5-thiadiazine, 2/1 / _1,2,6_thiadiazine, 2 Dan_1,3,4 · thiadiazine, 1, 2,3-triazine, 1,2,4-triazine, 2 / ί_1,2-pyrazine, 2i / _l, 3 · moxazine, 2 // _ 1, 4_moxazine, 2 Kai-1, 2 _Thiazine, 2ί_1,3-thiazine, 2i / -1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4K-1,3_empirine, 1,4-pyrazine, 4 // _ 1,3-Dioxine, 1,4_Dioxin, 4i / -l, 3-dithia, 1,4 · dithia, pyridine, 2 / ί-pyran or 2 //-thien The term aryl refers to carbocyclic, aromatic systems such as phenyl and naphthyl. The acid addition salt of the present invention, preferably a pharmaceutically acceptable salt formed by the compound of the present invention and a non-toxic acid Examples of such organic salts are with maleic acid, fumaric acid, benzoic acid , Ascorbic acid, succinic acid, oxalic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid , Citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and 8-halogen theophylline, For example, 8-bromotheophylline forms salts. Examples of such inorganic salts are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid 200410938 acid, phosphoric acid, and nitric acid. In addition, the compounds of the present invention may exist in unsolvated forms and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, and the like). In general, for the purposes of the present invention, solvated forms are considered equivalent to unsolvated forms. Part of the compounds of the present invention include the palmar center, and such compounds exist as isomers (i.e., enantiomers or diastereomers). The invention includes all such isomers and mixtures thereof, including racemic mixtures. Racemic forms can be resolved into optical enantiomers by known methods, for example, by separating their diastereomeric salts with an optically active acid, and by releasing the optical activity by treatment with a base Amine compound. Other methods for resolving racemates into optical enantiomers are based on chromatographic analysis on optically active substrates. Racemic compounds of the present invention can also be resolved into their optical enantiomers, for example, by the layered crystallization of d- and 1- (tartaric acid, mandelic acid or camphorsulfonic acid) salts. The compounds of the present invention can also be resolved by forming diastereomeric derivatives. Other methods for resolving optical isomers known to those skilled in the art can also be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates and Resolution" John Wiley & Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials. Pharmaceutical composition: r · jealous · 17 ί 200410938 The pharmaceutical formulation of the present invention can be prepared by a method known in the art. For example, lozenges can be prepared by mixing the active ingredient with common adjuvants and / or diluents, and then compressing the mixture in a conventional tableting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum, and the like. Any other adjuvants or additives commonly used for this purpose can also be used, for example, colorants, fragrances, preservatives, etc., provided that they are compatible with the active ingredient. Injectable solutions can be prepared by dissolving the active ingredient and possible additives in a portion of the injectable solvent, preferably sterile water; adjusting the solution to the desired volume; sterilizing the solution; and filling it into a suitable ampoule Or vials. Suitable additives conventionally used in this technique can be added, such as isotonic agents, preservatives, antioxidants, and the like. The pharmaceutical composition of the present invention or the pharmaceutical composition manufactured according to the present invention can be administered by any suitable route, such as oral administration in the form of tablets, capsules, powders, syrups, etc., or injectable solutions. Form rather than gastrointestinal administration. For preparing such a composition, methods known to those skilled in the art can be used, and any pharmaceutically acceptable carrier, diluent, excipient, or other additives normally used in this technology can be used. Conveniently, the compounds of the present invention may be administered in unit dosage forms, which contain an amount of such compounds from about 0.01 to 100 mg. The total daily dose suspension is in the range of about 0.05-500 mg ', most preferably about 0.1 to 50 strokes; grams of the active compound of the present invention. The compounds of the present invention are prepared by the following general method: alkylation of an amine of formula 200410938 Π with an alkylating agent of formula III:

L is a suitable ion group, for example, halogen or tosylate. The substituents AR, ri_R4 s are as defined above. The reaction is usually carried out at a high temperature of 40-120 ° C in a suitable solvent, for example, ethanol, N, N-dimethylformamide or acetonitrile, which contains an inorganic base (for example, potassium carbonate or carbonate) Or an organic base (for example, N-ethyldiisopropylamine). Compounds of formula I (where Q is carbon and A is OR6, where R6 is hydrogen) can be obtained from the corresponding ester COOR6 (where R6 is an insoluble polymer or CV6-alkyl, aryl, or aryl-CV6-alkyl)中 制备。 Preparation. For polymers where R6 is tert-butyl or insoluble, the conversion can be performed under basic conditions (for example, using an aqueous solution of sodium hydroxide in an alcohol solvent) or under acidic conditions. Compounds of formula II can be prepared by any of the following reactions: (a) with formula IV: 19 200410938 HNMirQR2) q

IV where R1, R2, m, p, q, X, Y, and Z are as defined above, chemically convert the compound into the corresponding diazo compound, and then react with the compound hx-ar- (R3) s, where AR1, X, R3 and s are as defined above. (b) Chemical synthesis as described in Reaction Scheme I:

HX-AR- (R3) s-

(π)

Reaction Scheme I wherein AR, R1, R2, R3, s, m, p, q and X are as described above, and the circle S represents a solid support. 20 200410938 (c) Chemical synthesis as described in Reaction Scheme II, where X is 0 and Y is N:

im Η,

* ^

Reaction Scheme II (d)

, (R3) S

x G

V (R2) c where R2, R3, X, s, and q are as described above, and G is a bromine or iodine atom; chemical conversion with a compound of formula IV: 21 200410938

(R1) P

VI where R1, m and p are as defined above. (e) Dehydrating the compound of formula VII, and simultaneously deprotecting if necessary

Wherein R1, R2, R3, X, m, p, q and s are as described above, and R is a hydrogen atom or a BOC group. (f) hydrogenating the double bond in the compound of formula VIII:

VIII wherein R1, R2, R3, X, m, p, q and s are as described above. (g) Deoxygenation and deprotection of compounds of formula VII: 22 200410938

R is a hydrogen atom or a BOC group. P, q, and S are as described above, and

Diazotization after reaction with HS-Ar- (R3) s according to method (a) is by adding the corresponding diazonium salt of aniline to the sodium salt of thiophenol in water containing copper suspension Solution. The starting material of formula IV is prepared by the method described below. The fluoronitrobenzene derivative is reacted with a morphazine derivative in a solvent such as dmf, nmf or other dipolar aprotic solvent (which contains an organic base such as triethylamine) to obtain o-nitrophenyl Azine derivatives. The nitro group is then reduced using methods well known to those skilled in the art to obtain the starting material of formula IV.

For 2,5-dimethylxazine derivatives, N-benzyl_2 (70,5 (p-dimethylxazine) was prepared according to known literature methods (Aicher et al., J.

Chem. 43: 236-249 (2000)). N-benzyl_2 (S), 5 (i?)-Dimethylpiperazine is prepared according to patent application WO 00/71535. The reaction sequence in method (b) is prepared according to the method described in patent application WO 01/49681. Diamines are commercially available or synthesized by methods well known to chemists familiar with the art. Iron complexes such as rhenium 6_1,2-dichlorobenzene-7 / 5-cyclopentadienyl iron (II) hexafluorophosphate and substituted analogs are synthesized according to methods known in the literature (Pearson et al., 23 200410938 J. Org. Chem. 61: 1297-1305 (1996)), or synthesized by methods well known to chemists familiar with the art. The starting material in method (c) is prepared by coupling o-bromophenol with a suitable arylboronic acid or boronic acid ester by well-known literature methods (Evans et al., K.Z. 39: 2947- 2940 (1998)). The resulting diaryl ether bromide is then coupled to a protected morphazine using a palladium catalyst, where the protecting group can be typically, but not exclusively, a third-butoxycarbonyl (BOC) derivative or benzyl Oxycarbonyl (CBZ), then protecting group (PG) is removed by acidic cleavage, for example, using hydrogen chloride in an alcohol solvent to remove BOC groups, or catalyzed hydrogen in the example of removed CBZ Solve to obtain the intermediate product of Formula II, where X is 0 and Y is N. A general method for removing suitable protecting groups is described in the textbook "Protective Groups in Organic Synthesis", T.W. Greene and P.G.M. Wuts, Wiley Interscience (1991) ISBN 0471623016. In method (d), the reaction of the compound of the formula V with the diamine of the formula VI is performed in a manner similar to that described in Nishiyama et al. 7 ^ 1 state 39: 617_620 (1998). The starting material of formula VI is prepared in a manner similar to that described by Schopfer et al., ⑽ 57: 3069-3073 (2001). In method (e), the dehydration reaction and, if necessary, simultaneous deprotection of the compound of formula VII is performed in a manner similar to that described by Palmer et al. J. MW. CAem. 40: 1982-1989 (1997). The starting material of formula VII is prepared from a compound of formula VII (wherein R is a BOC group) by deprotection with hydrochloric acid in methanol. Compounds of formula VII can be as described in Palmer et al. J. 24 200410938

Md. CAem. 40: 1982-1989 (1997). According to method (f), the reduction of double bonds is generally performed by catalytic hydrogenation at a low pressure (< 3 atmospheres) in a Pan < > device, or by using a reducing agent (e.g., two Borane, or a hydroboron derivative produced in situ from NaBH4 in trifluoroacetic acid, is performed in an inert solvent (eg, tetrahydrofuran (THF), dioxane, or diethyl ether). In method (g), the deoxidation of the tertiary alcohol intermediate of formula VII (where R is a BOC group) is reduced by a modified Barton in a manner similar to that of Hansen et al. WAeds 1925-1930 (1999) Proceed in the manner illustrated. Intermediate tertiary alcohols are appropriately substituted from the corresponding; U Mo, phenylthiobenzene or its corresponding ester, by metal-halogen exchange and then add a suitable electrophile of formula IX, similar to Palmer et al. / · Med · C7ieWe 40: 1982-1989 (1997). A suitably substituted 1-bromo-phenylthiobenzene is similar to that described in the literature by reacting a suitably substituted thiophenol with a suitably substituted aryl iodide, according to Schopfer et al. 57: 3069-3073 (2001), Jueren / on I. 4: 2803_2806 (2002) and Kwong et al. Bates Temple Entering People 4 (2002) (in print). The corresponding substituted bromo-phenoxybenzene can be prepared as described by Buck et al. 6 ^ g · 1 · 4: 1623 · 1626 (2002). BOC-based removal is performed by standard methods well known to those skilled in the art.

25 200410938 Example General method

The analyzed LC-MS data was obtained on a PE Sciex API 150EX instrument equipped with an IonSpray source and a Shimadzu LC-8A / SLC-10A LC system. Column: Water x symmetry C18 column with a particle size of 3.5 μm, 30 x 4.6 mm; solvent system: A = water / trifluoroacetic acid (100: 0.05), and B = water / acetonitrile / trifluoroacetic acid ( 5: 95: 0.03); method: a linear gradient of 4% at a flow rate of 90% A to 100% B at a flow rate of 2 ml / min. Purity is measured by integration of ultraviolet light (254 nm) and tracking by an evaporative light scattering detector (ELSD). The dead time (RT) is expressed in minutes. Preparative LC-MS purification was performed on the same instrument. Column: 50 x 20 mm YMC ODS-A with 5 micron particle size; Method: Linear gradient elution with a flow rate of 80% A to 100% B at 22.7 ml / min in 7 minutes. Fraction collection was performed by separate flow MS detection. Beta NMR spectra were recorded on a Bruker Avance DRX500 instrument at 500.13 megahertz (MHz) or on a Bruker AC 250 instrument at 250.13 megahertz. Deuterated dichloromethane (99.8% D), chloroform (99.8% D), or dimethylimine (99.8% D) were used as solvents. Use TMS as an internal reference. The chemical drift number is expressed in ppm. The following abbreviations are used for the diversity of NMR signals: s = single absorption peak, d = double absorption peak, t = triple absorption peak, q = quaternary absorption peak, qui = quinta absorption peak, h = seven absorption peak , Dd = double double absorption peak, dt 200410938 = double triple absorption peak, dq = double quartet absorption peak, tt = three triple absorption peaks, multiple absorption peaks, and b = broad single absorption peak. For ion exchange chromatography analysis, the following materials were used: SCX-column (1 g), purchased from Varian Mega Bond Elut®, Chrompack catalog number 220776. Prior to use, the SCX-column was preconditioned with a 10% acetic acid solution in methanol (3 mL). For recombination by irradiation, a Philipps UV light source (300 watts) was used. Wang-resin (1.03 mmol / g, Rapp-Polymere, Tuebingen, Germany) was used as the starting polymerization support for solid-phase synthesis. Preparation of intermediate product of formula IV: 2- (3-methyltonazin-1-yl) aniline: 2-fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in triethylamine (10 g, 100 Millimoles) in DMF (100 ml) and placed under a nitrogen atmosphere. 2-Methylazine (5.0 g, 50 mmol) was added to the reaction. The reaction was heated to 80 ° C for 16 hours. The reaction was allowed to cool to room temperature and the solvent was reduced to half the volume in vacuo. Ethyl acetate (200 ml) and ice water (250 ml) were added to the solution, and the product was extracted with diethyl ether (2 X 200 ml). The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2 X 200 mL). The organic phases were combined, washed with a saturated saline solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The product (10-5 g) was dissolved in ethanol (250 ml). A palladium catalyst (10% (w / w), 2.2 g) on carbon was added to the solution, and the solution was hydrogenated in a Parr apparatus at a pressure of 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Yield: 8.0 g, 83% 27 jr. 200410938 The following intermediates were prepared in a similar manner: 2- (3,5-dimethylmorphazin-1-yl) aniline; 2- (3,3- Dimethylmorphazin-1-yl) aniline; 4-methoxy-2- (3-methylmorphazin-1-yl) aniline. 2- (2⑺, 5 (io-dimethylnazine-1-yl) aniline: 2 (io, 5⑺-dimethyl · 1-_N, kislimazine (6.0 g, 29 mmol)) was dissolved in Dimethylformamide (100 ml) and triethylamine (6.4 ml, 44 mmol), and the mixture was placed under a nitrogen atmosphere. 2-fluoronitrobenzene (3.5 ml, 31 mmol) ) Was added to the solution. The reaction was heated at 100 ° C for 72 hours. The solution was evaporated in vacuo and redissolved in ethyl acetate (100 ml). The solution was then saturated with sodium bicarbonate solution ( 100 ml) and saturated saline solution (100 ml). The separated organic phase was dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The crude product was then purified by rapid chromatography, Extract with ethyl acetate / methanol / triethylamine (85: 10: 5). The product (8_2 g) was dissolved in ethanol (250 ml). The palladium catalyst on carbon (10% (w / w), 2.2 g) was added to the solution, and the solution was hydrogenated in a Parr apparatus at a pressure of 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Yield 5.2 g of '87 .7% The following intermediates were prepared in a similar manner: 2- (2 (i?), 50S) -dimethylpiperazin-1-yl) aniline. 28 200410938 4- Chloro-2- (3,3-monomethylpyridin-1-yl) aniline: 2,2 · dimethyldimethylazine (9.55 g, 84 mmol) was dissolved in dimethylformamide (140 ml). Triethylamine (12.07 ml, 83.6 mmol ... ear) was added to the solution, and the reaction was placed under a nitrogen atmosphere. The solution was heated to 80 ° C and treated with dimethylformamide. As a solution in amidine (35 ml), 4-chloro-2-fluoronitrobenzene (13.5 g, 76 mmol) was added. The reaction was stirred at 40 ° C for 16 hours. The solvent was removed in vacuo, and The residue was dissolved in ethanol (250 ml). Ammonium chloride (28 g) and zinc powder (π g) were added. The reaction was boiled at reflux at 80 ° C for 1 hour, and then stirred at 40 ° C for 72 hours. The reaction was then filtered, and the filtrate was evaporated in vacuo. The solid was then rinsed with ethyl acetate and then with a small amount of methanol. Yield: 16_04 g, 88%. The following intermediates were prepared in a similar manner. Preparation: '4-Chloro-2- (3- (io-methylmorphazin-1-yl) aniline; 4-Chloro-2- (3_ (phenyl-methylmorphazin-1-yl) aniline. Borrow An intermediate product of formula II is prepared by method (a): 1- [2- (4-chloro · phenylthio) phenyl] -3-methylpentamidine · ⑩ 2- (3-methylpyrazine-1 -Yl) aniline (0.96 g, 5 mmol) was dissolved in water (30 mL) containing concentrated sulfuric acid (0.28 ml, 5_2 mmol), the solution was cooled to 0 ° C and sodium nitrite (0.36 G, 5.2 millimoles). The reaction was stirred for 30 minutes, and then the pH of the reaction was adjusted to pH 7 with sodium acetate. The diazonium salt solution was then added dropwise to a solution of cardochlorothiophenol in 2M sodium hydroxide (4 ml) containing a copper suspension (0β3 g, 5 mmol). After the addition, the mixture was heated to 60 ° C for 30 minutes, 29 200410938 and then allowed to cool to room temperature, and ethyl acetate (10 ml) was added. The mixture was filtered, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 X 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered off in a plant and evaporated in vacuo. The crude product was purified by rapid ... chromatographic analysis using silica gel, and extracted with ethyl acetate / methanol / aqueous ammonia (96: 3: 1). The alcohol product was separated into a colorless oil. Yield: 0.18 g, 11%. W NMR (CDC13, 500 MHz): 1.12 (d, 3H); 2.6-2.72 (bi *, m, 2H); 3.0-3.15 (m, 5H); 6_9 (m, 2H); 7.08 (d, 1H) 7.15 (m, 1H); 7.25-7.35 (m, 4H); MS (MH +) 319.1. The following compounds were prepared in a similar manner: 1- [2_ (4_Ga_phenylthio) phenyl] _3,5_dimethylpyridine; (+/- M_ [2- (4-methoxy Phenylphenylthio) phenyl] -trans-2,5-dimethylnazine; (+/- M- [2- (4-chloro-phenylthio) phenyl] -trans-2,5 -Dimethylxazine; tert-butyl-phenylthio) phenyl] -trans · 2,5-dimethylpiperazine; (+ / + '〇 (4-fluoro_phenylthio) benzene Group] _trans_2,5_dimethylmethylazine; (+ / _ M- [2_ (4_third-butyl-phenylthio) phenyl] _2_methylpyrazine; (/) _4_ [2- (4-Isopropyl_phenylthio) phenyl] _2_methylnesamidine; 4- [5_chloro_2- (4-methoxy-phenylthio) phenyl] -2 ( i?) _ methylpiperazine; 4- [2_ (4-methoxy-phenylthio) phenyl] -2 (7?), 5 (phenyl-dimethylpiperazine. b) Preparation of intermediate product II (where A represents an insoluble polymer): 200410938 Preparation of iron complex: 7? 1,2-dichlorobenzene π 5-cyclopentadienyl iron (II) hexafluorophosphate: Ferrocene (167 g), anhydrous aluminum trichloride (238 g), and powdered aluminum (24 g) were suspended in 1,2-dichlorobenzene (500 ml) and heated to 90 ° under a nitrogen atmosphere C total 5 hours while intensifying stirring. The mixture was cooled to room temperature, and water (1000 ml) was carefully added in portions while cooling on an ice bath. Diethyl ether (500 ml) was added, and the mixture was left at room temperature. The mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether (3 X 300 ml). The aqueous phase was filtered, and under stirring, an aqueous solution of ammonium hexafluorophosphate (60 g in 50 ml of water) was added in portions. Precipitate at room temperature. After 3 hours, the precipitate was filtered off, rinsed with water, and dried in vacuo (50 ° C) to give 81 g (21%) of the title compound as a pale yellow powder. 1H NMR (D6-DMSO, 500 MHz): 5.29 (s, 5H); 6.48 (m, 2H); 7.07 (m, 2H). Preparation of polystyrene-bound amines: 4 _ [(Pyrazin-1-yl ) Carbonyloxymethyl] phenoxymethyl polystyrene: 4-[(4-nitrophenoxy) curoxymethyl] phenoxymethyl polystyrene (267 g, 235 mmol Mol) suspended in anhydrous N, N-dimethylformamidine (2 liters). Add N.methylmorpholine (23.80 g, 2.35 mmol) and morphazine (102.0 g '1.17 mmol), and the mixture was stirred at room temperature for 16 hours. The resin was filtered off and filtered with N, N-dimethylformamide (2 X 1 liter), tetrahydrofuran (2x1 liter), water (ιχ 500 ml), methanol (2x1 liter), tetrahydrofuran (2χ liter), and methanol (以及 χ 1 liter). Finally, the resin was washed with dichloromethane (3 x 500 ml) 200410938 and dried under vacuum (25 ° C, 36 hours) to obtain almost colorless resin (240.0 g). The following polystyrene-bound diamines were similarly prepared: Γ 4-[(2,5-dimethyl-nazine-1-yl) carbonyloxymethyl] phenoxymethyl polyphenyl ... ethylene; 4-[(3-methyl-morphazin-1-yl) carbonyloxymethyl] phenoxymethyl polystyrene. Preparation of resin-bound 77, aryl-7? 5-cyclopentadienyl iron (II) hexafluorophosphate: 4-({4- [77 6- (2-chlorophenyl) -7? 5- Cyclopentadienyl iron (II)] donazin-1-yl} carbonyloxymethyl) phenoxymethyl polystyrene hexafluorophosphate: 4-[(Nerazine-1-yl) carbonyloxy Methyl] phenoxymethyl polystyrene (115.1 g, 92 mmol) was suspended in anhydrous tetrahydrofuran (1.6 liters), and 7? 6 · 1,2 · dichlorobenzene-π 5_cyclopentadiene was added Iron (II) hexafluorophosphate (76-0 g, 184 mmol) followed by potassium carbonate (50.9 g, 368 mmol). The reaction mixture was stirred at 60 ° C for 16 hours. After cooling to room temperature, the resin was filtered off, and tetrahydrofuran (2 X 5000 ml), water (2 X 250 ml), tetrahydrofuran (2 x 500 ml), water (2 x 250 ml), methanol (2 x 250 ml), dichloromethane (2 x 250 ml), and methanol (2 x 250 ml). Finally, the resin was rinsed with dichloromethane (3 × 500 ml) and dried in vacuum (25 ° C, 36 hours) to obtain a dark orange resin (142 g). The following polystyrene-bonded iron composites were also prepared similarly: 4 _ ({4-U 6- (2-chlorophenyl) _τ / 5-cyclopentadienyl iron (11)]-2,5_dimethyl 32, ·. Λ ~ 200410938 azine-i-yl} carbonyloxymethyl) phenoxymethyl polystyrene hexafluorophosphate; 4-({4-U 6- (2-chlorophenyl 5 _Cyclopentadienyl iron (π)] _ 3-methylnazine "_yl} carbonyloxymethyl) phenoxymethyl polystyrene hexafluorophosphate. O- (Sulcanyl) phenyl Preparation of osmium: (+ /)-1 · [2_ (4-methylphenylthio) phenyl] trans_2,5 · dimethyltonazine: Sodium hydride (7.4 mmol, 60 % In mineral oil) carefully add 4-methylthiophenol (1 · 4 g, 9.8 mmol) to a 1: 1 mixture of tetrahydrofuran / dimethylformamide at room temperature (5 ml) Solution (caution: generation of hydrogen). After the generation of hydrogen is terminated, the mixture is stirred for another 30 minutes. Then 4-({4- [6- (2-chlorophenyl) -7? 5-cyclopentane Dienyl iron (II)]-trans ^ methylneshen-1-yl} methoxymethyl) phenoxymethyl polystyrene hexafluorophosphate (3.5 g, 2-45 millimoles), and Mix the mixture at 55 C was stirred for 6 hours. After cooling to room temperature, the resin was filtered off, and tetrahydrofuran (2 X 50 ml), tetrahydrofuran / water (1: 1) (2 X 50 ml), N, N-dimethylformamidine Rinse with amine (2x50ml), water (2x50ml), methanol (3x50ml), tetrahydrofuran (3x50ml), and then rinse with methanol and tetrahydrofuran (50ml each, 5 cycles). Finally, the resin was washed with two Methyl chloride (3 X 50 ml) was rinsed and dried under vacuum (25 ° C, 12 hours) to obtain a dark orange resin. The obtained resin and 1,10-phenanthroline in pyridine / water The 0.5M solution of the 3: 1 mixture (20 ml) was placed in a light-transmissive reaction tube. The suspension was agitated by rotation under visible light for 12 hours. The resin was filtered, and methanol was used. (2x25 ml), water (2x25 ml), and tetrahydrofuran (3 x 25 ml), rinse until the lotion becomes colorless (approximately 5 200410938

Cycles), and repeat the irradiation procedure until decomplexation is complete (about 5 cycles). After decomplexation was completed, the resin was rinsed with dichloromethane (3 X 25 ml) and dried in vacuum (25 ° C, Γ 12 hours) to give a light brown resin. 3.7 g (24 mmol) of the obtained resin was suspended in a 1: 1 mixture of trifluoroacetic acid and dichloromethane (2 ml) and stirred at room temperature for 2.5 hours. The resin was filtered off and washed with dichloromethane (5 X 0.5 ml). After the filtrate was evaporated from the volatile solvent in vacuo, an orange oil was obtained. The crude product was purified by preparative LC-MS and then purified by ion exchange chromatography. LC / MS (m / z): 312.2 (MH +); RT- 2.14; purity (UV, ELSD): 87.1%, 98.7%; yield: 47.8 milligrams (6%). The aryl morphazine below is also similar Preparation: '(+/-)-1- [2- (4-isopropylphenylthio) phenyl] -trans-2,5-dimethylpiperazine; (+ /) 1-[2- (2,4 · monomethylphenylsulfanyl) phenyl] -trans_2,5-dimethyl mouth oxazine; '(+/-)-1 _ [2 · (4-third-butyl Phenylthio) phenyl] -trans-2,5-dimethylpiperazine; (+/-) _ 1- [2_ (4 · methoxyphenylthio) phenyl] -methylnephrine; (+/-)-1- [2- (4-Isopropylphenylthio) phenyl] piperazine. Preparation of an intermediate product of formula III (where A is an insoluble polymer): 4- [chloroethenyloxymethyl] phenoxymethyl polystyrene: Wang resin (10 g, 10.3 mmol) Suspended in dichloromethane r · aar? 4 ^ · 34 200410938 (100 ml) and cooled to 0 ° C. Add diisopropylethylamine (9 mL, 52 mmol). Chloroethenyl chloride was added slowly. The reaction mixture was stirred at 0 ° C for 30 minutes. Then warm to room temperature. The reaction mixture y was stirred at room temperature for 16 hours. The resin was filtered off, and N, N-dimethylformamidine (3x100 ml), dichloromethane (2x100 ml), dimethylformamide (3 X 100 ml), and dichloromethane (2 X 100 ml), rinsed and dried under vacuum (25 ° C, 16 hours). The following resins were prepared in a similar manner = 4- [2-chloropropanyloxymethyl] phenoxymethyl polystyrene. Intermediate II was prepared by method (c): 4- (2-bromo-phenoxy) biphenyl: 2-bromophenol (2.08 g, 12 mmol), 4-biphenylboronic acid (4.75 g , 24 mmol), Cu (OAc) 2 (2.20 g, 12 mmol) and a solution of triethylamine (6.1 g, 60 mmol) in dioxane (100 ml), and stirred for 48 hours . The crude mixture was evaporated on silica gel and purified by column chromatography, eluting with ethyl acetate / heptane (1: 9). Yield: 0.73 g (19%). 4 NMR (CDC13, 500 MHz): 7.65 (m, 1 1H); 7.55 (m, 4H); 7.43 (m, 2H); 7.25-7.38 (m, 2H); 7_00_7 · 08 (m, 4H); MS (m / z) 325.1. (+/-)-1_ [2_ (biphenyl_4_yloxy) phenyl] _3_methylmorphazine: 4_ (2_bromo-phenoxy) biphenyl (0_73 g, 2 25 millimoles), racemic 2-methylpiperazine (0.285 grams, 0.285 millimoles), pd2dba3 (0.022 grams' 1 mole%), racemic_binap (〇〇43 grams 3 mol%) and a mixture of NaOBu1 (0.300 g, 3.12 mmol) in anhydrous toluene (15 35 r · ^ r 200410938 ml) and stirred overnight at 90 ° C under argon. After cooling to room temperature, the mixture was purged, evaporated on silica gel, and purified by column chromatography, eluting with ethyl acetate / heptane (1: 2). Yield: 0.264 g (34%). 4 NMR (CDC13, 500 MHz): 7_55 (m, 2H); 7.49 (m, 2H); 7.38 (m? 2H); 7.27 (m, 1H); 7.10 (m, 1H); 6.90-7.00 ( m, 5H); 3.30-3.35 (m5 2H); 2.88 (m, 1H); 2_62_2 · 80 (m, 3H); 2.30-2.40 (m, 1H); 1.60-2.00 (br5 1H); 0.99 (d, 3H); MS (m / z) 345.1 o Preparation of compounds of the invention: Example 1 la (+/-)-{4- [2- (4-methoxy-phenylthio) phenyl] -trans -2,5-Dimethyrazine_1_yl} acetic acid · hydrochloride: 4_ [2_ (4-methoxyphenylthio) phenyl] -trans_2,5_dimethyl Azine (0.5 g, 1.5 mmol) and N-ethyldiisopropylamine (0.315 ml, 1-8 mmol) were dissolved in acetonitrile (10 ml) and placed under a nitrogen atmosphere. Ethyl bromoacetate (0.19 ml, 1.7 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. A small amount of silicone was then added to the mixture and the solvent was evaporated in vacuo. The product absorbed on the silica gel was poured onto a silicon dioxide cylinder, and was washed with dichloromethane / heptane / ethyl acetate (60: 35: 5). The ester was separated from the relevant fractions as a light oil (300 mg, 48%). The ester was then dissolved in ethanol (10 ml) and 2 N sodium hydroxide (5 ml) was added. The reaction was stirred at room temperature for 16 hours. The reaction was evaporated in vacuo and the residue was dissolved in ethyl acetate 200410938 (50 ml). 2N hydrochloric acid (15 ml) was added and the phases were separated. The aqueous phase was re-extracted with ethyl acetate (2 X 50 mL). The combined organic fractions were dried (magnesium sulfate), filtered and evaporated. The residue was dissolved in a small amount of dichloromethane, precipitated by adding heptane, and the solvent was removed in vacuo. Yield: 280 mg, 100%. β NMR (CDC13, 500 MHz): 0.887 (d, 3H); 1.35 (d, 3H); 3.04 (m, 1H); 3.12 (m, 2H); 3_6 (m, 3H) ); 4.11 (d, 1H); 4.31 (d? 1H); 3.81 (s, 3H); 6.55 (d, 1H); 7.02 (d, 2H); 7.13 (dd, 1H); 7.2 (m, 1H) ; 7.42 (d? 2H); LC-MS (m / z) (MH +) 3 87 · 4; RT: 2.22; purity (UV, ELSD): 98%, 97%. Preparation: lb (+ / _) _ {4- [2_ (4-chloro-phenylthio) phenyl] trans-2,5-dimethylfluorazin-1-yl} acetic acid • hydrochloride: 4 NMR (CDC13, 500 MHz): 0 · 80 (d, 3H); 1.28 (d, 3H); 2.92-3.18 (m5 3H); 3.64 (m, 3H); 4.06 (d, 1H); 4.29 ( d, 1H); 6.78 (d, 1H); 7.12 (t, 1H); 7.26 (m, 2H); 7.50 (m, 4H); LC-MS (m / z) (MH +) 391.2; RT = 2.43; purity (UV, ELSD): 99%, 99%; yield: 420 mg. lc (+/-)-{4- [2- (4-Third-butyl-phenylthio) phenyl] • trans_2,5-dimethylpiperazine-l-yl} acetic acid salt Acid salt:! H NMR (CDC13 5 500 MHz): 0.76 (d, 3H); 1.01 (d, 3H); 1.30 (s, 9H); 2.4-2.6 (m, 2H); 2.9-3.0 (m5 200410938 3H); 3.28 (m, 1H); 3.32 (d, 1H); 3_48 (d, 1H); 6.65 (d, 1H); 7.01 (t, 1H); 7_13 (t, 1H); 7.24 ( d, 1H); 7.39 (d, 2H); 7.47 (d, 2H); LC-MS (m / z) (MH +) 412.9; RT = 2.70; purity (UV, ELSD): 95%, 99% Yield: 550 mg.

Id (+/-)-{4- [2- (4-fluoro_phenylthio) phenyl] _trans-2,5-dimethylnazine-1-yl} acetic acid • hydrochloride: lR NMR (CDC13 J 500 MHz): 0.80 (d, 3H); 1.25 (d, 3H); 2.8-3.0 (m5 2H); 3.08 (m, 1H); 3.4-3.6 (m, 3H); 3.87 (d, 1H); 4.06 (d, 1H); 6.64 (d, 1H); 7.07 (m, 1H); 7.20 (m, 1H); 7.26 (m, 1H); 7.32 (

dd, 2H); 7.54 (dd, 2H); LC-MS (m / z) (MH +); RT = 2.24; purity (UV, ELSD): 95%, 99%; yield: 180 mg. le (+/-)-{4- [2 · (4-Third-butyl-phenylthio) phenyl] -2-methylmorphazin-1-yl} acetic acid · hydrochloride: LC-MS (m / z) 399.2 (MH +); RT = 2.54; Purity (UV, ELSD): 100%, 100%; Yield: 10.4 mg.

If (+/-)-{4- [2- (4 · isopropyl-benzylthio) phenyl] methyl? -1-methyl} acetic acid • hydrochloride: LC-MS (m / z) 385.1 (MH +); RT = 2.45; purity (UV, ELSD): 88%, 100%; yield: 11 mg. lg (+/-)-2- {4- [2- (4-Third-butyl-phenylthio) phenyl] -trans-2,5-dimethylmorphazin-l-yl} propyl Acid • Hydrochloride: 200410938 LC-MS (m / z) 427.0 (MH +); RT = 2.76; purity (UV, ELSD): 86%, 98%; yield: 27 mg. lh {4- [5_chloro-2_ (4_methoxy-phenylthio) phenyl] methylpyrazine_i-yl} acetic acid · hydrochloride: W NMR (DMSO, 500 MHz): 1 · 40 (d, 3H), 3.16 (m, 1H), 3.25-3.48 (m, 4H), 3.63 (m, 1H), 3.75 (m, 1H), 3.80 (s, 3H), 4.15 (d, 1H) , 4.30 (d, 1H), 6.55 (d, 1H), 7.02 (d, 2H), 7.13 (dd, 1H), 7.2 (m, 1H), 7.42 (d, 2H). LC-MS (m / z) 407.3 (MH +); RT = 2.79; purity (UV, ELSD): 95%, 100%; yield: 225 mg. U {4 + 2- (4-methoxyphenylthio) phenyl] -2 (and), 5 (exodimethyl) acetic acid • hydrochloride:! H NMR (DMSO-d6 ^ 500 MHz) : 0.85 (d, 3ί > 'α 53 (d, 1.30 (d5 3H), 2.95 (t, 1H), 3.05 (m, 2H)' 夂

(d? 1H 1H), 3.60-3.65 (m, 2H), 3.80 (m, 3H), 3.92, τ: γλ, 7.13), 4.10 (d, 1H), 6.55 (d, 1H), 7.02 ( d, (dd, 1H), 7_2 (m, 1H), 7.42 (d, 2H).

Sister Yu (UV LC-MS (m / z) 387.3 (MH +); RT = 2.22; Sheng ", ELSD): 97%, 96.9%; Yield: 607 mg. Life u Qin-1 -yl lj {4- [5-Chloro-2- (4-methoxy-phenylthio) phenyl] -2,2-dimethylamine%

} Acetic acid • hydrochloride: 1U NMR (DMSO-d6 ^ 500 MHz) 3_20 (s, 2H), 3 · 20 · 3 · 60 (br, m, 4H 1 · 58 (s,, 3.80 (s, 6H) 3H) 39 §49 '200410938 3.92 (d, lH), 4.10 (d, lH), 6.55 (d, lH), 6.90 (dd, 1H), 6.96 (d, 2H), 7.13 (s, lH) , 7.40 (d, 2H). LC-MS (m / z) 421.1 (MH +); RT = 2.41; purity (UV, ELSD): 96%, 98%; yield: 1.18 g. Lk {4- [5-Chloro_2- (4 · trifluoromethylphenylthio) phenyl] · 2-methylnonazinyl) acetic acid · hydrochloride: LC-MS (m / z) 445.1 (ΜΗ +); RT = 2.50; purity (UV, ELSD): 88%, 72%; yield · 20 mg. 11 {4- [5-Chloro-2- (3-methoxy-phenylthio) phenyl] _2 (and) -methylmorphazin-1-yl} Acetic acid • Hydrochloride: lR NMR (DMSO- d6-500 MHz) ·· 1.32 (d, 3H) '3.05 (m, 1H), 3.10-3.40 (m, 4H), 3.50-3.60 (m, 2H), 4.10 (d, 1H), 4.24 ( d, 1H), 6.82 (d, 1H), 6.95 (m, 3H), 7.11 (dd, 1H), 7.2 (s, 1H), 7.38 (dd, 1H) o LC-MS (m / z) 407.2 ( MH +); RT = 2.41; purity (UV, ELSD): 99.6%, 100%; yield: 1.26 g. lm {4_ [2 · (biphenyl-4-yloxy) phenyl] _2-methylnefluoren-1-yl} acetic acid · hydrochloride:! H NMR (DMSO-d6 J 500 MHz): 7.60 ( m, 4H), 7.40 (m, 2H), 7.32 (m, 1H), 6.95-7.20 (m, 6H), 5.00-6.50 (br, 1H), 4.00-4 · 10 (m, 1H), 3.80- 3.90 (m, 1H), 3.20-3.50 (m, 6H), 3.05-3.15 (m, 1H), 1.17 (m, 3H). 40

/ v 广 产 V 200410938

LC-MS (m / z) 403.0 (MH +); RT = 2.45; purity (UV, ELSD): 96.7%, 99.4%; yield: 16 g (43%). Example 2 ^ 2a (+ / _)-{4_〇 (4-methylphenylthio) phenyl] -trans-2,5-dimethylpiperazine_ ·· 1-yl} acetic acid • salt Acid salt: [2- (4-methyl-phenylthio) phenyl; trans-2,5-dimethylpiperazine (10 mg, 0.03 mmol) and diisopropylethyl A solution of succinylamine (0.02 ml, 0.11 mmol) was added to 4- [chloroethoxymethyl] phenoxymethyl polystyrene (100 mg, 0.09 mmol). The reaction mixture was stirred by shaking overnight at 70 ° C. The resin was decanted and washed with N, N-dimethylformamide (4 ml), methanol (4 ml) and dichloromethane (4 ml). The resin was suspended in a 1: 1 mixture of trifluoroacetic acid and dichloromethane (1.5 ml) and shaken at room temperature for 1 hour. The resin was filtered off and washed with dichloromethane (1 ml). The organic extracts were collected and evaporated in vacuo. The crude product was purified by preparative LC-MS.

LC-MS (m / z) 371.1 (MH +); RT = 2.24; purity (UV, ELSD): 100%, 100%; yield: 1.6 mg. The following compounds were prepared in a similar manner: 2b (+/-)-{4- [2- (4-isopropyl-phenylthio) phenyl] -trans-2,5-dimethyl Azine-l-yl} acetic acid · hydrochloride:

LC-MS (m / z) 399.0 (MH +); RT = 2.48; purity (UV, ELSD): 98.3%, 100%; yield: 2.2 mg. 2c (+/-)-{4-[2- (2,4- ^ methyl-phenylthio) phenyl] -trans-2,5 ·-^ methylpyrazine-l-yl} acetic acid • Hydrochloride: 200410938

LC-MS (m / z) 385.0 (MH +); RT = 2.37; purity (UV, ELSD): 99.8%, 100%; yield: 4.7 mg. 2d (+ / ·) -2- {4- [2- (4-Third-butyl-phenylthio) phenyl] -3-methylpyrazine · 1-yl} propionic acid • hydrochloride:

LC-MS (m / z) 386.7 (MH +); RT = 2.14; purity (UV, ELSD): 91.9%, 99.2%; yield: 3.2 mg. 2e (+/-)-{4_ [2- (4_isopropyl-phenylthio) phenyl] -nazine-l-yl} acetic acid • hydrochloride:

LC-MS (m / z) 370.8 (MH +); RT = 2.35; purity (UV, ELSD): 89.0%, 99.9%; yield · 3.2 mg. 2f (+/-) _ 2- {4- [2- (4-methoxy-phenylthio) phenyl] methylerazin-1-yl} propionic acid • hydrochloride:

LC-MS (m / z) 386.7 (MH +); RT = 2.63; purity (UV, ELSD): 91.9%, 99.2%; yield: 3_2 mg. Pharmacological test: The compounds of the present invention are tested in well-recognized and reliable tests that measure glycine uptake. [3H] -Glycine uptake: Human GlyT-lb transfected cells were seeded in 96-well culture plates. Prior to the experiment, the cells were washed twice with HBS (10 mM Hepes-tfis (pH 7.4), 2.5 mM potassium chloride, 1 mM calcium chloride, 2.5 mM magnesium sulfate), and pre-cultured with the test compound 6 minute. Thereafter, 10 nM of 3H-glycine was added to each well, and the culture was continued for 15 minutes. Cells were washed twice with HBS. Add scintillation fluid and place the plate in Trilux (42 200410938

Wallac) counts on a flicker counter.

The test results show that the compounds of the present invention all show inhibition below 2000 nM, such as the half inhibitory concentration (IC5Q) in the analysis described above. Most of the two compounds are between 150 nM and 850 nM. V microdialysis experiments in rodents have shown that administration of the selected compounds of the invention can result in increased glycine concentrations in the brain. In addition, in rodent mental illness models, the compounds of the invention are selected to reverse the symptoms of amphetamine-induced overactivity. 43

Claims (1)

200410938 Scope of patent application 1. A compound represented by the general formula (R4) r Y is N, C or CH; X is 0 or S; m is 1 or 2; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; s is 0, 1, 2 or 3; r is 0, 1 or 2; Q represents C, P-OR5 or S = 0, where R5 represents hydrogen or CV6-alkyl > A is OR6, where R6 represents hydrogen, Cm-alkyl, aryl or aryl -CV6-alkyl, wherein the aryl group may be substituted by halogen, CF3, OCF3, CN, NO2 or CV6-alkyl; AR represents a phenyl group or a square group; each R4 represents a CV6-alkyl group, C3. 8-Cycloalkyl or C3.8-Cycloalkyl group »Dotted lines indicate bonding as needed; 44 05200410938 Each R1 is independently selected from the group consisting of free ci-6_alkyl 'or Two R1 connected to the same carbon atom can form a 3- to 6-membered helical ring base; ^ Each R2 is independently selected from free halogen, cyano, nitro, and G_6-alkane "~ (diluted / block ) Group, Ci. 6- (dilute / block) oxy group, Ck group (fine / fast) thio group, hydroxyl group, hydroxy-cv6-alkane (alkene / alkyne) group, halogen-(^ _ 6-alkane (ene / Alkynyl) group, halogen-CV6-co (synthetic / alkynyl) oxy group, c3_8-cycloco (synthetic group), c3_8-cycloalk (en) ylalkene (ene / alkynyl) group The group consisting of fluorenyl, (^ .6-alk (en / alkynyl) oxycarbonyl, C ^ -alk (en / alkynyl) sulfonyl, or -NR9R1 (), among which R9 and R1 () Independent of each other, it means hydrogen, Cw-alkane (susceptible / quick) group, C3.8-ring courtyard (susceptible) group, C3.8-ring courtyard (susceptible) group-Cw-alkane (ene / alkynyl) group or aromatic group Group, or R9 and R1 () together to form a 3- to 7-membered ring, which may contain another heteroatom as required; each R3, which is substituted on AR, is independently selected from free halogen, cyano, nitrate Group, CV6-alk (en / alkynyl) group, cv6-alk (en / alkyn) oxy group, CV6-alk (en / alkyn) thio group, hydroxyl, hydroxyl- (γ6-alk (en / alkyn) group, halogen -cv6-alk (en / alkynyl), halogen-cv6-alk (en / alkynyl) oxy, c3. ® 8-cycloalk (en) yl, C3_8-cycloalk (en) yl-Cl.6-alkane (Ene / alkyne) yl, CV6-alk (alkene / alkynyl) sulfonyl, aryl, aryl- (ν6-alk (ene / alkyn) oxy, aryl-c ^ -alkane (ene / alkyne) In the group consisting of alkyl, alk (alkene / alkynyl) oxycarbonyl, fluorenyl, -NHCO-Cw alk (alkene / alkynyl), and -CONRnR12, R11 and R12 are independent of each other, and they represent hydrogen, alkane ( / Alkynyl), C3_8-cycloalkane (en.) Yl, C3.8-cycloalk (en) yl-cv6-alk (en / alkynyl) or aryl, or R11 and R12 together with the nitrogen to which they are attached 45 200410938 forms a 3- to 7-membered ring, which may contain another heteroatom as required; or NR13R14, where R " and R "are independent of each other, meaning hydrogen, c 1 _ 6-institutional (alkynyl), C3- 8-ring ring (dilute) group, c3.8-ring ring (alkenyl) alkane (alkene / alkynyl) group or aryl group, or the nitrogen to which R13 and R14 are connected to them to form a 3- to 7-membered ring, It may contain another heteroatom as required; or two adjacent R3 substituents together form a ring fused with AR, which is selected from the following groups: Where W is 0 or S 'and R' and R "are hydrogen or Cm-institution; or two adjacent R3 substituents together form a fused heteroaromatic system comprising one or two fused to AR Or an acid addition salt thereof. 2. A compound according to item 1 of the scope of patent application, wherein Y is N. 3. A compound according to any one of the scope of patent application, wherein X is S. 4. According to A compound according to any one of the aforementioned patent applications, wherein Q is C. 5. A compound according to any one of the aforementioned patent applications, where A is OH. 6 A compound according to any one of the aforementioned patent applications, of which P 46 200410938 7. A compound according to any one of the aforementioned patent applications 'where m is 1. 8. A compound according to any one of the aforementioned patent applications' where q is 〇09. A compound according to one of the clauses, wherein Γ is 0 or 1. 10. A compound according to any one of the aforementioned patent ranges, wherein s is 1 or 2. 11. A compound according to any one of the aforementioned patent ranges, wherein AR is Phenyl, thiophene, Pyridyl, pyrimidinyl, thiazolyl, imidazolyl, or benzothiazolyl. 12. Compounds according to items 1 to Π of the application, wherein AR is phenyl; r and q are both 0; p is 1 or 2; s is 1 or 2; r is 0 or l; m is liR1 is CH3; A is OH; Q is C; Y is N; and X is S 〇 13. Compound according to item 12 of the scope of patent application, wherein each R3 is independently selected from halogen, Cm-alkoxy or Cw-alkyl. 14. The compound according to item 13 of the scope of patent application, wherein R3 is selected freely from C, F, OCH3, tert-butyl, 2- In the group consisting of propyl or methyl. 15. The compound according to any one of the aforementioned patent applications, wherein R4 is CH3. 16. The compound according to the first patent application scope, which is 200410938 (+ / _ ) _ {4- [2- (4-methoxy-phenylthio) -phenyl] -trans-2,5-dimethyl-pyrazine-l-yl} -acetic acid; (+/-) -{4- [2- (4-chloro-phenylthio) -phenyl] -trans-2,5-dimethyl-tetrazine-l-yl} -acetic acid; (+/-) _ {4 -[2- (4-Third-butyl-phenylsulfanyl) -phenyl] -trans-2,5-dimethyl-naphthyl-1_yl} -acetic acid, (+ / _) _ { 4- [2- (4-fluoro-phenylthio) -phenyl] -trans -2,5-dimethyl-erzine-1-ylacetic acid; (+/-)-{4- [2 · (4-third-butyl-phenylthio) -phenyl] _2_form -Methazin-1-yl} -acetic acid; (+/-)-{4- [2- (4-isopropyl-phenylsulfanyl) · phenyl] _2_methyl-naphthyl-1-yl } -Acetic acid; (+/-)-2- {4- [2- (4-second-butyl-phenylthio) -phenyl] -trans-2,5-a. Methyl-piperazine -1-yl} _propionic acid; {4_ [5_chloro_2_ (4-methoxy-phenylthio) -phenyl] methyl-Phinazin-1-yl} -acetic acid; {4- [ 2- (4-methoxy-phenylthio) -phenyl] -2 (phenyl, 5 (phenyl-dimethyl-morphazin-1-yl) -acetic acid; {4- [5-chloro-2- (4-methoxy-phenylthio) -phenyl] -2,2-dimethyl · erzin-1-yl} -acetic acid; (+/-) _ {4- [5-chloro-2 · (4-trifluoromethyl-phenylthio) · phenyl] -2-methyl-pyrazine-l-yl} -acetic acid; {4_ [5-chloro-2- (3-methoxy-phenylthio ) -Phenyl] _2 (and) -methyl-nano-1-1-yl} -acetic acid; 200410938 (+ Phenyl-phenoxy) _phenyl] _2_methyl-tetrazine_ ^ yl} _acetic acid; (+/-)-{4- [2_ (4-methyl_phenylthio)- Phenyl] -trans-2,5-dimethyl-Pyrazine-1-ylb-acetic acid;, (+/-)-{4- [2- (4-isopropyl-phenylthio)- Phenyl] -trans-2,5-dimethyl · pyrazine-1-ylacetic acid; (+/-)-{4- [2- (2,4-monomethyl-phenylthio)- Phenyl] -trans-2,5-dimethyl-erazine-1-ylacetic acid; (+/-)-2- {4- [2- (4-second-butyl-phenylthio) ) -Phenyl] -3 -methyl-naphthyl-1-yl} -propionic acid; H-IX4-isopropyl-phenylthio) · phenyl] -morphazine-l-yl} -acetic acid; ( +/-)-2_ {4- [2- (4-methoxy-phenylsulfanyl) -phenyl] -3 -methyl-ne D D-1--1-yl} _propionic acid; or pharmaceutically acceptable Accepted acid addition salts. 17. A pharmaceutical composition comprising a compound as claimed in claims 1 to 16 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent. 18.-Use of a compound in the scope of claims 1 to 16 or a pharmaceutically acceptable acid addition salt thereof for the preparation for the treatment of free choice schizophrenia (including both positive and negative symptoms of schizophrenia ) And other psychiatric diseases, and preparations for improving cognition in situations where cognitive processes are weakened, that is, Alzheimer's disease; multiple vascular infarct dementia; AIDS Dementia; Huntington's disease; Parkinson's disease; Amyotrophic lateral sclerosis; or 49 200410938 Diseases of the midbrain that are damaged by internal or external effects, such as head trauma or stroke; and cramps Sexual disorders, such as epilepsy, cramps, or myoclonus. 19. A positive and negative symptom (including both positive and negative symptoms of schizophrenia) for the treatment of free choice schizophrenia in living animals, including humans As well as ways to improve cognition in situations where cognitive processes are weakened, Alzheimer's disease; multiple vascular infarct dementia; AIDS dementia; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; or where the brain is damaged by internal or external effects Diseases, such as head trauma or stroke; and spastic diseases, such as epilepsy, cramps, or myoclonus; the method includes administering a therapeutically effective amount of a compound as claimed in claims 1 to 16 or a pharmaceutically acceptable compound Accepted acid addition salts. One, schema-frrr no 200410938 Lu, (a), the designated representative of the case is: No diagram (b), the representative symbols of the components of the representative are simply explained: sister, if there is a chemical formula in this case, please disclose the most Chemical r · a- a- ΟΙΛ (R4) r (R2) q 4