TW200811131A - Piperidine derivatives as CXCR3 receptor antagonists - Google Patents

Abstract

The present invention relates to a compound of formula (I), a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof, wherein X represents N or CH; Y represents a direct bond, CH2-C(=O) wherein the CH2 is attached to the N of the piperidine ring, C(=O) or S(=O)p; p represents an integer of value 1 or 2; R1 represents CH(R4)-aryl or CH(R4)-heteroaryl; R2 represents aryl2 or heteroaryl; R3 represents hydrogen, C1-6alkyl, polyhaloC1-6alkyl, C1-6alkyloxy, aryl1,aryl1-NH-, heteroaryl, heteroaryl-NH-, C3-7cycloalkyl, amino or mono or di(C1-4alkyl)amino. The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for preventing or treating a disease mediated through activation of the CXCR3 receptor; to processes for preparing the compounds of formula (I) and pharmaceutical compositions comprising them.

Description

200811131 IX. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a hexahydropyridine derivative having CXCR3 receptor antagonistic properties. The invention also relates to a process for the preparation thereof and a pharmaceutical composition comprising the same. The invention also relates to the use of the compound for the manufacture of a medicament for the prevention or treatment of a disease mediated by activation of the CXCR3 receptor. [Prior Art] U.S. Patent No. 3,125,578 discloses a 2,6-diketo-hexahydropyridine derivative having anticholinergic activity. WO 95/11234 is a N-derivative of dexetimi (je) for pET studies and SPECT studies suitable for use in sputum test receptors. [Inventive content] Compounds of the invention differ from prior art compounds Structure, pharmacological activity and/or pharmacological efficacy. One aspect of the invention relates to a compound of the formula

An N-oxide, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, or a solvate thereof, wherein X represents N or CH; Y represents a direct bond, CHrC (==〇) wherein Ch2 is attached to N, C (=0) or S (= 〇) p; 6 200811131 P represents an integer of 1 or 2; R represents CH (r4 > aryl or CH (R4)-heteroaryl; R represents an aryl 2 or a heteroaryl group; ί represents an aryl fluorenyl group, a tender Cl 6 wire, an alkoxy group, an aromatic group, a aryl group, a heteroaryl group, a heteroarylamino group or a mono or a di aryl group. Amino group; c3.7 city base, R4 represents hydrogen or cM alkyl; m each independently replaces money, or treats bribes and replaces it with m6 and its connection Wei-axis is selected from field (four) base, six a single ring heterocyclic ring of nitrogen == thiofolf group, each ring R7 represents hydrogen or cK4 alkyl; aryl represents unchained m or each phenyl or naphthyl group substituted by at least one substituent, In particular, each of the substituents of "-, two or three substituents" is independently selected from the group consisting of ruthenium, silk, Ci6 alkyl, 匸1-6 alkoxy, CK6 alkoxy, qj benzyloxy, Ck sulphur Base, polyhalogen group c · 6 alkyl, polyhalo Ci 6 alkoxy, cyano, nitro, Base, HO-S〇2-, Ci-4 alkyl-S02-, R6R5N-C(=〇)·, amine group, mono- or di(Ci 4 alkyl)-amine group, Cm alkylcarbonylamino group, Aryl!, aryl iCm alkoxy, aryl, oxy or aryl 1 C(=0)-; aryl represents phenyl or phenyl substituted with 1, 2 or 3 substituents, each substituent Independently selected from the group consisting of i, hydroxy, c] 6 alkyl, Ci 6 alkoxy 7 200811131, Cy alkoxy, Cw alkyloxy, decylthio, polyhalo Cm alkyl, Polyhalo CK6 alkoxy, cyano, nitro, carboxy, aminocarbonyl, mono- or bis((γ4 alkyl)aminocarbonyl, amine, mono- or di(CN4 alkyl)amine; The base 2 represents a phenyl group or a naphthyl group, each of which is optionally substituted with at least one substituent, especially one, two or three substituents, each substituent being independently selected from the group consisting of a _ group, a hydroxyl group, a c -6 alkyl group, a Cl_6 group. Alkoxy, Ci6 alkoxycarbonyl, alkylcarbonyloxy, Cl 6 alkylthio, polyhaloalkyl, polyhalo Cw alkoxy, cyano, nitro, carboxyl, H0-S02, Cm alkyl -S02-, R6r5N-C(=0)-, amine, mono- or di(Cw alkyl)amine, cM alkylcarbonylamino, aryl 1, aromatic a radical iQ-4 alkoxy, aryloxy or aryl ic)); a monocyclic heterocyclic ring; or a fluorenyl heteroaryl group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolium Base, furanyl, thiol, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, "specific" sityl L-based, hetero-radical, aryl-4, trimethyl, oxazolyl, Pyridyl, fluorenyl, pyrimidinyl, pyridinyl, hexamethylene, hexahydro (tetra), fluorene, #基, thiophene, 吲哚, 吲哚, ϋ Succinyl, benzoxanthyl, iso-U-quinolinyl, linyl, benzyl, naphthyl sigma, fluorenyl, J benzoindole, bicyclic heterocyclic ring Furamyl, benzodiyl, ♦ sitting, stupid to be replaced by at least one substituent, ', 嘌呤 base, 喳咁 基 、, 0 奎 咐, enemy σ well base, 4 ° ° 林 基, π 奎 σ No. 林 啐 啐 oxadiazolyl, benzoxazolyl, each of the monocyclic or bicyclic heterocyclic ring as needed, especially one, two or three take 8 200811131 algebra, each substituent is independently selected from _ Base, hydroxyl group, Cl6 alkyl C!-6 alkoxy group, Q_6 alkoxycarbonyl group, Cl_6 alkylcarbonyloxy, & thiol group, poly"c]-6 alkyl, polyhalo Ci 6 methoxy, hexyl 6, nitro, carboxyl, H0-S02-, CM alkyl _S〇2_, R6R5N-C(=〇)-, an amine group, a mono- or di(Ci 4 alkyl)amino group or a Cm alkylamino group. The invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by the activation of a CXCR3 receptor, in particular for the treatment of a disease mediated by activation of the CXCR3 receptor, more particularly It is used to prevent or treat inflammatory diseases, and more particularly to treat inflammatory diseases. When a leuco group as used above or hereinafter is used as a part of a group or a group, it is a straight-chain or branched-chain saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1 -methylethyl, butyl; when a part of a group or a group is defined as a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, a group defined by a Cm alkyl group and a pentyl group The base group, the hexyl group, the methyl butyl group and the like, the C:}-7 cycloalkyl group are collectively referred to as a cyclopropyl group, a cyclobutyl-pentyl group, a hexyl group and a cycloheptyl group. When used above, (=0) - the word forms a few groups when attached to a carbon atom, the stony group is attached to the sparse atom and the ε wind group when the two terms are attached to the sulfur atom. . The term halo also refers to fluorine, chlorine, bromine and hard. When a polyhalogenated Ck alkyl group as used above or hereinafter is used as a part of a group or a group, it is defined as a mono- or polyhalogen-substituted C]-6 alkyl group, for example, one or more fluorine groups. The atom is a methyl group of 9200811131, such as a monofluoromethyl group or a trifluoromethyl group, an i, i-difluoroethyl group or the like. In the definition of a polyhalogenated Ck alkyl group, if more than one dentate atom is attached to the Ci-6 alkyl group, they may be the same or different. The term heteroaryl, for example in the definition of R1 or R2, is meant to include all possible isomeric forms of the heterocyclic ring, for example pyrrolyl includes sigma and 2-Hal:b. The aryl, aryl, aryl 2 or heteroaryl group of the substituent of the compound of the formula (I) mentioned above or hereinafter (see, for example, R, R and R), if specifically stated, The remaining molecules of formula (I) can be attached via any suitable carbon or heteroatom. Accordingly, for example, when the heteroaryl group is an acridinyl group, it may be, for example, a 3-pyridyl group or a 4-pyridyl group. When any variable occurs more than once in any component, the definitions are independent of each other. When used medically, the salts of the compounds of formula (1) are those in which the counterion is pharmaceutically acceptable. However, it is not found that pharmaceutically acceptable acids or salts have been found, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention. The pharmaceutically acceptable salts mentioned above or below are those which comprise a medically active non-toxic acid addition salt formable by the compound of formula (1). The latter can conveniently be obtained from the test form with a suitable acid, such as a mineral acid such as a hydrohalic acid such as hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or an organic acid such as acetic acid, propionic acid, Hydroxyacetic acid, 2-hydroxypropionic acid, fluorenyl propionic acid, oxalic acid, malonic acid, humic acid, maleic acid, fumaric acid, pigment 200811131, acid, tartaric acid, 2, thiol-like M-magnetic acid, phthalic acid benzoic acid, 4-methyl phenoxycyclohexane, 2 benzoic acid, 4-amino-2-benzoic acid f_. The land reduction and chest-type treatment can be transformed into a form of free grief. The compound of formula (1) of s s-sex shellfish is converted to its medically non-toxic metal or amine addition salt form by treatment with an appropriate organic and inorganic treatment. A pharmaceutically acceptable salt as referred to above or hereinafter means a medically active non-toxic metal or amine addition salt form (acceptable addition salt form) which may also be formed by the compound of formula (I). Suitable addition salt forms include, for example, ammonium salts, metals and soil metal salts such as clocks, sodium, potassium U salts, etc., salts of organic bases such as -, secondary and tertiary aliphatic and aromatic amines, for example Methylamine, hexylamine, propylamine, isopropylamine, four butylamine isomers, diamine, diethylamine monoethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, hexapyridine, Frucene, triterpeneamine, triethylamine, tripropylamine, quinuclidine, pyridine, hydrazine and isoindole, ethylenedibenzylamine, N-methyl-D-glucosamine, 2-aminol-2_( Hydroxymethyl)-1,3-propanediol, a sea-pappaamine salt, and a salt with an amino acid such as arginine, lysine, or the like. Conversely, the salt form can be converted to the free acid form by treatment with an acid. The term salt also includes the quaternary ammonium salt (quaternary amine) which can be formed by the compound of formula (I). The anthraquinone of the compound of formula (I) is substituted with a suitable quaternizing agent such as a Ci_6 alkane which is optionally substituted. The base halide, the aryl halide, the Ci-6 alkylcarbonyl ilide, the arylcarbonyl halide, or the aryl C 6-6 alkyl halide such as methyl moth or benzyl iodide. Other reactants having a good release group can also be used, such as Q-6 alkyl trifluorosulfonate, Cw alkyl sulfonate 200811131 and Q-6 alkyl p-toluenesulfonate. The quaternary amine contains a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride, bromide, iodide, diacetate, acetate, trifluoromethyl sulphate, sulfate, and sulphate. The selected counterion can be added via the use of an ion exchange resin. The term solvate includes hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are, for example, hydrates, alkoxides and the like. The N-oxide of the compound of the present invention is meant to include a compound of the formula (1) wherein one or more tertiary nitrogen atoms are oxidized to a so-called cerium oxide. Part of the compound of formula (I) and its N-oxides, salts, stereochemically isomeric forms and solvates may contain one or more pairs of palms and exist as stereochemically isomeric forms. The term "stereochemical isomer form" as used hereinabove or hereinafter is intended to define all possible stereoisomers that a compound of formula (I) and its N-oxides, salts, solvates or physiologically functional derivatives may have. Form of matter. Unless otherwise mentioned or indicated, the chemical nomenclature of a compound refers to a mixture of all possible stereochemically isomeric forms containing all of the non-parsing isomers and palmar isomers of the basic molecular structure and formula (1) Each isomeric form of the N-oxide, salt or solvate is substantially free, that is to say less than 10%, more preferably less than 5%, in particular less than 2% and most less than 1% Isomer. Accordingly, when the compound of the formula (I) is, for example, R, it means that the δ substance is on the κ, and there is an S isomer. When the compound of the formula (1) is, for example, referred to as RS, this means that the compound is a mixture, particularly a racemate of the ruler and the s isomer. More specifically, the stereocenter may have an R- or S-configuration, and the substituent on the saturated base of the divalent ring 12 200811131 may have a cis-reverse = this = may have a £ or a stereochemistry. The cis, the reverse, the R, the S, and the e^z are well known to those skilled in the art. The isomeric form 3_ is included in the scope of the present invention. According to the CAS_ naming convention, when two stereocenters of absolute configuration are known to be specified in the knife 4' (in accordance with the centroid of (10) η 〇:===, refer to the center. Use phase 4 '] or [, S ] Specify the configuration of the second stereo center, where the water far distance is not the reference center and the 标示 is marked with the same pair of palms = and [r, s*] indicates the center with different palms. If the timid in the molecule is numbered to the center of the palm and the right At is marked as the s-team factory, if: make: r on the postal high material substitute base II I 疋隹 糸,, the plane of the premise “ "α , position. The position of the highest priority substituent on the ring system: relative to the position of the (10) pre-substituent on the reference atom, if it is on the same side of the plane of the ring system, it is called 'V,' if it is The side of the ring system is referred to as "β,, and the other material can be synthesized as a racemic mixture of the palmomerisomers ^ which can be separated from each other according to the dissociation method known from the prior art; The compound can be converted to a non-paired (tetra) compound salt form by reaction with a suitable pair of palmitic acid. The isomeric salt form is released from the cockroach (4) 4 or the gradual end of the day and is released from the palm of the hand by the peak. The other form of the isomerism of the compound of formula (1) is 13 200811131 Liquid chromatography using a palmitic solid phase. The pure stereochemically isomeric form can also be derived from the corresponding stereochemically isomeric form of the alcohol of the appropriate starting material, provided that the reaction is stereospecific. Preferably, if a specific stereoisomer is desired, the compound is synthesized via stereospecific preparation, and these methods are suitably used as a starting material which is pure to the palm of the isomer. Some of the compounds of formula (I) may also be present. The tautomeric form of this form, although not explicitly indicated in the above formula, is also included within the scope of the invention. The scope of the invention also includes that the compound of formula (1) forms all possible polymorphic forms. When, the term "compound of formula (1)" or any of its sub-systems, also includes its N-oxide form, its salts, its stereochemically isomeric forms, and its solvates. Particularly valuable is pure Stereochemical (1) The substituents on the chemistry of the two groups can be unique. Each of the possible groups of the purely tangible energy can be tested, and the specific embodiment of the formula is (1) the compound X represents N4CH; Represents C(=0) or SH3)p; P represents an integer of 1 or 2; R: represents CH(R4).aryl or ch(r4)yucyl; R represents aryl 2 or heteroaryl; 14 200811131 R3 Represents A, cv6 silk, Cl 66 oxy, technical amine or mono or di (cM alkyl) amine; soil, R4 represents hydrogen or cU4 alkyl; = and ^ each independently represents hydrogen, or as needed (d) Substituted to burnt ί, the nitrogen of its connection - formed from L (tetra) - hydrogen

a single-ring heterocyclic ring of StcTf or thioristhenyl, each of which is optionally substituted by a C alkyl group; a core-like or a secret, each of which is substituted with a phenyl group or a substituent, especially - Two or three substitutions c] ritual, c to burn eve 7 d oxygen group, C1_6 alkyl group oxy, c] _6 sulfur base, $ ^ 6 silk, poly _ base 01-6 courtyard oxygen , cyano, succinyl, carboxy, 〇S〇2, C] _4 alkyl-S〇2-, R6R5N-C(=〇)_amino-mono- or di(CM-mercapto)amine, Ci_4 alkane a carbonyl group, an aryl group, a fluorenyl group, an aryl group, an aryl group, an aryl group, an aryl group, an aryl group, a aryl group, a phenyl group, a phenyl group, or a phenyl group The group is independently selected from the group consisting of paper, k-wire, k'-group, and mouth "6-oxygenated carbon group, qj-yl-yloxy group, α-decylthio group, polyhalogen group #山其元夕基基6 alkoxy group , cyano, nitro, carboxyl, amine-based, mono- or di(CM alkyl)aminocarbonyl, amine, single

Alkylamino; (M-aryl 2 represents phenyl or naphthyl, each of which is optionally substituted with at least one substituent, each substituent being independently selected from halo, aryl, Cl, c] _6 15 200811131 Alkoxy, Cw alkoxycarbonyl, Cm alkylcarbonyloxy, Ci 6 alkylthio, polyhalo Cw alkyl, polyhaloCl-6 alkoxy, cyano, nitro, fluorenyl, h〇-S 〇2-, c〗 4-alkyl group _s〇2_, Wn-c^o)·, amine group, mono- or mono(Cm alkyl)amine group, cM alkylcarbonylamino group, aryl group 1, aromatic The base i C1-4 alkoxy, aryloxy or aryl lc (=r〇)_; heteroaryl represents a selected from pyrrolidinyl, imidazolium, pyrazolyl, furyl, thiol, Pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyldipyridyl, hydrazine, pyrimidinyl, Pyridyl, hexahydropyridyl, /, hydropyridyl, fenfludyl, thiofolfonyl monocyclic heterocyclic fluorene or selected from the group consisting of aryl, aryl, rim, lenyl Benzene, benzo-4-yl, thiol, benzoinyl, benzofluorenyl, noisy, . Kui t well base, ah base, different, forest base cultivating base, material wheel, (four) silk, grade base, private base, benzo = t base, / silk, benzene filament, two heterocycles, each of which needs Substituted by at least one substituent, each substituent is mono-, hydroxy, C]-6 alkyl, oxy (: 丨6 oxycarbonyl, CV6 alkylcarbonyloxy, Cl-6 alkane^-S02 RVn.c(=〇k ^^(C;4^}; soil or benzylamino group. Matter::::== fine specific embodiment is the formula (1) compound represents c (4 consumption _ concrete Any subset of _, wherein 丫16 200811131 A third valuable embodiment of the invention is a compound of formula (1) or any subset thereof as a valuable embodiment, wherein γ represents s (=0) p, in particular S(=〇) 2. The fourth valuable embodiment of the invention is a compound of the formula (I) or any of the above as a valuable embodiment of any of the specific embodiments, wherein γ represents CH2-C(=K)). A fifth valuable embodiment of the invention is the compound of formula (I) or a group thereof as a subset of valuable specific embodiments, wherein x represents N. The seventh of the present invention A specific embodiment of the invention is a compound of the formula (I) or any of the above as a specific embodiment of a valuable embodiment, wherein the aryl group replaces the Wei; or the miscellaneous or the money, each fresh or steamed group Substituted by one or two substituents, preferably one or two substituents, each of which is a green genus, a Cl. (tetra), a Cl anthracene group, a k-alkyl group oxy group, a Ci-6 thiol group, and a polydentate group. Earth II / X soil C "6 alkoxy, cyano, nitro, carboxyl, h〇-so2-, Wu: oxygen 2 = alkylamino, aryl!, aryl 1 Cl-4 alkoxy, Aromatic oxy or aryl group. Grab + i (four) 帛 八 八 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Is the +R^eH (the g-square represents the non-dished naphthyldiyl- or the two-substituted quinone-n-yl) each of the base or naphthyl, each substituent independently selected 17 200811131 , Cw alkyl, alkoxy, Ci6 alkoxycarbonyl, alkylcarbonyl, yl, alkylthio, polyhaloCi 6 alkyl, polyhalo [decyloxy, aryl, nitro, carboxy, Haso2 , cK4 alkyl-S02-, R6R5N-C(=0)-, ,, 1, mono- or di-(cM alkane) Amino group, Cm alkylcarbonylamino group, aryl group, aryl CM alkoxy group, aryl 1 oxy group or aryl group 1 (: (= 〇) _. The ninth valuable embodiment of the present invention An example is a compound of the formula (1) or any one of the above as a valuable embodiment, wherein r1 = a CH(R)-aryl group, the aryl group of which represents a group substituted with at least one substituent More preferably one or two substituents, each substituent being independently selected from the group consisting of a dentate group, a = alkyl group, a C alkoxy group, a c-6 oxyalkyl group, a CV6 alkyl carbonyl group: a clay, Cl ·6 sulfur-soluble, multi-grain Gw alkyl, polyhalo-Cl_6 alkoxy 6, 5 chaotic, nitro, county, H0.S02_, Cl.4 alkyl-S〇2, amine, single Or a di(c)·4 alkyl group) an amine 'cm alkyl group a few nt·, a group, an aryl group 1 (: anthracene oxy group, a silk 1 oxy group or an aryl group 1 main one _', more especially It is a phenyl group in which + Rl represents a CH(R4)-aryl group, wherein the aryl group is a di- or di-substituted group, and two substituents are selected from a substituent of a group or a hexyl group. Further, R represents a 4_dentyloctyl group, particularly a 4_indicarbyl group or a 4_indolyl group. The tenth specific embodiment of the present invention is any subset of specific examples of their compounds or their above-mentioned riding values, wherein the R1 group, wherein the aryl group represents at least one substituent, as desired. ^ soil, preferably - or two substituents, each substituent is independently selected from the group consisting of U group, CK6 fluorenyl group, Ci6 alkoxy group, alkylcarbonyloxy group, cl6 alkane quinone, and hexapeptide, more than Halogen-based Cm alkyl, polyhalogen Ci6 yuan, soil, nitro, carboxyl, H〇s〇2, C"alkyl-S〇2, 18 200811131 R6R5N-C(=0)-, amine group ,single

CpO)-, especially J: in the middle 4 / square soil without replacement. A specific example of a value representative of CH(R)·Silk's aryl arylate ίί:::::: is the formula (1) ϋ ϋ = square base 'where aryl represents a substituted phenyl group, When the band is in the second::: base disubstituted group is paper especially and the 4 position is substituted. A preferred embodiment of a preferred composition is that the formula _W represents any subset of the specific examples wherein the hetero-oil is where R1 represents CH (R4>heteroaryl, fluorene, 吼/ f its flavor ♦ forest base, 吼 ° ° forest base, seven south, sit-base, iso-salt base, sit-base, taste sulphate, 吼 基 base, the heterocyclic ring as needed, at least L two == money u sit , each substituent, each substituent is independently 'di or tri C】-6 methoxy, C16 aerobic self-purification, silk, k alkyl, benzyl, poly1-6 alkyloxy, Ci- 6 sulphur-suppressing base, _0^%^yloxy, cyano, deterministic, mono- or di-(c)-4-alkane 2 2·, Rr5n_C (=0>, amine group, CH(R4)- Heteroaryl^ in the diCl·4 alkylamino group or wherein R1 represents, for example, a well base, '(4) base = representing a hydroxy group, 荅 paper 咖定基, 土,, 风吼呼基, 福福嘴基, Thiofolin 19 200811131; each of the heterocyclic rings is optionally substituted with at least one substituent, particularly one, two or three substituents, each substituent being independently selected from halo, hydroxy, alkyl, CK6 decyloxy , Ci 6 aerobic group, c] 6 alkyloxy, k, sulfur , multi-functional C^6 alkyl, polynanyl Cw pitoxy, cyano, nitrous oxide, base, H0-S02-, alkyl-S〇2, R6R5N C(=〇), amine group, early Or a di((:1·4 alkyl)amino group or a Cm alkylcarbonylamino group or wherein Ri represents CH (R>heteroaryl wherein the heteroaryl group is selected from the group consisting of ah, aryl, phenylidene, heterogeneous'朵基,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, a base, a ruthenium, a ruthenium, a ruthenium, a ruthenium, a benzo, a di-, a benzofluorenyl, a benzopyrene, and a heterocyclic ring At least one substituent is taken as =, particularly one, two or three substituents, each substituent being independently selected from the group consisting of halofluorenyl 苴Cl_6 alkyl, Cl-6 alkoxy, C]-6 aerobic county, Cw Burning two techniques: Ui.6 burning sulfur base, township halogen group. 16 burning base, multi-counter amine group, base, early or U-based) amine group or Ci-4 burning basic U of the twenty-two valuable specific An embodiment is any subset of the specific embodiments in which the formula (1) is di- or /, and is a CH(R)heteroaryl group. The ring system representing a heteroaryl group is optionally substituted by - or two: a silk, preferably a substituent. The fourteenth valuable embodiment of the human 仏t month is the formula (1), 〃 any of the above as a subset of valuable specific embodiments, wherein 20 200811131 R represents _?, ci! (r4> heteroaryl wherein heteroaryl represents fluorenyl, benzofuranyl, stupid, yl, Each of the loops is optionally substituted with an i group. The fifteenth valuable embodiment of the present invention is any subset of the formula (1) of the formula (1) or the material of the above 14 materials (4), wherein R represents a part of The base 2'. particularly wherein r2 represents aryl 2 wherein the filament 2 represents a phenyl group which requires at least a repentant silk, and is made into two or two groups, each substituent being independently selected from a halo group, Base, α6 filament, Cl.6 = group, Cl-6 filament group, Ci-69 benzyloxy group, CK6 thiol group, bis(yl)Cl.6 alkyl group, polyhalogen Ci-6 alkoxy group , cyano, succinyl, carboxyl, -S〇2·, CM alkyl _S 〇 2, r6r5n_c (= 〇) ·, amine mono- or di, ") amine, CM alkyl base amine, aryl 1, aryl lQ4 burning emulsion, aryl 1 oxygen Or an aryl group lC(=0)_; more particularly wherein R2 represents a benzene tomb substituted with one or two spectrin atoms as desired. The sixteenth valuable embodiment of the present invention is the sub-formula (1) or any of the above-mentioned as a specific embodiment of a valuable embodiment, wherein R2 represents a trans-substituted filamentous benzene. Suitably, the substituent is preferably at a position of 3 or 4, or wherein R2 represents a phenyl group substituted with two substituents, and the substituent is preferably at the 2 and 4 positions. Preferably, the substituent is fluorenyl, especially fluoro. A seventeenth valuable embodiment of the invention is the formula (1) or any of the above as a valuable embodiment, wherein R3, hydrogen, Ci-6 alkyl , Cm alkoxy, aryl, aryl _NH_, heteroaryl, heteroaryl-NH-, amine, C3-7 cycloalkyl or polyhalo c] 6 alkyl; especially R3 stands for Cw Alkyl, aryl 1, aryl! _NH_ or heteroaryl 21 200811131 The specific embodiment of the base-NH complex or the binary value is any subset of the specific examples of the formula (1) 3 ... having a depreciation value, , = Yim, M shoulder base, different drink base, base, Sancha, ^ base, shouting, Fuji, thiophene like hydrogen money base, hexahydrogen ratio. Well base, ii ii: ί, (4) is -, two or three substituents, each taking =, base, basis,. ... Gu, alkyl, oxy, Cl·6 sulfur-based, multidentate 'Q MS: ' 5 , cyano, schiffyl, county, H〇-S〇 2 ·, amine 2 C: Γ (which, amine a group, a single seven (k-alkyl) county amine group; or wherein R3 represents a selected from the group consisting of, aryl, r-isoindenyl, 吲哚d-linyl, benzofuranyl, benzothiophene, benzene (tetra) Pin, benzoin-based, base, correct 0 well = ' γ-based, l-based, seven-lin, base, 4 drive base, hydrazine, base, benzo Df, benzo a bicyclic ring of a thiol group or a benzoxyl group, each of which may optionally have at least one substituent 'specifically, two or three substituents, each substituent being independently selected from 1 to 6

, =f, 录, c]·6 alkyl, Cl·6 alkoxy, c^oxyl, C 1-6 , dinyl group, c] _6 sulphur group, township-based ke group, Polydentate ct group, cyano group, nitro group, county, Has02_, c14 alkyl group _S (V, RN-C(〇), amine group, mono- or di-(c"4-alkyl) amine group or Cm-burning Base 22 200811131 carbonylamino group. More specifically a ^, isoindole-based K-based definition + the genus represents 喧 基, Μ Μ or ° 疋 疋, each of which needs to be replaced by a halogen group. A specific embodiment of the above value is that the equation (1) R4 represents 氕.... any subset of specific embodiments having a devaluation, wherein the tenth of the tenth valuable embodiment of the person %, tf is the equation (1) 2 2 4 7 4 as any subset of * (4) concrete complements, where K represents CV4 alkyl. #八j第第十一十一的价值的实施实施例(1) :J上上As any subset of valuable specific embodiments, the square soil & represents a stupid base, which is replaced by an i-base as needed. ^The first - twelve valuable embodiments are those of the formula (I). Or any of the above as a valuable embodiment The set, one or more, preferably all of the following limitations apply: a) a aryl group representing a phenyl group substituted with at least one substituent, especially ^ or 2", each substituent being independently selected from halo or CK6 alkyl;) a square group representing a phenyl group substituted by a 13⁄4 group; C) R2 represents an aryl group; ^.d) aryl 2 represents a phenyl group optionally substituted with one or two halogen atoms, -e The heteroaryl group represents a sulfhydryl group, a (iv) spanyl group, a carbyl group, a benzyl group, a benzoquinone group or a benzoh group. (10) The system requires a generation; 23 200811131 g) p is 2. The twenty-second compound of the present invention or the above-mentioned: '&-specific embodiment is any subset of the specific embodiments in which the formula (I) is present, having R1 2 and having the formula

The carbon atom of the group has an R configuration, also

(Di Α > R2 π Its stereochemical isomer form =: pharmaceutically acceptable salt, the first fourteenth valuable embodiment of this month is the equivalent of the formula (1) or its As any subset of valuable embodiments, with R2 and having the following formula

The carbon atom of the group has an S configuration, also

(Ι-Β) 24 1 A quinone-oxide, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof. 2 Preferred compound of formula (1) is selected from the group consisting of: 200811131 ^R3

Rl R3 Y R2a R2b Stereo Label/Salt-H oo HH *(RS) -ch3 oo HH *(RS) •nh2 o=s=o HH *(RS) oo HH *(RS) u^CX^CHj oo HH *(RS) -ch3 c=o HH *(RS) CXX> •ch3 oo HH *(RS) -ch3 oo HH *(RS) :XT" -CHj c=o HH *(RS) -ch3 oo HH * (RS) -ch3 oo HH *(RS) -ch3 oo HH *(RS) 8χ^ -ch3 c=o HH *(RS) f" -ch3 oo HH *(RS) ¢0^ ^ch3 c=o HH *(RS) 25 200811131 R1 R3 Υ R2a R2b Stereolabel/Salt-νη2 -ch2-c(=o)· HH *(RS) -ch3 C(=〇) HH *(R); .HC1 π -ch3 c (=o) FF *(RS); HC1 salt-CH2CH3 c=o HH *(RS) -νη2 c=o HH *(RS) c=o HH *(R); HC1 salt % c=o HH *( RS) ?Η, HjC c=o HH *(RS) c;o HH .*(RS) 00 HH *(RS) -νη2 -H... HH *(s); Fumarate N-oxide, A pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, or a solvate thereof. A particularly preferred compound of formula (I) is selected from the group consisting of: /R3

R1 R3 Y R2a R2b Stereo label/salt-ch3 c=o HH *(RS) 26 200811131 R1 R3 y R2a R2b Stereo label/salt c=o HH *(RS) -CH3 c=o HH *(RS) c^ 〇r> -ch3 00 HH *(RS) -ch3 c=o HH *(RS) -nh2 -ch2-c(=o)- HH *(RS) -ch3 C(=0) HH *(R); .HCI jy^ •ch3 c(=o) FF *(RS);HC1 salt-CH2CH3 c=o HH *(RS) -nh2 00 HH *(RS) c=o HH *(R);HC1 salt c= o HH *(RS) ΎΝ H., C c=o HH *(RS) c=o HH *(RS) ΒΧΧ" 00 HH *(RS) ^nh2 5: ? —**c a c···· HHH*(s); fumarate, an N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, or a solvate thereof. The invention also relates to compounds of the formula: 27 200811131

R3 I Y I

Wherein R, R3, x and Y are as defined according to the compound of formula (1). The invention also relates to compounds of the formula:

Wherein R, R2, X and Y are as defined according to the compound of formula (1). In general, the preparation of a compound of formula (1) can be carried out by passing an intermediate of formula (π) with an intermediate of formula (々ΠΙ), wherein W1 represents a suitable excipient group such as, for example, a molybdenum, etc., in a suitable base such as N,N-diethyl. Ethylamine or N,N-diisopropylethylamine is reacted with a suitable solvent such as N,N-dimethylformamide, dichloromethane or an alcohol such as decyl hydrazine.

The compound of the formula (1) wherein the R4 substituent in the definition of R1 represents hydrogen, the R1 is represented by R a-CH2 and the compound is represented by the formula (I-a), which may be intermediate between the intermediate of the formula (11) and the formula (III') Wherein Rla represents an aryl or heteroaryl group, which is prepared by reacting in the presence of a suitable reducing agent such as NaBH(OAc)3, a suitable acid such as acetic acid and a suitable solvent such as dichloromethane.

Ο

o-P (II) (πη

a compound of the formula (I) wherein Y-R3 is 3 according to the scope of the patent application, but is not a view-cis 2 C (Nan-aryl!, _c (which should be a hetero group, the Ym_R3a represents and the compound Using an intermediate of formula σν) and an intermediate of formula (V), wherein W2 represents a group such as a secret such as chlorine or the like, an alkoxide such as a C1 base, and a fine base such as Q_6 _c (which σ (CH3_C( Which σ I -C (which σ (CF3-C(=0)_a) ^ red w silk r, loose), depending on the appropriate base such as N, di-n-amine, N, N-diisopropyl The presence of methyl ethylamine or K2C〇3 is prepared in the next day, and the drying in a suitable solvent such as tetrahydrofuran is carried out under the rain. ^, - the surface of the milk, such as ethanol, etc. ο-Ρ R3a.y, w〇γΆ-οό (IV) (V) (i-fa) A compound of the formula (i) wherein R3 represents 1^2 and Y represents S(=C〇2, and the compound is represented by the formula (IV), which is _ intermediate^ the 29 200811131 s ( o) 2-(nh2)2 is prepared by reaction in the presence of a suitable solvent such as ruthenium.

a compound of the formula (1) wherein Y_R3 represents c (which NH-aryl 1 or = which leg is heteroaryl), and (d) uses c (na, which represents R3b, a pendant or a heteroaryl group, and the compound is of a formula (d) Representative, prepared by reacting an intermediate of the formula with a compound of formula (VI) in the presence of a suitable, for example, di-sinter.

v J (f-d) Formula (1). Wherein Y represents c(=〇) and r3 represents leg 2, and the compound is represented by the formula (Ι-e), which can be calcined via an intermediate of formula (IV) with isocyanatotrimethyl sulfoxide in a suitable solvent such as Prepared by the reaction of the sister.

30 200811131 A compound of formula (I) wherein the ring group of the R 2 substituent is substituted by R 5 R 6 N-C(dioxa)-, the R 2 substituent is represented by _R 2a —c(=〇)_NR 5 R 6 and the compound is represented by the formula, or 1) A compound in which R1 is substituted with a ring of the ring is substituted by R5R6N_C(=〇)-, which is substituted for the US soil ^ (which dish represents ^ and the compound is used by the formula (I_f•^ is expressed by the formula (xxxm·complement XX view) The towel W2 represents ς ς 6 such as a halogen group such as chlorine, <1 Η 料 or azide, etc., = R * R NH = suitable · in a suitable solvent such as di 4-anthracene or alcohol such as, I alcohol And methanol is prepared in the presence of a reaction.

-Ο-D nhr5r6 R1- X-

妒 r5n’, (K-1) r6r5n

(XXXlll-a) °^〇-0+ _, β R2 (Xxxm-b) The compound of the formula (I): a compound of the formula () is prepared by a known formula in the formula ===:. It is converted into its N·oxide shape to convert the trivalent gas to a suitable formula. The conversion of the N-oxidation anti-reservoir tff to the corresponding (iv) oxide form is carried out by reacting an organic or inorganic peroxide at the initiation of the formula (1) 200811131. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxyacids such as phenylperoxyformic acid or substituted benzene. Oxyacids such as 3-chlorobenzene peroxydecanoic acid, peroxyacid acids such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, _hydrocarbons such as dichloromethane, and mixtures of these. A compound of formula (I) wherein the ring group of the R1 or R2 substituent is substituted with a methoxy group and can be converted to a compound of formula (1) by reaction with a suitable alkylating agent such as BBr3 in the presence of a suitable solvent such as di-methane. The ring group in which the substituent of 1 or R is substituted by a base group. Compounds of formula (I) wherein the ring group of the R or R2 substituent is substituted by a carboxy group, via a suitable solvent such as dichloromethane, a suitable coupling agent such as diimidazolecarbonyl or carbodiimide, for example with a suitable amine HNR5R6 Diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N,-dicyclohexylcarbodiimide, and optionally a base For example, in the presence of N,N-diisopropylethylamine, it can be converted to a compound of formula (I) wherein the ring group of the R1 or R2 substituent is substituted by C(=〇)-NR5R6. This conversion can also be carried out by reacting with SOC12 in the presence of a suitable solvent such as toluene or di-methane to convert the carboxylic acid to a thiol-based compound, followed by the above reaction. A compound of formula (I) wherein the ring group of the R1 or R2 substituent is substituted by a nitro group, via a suitable catalyst such as Pd/C, a suitable catalyzed poison such as thio 32 200811131 phenous solution, V 2 〇 5 and suitable The reaction of a solvent such as tetrafurfuran with a suitable reducing agent such as Ha can be converted to a compound of formula (1) wherein the ring group of the R1 or R2 substituent is substituted with an amine group. The compound of formula (I) wherein the ring group of the R1 or R2 substituent is substituted by a nitro group can be prepared from an unsubstituted compound by reaction with ^11^3. A compound of formula (1) wherein the ring group of the R1 or R2 substituent is substituted with an amine group, via a suitable anhydride in the presence of a suitable solvent such as dichloromethane and a suitable base such as N,N diisopropylethylamine. (c(K))-Ci6 alkyl or a suitable mercapto chloride C!_6 alkyl-c(=〇)-Cl reaction, which can be converted to a compound of formula (1) wherein the ring group of the R1 or R2 substituent is via Ci 6 The compound of the formula (1) and a part of the intermediate of the present invention contain an asymmetric carbon atom: the pure stereochemically isomeric form of the compound and the intermediate can be obtained by a method known in the art. For example, the non-palphaliomer may be aliquoted by lysine, such as selective crystallization or chromatography, and 2, using a suitable dissociating agent such as a palmitic acid, the racemic palmomeric salt or compound. The mixture is separated from the === technique such as liquid chromatography or the like, or a mixture of compounds; and finally the pure stereochemically isomerized palm isomer is converted. Learning disregards first; = should be the beginning 33 200811131 Separation of the compound (1) to the palm-isomeric form Liquid chromatography or SCF (supercritical fluid) layer 曰, the method involves the solid phase method. The correction is made using a compound known to the palm intermediate and the starting material or may be prepared according to methods known in the art. The phyllolation of the intermediate of formula (II) can be via the intermediate of formula (VII) which gives p a suitable protecting group such as C6H5-CH2_〇_C (in the appropriate catalyst such as Pd/C and suitable Prepared by removing the protection with H in the presence of a solvent such as an alcohol such as methanol. ' 2

An intermediate of formula (VII) wherein Y-R3 represents γ_κ' as defined above. The intermediate is represented by formula (VII-a) by allowing the intermediate of formula (νιπ) and intermediate of formula (v) to be in the appropriate base as desired. For example, in the presence of hydrazine, κμ diethylethylamine or N,N-diisopropylethylamine, and optionally in the presence of a suitable solvent such as tetrahydropyrene or dioxane.

(VIII) (V) (Vll-a) 34 200811131 The intermediate of formula (VIII) can be obtained by using a suitable reducing agent such as trihydrogen (tetrahydrogen) in the presence of a suitable intermediate of the formula (ι) in a suitable solvent such as tetrahydrofuran. Chlorobene is prepared by reduction of boron (borane-tetrahydrofuran complex).

The intermediate of formula (IX) may be via an intermediate of formula (χ) with an intermediate of formula (W1) wherein W3 represents a suitable release group such as a halide such as a gas, etc., in a suitable base such as hydrazine, hydrazine-diethyl It is prepared by reacting an amine or hydrazine, hydrazine-diisopropylethylamine with a suitable solvent such as hydrazine or hydrazine-dimethylformamide.

(X) (Χ1) (IX) The intermediate of formula (X) may be present via the presence of an intermediate of formula (ΧΠ) in hydrazine, a suitable catalyst such as Pd/c and a suitable solvent such as an alcohol such as decyl alcohol. It is prepared by benzylation in the case where X represents CH. The debenzylation of the intermediate of the formula (χιι) can also be carried out in the presence of a chloroethyl chlorate and a suitable solvent such as dioxane, followed by the addition of an alcohol such as decyl alcohol, etc., preferably at elevated temperature. wine

(XII) (X) 35 200811131 Formula (X) intermediate wherein X represents N, the intermediate is represented by formula (X_a), and may also be via an intermediate of formula (XIII) with a suitable acid such as hydrochloric acid, etc. It is prepared by reacting in the presence of a suitable solvent such as 2-propanol.

(XiM) (Xa) an intermediate of formula (XII) wherein X represents CH and the intermediate is represented by formula (xn-a) which can be reacted by reacting an intermediate of formula (XIV) with a suitable acid such as H2S04 and acetic acid. preparation.

An intermediate of formula (XII) wherein X represents N, and the intermediate is represented by the formula (χπ-b), which can be reacted with a suitable test such as NaOer in the presence of a suitable solvent such as tetrahydrofuran via a suitable formula (χν) intermediate And prepared.

The intermediate of formula (XIV) can be prepared by reacting an intermediate of formula (XVI) with CH2=CH-CN in the presence of a suitable catalyst such as Triton B and a suitable solvent such as dioxane. 36 200811131

The intermediate of formula (XVI) can be reduced in the presence of a suitable catalyst such as Pd/C or Rh/C, a catalyzed poison such as a porphin solution, and a suitable solvent such as an alcohol such as methanol, via a suitable reducing agent such as H2. Prepared by the formula (χνπ) intermediate. This reaction can also be carried out using NaBH4 as a reducing agent in the presence of a suitable solvent such as an alcohol such as 2-propanol.

The intermediate of formula (XVII) can be prepared by reacting an intermediate of formula (XVIII) with an intermediate of formula (χΙΧ) in the presence of a suitable base such as, for example, Na〇CH3, and in the presence of a suitable solvent such as an alcohol such as methanol. .

(XVIII) (XIX) (XVli) The intermediate of formula (XV) may be in the presence of a suitable coupling agent such as 1,1,- benzyl bis- hydrazine, and in the presence of a suitable solvent such as di-methane. Prepared by reacting an intermediate of formula (XX) with NH3. 37 200811131

The intermediate of formula (xx) can be prepared by hydrolysis of the intermediate of formula (XXI) with a suitable reagent such as NaOH in the presence of a suitable solvent such as dioxane.

The intermediate of formula (XXI) may be in the presence of a suitable assay such as NaH and a suitable solvent such as N,N-dimethylformamide via the intermediate of formula (χχπ) and intermediate of formula (XXIII) wherein W4 represents suitable The release group is prepared by a reaction such as a halogen group such as bromine.

The intermediate of formula (XXII) can be intermediates of formula (XXV) with an intermediate of formula (XXV) in the presence of a suitable assay such as hydrazine, hydrazine-diethylethylamine and a suitable solvent such as dichloromethane. Wherein w5 is prepared by reaction of a suitable excipient group such as a dentate group such as bromine. (XX») Cm alkyl + N^vCm alkyl (XXIV) 5 (XXV) 38 200811131 The intermediate of formula (XIII) can be obtained by reacting an intermediate of formula (xxvi) in the presence of a suitable solvent such as tetrazobite A suitable test, such as your gamma reaction, is prepared.

The intermediate of the formula (XXVI) can be prepared according to the method disclosed for the intermediate of the formula (χ). d > 中间 An intermediate of formula (VIII) wherein P represents benzyl and further represents a compound represented by formula (VIII-a), which may also be cyclized in a suitable solvent such as H2 via a suitable acid such as HBr. Formula (χχχΙν) intermediate and 痹横

(XXXIV) (Vlll-a) The intermediate of formula (XXXIV) can be reacted with trihydrogen (tetrahydrofuran) by a suitable solvent such as tetrahydrofuran.

Ready.

Cl-6 alkyl group 0 (χχϊχ) (xxxiv) "U.S. (IV) substrate can be made by formulating the final compound of formula (1), wherein the final compound is represented by formula (ig). Prepared by reacting with an acid such as HBr. 39 200811131 R1

CN6 alkyl

The intermediate of formula (I-g) can be prepared starting from the intermediates of formula (II) and (III) for the compound of formula (I). The following method (IV) intermediate can also be used in a suitable solvent such as =rxvn) with a suitable reduction _= two

(XXVII)

(iv) The intermediate of the formula (χχνιι) may be in the middle of the intermediate (v) with a suitable solvent such as N,N-didecylamine and a suitable _•diethyl sulphate Material reaction (four) preparation. ...

(XXVIII) (III) (XXVII) The intermediate of the formula (XXVIII) wherein χ represents CH, and the intermediate is stored by the formula (xxvm_a), which can be combined with a suitable solvent such as an alcohol such as methanol. Prepared by the reaction of XXDQ intermediate with H2 200811131. After initial hydrogenation for debenzylation, Raney Ni can be used as a catalyst to further cyclize. Alternatively, Raney Ni can be used as the reaction. The first catalyst for the cyclization reaction is followed by the use of Pd/C as a catalyst in the debenzylation.

〇, (XXIX) (XXVIll-a) The intermediate of formula (XXIX) can be via formula (χχχ) intermediate with formula (XXXI) in the presence of a suitable solvent such as bisaki and a suitable base such as an alkoxide such as sodium methoxide. The intermediate is prepared by reaction. This reaction can also be carried out in the presence of a suitable catalyst such as butyl riton B and a suitable solvent such as dioxane.

Cl-6 base (XXX) (XXXI)

The Ci-6-based compound of formula (I) and any subset thereof exhibit CXCR3 receptor antagonistic properties. This CXCR3 antagonist inhibits the binding of one or more chemical hormones (eg, cXC chemical hormones such as IP-10, MIG, and/or I-TAC) to CXCR3 by chemical hormones (short for "chemokine cytokines") The most important agent for white blood cell exchange. This bioshade is carried out on the target cells by interaction with the seven M domain receptors coupled to the heterozygous egg. The chemical hormones are mainly divided into four groups (c_c, c_x_c, c, and c_X3_c). Depending on the two amino-based cysteamine bases (represented by c), 41 200811131 Whether via a single amino acid (represented by x) Isolation (cxc), and adjacent (cc) has a lost cysteine pair (eg separated by three amino acids (C-X3_c). CXCR3 chemical hormone receptor is a g protein coupling Body, also known as:,,, coffee 83. CXCR3 f body is mainly expressed in activated or stimulated Ding lymphocytes, natural killer cells (sputum cells), malignant 6 lymphocytes, endothelial fine. The selective expression of CXCR3 receptor makes It is suitable for inappropriate T cell exchange in the intervention. The ligand acting on the CXCR3 receptor is cxc chemical hormone nc = interferon-inducible T cell α_chemical agent), ΙΡ·1() (interferon) Proteins 丨0) and MIG (mononuclear factors elicited by interferon); -TAC has the highest receptor affinity. Clinical indications for intervention by interfering with the CXCR3 receptor, especially for inappropriate T-cell exchange, are: (1) Inflammatory or allergic diseases such as systemic allergies or allergic reactions, drug allergies (eg for penicillin, cephalosporins) ), insect licking allergies; inflammatory bowel disease, such as CK) hn's disease, (four) inflammation (such as ulcerative colitis), ileitis and enteritis; vaginitis; psoriasis and inflammatory skin diseases such as dermatitis; Atopic dermatitis, allergic contact dermatitis, Zunma therapy; vasculitis (eg necrosis: skin and allergic vasculitis); vertebral joint disease; scleroderma; respiratory allergies such as asthma, allergic rhinitis, obstructive Pulmonary disease (COPD), allergic lung disease, hypersensitivity pneumonitis, interstitial lung disease _) (eg congenital pulmonary fibrosis, or IU) accompanied by wind 42 200811131 arthritis, or other autoimmune conditions), congenital pneumonia ( 2) Autoimmune diseases such as arthritis (eg rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, polyarthritis, vertebrae), multiple sclerosis, total Lupus erythematosus, myasthenia gravis, diabetes (including 2 urinary diseases in diabetes and adolescents); Sjogren's syndrome, glomerulonephritis and other nephritis, autoimmune thyroid disorders such as thyroiditis; (3) Transplant rejection (including allograft rejection (eg, heart, kidney, and lung rejection), xenograft rejection, and graft versus host disease), and (4) other diseases in which unwanted inflammatory responses are inhibited (eg, atherosclerosis, re Stenosis, cytokine-induced toxicity, myositis (including polymyositis, dermatomyositis), neurodegenerative disease, Alzheimer's disease, inflammatory inflammation, meningitis, hepatitis, nephritis, septicemia, sarcoma Disease, conjunctivitis, otitis, retinitis (eg premature retinitis, diabetic retinitis), retinal vein closure, macular degeneration (eg age-related macular degeneration), hemangioma, chronic obstructive pulmonary disease, sinusitis and Behcet's Symptom group). The kite literature is for example Arimili et al, Immunological Reviews, 2000, vol 177, 43_51; Xanthou et al./Eur·J. Immunol., 2003, vol 33, 2927-2936; WO 01/16114 and WO 02/85861, And in this article for tea test. Due to its CXCR3 receptor antagonistic activity, a compound of formula (I), its N-oxide, a pharmaceutically acceptable salt, a stereochemically isomeric form or a solvate 43 200811131 can be used for therapeutic or prophylactic, especially therapeutic, via The disease or condition involved in the activation of the CXCR3 receptor. In view of the above pharmacological properties, the compound of the formula (I), its N-oxide, pharmaceutically acceptable salt, stereochemically isomeric form and solvate can be used as a rate agent. In particular, the compounds of the invention are useful in the manufacture of a medicament for the treatment or prevention of diseases which are via the activation of the CXCR3 receptor, particularly for the treatment of diseases which are involved via activation of the CXCR3 receptor. More specifically, the compounds of the present invention can be used in the manufacture of a medicament for treatment or prophylaxis, in comparison to sputum therapy, inflammatory or allergic diseases involving CXCR3 intervention, autoimmune diseases involving CXCR3 intervention, transplant rejection of CXCR3 intervention, and other CXCR3 interventional diseases. The unwanted inflammatory response is inhibited. Even more certainly, the compounds of the invention are useful in the manufacture of a medicament for the treatment or prevention of (1) inflammation or allergies = diseases such as systemic allergies or allergic reactions, drug allergies (eg for penicillin, cephalosporins), insect stings Allergies; inflammatory bowel disease, such as stagnation, ulcerative colitis, ileitis and enteritis; vaginitis, psoriasis and skin diseases such as dermatitis, _, heterozygous dermatitis, allergic dermatitis, • acupuncture ; blood vessels such as necrosis, skin and over = vasculitis); vertebral joint disease; scleroderma; respiratory allergies such as gas two lungs, sensitive rhinitis, and sputum lung disease (cQpD), allergic lung disease, allergy two: Interstitial lung disease (ILD) (eg congenital pulmonary fibrosis, or ILD t rheumatoid arthritis, or other autoimmune conditions), congenital lung disease, autoimmune diseases such as arthritis (eg rheumatoid joints) Inflammation, bovine arthritis, juvenile rheumatoid arthritis, township arthritis, vertebrae, human, sclerosis, systemic lupus erythematosus, myasthenia gravis, 44 200811131 diabetes (including diabetes and adolescents) Diabetes); sj〇gren's syndrome, K-month glomerulonephritis and other nephritis, autoimmune thyroid disorders such as thyroiditis; (3) transplant rejection (including allograft rejection (eg heart, kidney and lung rejection), fine transplantation Rejection and graft versus host disease), and (4) other diseases in which unwanted inflammatory responses are inhibited (eg atherosclerosis, restenosis, cytokine-induced toxicity, myositis (including polymyositis, skin) Myositis), neurodegenerative disease, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, septicemia, sarcoma, conjunctivitis, otitis, retinitis (eg premature retinitis, diabetic retinitis) ), retinal vein occlusion, macular degeneration (eg, age-related macular degeneration), hemangioma, chronic obstructive pulmonary disease, sinusitis, and Behcet's syndrome. The compounds of the invention may also be used in the manufacture of a medicament for the treatment or prevention of rheumatoid Arthritis, inflammatory bowel disease such as Crohn's disease and colitis, transplant rejection (eg heart, kidney and lung allograft rejection), multiple sclerosis c〇PD, glomerulonephritis allergic contact dermatitis, lupus, psoriasis, atherosclerosis, Sj〇gre^ syndrome, autoimmune thyroid disorders. The compounds of the invention are preferably used for treatment or prevention, In particular, treatment, rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and colitis, transplant rejection (eg heart, kidney and lung allograft rejection). In view of the use of the compound of formula (I), providing a A method of treating a disease involved in the activation of a CXCR3 receptor, including a human mammal, or a method of treating a mammal, including a human, in a disease to be involved in activation via a CXCR3 receptor, particularly A disease that is implicated in the activation via activation of the CXCR3 receptor. 200811131 includes human, mammalian treatments. A compound of formula (1), an N-oxide thereof, a pharmaceutically acceptable stereochemical form thereof, or a warm mammal of the fox-like composition. The present invention also provides a composition for preventing or treating a disease in which cxc is activated by activation of f, in particular, a therapeutically effective substance comprising a compound of formula (I) via activation of CXCRt style. And an N_oxide thereof, a pharmaceutically acceptable salt thereof, a possible stereochemical isomer thereof or a solvate thereof, and a pharmaceutically acceptable carrier or diluent. The compounds described herein can be formulated into different pharmaceutical forms for administration purposes. A suitable composition can be generally used for a systemic administration. In the preparation of the pharmaceutical composition of the present invention, an effective amount of the specific compound as an active ingredient, if necessary, is intimately mixed with a pharmaceutically acceptable carrier in the form of a salt, depending on the form of the preparation required for administration, the carrier There are many different forms. These pharmaceutical compositions need to be in unit dosage form, and + are particularly suitable for oral, rectal, subcutaneous, or parenteral administration. For example, in the case of preparing a composition for oral administration, in the case of oral liquid preparations such as suspensions, slurries, elixirs, lotions, and solutions, any conventional pharmaceutical medium such as water, glycol, oil, or the like may be used. Alcohols and the like; In the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, diluent, lubricant, adhesive, decomposing agent and the like can be used. Because of their ease of administration, tablets and capsules represent the most advantageous form of oral administration unit, in which case solid pharmaceutical carriers are obviously employed. 46 200811131 For parenteral compositions, the carrier usually comprises sterile water, at least in large part, although other ingredients may be included, for example to aid solubility. For example, an injectable solution may be provided, wherein the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared. In this case, suitable liquid carriers, suspensions and the like may be employed. Also & includes a solid form preparation which is intended to be converted into a liquid formulation in a short time before use. In a suitable subcutaneous administration composition, the carrier optionally contains a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small amount of an additive which does not cause significant adverse effects on the skin. This addition can facilitate administration to the skin and/or can aid in the preparation of the desired composition. ^ These compositions can be administered in a non-modal manner, for example as a point or as an ointment. The oral compound and the compound are also administered via a method or a slave, and are carried out by a method and a formulation used in the art. According to this,: often, the substance can be administered to the eye drops in the form of a solution, a suspension or a dry powder. (2) = can be administered locally in the form of a drop, especially the X-ray drop can be a solution or a suspension. - Sexuality, especially for the formulation of the formula. The unit dosages used herein are shaped as separate units of early indica and 5, each unit containing 47 200811131 having a predetermined amount of active ingredient calculated to produce the desired medical effect and the desired pharmaceutical system. Examples of such unit administration forms are tablets (including scored or coated tablets), capsules, pills, powder packets, glutinous rice, plug M, injectable solutions or suspensions, and the like, and isolated therefrom. Multiple packaging. Those skilled in the art are familiar with the exact (4) and frequency of administration depending on the use of the compound of the specific formula (I), the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disease and general Physical condition and other medical treatments performed by the individual. Moreover, depending on the response of the patient being treated and/or depending on the evaluation of the physician who prescribed the compound of the invention, the effective daily amount may be significantly reduced or increased. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 5 to 99% by weight, preferably from 1 to 70% by weight, more preferably from 5 to 50% by weight of active compound, and from 1 to 99.95 wt%, preferably from 3 to 99.9% by weight, more preferably from 50 to 99.9% by weight of the pharmaceutically acceptable carrier 'all percentages are based on the total weight of the composition. The compound of formula (1) may also be used in combination with other conventional anti-inflammatory or immunosuppressive agents, such as steroids, cyclooxygenase-2 inhibitors, non-steroidal anti-inflammatory agents, TNF-α antibodies, such as acetamidine salicylic acid, butadiene Acid (bufexamac), diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen (ibuprofen), naproxen, napr〇xen sodium, tiaprofen acid, flurbiprofen, mefenamic acid, nevi Formal acid 48 200811131 (nifluminic acid), 曱 曱 曱 a me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me me (nabumetone), paracetamol, piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, chlorinated Rice pine dipropionate (beclomethasone dip Roponate), betamethasone, beclamethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methyl Prednisolone, prednisolone, prednisone, triamcinelone, celecoxib, rofecoxib, valdecoxib , because of infliximab, lefhmomide, etanercept, CPH 82, methotrexate, sulfasalazine, anti-lymphocyte immunity Antilymphocytory immunoglobulines, antithymocytory immunoglobulines, azathioprine, cyclosporine, tacrolimus substances, ascomycin , rapamycin, moromona-CD3 (muromonab-CD3). Accordingly, the invention also relates to the combination of a compound of formula (1) with other anti-inflammatory or immunosuppressive agents. This combination can be used as a medicament. The invention also relates to a product comprising (8) a compound of formula (1) and (b) other conventional anti-inflammatory or immunosuppressant 49 200811131, #为组合_ for simultaneous, separate or sequential use to treat activation via CXCR3 f body Human disease. The different agents in this product can be combined with a pharmaceutically acceptable carrier to form a single formulation. Alternatively, the product may comprise, for example, a kit, &> a <RTI ID=0.0>>>><>> An advantage of such a product is that the physician can select the appropriate amount of each component and the order of administration based on the diagnosis of the patient being treated. The following examples are illustrative of the invention. [Embodiment] Hereinafter, "THF" means tetrahydrofuran, "Qing" means 邸_dimethylene, and "mPEA" means N-ethyl, μ-ethyl)-2-propylamine.

A plurality of compounds are purified by a reverse phase high performance liquid (four) analyzer using the following method (in the compound step method and method HPLC method A product, work, reverse phase performance liquid chromatography (muscle 8 8) Micron, AW XTR A 77) purification. Three mobile phases were used (mobile phase A: 90% NH4〇AC solution + 1〇% CHsCN; mobile phase B: CH3〇H; mobile phase C: CH3CN). First m and B, the flow rate is 40 ml / min for 0.5 min. The defect is w and 50% C and the flow rate is 8 Gm; the gradient is applied to 5〇% B ζ, ιηπ〇 / r « ^ l / Knife. Then at 20 Minute gradient application

to. C and the post-speed is 8 〇 ml / min and keep 4 points. HPLC method B product, work, reverse phase South Vietnamese liquid chromatography (10) (four) still 8 microns 50 200811131 25 grams; I. D. 5 cm) purification. Three mobile phases were used (mobile phase a: 0.25% 丽 〇 3 solution; mobile phase b: CH3 〇 H; mobile phase c: CH3CN). First, 75% A and 25% B, the flow rate was 4 〇 ml/min for 0.5 minutes. The gradient was then applied to 5 〇 % β and c at 41 minutes and the flow rate was 80 ml/min. A gradient of 2 Torr was then applied to 匸 and the flow rate was 80 ml/min and held for 4 minutes. A. Preparation of intermediate materialization Example A1 a) Preparation of intermediate 1

Phenylmethyl chlorate (0.116 mol) was added dropwise to 3-phenyl-[3,4'-bishexahydropyridine]-2,6-dione (0.1 mol), DMF, pa· (3 〇〇 ml) and EtsN (0.3 mol) in a stirred mixture. The reaction mixture was stirred at room temperature for 18 hours. Pour the mixture into cold water (1 liter). Use B_(2χι升) to draw the product. The combined organic layers were dried (MgSO.sub.4), filtered and evaporated. The residue was stirred in diethyl ether (200 ml), filtered, washed and dried (vac., 50 </ </ RTI> </ RTI> yield: yield: 29 g of intermediate 31.

51 200811131 Mixture of Intermediate 1 (0.00246 mol) in THF (20 mL; p.a., dried on a molecular sieve). Trihydro(tetrahydrofuran)-boron (12. 3 ml; 1 M in THF) was slowly added and the mixture was stirred and refluxed for 6 hours under n2 atmosphere. The reaction mixture was cooled to room temperature and poured slowly 1N EtOAc (EtOAc). Stirring was continued for 1 hour and then diethyl ether (5 mL) was added. Stir for 30 minutes. NaHC03 was added to the separated aqueous layer until pH 28. This mixture was extracted with CH2C12/CH30H 90/10. The separated organic layer was dried (MgSO.sub.4), filtered and evaporated. Yield: 0.96 grams of intermediate 2. Preparation of intermediate 3

A solution of intermediate 2 (0.00253 mol) and Et3N (1 ml) in CH2Cl2 (15 liters ^ p.a.,) was stirred on an ice bath. Ethyl chlorate (0.0028 stock) was added and the reaction mixture was taken up in hydrazine. The turbulence was dropped for 1 minute and stirred at room temperature for 18 hours. Aqueous (1) 3 aqueous solution (25 ml, money and) was added to the reaction mixture for 15 minutes. The separated organic layer was dried (MgS 〇 4), and the solvent was evaporated. The residue was purified on silica gel by S-flash column chromatography (eluent: CH.sub.2Cl.sub.2/CH.sub.3H. The products were combined, evaporated by a solvent and evaporated together with 〇Η3〇η and toluene. Intermediary · 〇 · 42 grams of intermediate 3 (36.8%). 52 200811131 _d) Preparation of intermediates 4

A solution of Intermediate 3 (0.0009 mol) in CH3 〇H (50 mL; p a) was hydrogenated with Pd/C 10% (0.1 g). After consumption of H2 (1 equivalent), the catalyst was filtered and the filtrate was evaporated. Yield: 〇·28 g of intermediate 4 (98%) 〇 Example Α 2 a) Preparation of intermediate 5

Acetic anhydride (5 ml) was added to a stirred solution of Intermediate 2 (0.00819 mol) in THF (2 liters; P.a.). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated. Xylene was added and the mixture was again evaporated on a rotary evaporator. The residue was purified on silica filter paper by silica gel (wash: liquid: CH.sub.2Cl.sub.2/CH.sub.. The product fraction was collected and the solvent was burst. Toluene was added and co-evaporated on a rotary evaporator. Yield: 1 2 of intermediate 5.

53 200811131 A solution of Intermediate 5 (0.0028 mol) in CH3〇H (5 mL) was hydrogenated with Pd/C 10% (0.5 g) as a catalyst. After consuming % (丨 equivalent)

The catalyst was filtered and the filtrate was evaporated. Yield · 0.56 g of intermediate 6'. Example A3 A Preparation of Intermediate 7

A solution of the final compound 9 (0.00045 mol) in HBr (10 mL; 48% p. a.) was stirred and refluxed for 2 hrs and then stirred overnight at room temperature. The solvent was evaporated and co-evaporated with toluene. The residue was taken up in CH.sub.2Cl.sub.2 (2 mL). Stirring was continued for 18 hours. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (eluent · CH2Cl2 / (CH3 〇 H/NH3) from 100/0 to 93/7) on a 12 gram of RediSep. The product fractions were combined and the solvent was evaporated. Yield: 〇·13 g of intermediate 7 (69.9%). Example Α3ΓΒ) a) Preparation of intermediate 8

The reaction was carried out under N 2 gas pressure. Diphenylbenzene (206 liters) was poured into a 500-liter RVS reactor first flushed with n2 gas. Add α-phenyl phenylmethyl)-4- 54 200811131 Hexahydroindole acetonitrile (60 kg) and heat the mixture to reflux temperature. Use the water to make the solution steamed until there is no water. Pass ν2 gas. Cool the mixture to ±65 °C. CH3ONa 30% (9 J kg, 51 · 6 mol) was added dropwise at ±65 °C. The 2-methylpropionate (26.7 kg, 310 m) was added dropwise at 65 ° C for 30 minutes. The addition vessel was rinsed with dimethylbenzene (20 liters). The reaction mixture was stirred at ±7 (TC for 4-6 hours, then cooled to room temperature. NaCl (5.2 kg) and water (133 L) were added and the mixture was stirred for at least 5 minutes. The liquid layer was slowly separated. The layers were separated, treated with NaCl (2.6 kg) in water (67 liters) and stirred for at least 15 minutes. The liquid layer was slowly separated. The organic layer was separated, dried (Na.sub.2, 4, 5 kg), filtered through a cotton bag. The solvent of the filtrate was evaporated (in vacuum, vessel temperature: 1 〇〇 c &gt; c). Yield: 71.7 kg of intermediate 8 (92%) b) Preparation of intermediate 9

Intermediate 8 (up to 0.01 mol) was dissolved in CH 3 〇H (2 〇〇 ml and this lysed Pd/C 1G% (q's.) was hydrogenated at room temperature. After consumption (1 equivalent), Jianmo County and the filtrate (containing the basic starting material intermediate 8) with Raney Nickle (1 g) as a catalyst at room temperature

55 200811131 Same as evaporation. Yield: 1.45 g of intermediate 9 (56.1%). c) Preparation of intermediate 10

Add 1-bromo-4-(1-chloroethyl)benzene (0·00035 mol) to intermediate 9 (0.00019 mol) in Et3N (0.2 mL) and DMF (4 mL; pa·) In solution. The reaction mixture was shaken at room temperature for 18 hours and then shaken at 55 ° C for 40 minutes. The residue was subjected to reverse phase high performance liquid chromatography (column: XterraPrepMS C18, length · 10 cm, ID: 19 mm particle size: 5 μm: eluent: (〇. 2% NH4HC03 in H2〇) /CH3〇H/CH3CN gradient) purification. The product fractions were combined and the solvent was evaporated. Add methanol and co-evaporate on a rotary evaporator to obtain an intermediate 10 〇 d) Preparation of intermediate 7

BH3.THF (30 mL; 1M in THF) was added to crude intermediate 10 (2 g). After the initial foaming was stopped, the reaction mixture was heated to reflux temperature, then stirred and refluxed for 18 hours. The mixture was allowed to cool to room temperature. Then pour it into a mixture of concentrated HC1 (20 liters) and ice (40 grams). This mixture was stirred for 3 hours. The resulting mixture was cooled on an ice bath. Solid K〇H was added portionwise until pH &gt; This mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO.sub.4), filtered, and evaporated. Add a copy and co-evaporate on a rotary evaporator. Yield gram of intermediate 7 (crude yield). Intermediate 7 can be converted to a different final compound according to the description of Example 61. Example A4 kl) Preparation of Intermediate 11

Inter-substance 11. A-2) Preparation of intermediates to add CH3〇Na_7〇莫耳) to Bu (phenylmethyl^large hydrogen hydrazine bite (〇._mole) and 2,4_two phenylacetonitrile _27 mole) In a solution of anhydrous CH3OH (50 liters) under a nitrogen atmosphere, the mixture was stirred under reflux for 4 hours. The reaction mixture was then cooled to room temperature and poured into ice (g). The mixture obtained from the purpose of extraction. The separated organic layer was dried (Na 2 SO 4 ), and the solvent was evaporated in vacuo. Yield: 5 3 grams in the middle

57 200811131 Add CH3ONa (47.2 ml, 0·26 mol; 3〇% in CH3〇H) to 2,4-difluorophenylacetonitrile (39.7 g, 0.259 mol) and __(phenylmethyl) 4-, hydropyridone (24.5 g, 0.129 mol) in CH3〇H (25 mL; pa·) in a solution under nitrogen. The reaction mixture was stirred and refluxed for 18 hours. The solvent was evaporated and the residue was stirred in 250 mL ice EtOAc. The product was stroked twice with DCM. The combined organic layers were dried (MgSO.sub.4), filtered and evaporated in vacuo. The residue was filtered through silica gel (eluent: DCM / MeOH 99.5 / 0.5). The pure fractions were combined and the solvent was evaporated and evaporated with toluene. Yield · · 27. 6 grams of intermediate 11 . B-υPreparation of intermediates 12

Add NaBH4 (0.0245 mol) to a solution of intermediate η (0.0163 mol) in 2-propanol (2 mL). The mixture was stirred at reflux for 4 hours and cooled to room temperature. Then, a mixture of water and ice (200 ml) was added and extracted with dichlorohydrazine. The extract was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was subjected to flash chromatography (eluent: hexane / ethyl acetate 4/1). The product fraction was collected and the solvent was evaporated. Yield: 3·464 g of intermediate 12 (65%; 2-(1-benzylhydrohexahydropyridyl)-2-(2,4-difluorophenyl)acetonitrile 58 200811131

(raxrF

i F A solution of intermediate 11 (27 g, 0.083 mol) in porphin solution (2 ml) and CH3 〇Ii (250 ml; pa) via pd/c 1% (3 g catalyst) . After the calculated amount of (1 equivalent) is consumed, the catalyst is overdone. The transition solution was evaporated and co-evaporated with Μ·二. The residue is used in the next step. Yield · Intermediate 12 (residue). Intermediate

Intermediate 12 (0.083 mol; residue) and methyl acrylate (9 liters, 0.1 mol) in 1,4-dioxane (250 ml; pa·; dried on molecular sieves) The solution was stirred under N2 pressure and ice to cool. When stirring became difficult, Triton-B (1 ml; catalyst) was added and the reaction mixture was continuously stirred on an ice bath for 5 minutes and then stirred at room temperature for 3 days. More methyl malate (3 ml) and Triton-B (0.5 ml) were added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated. The residue was filtered through silica gel (eluent: DCM/CH3 〇H99/l). The desired fractions were combined and evaporated to co-evaporate with toluene. Yield: 32 grams of intermediate 13 (93.5%). 59 200811131 d) Preparation of intermediates 14

BH3 THF (1M in THF; 100 mL; &lt;RTI ID=0.0&gt;&gt; After the initial foaming, the reaction mixture is heated. The mixture was stirred and refluxed for 2 hrs. The solvent was then evaporated and co-evaporated with toluene. Yield · Intermediate 14 (residue). gL preparation intermediate 15

H2 〇 (1 liter) was added dropwise to the intermediate (residue; 0 0288 mole) (exothermic reaction). HBr 48% (25 ml) was added dropwise (exothermic) and slowly added to HBr 48% (75 mL). The mixture was stirred and heated on an oil bath for 1 hour and then stirred at room temperature for 18 hours. The precipitate was filtered and washed with a small amount of HBr 48%. The filtrate was added dropwise to a mixture of 50% NaOH (100 mL) and crushed ice and cooled on an ice bath. After the addition, the mixture was stirred for 1 hour, and then the product (aqueous layer ph &gt; 9) was extracted with CH2C12. The separated organic layer was dried (MgSO.sub.4), filtered and evaporated and evaporated. The crude residue (intermediate 15) was used as such in the next reaction. 60 200811131

... The intermediate 15 (1 g; 0.0027 mol) and acetic anhydride (15 ml) / trough solution were stirred at 60 ° C for 1 hr. The solvent was evaporated and co-evaporated with toluene. The residue was stirred in aq. aq. The separated organic layer was dried (MgSO.sub.4), filtered and evaporated.

2 The residue was purified on silica gel by flash chromatography (eluent: CH.sub.2Cl.sub.2/Me.sup. The desired fractions were combined and the solvent was treated and co-evaporated with MeOH. The product was crystallized from Et 2 oxime, filtered, washed with EkO and dried (vacuum, 5 〇. 〇. yield · 〇 · 24 g of intermediate 16 〇 intermediate 17 intermediate 16 (〇·24 g; 〇·〇〇 The solution in MeOH (100 ml; Pa) was hydrogenated at room temperature with Pd/C 10% (0.05 g) as a catalyst. After consumption of H2 (1 eq.), the catalyst was filtered and the filtrate was evaporated. Production 61 200811131 Quantities: Intermediate 17. The residue is used in the next reaction. _Preparation of final compound example B1 a) Preparation of compound 1

A solution of Intermediate 7 (0.000109 mol) in butyl formate (1 mL) was stirred at 100 ° C for 4 h. The solution was then allowed to cool to room temperature. The volatiles were evaporated and the residue was purified via flash flash (eluent: CH2C12/CH3 〇H90/1 。). The collected product fractions were scrambled in CH2C12/CH3〇h 90/10, filtered and washed. The filtrate was evaporated. Yield; 0.016 g of Compound 1 (33.3%). Compound 2

Intermediate 7 (0.00012 mol) was stirred in / THF in THF (2 mL; p. a.). Acetic anhydride (2 ml) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dissolved in EtOAc (3 EtOAc). The organic layer was filtered and dried over Is </ RTI> </ RTI> <RTI ID=0.0> </RTI> HM-N filter paper and the filtrate was evaporated. Yield; 〇 〇 5 gram of compound 2 (90 8%). _C) Preparation of compound λ

A solution of intermediate 7 (〇·〇〇〇1〇92 mol) and Et3N (01 ml) in CH2C12 (3 ml; p.a.) was stirred. Methylsulfonium chloride (0.00012 mol) was added and the reaction mixture was stirred at room temperature for 18 h. An additional amount of EtsN (0.2 ml) and sulfonium chloride (0·_13 mol) were added and the reaction mixture was stirred at room temperature for 24 hours. Na2C03 (2 mL; 10 〇 / 水溶液 aqueous solution) was added and the mixture was stirred vigorously for 15 min. The organic layer was separated, dried (MgSCg, filtered and evaporated). The residue was purified from EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: Stir, filter (removed tannin) and wash with 7 &gt; month. Filtration and liquid strips were produced. Yield, 〇·〇 19 g of compound 3 (35 5%).

A solution of Intermediate 7 (0.000109 mol) and EtsN (0.1 mL) in CH2C12 (3 mL; p.a.) was stirred. Propionyl chloride (〇(8)12 mol) was added and the reaction mixture was stirred at room temperature for 18 hours. Na2c〇3 63 200811131 (1.5 ml; 10% aqueous solution) was added and stirring was continued for 5 hours. The organic layer was separated, dried (MgSO.sub.4), filtered and evaporated. The residue was purified via a flash (eluent: CHzCl2 / CHsOH 90/10). The product fraction was separated, stirred in CH2C12/CH3 〇H90/10, filtered (removed silica gel) and washed. The filtrate was evaporated and co-evaporated with CHsOH. Yield; α 〇 33 g of compound 4 (64.5%). e) Preparation of compound 5

Benzamidine chloride (0.00012 mol) was added to a solution of Intermediate 7 (〇 〇〇〇1〇9 Mo) and Et3N (0.1 mL) in mL). The reaction mixture was stirred at room temperature for 4 days. Me 〇H (1 mL) was added and the solvent was evaporated. The residue was purified on a flash tube by flash column chromatography (eluent, CH2C12/CH3 〇H90/1). The product fractions were collected and stirred in CH2C12/CH3OH90/10, filtered, and the filtrate was evaporated and the filtrate evaporated. Yield; 0.03 gram of compound 5 (53.2%). ^ f) Preparation of compound 6

64 2〇〇8Ul31 decylamine 18 〇120 ;: coffee by reverse phase high performance liquid chromatography (two and the Wei liquid evaporated. Add methanol and co-purified on the rotary evaporator (5). Yield; 〇 '() 〇 84 g of compound 6 (15 6%). gl recovery compound 8

Isocyanobenzene (0.00012 mol) was added to a solution of intermediate 7 (〇 〇〇〇 1〇9 mol) in CHzCbG ml; p.a·) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated. The residue was purified by a flash tube (eluent: CH2C12/CH3OH90/10). Part of the desired product was separated and scrambled in CH2C12/CH3 〇H90/10, and the sputum was removed by tearing and the filtrate was evaporated. Yield; 〇·〇 37 g of compound 8 ^ (63.7%) 〇 h) Preparation of compound 29

65 200811131 Intermediate 7 (〇.〇〇〇1〇9mol, 0.045g) and isocyanotriyldecane (0·00015 mole, 〇·〇 2ml) in 1,4_dioxane ( The solution in 3 ml (dried on molecular sieve) was stirred in a sealed test tube of 9 (TC) for 2 hrs. A saturated aqueous solution of Ni^Cl (1 ml) was added. The solvent was evaporated. The product was extracted with CH3〇H (9〇/1〇). The separated organic layer was evaporated. The residue was purified by high-performance liquid chromatography (method A). The residue was dissolved in (5 mL) and aq. NaH.sub.3 (aq. The filtrate was washed four times with CH.sub.2Cl.sub.2 (5 mL). The filtrate was evaporated. Yield: </ RTI> </ RTI> 7 g of compound 29 (14.1%).

Add propylene-carbonated chlorine (0.014 ml, 〇·〇〇〇2 Mo) to Intermediate 7 (〇·〇5 g, 0·0001 Mo) in ch2C12 (3 ml; pa·) and EhN ( A stirred solution of 〇·〇 25 ml, 0.0002 mol) and the mixture was stirred at room temperature for 48 hours. NH3 (7 N, 1 mL) in CHsOH was added to the reaction mixture. The solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Method B). The desired product fraction was collected and the solvent was evaporated and co-evaporated twice with CHgOH. Yield; 〇·045 g of 66 200811131 Compound 30 (77.2%). 1) Preparation of compound 31

Add dimethylsulfazone chloride (0.013 ml, o.oooi Mo) to intermediate 7 (〇·〇45 g, 0.0001 mol) in CH2C12 (5 mL; pa) and 〇ΙΡΕΑ (〇· 2 ml, 〇·〇〇12 mol) in a stirred solution. The mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with aq. The separated organic layer was evaporated. The residue was purified via a flash tube (eluent: CH.sub.2Cl.sub.2/CH.sup. After collecting the desired product fraction, it was stirred with a portion of CH2C12/CH3〇H (90/10). The mixture was filtered and the filter paper residue was washed. The combined filtrates were evaporated. The residue was purified by reverse phase performance liquid chromatography (Method B). The desired product was collected and the bath was sprayed and co-evaporated 3 times with cH3〇H. Yield; 〇·〇 15 g of compound 31 (26.4%). k) Preparation of compound 35

Add isocyanobite (0. 018 g, 0.0002 mol) to intermediate 7 (0.05 g, 0.0001 mol) in ml; pa) in a stirred solution of 67 200811131 and then stir at room temperature 20 hour. (7 N, 1 mL) was added to the reaction mixture. 1 o'clock. NH3# will be in CH3OH. The solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (Method B). The desired product fraction was collected and the solvent was evaporated and co-evaporated 3 times with CH3〇h. Yield; 〇·〇 48 g of compound 35 (74 4%).

Difluoroacetic anhydride (1 mL) was added to Intermediate 7 (0.064 g, 0.000154 mol). The reaction mixture was stirred at room temperature for 4 days. The solvent was evaporated and the residue was stirred in CH2C12. The organic layer was washed with aq. aq. NaH.sub.3, and dried (MgSO.sub.4), filtered and evaporated. The residue was purified via this 8111 (^ eluent: €1120:12/€113〇1194/6). The product fraction was separated and stirred in CI^CWCHsOH 94/6. Filter and wash the stone gelatin. The filtrate was evaporated and the yield; 〇 29 g of compound 36 (36.8%). m) Preparation of compound 37

68 200811131 Intermediate 7 (0.000109 mol, 0.045 g), 2-gas, dense 17 (0·00011 m, 0.0126 g), K2C〇3 (0.00011 mΓ0 〇 152 g) and EtOH (4 ml) The mixture of pa·) was mixed for 18 hours in a sealed test tube of 85 qC. The solvent was evaporated. The residue was stirred in % 并 and the product was extracted with EtOAc. The separated organic layer was dried (MgSO.sub.4), dried and evaporated. The residue was subjected to high performance liquid chromatography (method = purification). The desired fractions were collected and evaporated, and evaporated with EtOAc.

H) Preparation of compound 3R

0.0002 mol) added to the middle to add 2-chloroacetamide (〇.014 g, 0.0002 mol) to: (0.05 g, _01 mol) in cha (3 ml) and to f example B2 9 liters, 0.0002 mol) of the stirred solution and stirred at room temperature for 18 mils to evaporate the solvent. The residue was purified by reverse phase high performance phase chromatography ( square y B). The desired product fraction was collected and the solvent was evaporated and co-evaporated twice with % 〇H. Yield; 0.028 g of compound 38 (492%).

69 200811131 Mix the intermediate 4 (0.00079 mol) and EtgN (0.001 mol) in CH2C12 (10 liter, p.a.) and CH3OH (10 ml, p.a.). 1-Bromo-4-(methylmethyl)benzene (0.0010 mol) was added and the reaction mixture was stirred at room temperature for 18 h. Then CH2C12 (20 mL), H.sub.2 (20 mL) and sat. Stirring was continued for 1 hour. The separated organic layer was dried (MgSO.sub.4), filtered and evaporated. The residue was purified by column chromatography (eluent CH2Cl2 / (CH3OH/NH3) from 100/0 to 96/4) on EtOAc (EtOAc). The product fraction was collected and the solvent was evaporated. Yield; 24 g of compound 9 (62.5%). Example B3

Preparation of compound η A mixture of intermediate 6 (0.000175 mol) and DIPEA (0.2 ml) in DMF (4 ml; p. a.) was shaken at room temperature. _Bromo-4-(glymethyl)-2-fluorobenzene (0.000244 mol) was added and the resulting reaction mixture was shaken at room temperature for 18 h. The solvent was evaporated. The residue was subjected to reverse phase high performance liquid chromatography (column: XterraprepMSC18, length · 10 cm, ID·: 19 mm, particle size: 5 μm: eluent: (0.2% NH4HC〇3 in H2〇) ) /CH3OH/CH3CN gradient) purification. The product fraction was collected and the solvent was evaporated. Add ch3oh and co-evaporate (2x) on a rotary evaporator. Yield; compound 13 (8.4%). 70 200811131 Example B4 Preparation of Compound 23

A solution of Intermediate 6 (〇·〇〇ηmol) and DIPEA (〇 28 mL) in CH2C12 (10 mL, p a) was stirred. The product was stirred in ice (chloromethyl)benzene (0.0015 mol) and the reaction mixture was stirred at room temperature for 18 hours. Et3N (0.5 mL) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was washed with a solution of samarium and NaHC 3 (saturated aqueous solution). The separated organic layer was dried (MgSO.sub.4), filtered and evaporated. The residue was purified by column chromatography (eluent · CH 2 Cl 2 /CH 3 〇H from 99/2 to 98/2). The product fractions were combined and the solvent was evaporated and co-evaporated. The product was converted to its HCl salt by the addition of hci/2-propanol (25 mL; 6N) in 2-propanol (1 mL). The solvent was evaporated and the residue was crystallised from diethyl ether. The product was filtered, washed and dried (vacuum, 5 〇. 〇 yield, 0.309 g of compound 23 (44.9%). Example B5 Preparation of compound 24 and compound 25

71 200811131 Via supercritical fluid chromatography on AD-H column (equal elution: 35% (: 〇2/65% sterol + 0.1% 2-propanol; flow rate: 50 ml/min; column) Furnace: 40 ° C; nozzle pressure: 1 bar) Separate compound 8 (〇·〇〇ΐ3 mol) into its palm counterpart. Collect the two product fractions and evaporate the solvent. The product was dissolved in diethyl ether and converted to the hydrochloride salt (1:1) using EtOAc (EtOAc) (EtOAc). Compound 24 and 0.22 g of compound 25. Example B6 Preparation of compound 26 and compound 27

Supercritical fluid chromatography on the AD-H column (extraction gradient: CCVHMO% methanol; HM0% methanol gradient was applied at 1.6%/min and the last condition was maintained for 4.5 minutes; flow rate: 50 ML/min; column furnace: 40 ° C; nozzle pressure: 1 bar) Separate compound 2 (0.0006 mol) into its palmomer. Both product fractions were collected and the solvent was evaporated. Each residue was dissolved in 2-propanol and converted to its hydrochloride (1:1) using HCl (6N)/2-propanol. The salts were filtered, washed with ether and dried. Yield: 0.079 g of compound 26 and 0.104 g of compound 27. 72 200811131 Examples 丞盖也金物39 and compound 40

On the AD-H column (20 x 250 mm) by supercritical fluid chromatography (special elution. 60% 〇: 〇 2 / 40% methanol containing 〇. 2% 2-propanol; flow rate: 50 ml / min ; column furnace: 40 ° C; nozzle pressure: 1 bar) Compound 38 (1.8 g) was separated into its palm counterparts. The "a" portion is the first palm isomer extracted from the column under a given preparative-to-palm separation method. The product portions of the "Α" portion were combined and the solvent was evaporated. The residue was dissolved in Et 〇H (25 mL) and fumaric acid was added. The solvent was evaporated after stirring for 2 hours. The residue was stirred in a 2 〇. Precipitate = filter, clean 3χ with Ε^Ο and at 50. (: (vacuum) drying. Yield: compound 39 (S, 〇R: +). The "B" part is the second preparation from the column at the given preparation level. The palms of the isomers were combined and the solvent was evaporated. The residue was dissolved in EtH (25 mL) and fumaric acid was added. In the Et2 〇中麟. The transition of the sect of the temple, using π 冼 3x and drying at 5 (rc (vacuum). Yield · · Compound 4 〇 (r 〇r • 10 73 200811131 Example B8 Preparation of compound 41

Acetic acid (0.053 ml) was added to the intermediate Η (residue; 0.00058 mol), 4-bromobenzaldehyde (0.14 g; 0.00075 mol) and sodium triethionate borohydride (〇·369 g; 0.00174 m) Ear) in a scrambled mixture of CH2Cl2 (l〇 ml, pa·). The reaction mixture was continuously disturbed for 18 hours at room temperature. Then HCl solution (1 N, 2.5 ml) was added and stirring was continued vigorously for 1 hour. Then a K2C〇3 semi-saturated aqueous solution (1 mL) was added. The organic layer was separated and washed with H2. The separated organic layer was then dried (MgSO.sub.4), filtered and evaporated. The residue was purified by cloning (eluent: CH2Cl2 / (MeOH / NH3 7N) from 100/0 to 99/1 to 98/2 to 97/3). The desired fractions were combined and the solvent was evaporated. The product was converted to its 11 (:1_ salt) using HC1/2-propanol (6 Ν; 0.5 mL) in propanol. The solvent was evaporated and the residue was triturated in EkO. The precipitate was filtered and washed with EkO And dried (5 (rC; vacuum). Yield; Compound 41 (68.8%; HCl) salt of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1

Comp. No. Exp. No. R1 R3 Y R2a | Stereo Label / Salt / Analytical Data 1 Bl.a -H c=〇 H Η *(RS) 75 200811131

Comp. No· Exp. No· Rl R3 Y R2a R2b Stereo Marker / Salt / Analytical Data 2 Bl.b -ch3 c=o HH *(RS) 3 Bl.c -ch3 o=s=o HH *(RS) 4 Bl.d -CH2CH3 c=o HH *(RS) 5 Bl.e , j〇00 HH *(RS) 6 Bl.f -nh2 o=s=o HH *(RS) 7 Bl.d 00 HH * (RS) 8 BLg c=o HH *(RS) 9 B2 π ^CX^CH, c=o HH *(RS) 10 B3 -ch3 00 HH *(RS) 11 B3 -CH3 00 HH *(RS) 12 B3 cxr^ -ch3 c=o HH *(RS) 13 B3 -ch3 c=o HH *(RS) 14 B3 -ch3 c=o HH *(RS) 15 B3 -ch3 c=o HH *(RS) 16 B3 -ch3 c=o HH *(RS) 17 B3 -ch3 00 HH *(RS) 18 B3 严·' &gt;ch3 00 HH *(RS)**(RS) 19 B3 -ch3 c=o HH *( RS)**(RS) 20 B3 ςΡ1 Cl -ch3 c=o HH *(RS) 76 200811131

Comp. No. Exp. No. R1 R3 Y R2a R2b Stereo Label / Salt / Analytical Data * (RS) 21 B3 Br -CH} c=o HH 22 B3 CXT&quot; -ch3 c=o HH *(RS) 23 B4 -ch3 oo HH HCl-salt *(RS) 24 B5 c=o HH *(R); HC1 salt 25 B5 c=o HH *(S); HC1 salt 26 B6 -ch3 oo HH *(R); HC1 salt 27 B6 -ch3 c=o HH *(S);HC1 salt 28 B3 -QTV -ch3 oo HH *(RS) 29 Bl.h .JX&quot; -nh2 oo HH *(RS) 30 Bl.ic=o HH * (RS) 31 Bl.j -N(CH3)2 o=s=o HH *(RS) 32 Bl.k oo HH *(RS) 33 Bl.k π h3c oo HH *(RS) 34 Bl.k oo HH *(RS) 35 Bl.k oo HH *(RS) 36 Bl.l 'CF3 c=〇HH *(RS) 37 B! .m , X) db HH *(RS) 38 Bi.n -nh2 - ·μ·- HHH *(RS) 39 B7 -nh2 HHH *(S); OR: +, fumarate 77 200811131

Comp. No. Exp. No. Rl R3 Y R2a R2b Stereo label/salt/analytical data 40 B7 -nh2 ••P... HH ,);〇R, fumarate 41 -ch3 c=o FF •HC1 〇R Refers to optical rotation; db refers to direct key C. Analyzes LChdS conditions ^ General side ~ HPLC gradient is via four-pole pump including degassing, auto-injector, official column oven (set at 4 〇. DA and DAD detector Provided by the Alliance HT 2790 (Waters) system. The flow of the official column is shunted to the Ms detector. The MS detector is assembled with an electron atomization free source. The mass spectrometer is from 100 in 1 second using a residence time of 1 second. Scan to 1000 and draw. The capillary true voltage is 3 kV and the source is maintained at 14 (TC. Nitrogen is used as the atomizing gas. Data shelving is performed using the Wat.Micromass MassLynx_〇penlynx data system.

General Method B LC gradients were provided via an Ac(4) y upLc (Waters) system including a dual feed pump, sample manager, column heater (set at 55 ° C), and diode-array debt detector (DAD). The flow from the column is split to the Ms detector. The ms detector is an electronic atomization free source. The f-spectrum was obtained by scanning the residence time of 2 seconds from 1 在 to 1 在 in 0.18 seconds. Capillary 78 200811131 The true voltage is 3.5 kV and the source temperature is maintained at 14 () t. Nitrogen was used as the atomizing gas. Series #1 mosquito made by Wate~Mi_assMassLynx_ Openlynx data system. Method 1 In addition to the general method A: reverse phase HPLC was carried out at a rate of 1.6 ml/min on a 018 column (3.5 μm, 4.6 x mm). Use three mobile phases (mobile phase A: 95% 25 millimoles acetic acid by +5% acetonitrile 'mobile phase B: acetonitrile; mobile phase c: methanol) for driven % A to 50% B and 50 〇 / 〇 &lt;: At 65 minutes to 1〇〇%8 at i minutes, the touch/〇B was subjected to a gradient condition of 1 minute and rebalanced for 15 minutes with just % a. The injection volume used was 1 G microliter. The cone voltage of the positive free mode is 10 V and the cone voltage of the negative free mode is 2 〇 v. Method 2 In addition to the general method A: reverse phase HPLC was carried out in a Chromo brain (4.6 x 25 mm) at a flow rate of 3 ml/min. Use three mobile phases A: 95% 25 millimolar concentration vinegar + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) from contact % a, to 5 〇 % β and 5 〇 % c 0.9 minutes, to 100 〇 / 〇 B in 〇 3 minutes and keep 〇 2 minutes gradient operation. The volume used is i microliters. The cone voltage of the positive free mode is 10 V and the cone voltage of the negative free mode is 2 〇 V. Method In addition to the general method A, the reverse phase HpLC was fed at 16 ml/min = flow rate on an XtermMSC18 column (3·5 μm, 4 6χ1 mm). Two mobile phases (mobile phase A: 7〇% methanol + 3〇%1^〇; mobile 79 200811131 5% acid (7) alcohol 95/5) were used to perform a two-minute gradient operation from the contact % B. Injection used - 疋 10 μl. Positive Free Mode The cone voltage is 20V. The voltage is 1 (^ and the negative free mode method 4 except the general method A · n flow rate in the fine aMsr tube head 3rLC is used h6 ml / entry mg mg column (3 · 5 microns, 4.6 x 100 mm) Enter A to iy month A 49〇/:B • B ride, move phase C: methanol) to carry a gradient from 100% B in the heart and ====-=. The injection Zhao product used is the second method (10) and the cone-free electric dust in the negative free mode is 2 〇V. In addition to the general time method B: reverse phase UPL: flow two: connect: ethyl Chenna just ^. ^ ^ A ·· ^ Hold these conditions by] minutes and Lin in the b clock and protect the free cone cone voltage It is 20 V. Method 6 In addition to the general method A: the column heater was set at 6 generations. Inverse 80 200811131 Phase HPLC was carried out at a flow rate of 1.6 ml/min on a XterraMs Cl8 tube (3.5 μm, 4.6 χ 100 mm). Use three mobile phases (mobile phase ^^: 95% 25 millimolar ammonium acetate + 5% acetonitrile; mobile phase β: acetonitrile.., phase C: methanol) from 1〇〇% a to 5〇% Β+ And 鄕c in the month 6 $ shift ^ G. 5 minutes and the conditions are 1 minute and 5 is the gradient condition of the minute. The injected volume cone voltage used is the cone voltage of the free mode is 1 〇 乂 and the negative free mode data (the residence time is in minutes green; MH+ refers to the mass of the compound). The peak, the mixture of structures, which gives the retention time of different specific components in the lcms method)

81 200811131 12 429 6.69 1 13 473 6.85 1 14 445 7.05 1 15 445 7.28 1 16 473 6.89 1 17 469 6.83 1 18 469 6.65 1 19 483 6.88 1 20 417 6.49 1 21 495 6.95 1 22 419 6.43 1 23 455 (Free Base 1.11 2 24 532 (free base) 7.47 3 25 532 (free base) 7.47 3 26 455 (free base) 6.29 3 27 455 (free base) 6.26 3 28 455 6.69 4 29 456 6.2 4 30 481 6.89 4 31 568 1.15 5 32 533 0.88 5 33 551 6.57 4 34 538 6.82 4 35 520 1.05 5 82 200811131 36 , 509 7.17 37 — 491 7.00 38 -_ 470 6.59 39 -------- 470 (Free 6.60 40 ——___ 470 (free state test) 6.58 41 491 (free state test) 7.72 Optical rotation j6 4 4 4 3 Optical rotation is used to make 帛 polarized light. [〇, 彳 The optical rotation of the first measurement of the wavelength of the line using sodium (589 nm). In addition to the actual value, N measures the solution for optical rotation: concentration and solvent.

Compound No. [a] D20 Concentration 5 Tolerance 1! 24 -78.35° ----— 03·51 mg/5 ml/ Seto N ch3oh 25 +86.85° 04.145 mg/5 ml ch3oh 26 -60.44° 04.55 mg / 5 ml CH30H 27 +60 C=5.75 Neck/5 ml CH30H Test method for testing CXCR3 receptor inhibition guanine 5'_[35s]triphosphate exchange is a membrane of human CXCR3-transfected CHO cells Measured on. The [35s] GTPys exchange assay was performed using a basic scintillation disk (Perkin Elmer) in a 96-well plate containing 10 micrograms of membrane protein per tank. The compound was dissolved in DMSO and diluted to the desired concentration of 9% DMSO with culture buffer. The culture buffer was composed of 2 〇 millimolar concentration 83 200811131 HEPES, 100 millimolar NaCl, 3 micromolar GDP, and i millimolar concentration MgCl2, pH 7.4. Membrane culture buffer is supplemented with 14 3 μg/3⁄4 liters of saponin culture buffer. The compound, membrane, hl-TAc (interferon-induced T-cell alpha chemoattractant) and [35S]GTPYS were added at a total volume of 2 〇〇 microliter. First, 20 μl of the appropriate compound dilution and 140 μl of the membrane from CXCR3-CHO cells were dissolved in a membrane culture buffer and preincubated at 30 ° C for 30 minutes. Then, 2 〇 microliters of hl-TAC dissolved in the culture buffer at a concentration of 3 〇 nanomolar was added to the membrane. The mixture containing 1% DMSO was further cultured at 30 ° C for 30 minutes. Finally, add 20 μl at a concentration of 2.5 nanomolar dissolved in the culture to slow down [[, just: m9Ci / millimolar and culture at 30 ° C for 30 minutes, the scintillation plate at 25 rpm and Centrifuge at room temperature for 5 minutes. The activity of the scintillation disc bond was determined via liquid scintillation counting. The substrate was measured for GTPyS-binding in the same volume in a tank of 1% DMs without I-TAC. The IC5G value of the maximum GTpyS_^J human, test compound molar concentration was measured in 8 membrane-containing tanks cultured with 1% DMS and 3 nanomolar I-TAC, which inhibited Cong I-TAC-induced GTPYS· combination. Using nonlinear regression at h

The IC5G value is calculated in Prism. P Pad Table 4 lists the values obtained for the compounds of formula (I) in the above tests. PIC50 defines _bg IC5G where IC5G is the molar concentration of the test compound that inhibits GTPyS-binding induced by C-I-TAC. J付疋84 200811131 Table 4 Compound number pic5〇1 7.0 2 6.9 3 6.0 4 6.7 5 6.4 6 6.7 7 6.1 8 7.2 9 6.5 10 6.6 11 6.8 12 6.8 13 7.3 14 6.5 15 6.7 16 6.9 17 6.9 18 6.7 19 6.4 20 6.1 21 6.5 22 6.8 85 200811131 Compound number pIC5〇23 6.7 24 7.5 25 5.2 26 7.0 27 5.6 28 5.5 29 6·7 30 6.7 31 6.1 32 7.3 33 7.3 34 7.2 35 7.5 36 6.1 37 5.5 38 7.1 39 7.2 40 6.1 41 7.2 86

Claims (1)

200811131 X. Patent application scope: 1. A compound of the formula R3 An oxide, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, or a solvate thereof, wherein X represents N or CH; Y represents a direct bond, CH2-C (=0) wherein CH2 is N, C(=0) or S(20)p attached to the hexahydropyridine ring; p represents an integer of 1 or 2; R1 represents CH(R4)-aryl or CH(R4)-heteroaryl; R2 Represents aryl 2 or heteroaryl; R3 represents hydrogen, Cm alkyl, polyhalo Q-6 alkyl, Cp6 alkoxy, aryl\aryl^NH-, heteroaryl, heteroaryl-NH-, 03_7 a cycloalkyl group, an amine group or a mono or bis(C^alkyl)amino group; R4 represents hydrogen or a Q4 alkyl group; and R5 and R6 each independently represent hydrogen or, if desired, a hydroxy group substituted with a hydroxy group; or R5 and R6, together with the nitrogen to which it is attached, forms a monocyclic heterocyclic ring selected from the group consisting of hexahydropyridyl, hexahydropyridinyl, morpholinyl or thiofenofyl, each of which is optionally substituted by an alkyl group; R7 represents hydrogen Or a Cm alkyl group; 87 200811131 The square group represents a genus; a filamentous filament, each of which is substituted with at least one substituent, especially a "," or two substituents, each substituent being independently Selected from i-based, trans-based, Cl.6-based k-fired Base, Cl_w oxygen county, Ci 6^M oxy group =, sulfur-burning group, multi-functional k-mercapto group, multi-recorded Ci_6 activating oxygen 6 group, exact base, county, HO-SCV, Cl_4 alkyl group _s 〇2, R6R5n-c (=〇k-amino, mono- or di(c)-4alkyl)amino, alkyl aryl, aryl], aryl iCi4, aryl, aryloxy Or aryl 1 c(=o&gt;; ^ aryl 1 represents a phenyl group or a styl group substituted with 1, 2 or 3 substituents, each substituent being independently selected from a functional group, a hydroxyl group, a Gw alkyl group, a Cw alkane Oxy, Cw alkoxycarbonyl, Cl-6 alkylcarbonyloxy, alkylthio, polyhalo Cm alkyl, polydentate alkoxy, cyano, nitro, carboxy, aminocarbonyl, single Or a di(Gw alkyl)aminocarbonyl group, an amine group, a mono- or di(CV4 alkyl)amino group; the group represents a radical or a naphthyl group, each of which is optionally substituted with at least one substituent, especially one , two or three substituents, each substituent being independently selected from the group consisting of a dentate group, a hydroxyl group, a Cw alkyl group, a (6) alkoxy group, a Cl-6 alkoxycarbonyl group, a Cw alkylcarbonyloxy group, a Q-6 alkane Thio group, polyhalo Cm alkyl group, polyhalo group (^_6 alkoxy group, cyano group, nitro group, carboxyl group, ho-so2, CM alkyl group) -S〇2-, R6R5N_C(=0)-, amine group, mono- or di(C)-4-alkyl)amino group, Ci-4 alkylcarbonylamino group, aryl group, square group C〗·4 Oxy, aryl 1 oxy or aryl 1 c (= 〇) _; heteroaryl represents a pyrroline group, imidazolium, pyrazolyl, oxime 88 200811131 base, when Ningji, Finance , base, base I/work,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, A cultivating base, a monocyclic heterocyclic ring; or an alkyl group selected from the group consisting of anthracenyl, XJi, fluorenyl, benzopyranyl, benzoxanyl, phenyl, succinyl, benzoxyl,嗓呤 base, addicted. Well base, 〇奎唯基, 异/奎°林基, 咐 咐 base, material base, Check ♦ Lin Ke L Lin, Nitidine, sulfhydryl, benzofluorenyl, benzoxyl benzobenzinoyl bicyclic heterocycle, each of which monocyclic or bicyclic heterocycle Substituted substituents, especially -, two or three substituents, each substituent being independently selected from the group consisting of _ group, hydroxy group, alkyl group, alkoxy group, c _6 sulphuric acid county, CU6 Base, c, alkyl sulfenyl, oxime 匚 6 "6 alkyl, polydentate oxime 6 alkoxy, cyano 6, schishyl, enradyl, H0-S02-, Cm alkyl-S02-, R6R5N -C(=〇)-, silk, mono- or di(C,4-alkyl)amine or c-alkylcarbonylamino. U4 2. A compound according to the scope of the patent application, wherein γ represents jS ( 0) #R3 represents hydrogen, c]6 alkyl, &amp;oxy group, aryl] aryl-NH-, amine group or mono or: (c]·4 alkyl) amine group 3. A compound of the second or second patent application, wherein C(=0). 4. According to the compound of the patent specification gj 丨 , , 丫 丫 丫 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 A compound according to any one of the patent applications, wherein χ represents 6 A compound according to any one of the preceding claims, wherein ri represents CH(R4)-aryl. 7. A compound according to claim 6 wherein the aryl group represents a phenyl group substituted with one or two substituents, each substituent Independently selected from the group consisting of halo, trans, Q-6 alkyl, Cl6 alkoxy, Ci-6 alkoxycarbonyl, alkylcarbonyloxy, Cw alkylthio, polyhalo.] 6 alkyl, polyhalo Cw alkoxy Base, cyano group, nitro group, carboxyl group, H0-S02-, Cm alkyl-S02-, R6R5N-C (=0), base, mono- or di(C1_4 alkyl)amino group, C1_4 alkylcarbonyl group An amine group, an aryl group, an aryl alkoxy group, an aryloxy group, or an aryl group 1 (: (= 〇) _ 8. The compound according to any one of claims 1 to 5, and R1 represents a compound of any one of the above-mentioned claims, wherein R2 represents a phenyl group which is substituted with one or two halo groups. A compound according to any one of the above claims, wherein the R3 generation 10. According to the compound of item 9 of the application, the towel wire 2 represents the genus of the genus of the genus, the genus of the genus, or the genus of the genus · X is CH; p is 2. 13. The compound according to claim 1 of the scope of the patent application, wherein the compound is , R3 R1, R1 R3 Y R2a R2b , Stereolabel / Salt B^v -Η oo HH *(RS) -ch3 c=o HH +(RS) -nh2 os=o HH *(RS) )/3⁄4 C- 0 HH *(RS) π o^o HH *(RS) -ch3 c=o HH *(RS) •ch3 oo HH *(RS) -ch3 oo HH *(RS) -ch3 oo HH *(RS) plus -ch3 oo HH *(RS) ixr^ -ch3 oo HH *(RS) •ch3 c=o HH *(RS) , ch3 oo HH *(RS) -ch3 oo HH *(RS) &lt;xr^ _ 1 -ch3 oo HH *(RS) 91 200811131 Or its solvate. 14. According to the compound of the patent application scope, the compound is selected 92 200811131 R1 R3 Y R2a R2b Stereolabel/salt c=o HH *(RS) :xr, -ch3 c=o HH *(RS) -ch3 00 HH *(RS) -ch3 c^o HH *(RS) -nh2 -CHrC(=0)· HH *(RS) -ch3 C(=0) HH *(R); .HCI -ch3 C(=0) FF *(RS);HC1 salt-CH2CH3 c=o HH *(RS) •nh2 c=o HH *(RS) π c=o HH *(R); HC1 salt c=o HH *(RS) H.'C c=o HH *(RS) c=o HH *(RS), &quot;HtX 00 HH *(RS) 2 •卄·HH *(s); fumarate, its N-oxide, its pharmaceutically acceptable salt, its stereochemically isomeric form or Its solvate. 15. A compound according to any one of the above claims, for use as a medicament. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a medically effective amount as an active ingredient, according to any one of the patents of claim 1 to claim 11, wherein the compound is in accordance with any one of the claims. A method of preparing a composition of claim 16 of the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a medically effective amount of a compound according to any one of claims 1 to 14. 18. Use of a compound for the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by activation of a subject, wherein the compound is a compound of any one of claims 1 to 14. 19. Use of a compound according to claim 18 of the scope of the patent application for the production of a medicament for pre-T or for the treatment of a disease mediated by activation of the CXCR3 receptor. 20. The use of a compound according to claim 18 or 19, The activation of the CXCR3 receptor is a syndrome of typhoon, inflammation, inflammatory bowel disease, sputum allograft rejection, multiple disease, COPD, glomerulonephritis, allergic contact dermatitis, lupus Psoriasis, atherosclerosis, Sjogren's disease, plague dysfunction. 2L is used according to the scope of claim 20, wherein the disease which is mediated by the activation of the receptor is rheumatoid arthritis, stagnation, colitis, allograft rejection. 22·—the compound of the following formula 94 2〇〇8lii3i where R2, R3, X and Y are based on the scope of the patent application! The definition of the item. 23·—the compound of the following formula Wherein R1, R2, X and Υ are defined in accordance with item i of the scope of the patent application. 24·—Preparation of patent application scope! The method of the compound defined by the item characterized by ^ ^ a) reacting the intermediate of the formula (II) with a suitable intermediate of the formula (in) wherein the Wir form is suitable, in the presence of a suitable solvent and a suitable test, (II) (Ml) 1 2 (I) wherein R, R, R, X and γ are as defined in the scope of the patent application; b) intermediates of formula (II) with intermediates of formula (III) Ru represents an aryl or heteroaryl group, in a suitable reducing agent, a suitable acid and a suitable solvent &amp; 95 200811131 where R, R3, x and γ are defined in accordance with item 2 of the scope of the patent application; 0 ^ (ιν) intermediate and formula (ν) intermediates, the towel % represents a suitable release and is suitable In the presence of a base and if necessary in the presence of a suitable solvent, R3a-Y-W2 R3a-oP wherein r1^2(,V), x and γ are as defined in the scope of claim i and are -solr The definition of Y-R3a in item 1 but not d)^^av)2t 'C(=〇)'NH^^; should, "”~〇ΜΝΗ2)2 in the presence of a suitable solvent (V (tb) | 〜op . R2 s(=〇)r(NH2)2 &lt; 〇=i=-op where Rl, R2 and Γ are w (.-〇e) make the patent application scope 1 Definition; should, (VI) intermediate in the presence of a suitable solvent, anti-R3b _~〇Ρ R2 ^*N=C=0 HN Xop (VI) (ld) 96 (IV) 200811131 and R3b represents the patent The definition of the first item of the scope, the thiophene group or the heteroaryl group; the presence of the intermediate and the isomeric trimethyl sulphate in a suitable dissolution reaction, Isocyanotrimethyl stone court D-e) (IV) where R1, R2 and X are in accordance with the scope of the patent application! Definition of the item; g) by using an intermediate of formula (XXXIII-a) or (XXXIII-b) wherein w2 represents a suitable ex-ion group and reacts with a suitable base of formula R R in the presence of a suitable solvent, { I X- NHR5Re W2 1 R6R5〆 (XXXIII-a) NHR5r6 (Ι-M) M Wherein X, Y, R3, R5 and R6 are as defined in the scope of claim i and wherein -R2a-C(=0)-NR5R6 represents an R2 substituent wherein the ring moiety is via R5R6N-C(=〇)_ Substituted and wherein -Rla-C(=〇)-NR5R6 represents a Ri substituent wherein the ring moiety is substituted by r5r6n-c(=〇)-; 97 200811131 or 'if necessary' according to the skill _ known transformation Converting compounds of formula (i) to each other' and, if desired, converting the compound of formula (1) to a medically active non-toxic acid addition salt by treatment with an acid, or converting the compound of formula (I) to a medical activity via treatment with a base a non-toxic base addition salt, or conversely, converting the acid addition salt to a free base via treatment with a base, or converting the acid addition salt to a free state acid by treatment with an acid; and if desired, preparing its stereo A chemical isomer form, a quaternary amine or an N-oxide form. 98 200811131 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 10 I5 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: