TW200300083A - Benzamide, heteroarylamide and reverse amides - Google Patents

Abstract

The present invention relates to novel to P2X7 inhibitors of formula I and to processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy. The active compounds of the present invention are potent inhibitors of P2X7 and as such are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

Description

200300083 发明 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings.) [Technical field to which the invention belongs] The present invention relates to novel benzamidine, Arylamidamine and antipyramine; their preparation methods; intermediate products 5 suitable for use in their preparation methods; pharmaceutical compositions containing them and their therapeutic uses. The active compounds of the present invention are suitable for the treatment of inflammatory diseases (such as osteoarthritis and rheumatic sacroiliac joint burn), asthma, COPD, cancer, stroke or recurrent infarction or ischemia, autoimmunity And other conditions. The active compound is also an antagonist of the P2X7 receptor. 10 [Prior art] P2X receptors (formerly known as P2Z receptors) are ion-gated channels that are gated by ligands in a variety of cell types (mostly known to involve inflammation / immune processes). These cells include Macrophages, mast cells and lymphocytes (Ting and B). The activation of 15 P2X7 by extracellular nucleotides (especially adenine nucleoside triphosphate) results in the release of interleukin · 1/3 (IL-1 / 3) and the formation of giant cells ( Macrophages / microglia), degranulation (mast cells) and proliferation (T cells), cell dysfunction and L_selectin divergence (lymphocytes). The P2χ7 receptors are also located in antigen-presenting cells (APC), keratinocytes, salivary gland cells (parotid cells), hepatocytes, and interstitial cells. P2 × 7 antagonists are known in the art, such as disclosed in International Patent Publications WO 01/46200, WO 01/42194, WO 01/44213, WO 99/29660, WO 00/61569, WO 99/29661, WO 99 / 29686, WO 00/71529 and WO 01/44170. 200300083 发明, invention description has also published the use of benzamidine, heteroarylamidamine and antipyramine in addition to P2χ7 inhibition, such as disclosed in international patent publications wo 97/22600, EP 138,527, WO 00/71509 , WO 98/28269, WO 99/17777, and WO 01/58883. 5 [Summary of the Invention] Summary of the Invention The present invention relates to a compound of formula I: R2

Where A is-(C = 0) NH- or -Nϋ ((: = 0)-; 10 X, y, and Z are = (CR6)-, = (CR7)-, and = (CR8)-, respectively; or, Two (CR7) -and = (CR8)-; or = (CR6) _, = N-and = (cr8) _; or = (CR6)-, gas CR7) -and, _; or, ... CRV and = n_; or = (CR6)-, '-and; or, = N- and = (CR8)-; R1 is a (Cl-C1G) heterocyclic group linked to nitrogen, which contains 丨 to 6 independent 15 sites A heteroatom selected from _N =, -N <, -NH ·, -〇-, and _s (0) n; wherein the (Ci-Cw) heterocyclic group attached to the nitrogen is substituted with at least one oxo group or One of these heteroatoms is S (〇) n (where η is 1 or 2); wherein the (CkC1g) heterocyclic group bonded to the nitrogen can also optionally be in any position capable of supporting additional substituents. One carbon atom is substituted by 1 to 3 and 9 groups per ring, and each R9 is independently selected from 20 suitable substituents in the following groups ... such as hydrogen, oxo, hydrazone, hydrazine, HCKC1-C4) alkane (Ci_ 200300083 玖, description of the invention C4) alkyl, optionally substituted with 3 to 3 fluoro groups 2 (c "c4) alkoxy, H02c -, (CVC6) alkyl-〇- (〇〇)-, R4R5n (〇2S)-, (Ci_c4) alkane -(02S) -NH-, (c) -c4) alkyl Oj-KCVQ) alkyl_N] _, R4R5N (〇0)-, r4r5n (CH2) ", (C6_Ci〇) aryl, (CVC8) Cycloalkyl, (CrCio) heteroaryl, (Ci-Cw) heterocyclyl, (c6-c1 ()) aryl-〇-, (C3-C8) cycloalkyl-〇_, (Ci-CiG) Heteroaryl and (C1_C1G) heterocyclyl_〇_; wherein the (CVC1 ()) heterocyclyl attached to the nitrogen can also be optionally substituted on any of the ring nitrogen atoms capable of supporting an additional substituent Each ring is substituted by 2 R] 0 groups, and each R10 is independently selected from suitable substituents in the following groups: such as hydrogen, (Ci-C4) alkyl optionally substituted with 1 to 3 fluoro groups , Hydroxyl, (C6-C1 ()) aryl, (Ci-C4) alkyl_ (〇〇) _, (Cl-C4) alkyl_s〇2_ (q-C8) cycloalkyl, (CVCi〇 ) Heteroaryl and (Ci_Ci〇) heterocyclyl; wherein the aforementioned (CVCi〇) aryl, cardiac cycloalkyl, (CrCWheteroaryl and (Cl-Cl0)) at any of the R9 and R10 substituents Each of the heterocyclic groups may be optionally substituted on any ring carbon atom by 3 to 3 suitable moieties per ring, and these moieties are independently selected from the group consisting of: a substituted group, a hydroxyl group, and an amine. , _ CN, (Cl-C4) alkyl, (Ci_C4) alkoxy, _CF3, CF3〇_, (c ^ c4) alkyl, -nh_, [(Cl-C4) courtyard] 2_N ·, (CVC4) Alkyl · s ... (Ci_q) Alkyl (s Ο)-, (CVC4) Alkyl-(S02)-, (CVC4) Central Office (c == 〇), Methyl and (CVC4) Alkyl -(〇〇)-; n is an integer from 0 to 2; q is an integer from 0 or 2; s is an integer from 1 to 3; t is an integer from 0 to 3; 20 200300083 玖, Description of the invention R2 is chloro, bromo, (CVC4) alkyl, _CF3 or -CN; R3 is selected from the group: (C4-C10) alkyl, (c3_Ci2) cycloalkyl_ (cr "r12 ) s-, (c6-Cl0) aryl · (Μνν (εΗ, (Ci_Ci〇) heterocyclyl- (CRnR12) s- and (CkC ^ o) heteroaryl_ (CRiiRi2) s-;- (CfCio) alkyl is optionally and independently substituted with 1 to 3 suitable substituents selected from the group consisting of halo, hydroxyl, _CN, (Ci_c4) alkyl, (Ci-CU) oxy , -CF3, CF3O-, (CVC4) alkyl-S-, (CVC4) alkyl- (S = 0)-, (CVC4) alkyl_ (S〇2)-, (c〗 -c4) alkyl -〇 (〇〇)-, formamyl, (CVC4) alkenyl- (〇〇)-, (c6-Cl〇) aryl, ((: 3 < 8) ring 10 alkyl group, (C1-C10) miscellaneous group, (Ci-Cio) heterocyclic group, (c6-C1 ()) aryl-0_, (C3-C8) cycloalkyl 〇-, (CVCio) heteroaryl_〇_ and (Ci_Ci〇) heterocyclyl. 〇-, wherein the R3 group member (CVCw) heterocyclyl_ (cRnR12) sj (c ^ -c ^ o) hetero Each of aryl- (CRnR12) s- contains! To 3 are independently selected from heteroatoms with _S (〇) n-; wherein the R3 group member (C3-Ci2) cycloalkyl-15 (CRllR12) s-, (C6-C10) aryl, Each of Cl-Cl〇) heterocyclyl- (CRnR〗 2) s- and ((^-(: 10) heteroaryl_ (cRnR12) s_) can optionally support an additional independent Any of the suitable substituents of the suitable substituents is substituted with 1 to 4 substituents per ring, such as a substituted group, a hydroxyl group, -CN, (CrC4) alkyl, (Cl_C4) alkoxy, -Cf3, 2〇CF3〇-, (CVC ^): ^ -S-, ((^-(: 4) alkyl- (S = 〇)-, (CVQ) alkyl_ (S02) ,, (CVC4) alkane -0- (〇〇)-, formamyl, ((^-(^ alkyl- (c = 0)-, (c6-c1 ()) aryl, (c3-c8) cycloalkyl, (Cl_c ] ()) Heteroaryl, (C1-C1 ()) heterocyclyl, (c6-C10) aryl-0 ... benzyl ... (c3-C8) cycloalkyl-7 ... (CVCw) heteroaryl_0 -And (C ^ Cio) heterocyclyl; wherein the R3 200300083 玖, the member of the description of the invention (C3_C8)% alkyl- (CRiiRn) s_ and K-.) Heterocyclyl (CR R) s_ optional Is substituted by oxo; the aforementioned (cvClG) aryl, (CVC8) cycloalkyl, Either Ci-Ci〇) heteroaryl and (crc1 ()) heterocyclyl can be optionally substituted on each ring by 5 carbon atoms with each ring standing and a suitable moiety, such as a function Radical, amino, -CN, (CVQ) alkyl, (Ci-C4) alkyl, cf3, cf3o, ((: 1 < 4) alkyl ... [(CVC4) alkyl], ( ~ C4) alkyl-S-, (CVC4) alkyl- (s = 0)-, (Cl_c4) alkyl- (s〇2) ... groups · 〇 _ ((::,-, formamyl and ( CVC4) alkyl_ (c = 〇) _; 10 R and 115 are each independently selected from the group consisting of hydrogen, (CVC6) alkyl, HO (CVC6) alkyl, and (CyCs) cycloalkyl, or R4 and R5 can optionally form a 3- to 8-membered heterocyclic ring together with the nitrogen atom to which it is attached; R6, R7, and R8 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, and optionally (Ci_c6) 15 alkyl substituted with 4 to 5 chloro or fluoro groups and ((: 146) alkoxy optionally substituted with 1 to 4 chloro or fluoro groups; R11 and R12 each independently Ground is selected from the group consisting of hydrogen, fluoro, cyano, hydroxy, -CF3, CF3O_, (CA) alkyl, (C3-C8) cycloalkyl, (Cl-C6) alkoxy (C3-c8) cycloalkoxy, phenyl, (cvc1G) heteroaryl20 and (Ci-ci0) heterocyclyl; wherein (Cl-c6) alkyl, (C3-c8) cycloalkyl, (c) -c6) alkoxy, (C3_c8) cycloalkoxy, phenyl, (Ci_cwheteroaryl and (Ci-C1G) heterocyclyl) may be optionally substituted with 1 to 3 suitable substituents, These substituents are independently selected from the group consisting of chloro, fluoro, cyano, mesityl, -CF3, CF3O_, (Cl-C4) alkenyl-S-, ((Vc4) alkane 10 200300083 玖, Invention description-(S-〇)-, (Ci-C4) alkyl- (S〇2)-, (CVC4) alkyl--0- (C = 〇)-, formamyl or ( CVC4) alkyl- (〇〇)-; provided that when R3 is (C3-C12) cycloalkyl- (CRUr12)]-, R1 and R2 are each hydrogen, and s is 1 or 2, then ( Cg-Cu) cycloalkyl must be a group other than a gold steel alkyl group which is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the present invention mentioned above are those which form non-toxic acid 10 addition salts, that is, containing pharmaceutically acceptable Salts of anions such as gaseous, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, Tartrate, hydrogen tartrate, succinate, cis-butenedioate, trans-butenedioate, gluconate, gluconate15, benzoate, mesylate, ethanesulfonic acid Salt, benzenesulfonate, p-toluenesulfonate, and paranaphthoate (ie, 1,1, -methylene-bis- (2-hydroxy-3-naphthoate)). The invention also relates to base addition salts of formula I. Chemical base 20 reagents which can be used to prepare the pharmaceutically acceptable base salts of the compounds of formula Ί have acidic properties and are those which form non-toxic base salts with the compounds. These non-toxic alkali salts include, but are not limited to, those derived from pharmaceutically acceptable cations, such as alkali metal cations (such as potassium and sodium) and alkaline earth metal cations (such as Wu and Zhen), ammonium, and water-soluble Amine addition salts (such as N-methyl phosphonium glucosamine, meglumine) and lower alkanolammonium and other pharmaceutically acceptable salts of organic amines that can be used in 2003. The present invention also encompasses pharmaceutical compositions containing a prodrug of a compound of formula. Compounds of formula I with free amine, amido, hydroxyl or carboxyl groups can be converted into prodrugs. Prodrugs include polypeptide chains in which the amino group 6 is fluorenyl or has one or more (such as two, three, or four) amino acid residues, via the free amino group, the hydroxyl group, and the compound of the formula j Or 'carboxyl peptide bond'. Amino acid residues include 2Q pseudo-naturally occurring amino acids (which are usually represented by three English letter symbols), and also include 4-aminoproline, hydroxylysine, and demomoic acid (dem. sine), 10 isodomoic acid, 3-methylhistamine, valerate, alanine, 7-aminobutyric acid, citrulline, cysteine-like, serine-like, ornithine and Methionine hydrazone. Prodrugs also include these compounds, among which carbonate, urethane, amido, and sulfanyl I are covalently bonded to the aforementioned substituents of the compound of formula I via side carbon bonds of the prodrug. 15 The invention also encompasses compounds of the formula: Skilled artisans will also understand that the compounds of the invention prepared may also have specific protective groups that are useful for purification or storage and can be removed before administration to a patient. The protective and deprotective effects of functional groups are described in "Protective Groups in Organic Chemistry," edited by JWF McOmie, Book 20 (Plenum Press, 1973) and Tw Gree_p G ^ Gah, "Organic Synthesis Protective Groups in Action, Book B, Second Edition (^ Published by Intersciences in 1991). The compounds of the present invention also include all stereoisomers (such as cis and trans isomers) and all optical isomers (such as r 12 200300083 Kan, invention description and s enantiomers) of the compound of formula j. Structure), and racemates, diastereoisomers, and other mixtures of these isomers.

The compounds, salts, and prodrugs of the present invention can exist in several tautomeric forms, including dilute alcohol and imine forms, keto and diamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are intended to be within the scope of this invention. Tautomers exist as a mixed tautomeric group of formula I in the valley fluid. It is usually one of the tautomers in the solid state. Even if only one tautomer is mentioned, the present invention covers all tautomers of the compounds of the present invention. One example of tautomeric structure is 10 examples in which R1 is a group having the following chemical formula ...

Skilled artisans will understand that this radical can also be plotted as its tautomer 0 Μ

〇Η

15: The invention also encompasses the atropine isomers (a- ·) of the present invention. Atropine isomers are chemical compounds that can be separated into spin-limited iso shopping I. The present :: compound may contain a fluorene type double bond. When such bonds exist as a mixture. ..., the existence of the trans configuration and its suitable substituents refer to chemically and pharmaceutically acceptable officials 13 20 200300083 玖, the description of the invention, if it will not eliminate the inhibitory activity of the compounds of the present invention a part. Such suitable substituents can be routinely selected by skilled artisans. Illustrative examples of suitable substituents include (but are not limited to) _ substituted group 'perfluoroalkyl, perfluoroalkoxy, alkynyl, alkenyl, alkynyl, mesityl, oxo, thiol, thiol Alkyl, alkoxy, aryl or heteroaryl |, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, H0- (c = 〇 ) -Amino, alkynyl and dialkylamino, aminomethylamino, amidinoyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl Carbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl and the like. Skilled artisans will understand that many substituents can be substituted with other substituents. As used herein, the term "spiral" refers to a connection between two groups, substituents, etc., where the connection can be illustrated by the following chemical formula:

As used herein, the term "alkyl," and the alkyl moiety of other radicals mentioned herein (eg, 15-alkyl) refers to straight or branched bonds (such as methyl, ethyl, N-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl); optionally by 1 to 3 suitable substituents as defined above (such as fluoro , Chloro, trifluoromethyl, (CVC6) alkoxy, (C6_C10) aryloxy, trifluoromethoxy, difluoromethoxy or (Ci-C6) alkyl). 20 Such as The term "each of the alkyl groups" as used herein refers to any one of the aforementioned alkyl moieties in a group (such as a alkoxy group, an alkenyl group, or an alkylamino group). Compared with 14 200300083 玖2. Description of the Invention Preferred alkyl groups include (CKC4) alkyl groups, most preferably methyl and ethyl. As used herein, "cycloalkyl '" means a monocyclic, bicyclic, or tricyclic carbocyclic (such as Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,% octyl, badnonyl, cyclopentenyl, cyclohexenyl, bicyclo [2.21] pentane 5-yl, bicyclo [3 · 2 · 1] octyl and bicyclic [5 · 2 · 0] nonyl, etc.) ; Optionally contains 1 or 2 double bonds and is optionally selected from 3 to 3 suitable substituents as defined above (such as fluoro, chloro, trifluoromethyl, (Ci-C6) alkane (C6_C10) aryloxy, trifluoromethoxy, difluoromethoxy or (C "C6) alkyl) · Substituted. 10 As used herein, the term" halogen "means fluoro Chloro, chloro, bromo or mothyl and fluoride, chloride, bromide or erbium. As used herein, `` halo-substituted alkyl, '' the term refers to a Multiple halogen-substituted alkyl radicals mentioned above, including (but not limited to) chloromethyl, dichlorofluorenyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloro15 Ethyl, etc .; optionally by 1 to 3 suitable substituents as defined above (such as fluoro, chloro, trifluoromethyl, alkoxy, (C6_Ci〇) aryloxy, trifluoromethyl Alkoxy, difluoromethoxy or (Cl-C6) alkyl). As used herein, "alkenyl," refers to a straight chain 20 or branched chain having 2 to 6 carbon atoms. Saturated radicals, including (but not limited to ) Vinyl,! -Propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl '2-butenyl, etc .; optionally 1 to 3 suitable substituents as defined above (such as fluoro, chloro, trifluoromethyl, (CrC6) alkoxy, (C6-C10) aryloxy, trifluoromethoxy, Fluoromethoxy or (CKC6) 15 200300083 (inventor). As used herein, "(qc: 6) alkynyl", the term refers to a straight or branched hydrocarbon radical having at least one triple bond, including (but not limited to) ethynyl, propynyl, butynyl Etc; optionally by 1 to 3 suitable substituents 5 as defined above (such as fluoro, chloro, trifluorofluorenyl, (cvc6) alkoxy, (c6-C10) aryloxy, tri Fluorofluorenyl, difluoromethoxy, or (Ci_c6) alkyl). As used herein, such as in alkylcarbonyl, alkyl_ (C = 〇 >, or alkoxycarbonyl) The term "carbonyl," or "(c > 0)," means the > c = 0 part and 10 a second part (such as an alkyl or amine group (i.e. Linker. An alkoxycarbonylamino group (that is, an alkoxy group (C = 0) _NH_) refers to an alkylcarbamate group. The carbonyl group is also defined here as (c = 0). A carbonylamino group refers to a group such as acetamide. As used herein, "oxo," as used herein, refers to a double bond oxygen radical 15 (= 0), where the other side of the bond is carbon Atom. The free radical can also be regarded as a few radicals. This' "(cvc4) alkyl -〇2S _ [(Cl_C4) alkyl · Ν] _ ,, a term herein means a radical having one of the following chemical formula: a group Ν-

I alkyl, as used herein, the term "aryl" refers to an aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, etc .; optionally one to three as defined above Suitable substituents (such as fluoro, chloro, trifluoromethyl, 16 200300083 玖, description of the invention C6) alkoxy, (CrC10) aryloxy, trifluoromethoxy, difluoromethoxy or ( Ci-C6). As used herein, the term heteroaryl ' refers to an aromatic heterocyclic group typically having a heteroatom selected from oxygen, sulfur, or nitrogen in the ring. In addition to the heteroatom, the aromatic group may optionally have up to 4 nitrogen atoms in the ring. For example, stilbene groups include ° ratio σ fixed base, σ ratio σ Qinyl, p dense σ fixed base, fluorenyl, fluorenyl, ureanyl, imidazolyl, pyrrolyl, humidyl (such as 丨, 3- Hexazolyl, 丨, ^^ azolyl), thiazolyl (such as 1,2-thiazolyl, u_thiazolyl), σbizolyl, tetrazolyl, triazolyl (such as 1,2,3-thiazyl) Oxadiazolyl, 1,2,4-thiadiazolyl), oxadiazyl (such as 1,2,3_humidazolyl), thiadiazolyl (such as 1,3,4_thiadiazolyl) Group), fluorinyl, isoquinolinyl, benzothienyl, benzodianyl, indpuryl, etc .; optionally by 1 to 3 suitable substituents as defined above (such as fluoro, chloro Substituted with a substituted group, trifluoromethyl, (cvc: 6) alkoxy, (CVCi0) aryloxy, difluoromethoxy, difluoromethoxy or (C ^ -C6) alkyl. Particularly preferred heteroaryl groups include humazolyl, imidazolyl, pyridyl, thienyl, furanyl, thiazolyl, and tonazolyl. The most preferred R3 heteroaryl is thienyl and β-anyl. As used herein, "heterocyclyl," the term refers to having from 1 to 9 carbon atoms and i to 4 selected from nitrogen, oxygen, s ( 0) n4 NR, a heteroatom ring group. Examples of this ring include: chlorobutane, dihydroxanthyl, tetrahydrodithio, glutaryl, sigma alkyl, and pyridine Group, oxazinyl, humazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, Tetrahydrodiazinyl, fluorenyl, humthionyl, indpuryl, isoindpuryl, quinuclidinyl, chromogen alkyl, isochromogen alkyl, benzo 17 200300083 pyrene, description of invention 5 Qin Ji et al. Examples of 4 monocyclic saturated or partially saturated ring systems are: tetraazafuran-2-yl, tetrahydrobisan-3-ylimidazolidinyl, pyrrolidin-1-ylpyridin-1- Radical, pyridin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, sigmadin-3-yl, pyrene- 1-base, 哏 _2_2_base 10 15 20 Qin Ji 丨, 3-humsalpin-3-yl, heterosexual base, 1, 3_ noisy. Sitting courtyard · base 1, 2 ^ Spit_2 · yl, 丨, 3 ′ bisazolidine_ 丨 _yl, thiomorpholin-yl, 12'hydrothiazine-2'yl, U'tetrahydrothiazine_3_yl, tetrahydrothiazide Diazine group, Malinki, 1,2-tetrahydrodiazine 1 group, ortho-tetrachlorodihydrazine small group, μ: azine I group, U'5-humithiazine_4 group, etc .; selectively One suitable substituent as defined above (such as fluoro, chloro, tris, fluorenyl, (Cl_c6) alkoxy, (C6-C1 ()) aryloxy, trifluorofluorenyloxy, difluoro Methoxy or (Ci-C6) alkyl). Preferred heterocyclyls include tetrahydrodiranyl, pyridyl, fluorenyl, fluorenyl, and morphinyl. A particularly advantageous one Group ^ Heterocyclic ring ㈣ Heterocyclic rings having two or more oxo substituents. Another group of R1 heterocyclic rings which are particularly advantageous are heterocyclic rings having three or more heteroatoms. Another group of R1 heterocyclic rings includes 2-oxo nitrogen material, 2-oxo material base, 2-oxo sulfonyl group, 2-oxo sulfonyl group, 2-oxo sulfonyl group and 2, substituted linyl group. The preferred R1 hetero The ring includes 6-nitrocarbidine, uridine, 2-oxoxidine, H-dioxo-xazine, 2-oxo-oxazole, and 2-oxo-benzothiazine, and the best are 6-nitrouracil Preferred R3 heterocyclyls include tetrahydrodiranyl, difluorenyl, tetrafluorenylthiophenyl, chromogen alkyl, isochromogen alkyl, and tetrahydrothiopheneyl groups such as `` nitrogen '' Heteroatom, refers to · N =, > N & _NH, where, refers to a nitrogen double bond; > N refers to a nitrogen containing two bonds connected; and 18 200300083, invention description NH refers to containing A nitrogen linked by a bond. A specific example here refers to a specific grouping of compounds or uses into different subclasses. These subclasses can be identified based on a specific substituent such as a specific R1 or R3 group. Other subgroups can be identified based on combinations of different substituents (such as all compounds where r2 is chloro and R3 is optionally substituted phenethyl). The term "combination with the foregoing specific examples" means the combination of the specific examples and the foregoing specific examples in the description. Therefore, the specific examples of compounds in which R3 is a phenethyl group that is selectively substituted "and the specific examples described above refer to the specific examples and descriptions that include r3 as a benzene 10 ethyl group that is selectively substituted Other specific examples of the combination of the foregoing specific examples. A preferred specific example of the present invention is a group of phenylated compounds having the formula I, where X, ¥ and 2 are = (CR6)-, = ( CR7)-and = (CR8)-, more preferably wherein R6, R7 and R8 are each hydrogen. Another specific example of Benmemin is a group of pyridyl compounds of formula I where X, ¥ and 2 are, = (CR7)-and = (CR8)-, more preferably wherein R7 and R8 are each hydrogen. Another specific example of this & Ming is a group of pyrimidinyl compounds of formula I in which X, y and 2 are respectively == (cr6) ... N house (cr8) _, more preferably 20, where R6 and R8 are each hydrogen. Another specific example of this month is X, Y, and 2 in a group of pyridinyl compounds of formula I = (CR6)-, = (CR7)-, and = N-, more preferably R6 and R7 are each hydrogen. Another embodiment of the present invention is a group of pyridazine compounds of formula I 19 200300083 玖, invention theory Ming 'where X and γ blood Z eight M * knifes are = N-, qi CR7) _ and = N ·, more preferably bean R7 is hydrogen. Another embodiment of the present invention is a specific example of formula I A group of pyrimidine compounds' where X, ¥ and 2 are = (CR6)-, = N- and = N-, and more preferably 5 R6 in the basin is hydrogen. 〃 Υ Another specific example of this Maoming is A group of pyrazine compounds of chemical formula I, wherein X, Υ and ζ are, respectively, ',, and di (cr8) _, and more preferably R8 is hydrogen. Another more specific example of the present invention has a chemical formula 1 (and the benzene I hydrazone, aryl phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, and stilbyl) of the compound 10, and a group of aminated compounds, where A is gas C =: 0) As benzamidine, nicotine bispyridoxamine, isonicotinamide, pyridazine, pyrimidine, and pyridoxamine. Another specific example of the present invention has a chemical formula 1 (and the compound's phenyl 15-pyridyl, pyrimidyl, and 0-pyridyl) are a group of anti-amidamine compounds, in which A is -NH (C = 0)-and is called as formazan Aniline, Carboxaminopyridine, Carboxaminopyridazine, Carboxaminopyrimidine and Carboxaminopyridine Another specific example of the present invention has a chemical formula: (and the phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl of the compound and benzamidine 20 amine, nicotinamide, and pyridine of the compound Pyridamine, isonicotinylpyridine, pyridazinepyridine, pyrimidinepyridine, pyrazinepyridine, and toluidine, carboxamidopyridine, carboxamidopyridine, carboxamidopyrimidine, and carboxamido Pyrazinyl) a group of compounds in which R3 is a optionally substituted (C4-ClO) alkyl, more preferably substituted by j to 3 substituents independently selected from the group consisting of hydrogen, halogen Substituted group 20 200300083 fluorene, description of the invention, hydroxyl, -CN, (Cl-C4) alkyl, (CrC4) alkoxy, _CF3, cf3o-, radical, (Ci, c4) fluorenyl_ (s = r. )-, (Ci · fluorenyl- (S〇2)-, (CVC4) alkyl-0- (〇〇) •, formamyl and (CVC4) alkyl · (〇〇)-. 5 Another specific example of the present invention is Chemical Formula 1 (and the compound's phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl) and benzamidine, nicotinamide, and pyridine of the compound , Isonicotinylamine, pyridazidine, pyridazidine, pyrazinidine, and toluidine, carboxamidopyridine, carboxamidopyridazine, caramidopyrimidine, and carboxamido A group of 10 compounds, wherein R3 is a (C3-C12) cycloalkyl (CRnR12) s_ which is optionally substituted, wherein 11 and 12 are each independently hydrogen or hydrogen) Or at least one of R11 and R12 is hydrogen or (Ci-C4) alkyl (more preferably, R11 and R12 in CRUR12 which are directly connected to the A group are each hydrogen); Substituents include 1 to 3 substituted 15 groups independently selected from the group consisting of hydrogen, halo, hydroxyl, -CN, (Cl-C4) alkyl, (Cl_C4) alkoxyoxo, (Ci -C4) alkyl_〇_ (〇〇)-, formamyl and (Ci-C4) alkane (c)), more preferably, wherein these substituents are independently selected from the group consisting of hydrogen, halogen Substituent, hydroxyl, -CN, (C1_C4) Alkyl and (C1-C4) alkoxy. 10, ^ Another specific example of this matter is a chemical formula (and the compound's phenylfluorenyl, pyridazinyl, 1¾ alpha amidyl and benzoyl benzoate, nicotinamide, Pyridoxamine, isonicotinylpyridine, pyridazine, pyrimidinate, pyrazinamide, and toluidine, carboxamido, carboxamidopyridazine, carboxamidopyrimidine, and carboxylic acid of the compound A group of aminopyrazinyl groups 21 200300083 ίο 15 20 玖, the description of the invention, wherein R3 is (CVcy cycloalkyl- (CRnRl2) s_ (more preferably r1 in CRnRl2 directly connected to the A group) r12 are each nitrogen), which are optionally substituted with at least one (more preferably one) substituent selected from the group consisting of (C6-C1 ()) aryl, ((: 348) cycloalkyl, (CVCw heteroaryl, ⑷i_Ci〇) hetero-ring group, (c6-c10) aryl_〇_, (CVC8) cycloalkyl_〇-, (Ci-Cio) heteroaryl and (Cl-c10) heterocycle -0_, wherein each of the aforementioned (CVCi〇) aryl group, (CVC8) cycloalkyl group, (Ci_Ci〇) heteroaryl group and ((Vc-heterocyclyl substituent) may be optionally selected by each ring Partial replacement, these parts are independent The ground is selected from the following groups: halo, hafnium, oxo, (CA) alkyl, (cvc4) oxy, -CF3, CF3 0-(Ci_C4) ^ n, (C1_C4) alkyl (S-〇) , (Cvc4) fluorenyl- (S〇2) ·, (Ci_c4) alkenyl heptamidine, and (Ci-C4) alkyl- (〇〇)-. Another specific example of the present invention is of formula I (And the phenyl y-base of the compound, the base, the base, and the base and the benzyl group of the compound, the final test of the "bamine, the test of the test, the test, the test of the bite "Amine" is a group of compounds including aniline formate, aniline formate, acetamino group, acetamino group, acetamino group, and carboxyamino group (bitami group), where R3 is (C3-C12) cyclic group _ (CRllRl2) s_ (more preferably, each of r1 ^ r12 in CRnRl2 directly connected to the A group is chlorine), which is selectively at least one (more preferably one) ) Selected from the group consisting of helical substituents (c6-c10) aryl, (C3-c8) it, (Ci_c) 〇) heteroaryl,% _ "heterocyclyl, (C6_Cl0) aryl Group_〇_, (C3_C8) cycloalkyl group_〇_, (Ci_ = heteroaryl-0- and (Cl-Cl〇) heterocyclyl_〇 _, Wherein the aforementioned (c6_c ^ aryl earth (c3-c8) cycloalkyl, (Cl_ci〇) heteroaryl, and (Ci_Ci〇) heterocyclyl helix

22 200300083 Rose, invention description Each of the substituents may be optionally substituted with 1 to 3 moieties per ring, and these moieties are independently selected from the group consisting of halo, hydroxy, _CN, ( Ci-c4) alkyl, (c) -c4) alkoxy, -Cf3, cf30-, (CVC4) alkyl-S-, (K4) alkyl- (s = 〇) ... (CVC4) alkyl- ( s〇2)-, (Ci_C4) alkyl 5 (C-O) ... formamyl and (CVC4) alkyl-(c bis 0)-. Another specific example of the present invention has the chemical formula 1 (and the benzyl group, the specific ratio of the compound, the pyridazyl group, the pyridazinyl group, the pyrimidyl group, and the pyrazinyl group, and the benzamidine of the compound, the final test of amines, Pyridoxamine, isonicotinamide, pyridazidine, pyrimidine, pyrimidine, and toluidine, carboxaminopyridine 10, ketamine, carbaminopyrimidine, and carboxylic acid Aminopyrazinyl) a group of compounds' wherein R3 is a optionally substituted (C3_Ci2) cycloalkyl · (CRnR12) s .; wherein R11 and Ri2 are each independently hydrogen or (C "C4) alkane (More preferably, each of chi11 and 1112 in cr11r12 directly connected to the A group is hydrogen); 15 wherein the (CVCi2) cycloalkyl- (CRnR12) s- (C3-C12) cycloalkyl system is broken Substituted by a substituent selected from the group consisting of (C6_Cig) aryl, C8) cycloalkyl, (Cl-CH)) heteroaryl, (CVCW heterocyclyl, (C6_Cl〇) aryl O-, ( c3-c8) cycloalkyl-0-, (c) -Ci〇) heteroaryl-0 and (Ci_Ci〇) hetero% -0-, wherein the aforementioned (c6-c10) aryl, (c3-c8) Cycloalkyl, (Cl-Cl〇) _aryl and (Cl_Cl〇) heterocyclic group substitution Each of the moieties may be optionally substituted with 1 to 3 moieties per%, which moieties are independently selected from the group consisting of: i-based moieties, meridian moieties, -cN, (Crc4) alkenyl moieties, ( CVC4) Carbooxy, -CF3, CF3O-, (Cl-c4) Carbo-S-, (CVC4) Carbo-c-, (Cl-C4) Alkyl- (S〇2) ... (Cl_C4) Alkyl-0- (〇0)-, fluorenyl and (Cl_c4) alkane 23 200300083 玖, invention description group-(〇〇) _; and the (c3-c12) cycloalkyl- (crUr12: ^ (C3_Cl2) cycloalkyl is substituted with one or two substituents independently selected from the group consisting of hydrogen, halo, hydroxy, -CN, (CVC4) alkyl, ((VC4) alkoxy, Oxo 5, (Ci-c4) alkyl-〇- (〇〇)-, fluorenyl and (cvc4) alkyl- (〇0)-; more preferably, wherein these substituents are independently selected from In the following groups: hydrogen, oxo, hydroxy, -CN, (CVC4) alkyl, and (CVC4) alkoxy. Another embodiment of the present invention is represented by Chemical Formula 1 (and phenyl, pyridyl, Pyridyl, pyrimidinyl and pyridyl, and benzamidine 10 amine, nicotine pyridine, pyridine pyridine, isonicotyl pyridine, pyridazine, Amidine, pyrazine, amido, and toluidine, pyridoxine, carboxyaminopyridazine, carboxyaminopyrimidine, and carboxyaminopyrazinyl), wherein R3 is (C6 -C10) aryl- (CRUR12 ^^)-, wherein R11 and R12 are each independently hydrogen or (Cl-C: 4) alkyl (preferably R in CRnR12 in which the a group is directly connected to 15) 1 and Ri2 are each hydrogen); more preferably, the (CVCig) aryl group (CRnR12) q- (CH2) ·, the (CVCi〇) aryl group is substituted with a substituent independently selected from the group : Hydrogen, halo, hydroxy, -CN, (crc: 4) alkyl, (c) -C4) alkoxy, formamyl, benzyloxy, and (C "C4) alkyl- (〇0) -; More preferably, the (C6_CiG) aryl group of 20 of the (CVCi〇) aryl group is substituted with 1 to 3 substituents independently selected from the following groups: a functional group, _CN, (Ci-q ) Alkyl, benzyloxy and (Cl_C4) alkoxy. Another specific example of the present invention has the chemical formula 1 (and the phenyl group, the fluorenyl group, the sulfuryl group of the compound), and the dense stilbyl group and the stilbazine group and the benzamidine of the compound 24 200300083. Amine, nicotinamide, pyridoxamine, isonicotinamide, pyridazine, pyrimidinide, glutamidine, and toluidine, weimido, and carboxamido of the compound Hydrazine, carboxyaminopyrimidine and carboxyaminopyrazinyl), wherein R3 is (C6-C10) aryl- (crIIr '^ ch}, wherein R11 and 5 Rl2 are each independently selected from the following group : Hydrogen or (C ^ C4) alkyl (preferably each of feet 11 and 1112 in CRUR12 directly connected to the A group is hydrogen); and the (C6-C10) aryl- (CRuR〗 2) q The (cvCi0) aryl group in the-(CH2)-group is substituted with at least one (more preferably one) substituent selected from the group consisting of: (c ^ Cio) aryl, (C3-C8) ring Alkyl, (C ^ -Cio) heteroaryl, ((^ -C ^ o) heterocyclyl 10, (C6-Cl ()) aryl_〇-, (C3-C8) cycloalkyl-0- (CfCio) heteroaryl_〇- and (Ci-C10) heterocyclyl 'wherein each of the aforementioned substituents may be selected Is substituted by 1 to 3 moieties per ring, which moieties are independently selected from the group consisting of halo, hydroxyl, -CN, (cKc4) alkyl, (cvc4) alkoxy, -CF3, CF30-, (CVC4) alkyl-S-, (Ci-CU) alkyl- (s = 0) ·, 15 (Ci-C4) alkyl- (S02) ·, (Ci-Cd alkyl-0- (C = 0)-, T gf group, and (c ^ · c4) alkyl- (〇〇)-. Another specific example of the present invention is a chemical formula (and the phenyl group, σ-pyridyl group, Pyridazinyl, pyrimidinyl, and pyrazinyl, and benzamidine, nicotinamide, pyrimidine, isonicotinamine, pyridazine, pyrimidine 20, pyrazine, and pyrazinamide And a group of compounds of toluidine, carboxamidopyridine, carboxamidopyridazine, carboxamidopyrimidine and carboxamidopyrazinyl) of the compound, wherein R3 is (C6-C10) aryl- (CRUr ^ WHJ-, wherein R11 and R12 are each independently selected from the group consisting of hydrogen or (CrC4) alkyl (more preferably, R1 and R12 in CRUR12 in which R is directly connected to the A group are each hydrogen); and wherein 25 200300083 Rose, description of the invention (C6-Cl °) aryl is like llR, 2) q · (the aryl group in the group is at least-one (better -A) substituted with a helical substituent selected from the group consisting of: (cvc10) aryl, (C3-C8) cycloalkyl, (Ci_Ci〇) heteroaryl, (Ci_Ci〇) 5 10 ^ ring group, (C6 -Cl0) aryl_〇_, (C3_C8) cycloalkenyl_〇 ·, heteroaryl-〇 ·, and (CVC1 ()) heterocyclyl_〇_, wherein each of the aforementioned spiral substituents can be selected It is substituted by ⑴ moieties in each ring, and these moieties are independently selected from the group consisting of a 4th generation group, a warp group, a collar, (C1_c4m group, (CVC4) alkoxy group, _cf3, cF3〇_, group -(S = 0) ·, (CVC4) alkyl · (8〇2) -formamidine and (Cl-C4) alkyl- (〇〇) -〇

(Ci-C4) alkyl-S_, (Ci-C4) alkyl, (Ci-C4) alkyl-0-((3 = 0)-, and another specific example of the present invention is a chemical formula (and the compound Phenyl carbamoyl, daqinyl, pyrimidinyl and pyrazinyl, and the benzamidine of the compound, the test amine quot; Biazine amino group and a group of methyl phenyl hydrazone, sulfamidine ratio 15, carboxyaminopyridazine, carboxyaminopyrimidine and carboxyaminopyrazine group)

(Wherein R3 is (Cl-Cl0) heteroaryl is preferably Rn and Rl2 in Crhri2 directly connected to the A group are each hydrogen); it is optionally at any ring carbon atom capable of supporting an additional substituent It is substituted with 3 to 3 substituents per ring. The substituents are independently selected from the group consisting of: dentino, 20 hydroxy, -CN, (CVC4) alkyl, (CVC4) alkyl, and (Ci_C4 ) Alkyl group 〇 (〇〇) _, formamyl and (Ci_C4) alkyl- (c = 〇) _ (more preferably the substituent is independently selected from the following group: halo, -CN, ( CVC4) alkyl, (Cl_c4) alkyloxy, formamyl, and (Ci-C4) alkyl_ (c = 0) _). Another specific example of the present invention has Chemical Formula 1 (and the phenyl 26 of the compound, 200300083 & Description of the invention, ° pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl and benzamidine of the compound, Nicotinamide, pyridoxamine, isonicotinamide, pyridazine, pyrimidine, pyrazinamide, and toluidine, weamidopyridine, pyridazine, Carboxaminopyrimidine and Carboxaminopyrazinyl) a group of 5 compounds, in which r3 is (c "ci〇) heteroaryl- (CRuR12) s_ (more preferably in CRUR12 in which A is directly connected to the A group) R11 and R12 are each hydrogen); it is optionally substituted on at least one ring carbon atom capable of supporting an additional substituent with a substituent selected from the group: (cvCl0) aryl, ((: 3-(: 8) cycloalkyl, (CrC10) heteroaryl, (Cl_Cl0) heterocyclyl, (CVCi ()) aryl_〇_, (cv 10 C8) cycloalkyl_〇-, (Ci- C1 ()) heteroaryl-O- and (Cl-Cl ()) heterocyclyl, wherein the aforementioned (C6-C10) aryl, (c3-c8) cycloalkyl, ((^-(: 10 ) Heteroaryl (C1-C1 ()) heterocyclyl, (c6-c10) aryl-0-, (c3-c8) ring -O-, (Ci-C1G) heteroaryl-0- and heterocyclyl-0- substituents may be optionally substituted on any ring carbon atom by 1 to 3 moieties per ring, and these moieties are 15 is independently selected from the group consisting of halo, hydroxy, -CN, (CVC4) alkyl, (CVC4) alkoxy, -CF3, CF3O_, (CVC4) alkyl_s- (Ci_c ^ alkane -(S = 0) ·, (CVC4) alkyl- (S〇2)-, (Cl_C4) alkyl_〇 _ (& 〇) _, formamyl and (CVC4) alkyl- (〇〇〇 )-. Another specific example of the present invention has the chemical formula T (and the phenyl 20, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl of the compound and benzamidine, nicotinamide, Pyridoxamine, isonicotinylpyridine, pyridazinepyridine, pyrimidinepyridine, pyrazinepyridine and methylformanilide, carboxamidopyridine, carboxamidopyridazine, carboxamidopyrimidine and carboxamide A group of compounds in which R3 is (CkCm) heteroaryl_ (CRnR12) s_ (more preferably in which direct 27 200300083), R11 and R12 in CRnR12 connected to the A group are each hydrogen ); Optionally in any ring capable of supporting an additional substituent The carbon atom (more preferably one carbon atom) is substituted with 1 to 3 substituents per ring, which substituents are independently selected from the group consisting of halo, hydroxyl, -CN, (Cl_C4) alkyl, ( CVC4) alkoxy, oxo, (Cl-C4) alkyl_〇_ (〇〇) _, methyl and (Ci_C4) alkyl- (〇0)-(more preferably the substituents are independent Ground is selected from the group consisting of halo, -CN, (CVC4) alkyl, (CVC4) alkoxy, oxo, formamyl, and (CVC4) alkyl- (〇〇)-). 10 15 20 Another specific example of the present invention has a chemical formula: (and the phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl of the compound and benzylamine, nicotinamide, and pyridine of the compound Pyridoxine, isonicotinylpyridine, pyridazinepyridine, pyrimidine Sik, pyrazinepyridine, and toluidine, carboxamidopyridine, carboxamidopyridazine, carboxamidopyrimidine, and carboxylic acid Aminopyrazinyl) a group of compounds in which R3 is (Cl-C10) heterocyclyl_ (cr11r12) s_ (more preferably, Rn and Rl2 in CRY directly connected to the A group are each hydrogen); Optionally substituted on at least _ ring carbon atoms (more preferably one carbon atom) capable of supporting-additional substituents with _ substituents selected from the feedstock: heart ~) aryl, (kc8) ring (CVCi〇) heteroaryl, (cvCi〇) heterocyclyl, (C6-C10) aryl-O-, (CVC8) ring group seven ... (c "c ^ heteroaryl group and (Cl_ClG) Heterocyclyl_〇, wherein the aforementioned (c6-c1G) aryl, (c3-c8m alkyl), (CVC1〇) heteroaryl, (Cl.Cl〇) heterocyclyl, (CVCi〇) aryl, (C3-C8) Cycloalkyl, 0-, (讣 ~) The aryl group and the (Cl-C10) heterocyclyl-substituted group may be optionally substituted on the ring carbon atom by 1 to 3 moieties per ring. These moieties are independently selected from the following groups: Yanji, Jingji

28 200300083 玖, Description of the invention CN, (C "c4) alkyl, (CVC4) alkoxy, -CF3, cf3o-, (Cr C4) alkyl I, (C1-C4) alkyl- (S = 0) -, (CrC4) alkyl- (S〇2)-, (Cl C4) alkyl-7 ((> 0)-, formamidine and (CKC4) alkyl- (c = o)-. The present invention Another specific example of this group of compounds is where R2 is a chloro group or a shoulder group, and more preferably, where r2 is a chloro group. Another specific example of this matter is this group of compounds, where R2 is (CrC4) Alkyl or stilbene is more preferred, in which R2 is: fluorenyl. Another specific example of this month is this group of compounds, where R2 is a meridian. Another specific example of the present invention is this group of compounds, where R7 is not Hydrogen. Another specific example of Benmemin is the group of compounds of formula I, in which R is a selectively substituted (CrCW heterocyclic group) remote from the following group:

Another specific example of the present invention is the group of compounds, wherein ... is a selectively substituted (Cl_ClG) heterocyclic group selected from the group consisting of: 29 200300083

Another specific example of the present invention is the group of compounds, wherein R1 is a optionally substituted (C ^ -Cio) heterocyclic group selected from the group consisting of:

30 200300083 发明, description of the invention

Another specific example of the present invention is the group of compounds, wherein R1 is a optionally substituted (CkC ^) heterocyclyl selected from the group consisting of:

0

〇

〇 R9 5 Another specific example of the present invention is this group of compounds, in which R1 is a optionally substituted (CrCio) heterocyclic group selected from the group below 31 200300083 发明, description of the invention

Another specific example of the present invention is the group of compounds, wherein R1 is a optionally substituted (C ^ -Cb) heterocyclic group selected from the group consisting of:

Another specific example of the present invention is the group of compounds of formula I, wherein R is a (CVCio) heterocyclic group which k is selectively substituted from the following group:

32 200300083 发明, description of the invention

For the sake of brevity, the substituents R9 and R1G are not shown in the aforementioned R1 examples. Another specific example of the present invention is the group of compounds, wherein R1 is a optionally substituted (CkC ^) heterocyclyl selected from the group consisting of:

, ^, 0H __ y ^ (CH2) tNR4R5 / ~ (CH2) tNR4R5 200300083 玖, description of the invention wherein R4 and R5 are each independently selected from the following groups: hydrogen, (Cl_C6) alkyl, HO-((:: 2- C6) alkynyl and (CrC8) alkynyl; or R4 and R5 may optionally form a 3- to 8-membered heterocyclic ring together with the nitrogen atom to which they are specifically attached. Another specific example of the present invention is the group of compounds in which r1 Is a optionally substituted (Cl-C1 ()) heterocyclyl selected from the group consisting of:

Wherein R4 and R5 are each independently selected from the group consisting of: hydrogen, (CrC6) alkyl, H0- (C2-C6) alkyl, and (CVC8) alkyl; or R4 and R5 may be optionally connected to each other The nitrogen atoms together form a 3- to 8-membered heterocyclic ring. Another specific example of the present invention is the group of compounds, in which Ri is a optionally substituted (Ci_Cig) heterocyclic group selected from the group consisting of: 34 200300083 玖, description of the invention

35 200300083 发明, description of the invention

Wherein R9 is selected from the group consisting of: hydrogen, -CF3, (C! -C6) alkyl, HO- (C2-C6) alkyl and (c3-c8) alkyl; wherein R10 is selected from the following group: Hydrogen, (CVC6) alkyl, HO- (C2-5 C6) alkyl and (C3-C8) cycloalkyl. Another specific example of the present invention is the group of compounds in which R9 is independently selected from the group consisting of hydrogen, halo, -CN and optionally substituted with 1 to 3 fluoro groups ( Ci_c4) alkyl; more preferably hydrogen or methyl. Another specific example of the present invention is this group of compounds, in which R9 is independently 36 200300083 玖, the description of the invention is a substituent selected from the group consisting of a hydroxyl group, an amine group, and optionally substituted with 1 to 3 fluoro groups (CVC4) alkoxy, H02C ·, R4R5N (02S)-, (Cl_c4) alkyl- (〇2s) -NH — (CVC4) alkyl-C ^ S-IXCkCO alkyl_N] ㈣, R4R5N ( 〇〇)-, (Cl_c4) alkyl_NΗ, [(CVC4) alkyl] 2- and 5 R4R5N (CH2) r. Another specific example of the present invention is this group of compounds, in which each R9 is independently selected from the group consisting of: (C6_ClG) aryl, (A < 8) cycloalkyl, (cvc1 ()) heteroaryl (CVCl〇) heterocyclyl, (C6_Ci〇) aryl_〇-, (c3-c8) cycloalkyl_〇_, (Ci-CiG) heteroaryl_〇_ and (Ci_CiG) heterocyclyl · 10 ° Another specific example of the present invention is the group of compounds, wherein each Ri0 is a substituent independently selected from the group consisting of hydrogen and optionally substituted with 1 to 3 fluoro groups (Ci- C4) alkyl; more preferably hydrogen or methyl. 15 20

Another specific example of this matter is this group of compounds, wherein each R10 is a substituent independently selected from the group (CVC4) alkyl- (c == 〇), (C6_C10) square group, (C3-c8) cycloalkyl, wherein each of the aforementioned (CVCi〇) aryl group and (c3_Cs) cycloalkyl group may be optionally selected from 1 to 3 per ring at any position on the R10 substituent Independently substituted with a suitable moiety selected from the group consisting of: _ substituted, hydroxy, amine, -CN, (Cl_C4) alkyl, (CrC4) alkoxy, CF3 CF3〇-, (C1-C4) Alkyl_NH_, [(crc4) alkyl] 2 · N ·, (cr 4) alkyl S (C1-C4) alkyl- (S = 0)-, (crc4) alkyl- (s〇2) -, (CVC4) alkyl group and (Ci-c4 group). Another specific example of the present invention is the group of compounds in which each R] O is a substituent selected from the following materials ... ( CVCiG) heteroaryl and (c ^ io) 37 200300083 3, description of the invention, in which each of the (cvc10) heteroaryl and (CrCw) heterocyclyl is on the 忒 R substituent Can optionally be replaced by suitable moieties in the group of 1 to 3 independent k from the ring: a functional group, a meridian group, an amino group -CN, (CVC 4) Alkyl, (cvq) alkoxy, -CF3, -CF3-CH2-, CF3〇_, (CVC4) alkyl-NH-, [(CVC4) alkyl] 2-N-, (cKc4) -S ·, (CVC4) alkyl- (s = 〇)-, (CVC4) alkyl- (S02)-, (CVC4) alkenyl · 0- (〇〇)-, formamyl and (Ci_c4) Alkyl- (c = 0)-. Another preferred embodiment of the present invention is this group of compounds, wherein R1 is independently selected from the following groups:

Wherein R9 is selected from the group consisting of hydrogen, -CF3, (cKc6) alkyl, H0- (C2-C6) alkyl, or (c3-C8) cycloalkyl. Wherein R10 is selected from the group consisting of hydrogen, (Cl-C6) alkyl ... CF3-ch2-, H0_ (c2-c6) alkyl or (C3-C8) cycloalkyl. 15 A preferred embodiment of the present invention relates to a compound having Chemical Formula 1, wherein R1 is:

Wherein R0 is selected from the group consisting of hydrogen, (Ci-C6) alkyl, H0- (C2-38 200300083), description of the invention c6) alkyl and (c3-c8) cycloalkyl. A more specific embodiment of the present invention relates to a compound having Chemical Formula I, wherein the compound having Chemical Formula I has the following chemical formula:

5 where R3 is (CVC10) alkyl, where (c4-c10) alkyl is optional

Is substituted with 1 to 4 substituents independently selected from the group consisting of chloro, fluoro, (C6-C1 ()) aryl, (C3-C6) cycloalkyl, (Ci-C ^ o) Heteroaryl and (CVCW heterocyclyl); wherein (c6-c10) aryl, (c3-c6) cycloalkyl, (C ^ Cn) heteroaryl and (Cl_C1 ()) heterocyclyl Each can be optionally substituted with 1 to 3 moieties per ring on any carbon atom capable of supporting an additional part of the building. These moieties are independently selected from the following groups: halogenated Radical, vial, —CN, (CVC4) alkyl, (Cl_c4) alkoxy, (CrC4) alkylj, (C “C4) alkyl- (S = 0)-, (Cl-C4) alkyl- (s〇2) _, (Ci_c4) alkyl_〇 _ ((> 〇) _, methyl alcohol, (cKc4) alkyl- (〇〇)-, (c6-c10) aryl, (CVC8m 15 Aryl, (C1-C10) heteroaryl, (Ci-C) 〇) heterocyclyl, (c6_c10) aryl-〇 ·, (c3-c8) cycloalkyl-〇-, (Cl_Cl ()) hetero Aryl_〇_, (Ci-Ci ^ heterocyclyl-0- 'wherein the (C ^ -C: 8) cycloalkyl and (Ci-Cio) heterocyclyl substituents can also be optionally oxo Substituents; and R1G is hydrogen or (CVC4) alkyl; or a pharmaceutically acceptable salt thereof or Solvates. 39 20 200300083 发明. Description of the invention Another more specific embodiment of the present invention is related to a compound having the chemical formula I, wherein the compound having the chemical formula I has the following chemical formula:

Wherein R3 is (C6-C10) aryl- (CRnR12) q- (CH2)-, wherein the (c6- 5 ClG) aryl group can be optionally selected from 1 to 2 substituents independently selected from the following group Substitution: _ substituted, hydroxy, -CN, (Cl_C4) alkyl, (CVC4) alkoxy, (CkQ) alkyl-〇 (〇〇)-, formamyl, (Cl-C4) alkyl_ ( c = 〇) _, (C6-C10) aryl, (C3-C6) cycloalkyl, (Ci-Ci〇) heteroaryl, (c "c10) heterocyclyl, (c6_c10) aryl--0- (C3_C8) cycloalkyl_〇_, (c! _10 Cio) heteroaryl-〇 ·, and (Ci-Cio) heterocyclyl; wherein the aforementioned (c6_Cidaryl, (q-C6) cycloalkyl, Each of (Cl-Cl0) heteroaryl and (CVCi〇) heterocyclyl can be optionally substituted with 1 to 3 moieties per ring, which moieties are independently selected from the group consisting of halogenated Group, hydroxyl group ... CN, (CVC4) alkyl group, (cvco: ^ oxy group, -cf3, CF3o ... (Ci-c4) alkyl group, 15 alkyl group-(k〇)-, (crc4) alkyl- ( s〇2)-, (Cl-C4) alkyl_〇_ (c = 〇) _, formamyl and (CVC4) alkyl- (〇0)-; or a pharmaceutically acceptable salt or solvent thereof Another preferred embodiment of the present invention relates to a compound having a chemical formula. The compounds' wherein the compound has the formula I having the formula Nine-40200300083, the invention described

NH-R3 /, where R is an optionally substituted (c3-c12) cycloalkyl (R) S, wherein R11 and R12 are each independently hydrogen or (Ci-C4) alkyl, or /, At least one of R and R is hydrogen or (other than Ci_C4 group (more preferably, r11 and r12 in CR11R12 which are directly connected to the eight group are each hydrogen); halo group, meridian group, -CN, ΓΓ r, pf N (Ll-C4) alkyl, (CVC4) alkyl, (Cl_c4) alkyl--0- (〇〇) _, formamyl, (Ci_c4) alkyl- (c = 〇) _ A. C10) aryl, (C3-C8) cycloalkyl, (Ci_Ci〇) heteroaryl, (Ci_Ci〇) heterocyclyl, (c6-c10) aryl_〇_, (C3-C8) ring Yuanji___, (c 丨 _c〗 〇) heteroaryl_ 10 15

0- and (cvc10) heterocyclic groups; wherein each of the aforementioned (CVCi〇) aryl, (q_C6) cycloalkyl, (Ci-cwheteroaryl, and (Cl_CiG) heterocyclyl) may be The ring is substituted with 1 to 3 moieties, which are independently selected from the group consisting of halo, hydroxy, -CN, (Cl-C4) alkyl, (CVC4) alkoxy, -CF3, CF30-, (c! -C4) alkyl-S-. Examples of specific preferred compounds of formula I are as follows: 2-chloro-N- [2- (2-chloro-phenyl) -ethyl]- 5- (3,5-dioxo 5 3H- [1,2,4] triazin-2-yl) -benzidine; 2-chloro-5 · (3,5 · dioxo-4, 5-dihydro-3H_ [1,2,4] trione_2-US) N [2- (2-fluoro · phenyl) -ethyl] -benzoic acid amine; 20-chloro-5- ( 3,5-dioxo-4,5-dihydro-3Η · [1,2,4] triamidine_2 US) n 41 200300083 玖, description of the invention (2,2-biphenyl-ethyl)- Benzylamine, 1 ^-[2- (2-Gas-benzyl) -ethyl] -5- (3,5-dioxo-4,5-dimur-311 · [1,2,4 ] Dioxo-2-yl) -2 -fluorenyl-benzylamine, N- [2- (2-carbolactyl-phenyl) -ethyl] -2 -chloro-5_ (3,5-di Oxo-4,5_ 5 dihydro-3H- [1,2,4] triazin-2-yl) -benzamide; 2 · chloro-5- (3,5-dioxo -4,5-dihydro · 3Η · [1,2,4] triazin-2-yl) · N- (1-phenyl-cyclohexylmethyl) -benzamide; 2-chloro-5 · (3,5 · dioxo-4,5 · dihydro-3Η- [1,2,4] triazin-2-yl) -N- (1-p-tolyl-badhexylmethyl) -benzene Methylamine, 10 2-Ga-N- [2- (2-Ga-phenyl) -ethyl] -5- (4-methyl-3,5-dioxo-4,5dihydro 3H- [l, 2,4] triazin-2-yl) -benzimidamine; 2-chloro-5- (3,5-dioxo_4,5-dihydro-3 '-[1,2,4 ] Triazin-2-yl) · N- [2- (2-difluoromethyl-phenyl) -ethyl] -benzamide; and 2-chloro-N- [2- (2-chloro- Phenyl) -ethyl] -5- (3-oxo-2,3-dihydro-benzo15 [1,4] thiazin-4-yl) -benzamide. Other compounds of formula I An example is as follows: 2-chloro-5- (3,5-dioxo_4,5 · dihydro-3Η- [1,2,4] triazin-2-yl) -N · (2-ethyl -Butyl) -benzamide; 2-chloro-5- (3,5 · dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -N -20 (4-phenyl-butyl) -benzamide; 2-chloro-N- [2- (4-chloro-phenyl) -ethyl] -5- (3,5-dioxo-4 , 5-dichloro-3H · [l, 2,4] trisamidine · 2-yl) -benzamide; 2-chloro-5- (3,5-dioxo-4,5-dihydro- 3Η- [1,2,4] triazin-2-yl -N-phenethyl-benzamide; 200300083 玖, description of the invention N- [2- (4- > odor-phenyl) -ethyl] -2 -chloro-5-(3,5-dioxo -4,5-diazepine · 3H- [l, 2,4] triazin-2-yl) -benzamide; 2-chloro-5- (3,5-dioxo-4,5- Dihydro-3H_ [1,2,4] triazin-2-yl) -N- [2- (3-Ga-phenyl) -ethyl] -benzamide, 5 2-chloro-N- [ 2- (2,6 · dichloro-phenyl) · ethyl] -5- (3,5-dioxo-4,5-dihydro-3H- [1,2,4] triazine-2- -) Benzamidine; 2-chloro-5- (3,5-dioxo-4,5 · dihydro · 3 · _ [1,2,4] triazin-2 · yl) -N · [2 -(3-Methoxy-phenyl) -ethyl] -benzylidene; 2-chloro-5_ (3,5-dioxo-4,5-dihydro-3Η- [1,2,4 ] Triazin-2-yl) -N-10 amyl · benzidine; 2-chloro-5 · (3,5-dioxo-4,5-dihydro-3Η __ [1,2,4] Triazin-2-yl) -N- [2- (2 · Ethyl-phenyl) -ethyl] -benzoate amine, Ν- [2 · (5 · Bromo-2-methoxy-phenyl) ) -Ethyl] -2-chloro_5- (3,5-dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -benzamide; 15 2 · chloro · 5- (3,5 · dioxo-4,5-dihydro-3Η- [1,2,4] trimethyl-2-yl) -N-octyl · benzidine; 2 -Chloro-N- [2- (3 • chloro-phenyl) -B ] -5- (3,5-dioxo-4,5-diaza-3H- [l, 2,4] triazin-2-yl) benzidine; 2-chloro-N- [2- (2,4-dichloro-phenyl) -ethyl] _5- (3,5-dioxo-4,5-di20 hydrogen_3 '-[1,2,4] trifluoren-2-yl) -Benzamidine; 2-chloro-5 · (3,5 · dioxo-4,5-dihydro · 3Η- [1,2,4] triazin-2-yl) -N-hexyl-benzene Formamidine; 2-chloro-5- (3,5-dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl: (-N- [2- ( 4-Gas-phenyl) -ethyl] -phenylhydrazone, 200300083 玖, description of the invention 2-chloro-N-cyclohexylmethyl-5- (3,5-dioxo_4,5_ dihydro- 3H- [1,2,4] trifluoren-2-yl) -benzamide; 2-chloro-N- [2- (3,4-dichloro-phenyl) ethyl] -5- (3 , 5-dioxo-4,5-dihydro-3H- [1,2,4] triazin-2-yl) -benzamide; 5 2-chloro-5- (3,5-dioxo -4,5-dihydro-3H- [1,2,4] triazin-2-yl) -N- (2-phenyl-propyl) -benzidine; 2-chloro_5_ (3 , 5 · dioxo-4,5 · dihydro-3H_ [1,2,4] triazin-2-yl) -N- (2-thiobenzene-2 -yl-ethyl) -benzyl Amine, 2-chloro-5- (3,5_ dioxo-4,5-dihydro-3H- [1,2,4] triazin-2-yl) -N-10 [2- (2- 曱Oxy-phenyl) -ethyl] -benzamide; N- [2- (2-bromo-4-methoxy-phenyl) ) -Ethyl] -2-chloro-5- (3,5-dioxo · 4,5-dihydro-3Η · [1,2,4] triazin-2 · yl) -benzamide; 2-Ga-N_ [2- (4-Ga-phenyl) -propyl] -5- (3,5-dilacto-4,5-diaza-3H- [l, 2,4] triazine -2-yl) _benzidine; 15 2-chloro-5 · (3,5-dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -N- (1-hydroxy-cyclohexylmethyl) -benzidine; 2-chloro-5- (3,5-dioxo-4,5-dihydro · 3Η- [1,2,4] Triazin-2-yl) _N- (5-Cyclo-1,3,3-dimethyl-¾hexylmethyl) -benzamide, N-bicyclo [2.2.1] hept-2-ylfluorene 2-chloro-5- (3,5-dioxo-4,5-di20 hydrogen-3 '-[1,2,4] triazin-2-yl) -benzamide; 3- { [2-Chloro-5- (3,5-dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -benzylideneamino] -methyl } -Cyclohexanecarboxylic acid methyl ester; 1 ^ -bicyclo [2.2.1] hept-2-ylfluorenyl-2-chloro-5- (3,5-dioxo-4,5-dihydro- 3Η- [1,2,4] triazin-2 · yl) -benzidine; 200300083 玖, description of the invention 2-chloro-5- (3,5-dioxo · 4,5_ dihydro · 3Η · [1,2,4] triazin-2-yl) · N- (2-m-tolyl-ethyl) -benzamide, 2-Ga-1 ^-[2- (3-Ga-benzene Yl) -2-Ethyl-ethyl] -5- (3,5 -Dioxo_ 4,5_dihydro_3Η- [1,2,4] triazin-2-yl) -benzamide; 5 2-chloro-5- (3,5-dioxo- 4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -N- [2- (3-fluoro · phenyl) -2-hydroxy-ethyl] -benzidine ; 3- {2-Ι2-Chloro-5- (3,5-dioxo-4,5 · dihydro-3Η- [1,2,4] triazin-2-yl) -benzylideneamine Methyl] -ethyl} -benzoic acid methyl ester; 2-chloro-N · (6,6-dimethyl-bicyclo [3.1.1] hept-2-ylmethyl) -5- (3,5- Di 10 oxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -benzamide; 2-chloro · 5 · (3,5_dioxo-4 , 5-dihydro · 3Η- [1,2,4] triazin-2 · yl) -N- (2-hydroxy-2-phenyl-ethyl) -benzidine; 2 · chloro-5- (3,5 dioxo 4,5-dihydro-3H- [l, 2,4] triazine 2-yl) N-isochroman-l-ylmethyl-phenylhydrazine; 15 2-chloro -5- (3,5-dioxo-4,5-dihydro-3Η · [1,2,4] triazine · 2 · yl) · N- [2- (3-methylthiocythione free -Phenyl) -ethyl] -benzamide, 2-chloro-5- (3,5-dioxo-4,5-dihydro-3 氢-[1,2,4] triazine-2 -Yl) -N · (2-methoxy-2-phenyl-ethyl) -benzamide, 2-chloro-N- (6,6-dimethyl-bicyclo [3.1.1] heptane- 2-ylmethyl) -5- (3,5-di-20 oxo-4,5-di -3Η- [1,2,4] triazin-2-yl) -benzamide; 2-chloro-5- (3,5dioxo-4,5-dihydro-3H- [l, 2 , 4] triazin-2-yl) N- (l-phenyl-cyclopentylfluorenyl) -benzamide; 2-Ga-N- [2 · (2-Ga-phenyl) -ethyl ] -5- (2-oxo-fluorene. N-l-yl) -benzylamine; 45 200300083 玖, Description of the invention 2 · Ga-N- [2_ (2 · Ga · phenyl) ethyl] -5- (3-Methoxy_2_oxy -2H_. Sigma-1 -yl) -benzamide, 2-gas-1 ^-[2- (2-gas-phenyl) -ethyl] -5- (4-ethyl-2 , 3-dioxo-kouchen-1-yl) -benzamide; 5 2 -Ga-N- [2- (2-Ga-phenyl) -ethyl] -5- (2-oxo -11 thiophenanthrene-3-yl) _benzidine; 2-chloro-N- [1- (4-chloro-phenyl) -4,4 -digas-¾hexylmethyl] -5 -(3,5_ dioxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -benzamide; 2 -Ga-N- [3- (4Ga -Phenyl) -tetramurine-σbiran-3-ylmethyl] -5- (3,5 -di 10 oxo-4- (2,2,2) · trifluoro-ethyl) -4, 5-dihydro · 3Η- [1,2,4] triazin-2-yl) -benzamide; 2 -Ga-N- [2- (4-Ga-phenyl) -tetramethylene-fluorene ratio Nan-2-ylmethyl] -5 · (3-methyl-5-oxo-1,5 · dihydro- [1,2,4] triazol-4-yl) -benzamide; Ν -[2 · (4-fluoro-phenyl)-[1,3] dihuman-2-ylfluorenyl] -2-methyl-5- (5-15 oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -benzamide; 2 · chloro-N_ [2- (4-fluoro-phenyl) -tetrahydro ^ biran-2-ylmethyl] -2 -Methyl-5- [5 -Oxo_3- (2,2,2-trifluoro-ethyl) -1,5-dihydro- [1,2,4] triazol-4-yl] -benzamide; 5- ( 2,6-dioxo · 3,6-dihydro-2Η-pyrimidin-1-yl) -N- [2- (4 · fluoro-benzene-20yl) -2 -Ethyl-propyl] -2- Methyl-benzamide,] ^-[2- (2-chloro-phenyl) -2-meryl-propyl] -5- (2,4-dioxo-3,4-dihydro- 2Η-pyrimidin-1-yl) -2methylbenzidine; 1 ^-[2-qi-5- (3-methyl-2,5-dioxo-2,5-dimur-17 17 each-1-yl) -phenyl] -3- (2-gas-phenyl) -butylamine, 200300083 玖, description of the invention N- [2-chloro-5- (3-oxo-2,3 -Dihydro-benzo [1,4] thiazin-4-yl) -phenyl] -3- (2-gas-phenyl) -3-methyl-butylamine, 2-chloro-N- [ 2- (2 · chloro-phenyl) · 2-methyl-propyl] _5- (3-oxo-2,3-dihydro-benzo [1,4] pyrazin-4-yl) -benzene Formamidine; 5 2-chloro · N- [2- (2-Gathiothio-3-yl) -ethyl] -5- (3-oxo-2,3-diaza-benzo [1 , 4] Benzothi-4-yl) -phenylhydrazine, N · [2- (3-chloro-thioname · 2-yl) -ethyl] -2-methyl-5- (7- Methyl-3-oxo-2,3-diaza-benzo [1,4] pyrene. Qin-4-yl) -benzamide, 2-gas-1 ^-[2- (3-methyl-bisan-2-yl) -ethyl] -5- (3-oxo-2, 3-di-10 hydrogen- [1,4] thiazin-4-yl) -benzamide; 2-chloro-5- (2,4-dioxoG, 4-dihydro-2hydrazone-pyrimidine-1 -Yl) -N_ (2- «an-2-yl-ethyl) -benzamide, 2-chloro-5- (3,5-dioxo-4,5-dihydro-3Η- [1 , 2,4] triazin-2-yl) _N- (1-hydroxy-cycloheptylmethyl) -benzamide; 15 2-chloro-5- (3,5-dioxo-2,5 -Dihydro-3 '-[1,2,4] triazin-2-yl) -N- (1-hydroxy-cycloheptylfluorenyl) -benzamide; 2-chloro-N_ (4,4- Difluoro-l-transyl-cyclohexylmethyl) -5 · (3,5-dioxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) _benzene Formamidine; 2 -Ga-N-[4,4-Diran-1- (5-methyl-thiophenyl-2-yl) -¾hexylmethyl 20] -5- (3,5-di Oxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -benzamide; 2-chloro-5 · (3,5 · dioxo-4,5 -Dihydro-3Η- [1,2,4] triazin-2-yl) · N · [2- (5 -Ga-thiobenz-2-yl) -tetramidine · σbiran-2-yl Methyl] -benzamide, 2-amino-¾heptylmethyl) -5- (3-methyl-5-lacto-1,5-dihydro- [1,2,4] triazole -4-yl) -benzamide; 47 200300083 Rose, description of the invention 2. Chloro-N-cycloheptylfluorenyl 5- (5-oxo-3-trifluoromethyl-1,5-dihydro_ [1,2,4] triazole-4 -Yl) -phenylhydrazine; 2-chloro-5_ (3-fluorenyl-5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -N-tri Fluorofluorenyl-phenyl)-[1,3] dihenane-2-ylfluorenyl] -phenylhydrazine; 5 2-chloro-HUG-fluoro-phenyl)-[1,3] dihenane -2-ylfluorenyl] -5- (5-oxo-1,5-dihydro_ [1,2,4] triazol-4-yl) -benzidine; 2-Gas-N- [ 3- (4-Gas · Phenyl) · Tetrahydro-Koubikounan-3 -ylfluorenyl] -5- [5 -oxo-l- (2,2,2-trifluoro-ethyl) -1 , 5-Dihydro- [1,2,4] triazol-4-yl] -benzamide; 10 Ν_ [2 · 气 -5- (3-oxo-2,3-dihydro-benzo) [1,4] thiazin-4 · yl) -phenyl] · 3- [2- (1-hydroxy- 丨 -methyl-ethyl) _phenyl] -propanamide; and N · [2- Gas-5- (3,5_dioxo-4,5-dihydro-3Η- [1,2,4] triazin-2 · yl) -phenyl] _3- [2- (1-hydroxy_ ; μmethyl-ethyl) -phenyl] -propanamide. Examples of specific nicotinamides of the present invention include: 15 2-chloro-N- [l- (4-chloro-phenyl) -4,4-difluoro-cyclohexylmethyl] _5 · (3,5_ di Oxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -nicotinamide; 2-chloro-N- [3- (4-chlorophenyl) -tetra Hydrogen- " pyran-3-ylmethyl] -5- [3,5-dioxo-4- (2,2,2-trifluoro-ethyl) -4,5-dihydro-3Η- [1,2,4] triazin-2-yl]-Yuhanamine; 20 2-chloro-N- [2 · (4-fluoro-phenyl) -tetrahydropyranylmethyl] -5- (3.fluorenyl-5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -nicotinamide; N- [2- (4-fluoro-phenyl) )-[1,3] dihenane-2-ylmethyl 1.2-fluorenyl-5- (5-oxo-1,5-dihydro- [1,2,4] triazole-4- ) -Nicotinylamine; N- [2- (4-fluoro-phenyl) tetrahydro-pyranylmethyl] fluorenyl " fluorene 5-oxy 48 200300083 玖, invention description -3_ (2 , 2,2-trifluoro-ethyl) -1,5 · dihydro- [1,2,4] triazol-4-yl) -nicotinamide; 5- (2,6-dioxo- 3,6-2H-pyrimidin-1-yl) -N- [2 · (4 · fluoro-phenyl) -2-meryl-propyl] -2 -methyl-yumanamine, 5 1 ^- [2- (2-Gas-phenyl) -2-Cycloyl-propyl] -5- (2,4-dioxo-3,4-211- Methyldetermine-1 -yl) -2- methyl- Assay of amine, 2-chloro-N- [2-chloro-phenyl > -2-amidinopropyl] -5- (3-oxo-2,3-dirat-benzo [1 ， 4] ° ϋ ϋQin-4-yl) _Yu test amine, 2-Ga-1 ^-[2- (2-chloro-thiophenyl-3-yl) -ethyl] -5- (3 _Oxo-2,3-di10 murine-benzo [1,4] pyridin-4-yl) -yumamine, N- [2- (3-chloro-thiobenzene-2-yl ) -Ethyl] -2-methyl_5- (7-methyl_3_oxo-2,3 · diazepine-benzo [1,4] ¾.Qin-4-yl) -Yu Qin Amine, 2-chloro-N- [2- (3-methyl-bisan_2_yl) -ethyl] -5- (3-oxo_2,3-dihydro- [1,4] thio Azin-4-yl) -nicotinamide; 15 2-Ga-5- (2,4_ dioxo-3,4 -dimur-2 Η-^ dense bit -1 group) -N- (2- Diamyl-2 -yl-ethyl) -diamine, 2-chloro-5- (3,5-dioxo-4,5-dihydro-3Η- [1,2,4] triazine- 2-yl) -N- (1-hydroxy-cycloheptylmethyl) -nicotinamide; 2-chloro-5- (3,5-dioxo-2,5_dihydro-3Η · [1 , 2,4] triazin-2-yl) · N-20 (1-hydroxy-cycloheptylmethyl) -nicotinamide; 2-chloro-N- (4,4-difluoro-1-hydroxyl -Cyclohexylmethyl) -5- (3,5-dioxo-4,5-dihydro-3H_ [l, 2,4] triazin-2-yl) -nicotinamide; 2-chloro- Ν- [4,4-difluoro-1- (5 · methyl-thiobenzene-2 -Yl) -cyclohexylmethyl] _5- (3,5-dioxo-4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -nicotinamide; 49 200300083 玖, description of the invention 2-chloro-5- (3,5-dioxo-4,5-dihydro-3H- [1,2,4] triazin-2-yl) -N- [2- ( 5 -Gas-thiophenyl-2-yl) -tetraazapyran-2-ylmethyl] -Yu amine, 2-Gas-¾heptylmethyl) -5- (3-methyl- 5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -nicotinamide; 5 2-chloro-N-cycloheptylmethyl-5- (5- Oxo-3-trifluoromethyl-1,5-dihydro- [1,2,4] triazol-4-yl) -nicotinamide; 2.chloro-5- (3-methyl-5 -Oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -N- [2- (4-trifluoromethyl-phenylfluorene 1,3] dihumane-2 -Ylmethyl] -nicotinylamine; 2-chloro-N- [2- (4-Gas-phenyl)-[1,3] two-methyl-2-ylmethyl] -5- (5 -Oxygen 10,1,5-dihydro- [1,2,4] triazol-4-yl) -nicotinamide; 2 -Ga-N- [3- (4 · Ga-phenyl) _ Tetramurine-bipyran-3 -ylmethyl] _5 · [5-oxo-1- (2,2,2-trifluoro-ethyl) -1,5-dihydro- [1,2,4 ] Triazol-4-yl] -nicotinamide; 2-chloro · Ν_ [2- (2-chloro-phenyl) -ethyl] _5 · [3,5-dioxo-4,5-di Hydrogen · 15 3Η · [1,2,4] triazine-2- [Yl] -nicotinylamine; 2-chloro-5- (3,5-dioxo-4,5 · dihydro-3Η · [1,2,4] triazin-2-yl) -N- [ 2- (2-Gas-phenyl) -ethyl] -acetic acid amine, 2-chloro-5- (3,5-dioxo-4,5-dihydro-3Η · [1,2,4 ] Triazin-2-yl) -N- (2,2-biphenyl-ethyl) -yumanamine, 20 Ν- [2 · (2-chlorophenyl) -ethyl] -5- ( 3,5-dioxo-4,5-dihydro-3Η · [1,2,4] triazin-2-yl) -2-methyl-nicotinamide; Ν- [2- (2- Benzyloxy-phenyl) -ethyl] -2-chloro · 5- (3,5-dioxo-4,5-dihydro-3H- [l, 2,4] triazin-2-yl) -Nicotinamide; 2-chloro-5- (3,5-dioxo-4,5-dihydro_3Η · [1,2,4] triazin-2-yl) -N- 200300083 玖, Description of the invention (1-phenyl-cyclohexylmethyl) -nicotinamide; 2-chloro-5- (3,5-dioxo-4,5-dihydro-3Η · [1,2,4] Triazin-2-yl) · N · (1-p-tolyl-cyclohexylfluorenyl) -nicotinamide; 2-chloro-N · [2- (2-chloro-phenyl) -ethyl] -5- (4-methyl-3,5-dioxo-5 4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -nicotinamide; 2-chloro -5- (3,5-dioxo-4,5-dihydro-311- [1,2,4] triazin-2-yl) -dipper [2- (2-difluoromethyl-phenyl ) -Ethyl] -in the fermentation amine, and 2-chloro-1 ^ 1- [2- (2- - phenyl) - ethyl] -5- (3-oxo-2,3-gas - benzo [1,4] sigh hee-yl) - amine to acyl test. 10 Examples of specific isonicotinylamines of the present invention include: 5-chloro-N- [l- (4-chloro-phenyl) -4,4-digas-badhexylfluorenyl] · 2- (3, 5_ dioxo-4,5-dihydro-3fluorene- [1,2,4] triazin-2-yl) -isonicotinamine; 5-chloro-N- [3- (4-chloro-benzene ) -Tetramurine_bipyran-3-ylmethyl] 2- [3,5-dioxo-4_ (2,2,2-trifluoro-ethyl) -4,5 · dihydro- 3Η · [1,2,4] triazin-2-yl] -15 isonicotinamide; 5-chloro-N- [2 · (4-fluoro-phenyl) -tetrahydro-oriphanan-2 -Ylmethyl] -2- (3-methyl-5-lacto-1,5-diazine- [1,2,4] bis-11-sino-4-yl) -different from test amines, Ν- [2- (4-fluoro-phenyl)-[1,3] dihenane-2-ylmethyl] -5-methyl-2- (5-oxo-1,5-dihydro- [1 , 2,4] triazol-4-yl) -isonicotinamine; 20 Ν- [2- (4-Ga-phenyl) -tetrazine-σbiran-2-ylmethyl] -5- Methyl-2- (5 • lacto-3 · (2,2,2-trifluoro-ethyl) -1,5-dihydro- [1,2,4] triazol-4-yl) -iso Nicotinamide; 2- (2,6-dioxo-3,6-2} _pyrimidin-1-yl) -N_ [2- (4_fluoro-phenyl) -2-meryl-propyl]- 5 -Amidino · Different amine, 200300083 玖, Description of the invention N · [2- (2-chloro-phenyl) _2_hydroxy-propyl] -2 · (2,4 · dioxo-3 , 4-2H-pyrimidin-1-yl) -5-fluorenyl-isonicotinamine; 5-gas-N- [2- (2-gas-phenyl) -2 · methyl-propyl]- 2- (3-lacto-2,3-dihydro-benzo [1,4] humazin-4-yl) -isonicotinamine; 5 5-qi-1 ^-[2- (2- Gas-thiobenzene-3-yl) -ethyl] -2- (3-oxo-2,3-diaza-benzo [1,4] ¾fluoren-4-yl) -different amine , Ν- [2- (3-chloro-thiophenyl-2-yl) -ethyl] -5-methyl-2- (7-fluorenyl-3-oxo-2,3-dimur-benzene And [1,4] 17 group 11 Qin-4-yl) _different from the test 3 & amine, 5 -Ga-N- [2- (3 · methyl-β ran-2-yl) -ethyl]- 2- (3-lacto-2,3 di10 hydrogen- [1,4] thiazin-4-yl) -isonicotinamine; 5. · chloro-5- (2,4-dioxo-3 , 4-dihydro-2fluorene-pyrimidin-1-yl) -N- (2-rean-2-yl-ethyl) -isocyanate, 5-chloro-2- (3,5-di Oxo-4,5-dihydro 3H- [l, 2,4] triazin-2-yl) N- (l-hydroxy_cycloheptylmethyl) -isonicotinamine; 15 5-chloro- 2- (3,5_ dioxo · 2,5-dihydro-3Η- [1,2,4] triazin-2-yl) -N- (1-hydroxy-cycloheptylmethyl) -isonia Alkylamine; 5-chloro-N- (4,4-digas-1-fatyl · badhexylmethyl) -2- (3,5-dioxo-4,5-dihydro_3H- [ l, 2,4] tris (-2-yl) · isonicotine ; 5-Chloro-N-[4,4 -Diran-1- (5 -fluorenyl-thiophenyl-2-yl) -¾hexylmethyl] _ 20 2- (3,5-dioxo- 4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -isonicotinamine; 5-chloro-2 · (3,5-dioxo-4,5-di Hydrogen-3 '-[1,2,4] triazin-2-yl) -N- [2- (5-Gas-thiophenyl-2-yl) -tetramus-. Pyran-2-ylmethyl] -Different from test amine, 5-chloro-N- (l-hydroxy-cycloheptylfluorenyl) -2- (3-fluorenyl-5-oxo-1,5 -Dihydro- [1,2,4] triazol-4-yl) -isonicotinamine; 200300083 玖, description of the invention 5-chloro-N-cycloheptylfluorenyl-2- (5-oxo- 3-difluoromethyl · 1,5-dihydro- [1,2,4] triazol-4-yl) -isonicotinamine; 5-chloro-2- (3-fluorenyl-5-oxy -1,5-dihydro- [1,2,4] triazol-4-yl) -N- [2- (4-Dioxanyl-phenyl)-[1,3] dioxane-2 -Methylmethyl] -Different from S-amine, 5 5-chloro-N- [2- (4-fluoro-phenyl)-[1,3] dihuman-2-ylfluorenyl] -5- (5-oxo-1,5 -dimur- [1,2,4] difluoren-4-yl) -different S & amine, 5-chloro-N- [3- (4-gas-benzene Yl) -tetramidine- ° pyran-3-ylfluorenyl] -2- [5-oxo-1- (2,2,2-trifluoro-ethyl) -1,5-dihydro- [1 , 2,4] triazol-4-yl] -isonicotinamine; 10 5 -Ga-N- [2- (2-rat-phenyl) -ethyl] -2- [3,5-di Milk generation-4,5-diaza-3Η_ [1,2,4] triazin-2-yl] · isonicotinamine; 5-chloro-2 · (3,5-dioxo_4,5_ Dihydro-3 '-[1,2,4] triazin-2 · yl) -N- [2- (2-fluoro-phenyl) -ethyl] -isonicotinamine; 5 · chloro-2- (3,5_ dioxo-4,5 · dihydro-3Η- [1,2,4] triazin-2-yl) -N-15 (2,2-biphenyl-ethyl) -isocyanate, Ν- [2- (2 · chloro-phenyl) -Ethyl] -2- (3,5dioxo-4,5-dihydro-3H- [l, 2,4] trifluoren-2-yl) -2-methyl-isonicotinamine; 1 ^-[2- (2-carbolactyl-phenyl) -ethyl] -5-qi-2- (3,5-dioxo-4,5_ dihydro · 3Η- [1,2,4 ] Triazin-2-yl) · isonicotinamine; 20 5-chloro-2 · (3,5-dioxo · 4,5 · dihydro-3Η- [1,2,4] triazine- 2-yl) · N · (1-phenyl-cyclohexylfluorenyl) -different from amine, 5 · chloro-2- (3,5 · dioxo · 4,5-dihydro-3Η · [ 1,2,4] triazin-2-yl) -N- (1-p-tolyl-¾hexylfluorenyl) -isomeric amine, 5-chloro-N · [2- (2-chloro- Phenyl) -ethyl] -2- (4-fluorenyl-3,5-dioxo- 200300083), description of the invention 4,5-dihydro-3H_ [1,2,4] trifluoren-2-yl ) Isonicotinamide; 5-chloro-2- (3,5-dioxo-4,5-dihydro-3Η · [1,2,4] triazin-2-yl) -N- [2 -(2-Digasmethyl-phenyl) -ethyl] -different from the test amine, and 5-Ga-1 ^-[2- (2-Ga-phenyl) -ethyl] -2- ( 3-oxo-2,3-diaza-benzo5 [1,4] thiazin-4-yl) -isonicotinamine. Specific examples of other pyridin-2-carboxyfluorenamines include: 3-chloro-6- (3,5 · dioxo-4,5-dihydro-3 '_ [1,2,4] triazin-2-yl ) -Mouth-biting bis-carboxylic acid [2- (2-Gas-phenyl) · ethyl] -vinylamine, 3-chloro-6- (3,5-dioxo-4,5-dihydro -311- [1,2,4] triazin-2-yl) -pyridine 10 唆 -2-Junic acid (2,2-biphenyl-ethyl) -total amine, 6- (3,5-di Oxo · 4,5_ dihydro-3Η- [1,2,4] triazin-2-yl) -3-methyl-sigma-2-biterate [2- (2-chloro-phenyl) -Ethyl] -amine, 3-chloro-6- (3,5-dioxo-4,5-dihydro · 3Η- [1,2,4] triazin-2-yl) -pyridine- 2-Unsaturated acid [2- (2--methoxy-phenyl) -ethyl] -amine, 15 3-chloro-6- (3,5-dioxo-4,5-dihydro_311- [1,2,4] triazin-2-yl) -ring ratio of 0- 2-Junic acid (1-phenyl-¾hexylmethyl)-amine, 3-chloro-6- (3,5 · Dioxo-4,5-dihydro-3Η- [1,2,4] triazin-2-yl) -pyridine-2-carboxylic acid (1-p-tolyl-cyclohexylmethyl)- Hydrazine; 3-chloro-6- (4-methyl-3,5-dioxo-4,5-dihydro-3hydrazone- [1,2,4] triazin-2-20 group)-° ratio sigma-2-dicarboxylic acid [2- (2-Gas-phenyl) -ethyl] -amine, 3-chloro-6- (3,5 · dioxo-4,5-dihydro_3Η · [1,2,4] triazine- 2-yl) _orbitidine-2_carboxylic acid [2- (2-trifluoromethyl-phenyl) -ethyl] -fluorenamine; and 3-chloro-6- (3-oxo-2, 3-dihydro-benzo [1,4] thiidine-4-ylbipyridine-2-dicarboxylic acid [2- (2-chloro-phenyl) -ethyl] -vinylamine. 200300083 玖, Description of the invention The invention also includes isotopically labeled compounds, which are the same as those described in Formula I, but one or more of the atomic systems have an atomic mass or mass number different from that of atomic mass or mass number commonly found in nature Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, stone, nitrogen, oxygen, phosphorus, fluorine, and gas, such as: 2 hydrogen, 3 hydrogen, 13 carbon, 14 carbon, 15 nitrogen, and 18 oxygen. , 17 oxygen, 31 phosphorus 32 stone maggot 35 sulfur 18 ίο 15 20 and 36 chlorine. Compounds of the present invention a containing the aforementioned isotopes and / or other atom isotopes, their prodrugs, and the pharmacology of the compounds or prodrugs 7 Accepted salts are included in the scope of the present invention. The specific compounds of the present invention marked by the f-positions * such as those containing radioactive isotopes, such as 3 hydrogen and M carbon, are applicable to medicine And / or by mass analysis of the tissue distribution and the like in which the test preparation (iv) in terms of easiness to mark gas (i.e., carbon, such as 3, i.e., "carbon) isotopes are particularly preferred for the system. Going further—if replaced with a heavier isotope (such as 2), it can provide cancer treatment due to higher metabolic stability (such as increasing the half-life in vivo or reducing the required dose). Advantages, so it is better in some cases.-Generally can be replaced by the isotope-labeled reagents can be obtained by the following flowchart and / or examples and procedures disclosed in the preparation of Xianxian The isotope-labeled formula 5 is used to prepare the compounds of formula I and their prodrugs, which are not isotopically prepared according to the present invention. The compounds of formula I and the pelvic core are made with ^, and this is to the party that can receive the party Salt can be used to make a fun thing, the drug is used for the prevention or treatment of any disease state of ^ ^ ^ +, chant (or other mammals), 疗法 ^ ^, "therapy, the disease state It is due to the courtesy of animal cells (such as (but square,) early nucleus cells and / or giant salamander cells)

55 200300083 发明, description of the invention Exacerbated or caused by excessive or unregulated cytokine production. The present invention relates to a method for treating a disease withered by P2Xy in a mammal in need of such treatment, which comprises administering to the mammal an effective amount of a compound of formula I. 5 10 15 20 The present invention relates to a method for treating a condition in a mammal (including humans) selected from the following groups: arthritis (including psoriasis arthritis, Reiter's syndrome) , Rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatic spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's Disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, gas%, bronchitis, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, disease, pulmonary sarcomatoid disease, allergic reaction, allergy Contact hypersensitivity, wetness, contact dermatitis, psoriasis, sunburn, cancer, tissue ulcers, restenosis of the blood vessels, periodontal disease, watercraft epidermolysis, osteoporosis, bone pure money, artificial joint implants Relaxation, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, nerve trauma, spinal mineral injury, neurodegenerative diseases Alzheimer's disease, Parkinson's disease, migraine, dysplasia, peripheral nervous system disease, pain, brain-like powder J & L tube disease, Zhishi knife left shame θ increase Effect, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, sclerosis, sclerosis, abnormal wound healing, burns, autoimmunity Disease, Huntington's disease, diabetes, AIDS, cachexia, septicemia, septicemia 56 200300083 发明, invention description bloody shock, toxic pure shock, hugh ray inflammation, Gram-negative septicemia, toxic shock syndrome, brain type Dysentery, Heart and Kidney Reperfusion Injury, Thrombosis, Globululonephritis, #Plant and Host: Response, Rejection of Allograft, Organ Transplant Toxicity, Cancerous Bladder Triangitis or Muscle Degeneration It includes a compound of formula I for the mammal = administration-amount to effectively treat the condition. The present invention relates to a pharmaceutical composition for treating a disease regulated by p2 \ in a mammal, which comprises an effective amount of a compound of formula I and a pharmaceutically acceptable carrier. 10 15 20

The present invention relates to a pharmaceutical composition, which is used to treat _ conditions in ㈣ animals (including humans) selected from the following groups: joints including psoriasis arthritis, Reiter's syndrome, rheumatism Arthritis, gout, traumatic arthritis, rheumatoid arthritis, rheumatic spondylitis, | arthritis, gouty arthritis and acute synovitis), inflammatory bowel disease Crohn's disease, lung Emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic lung inflammatory disease, disease, pulmonary sarcoidosis, allergic reaction, contact sensitivity Hypersensitivity, wet sores, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis of the blood vessels, periodontal disease, water-derived epidermolytic disease, osteoporosis, osteolytic disease, artificial joint implanted characters Relaxation, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, neurotrauma, spinal cord injury, neurodegenerative disease, Alzheimer's (Alzheimer's disease), Parkinson's disease, migraine, A iron relieving eyebrow 1: depression, peripheral nervous system disease, pain 57 200300083 ί 15 20 玖, invention description, cerebral vascular disease, intelligence or Cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, f-meningitis, abnormal wound healing, burns, autologous Immune disease, Huntington's disease, diabetes, AIDS, cachexia, sepsis, 'septic shock, "pure shock, pure, septic inflammation, septic negative septicemia, asymptomatic shock syndrome, malaria, heart Viscera and reperfusion injury, thrombosis, gray tube nephritis, reaction between the graft and the host, the effects of allogeneic H grafts, gastrointestinal transplant toxicity, ulcerative bladder triangitis or muscle A degenerative disease comprising administering to the mammal an amount of a compound of formula Z and a pharmaceutically acceptable carrier effective to treat the condition. The compound is preferably suitable for the treatment of rheumatoid arthritis, osteoarthritis' psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperreactivity of the trachea, septic shock, glomerulonephritis, irritability Irritable bowel, Crohn's disease, cystitis triangitis, atherosclerosis, malignant cell growth and metastasis, myoblastic leukemia, diabetes, Alzheimer's disease, Meningitis, osteoporosis, burns, ischemic viscera, stroke and varicose veins. The present invention also provides a compound of formula I or a pharmaceutically acceptable salt or solvent thereof as defined above for use in the treatment. The present invention further provides a method for treating osteoarthritis, which comprises administering a therapeutically effective amount of a compound of the formula 化学, as defined in ±, or a pharmaceutically acceptable salt or solvate thereof. .

58 200300083 (ii) Description of the invention The present invention further provides a method for treating immunosuppressive effects (such as for treating rheumatoid arthritis, irritable bowel disease, osteoarthritis or psoriasis), which comprises administering to a patient A therapeutically effective amount of a compound of formula VII- or a pharmaceutically acceptable salt or solvent thereof as defined above is administered. The present invention further provides a method for treating obstructive airway diseases (such as asthma or chronic obstructive pulmonary disease (COPD)), which comprises administering to a patient a therapeutically effective amount of a compound of the formula ⑴ as defined above. A pharmaceutically acceptable salt or solvate. 10. As used herein, "treatment (" hi § "), the term refers to the reversal, alleviation, suppression of worsening or prevention of the condition or condition or one or more symptoms of the condition or condition in which the term is used." Treatment The term "treatment" refers to the effect of treatment, and "treatment" is as defined above. The present invention further provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as defined above and a pharmaceutically acceptable adjuvant, The diluent or carrier is used in combination with the present invention. The present invention further provides a method for preparing a pharmaceutical composition of the present invention, the pharmaceutical composition comprising the compound 20 of one of the chemical formula 如 as defined above or a pharmaceutically acceptable salt or solvent thereof. Compound and a pharmaceutically acceptable adjuvant, diluent or carrier. Apparently, the dosage used in the above treatments will vary depending on the compound used, the mode of administration, the desired therapeutic effect, and the condition being treated. Compounds / salts / solvates (active ingredients) with the chemical formula 59 59 200300083 玖, invention description d R " in the range of 1 ¾ to! G, preferably from i mg to mg, more preferably from 10 亳G to 100 mg. The invention also encompasses sustained release compositions. The invention is also related to having a chemical formula! Methods for the preparation of compounds and intermediates used in these methods. A specific example of the method of the present invention relates to the preparation of compounds having the following chemical formula:

Wherein, 乂, 丫, 2, ^, 2 and "are as above (including all the specific examples and preferred examples of the above chemical formula 1 with 10); they include the following reactions: a) one of the following chemical formulas Compounds (where X, Y, Z, R1 and R2 are as defined above and L is a _ or substituted group): R2 Ο

T reacts with a compound of one of the following formulae (wherein R3 is as defined above): 15 H2N-R3 II! And a base; or b) in the presence of a coupling agent, a base, and a solvent, one of the following formulae Compounds (where X, γ, Z, R1 and R2 are as defined above) · 60

IV 200300083 发明, Description of Invention

OH

Reacts with a compound of the following formula (where R3 is as defined above): H2N-R3 II!

C) or a compound of one of the following formulae (where X, γ, z, R1 and R2 are as defined above):

With a compound of one of the following chemical formulas (where L1 is one selected from

Leaving groups in the group: chloro, fluoro, bromo, iodo or dehydrated):

VI and a reaction with a solvent. Another specific example of this month is an intermediate product with the following chemical formula:

T 61 200300083 玖, description of the invention /, X Y, Z, R are as described above (including all the specific examples and preferred examples of the above, z, R1 and R2). Another specific embodiment of the present invention is an intermediate product having the following chemical formula:

5 where X, Y, Z, R, and R2 are as described above (including all the specific examples and preferred examples of the above X, γ, ζ, R1, and R2). Skilled artisans will appreciate that the compounds of the present invention are suitable for treating a variety of diseases. Skilled artisans will also appreciate that when using a compound of the invention in the treatment of a particular disease, the compound of the invention can be used in combination with a variety of existing therapeutic agents suitable for the disease.

For the treatment of rheumatoid arthritis, the compounds of the present invention can be used in combination with the following agents: such as TNF-α inhibitors such as anti-bimonal antibodies (such as (Renncade), CDP-870 and DA?) And TNF receptor immunity Globulin molecules (such as EnbM®); CD ^ inhibitors (such as meloxicam, I5 celecoxib, rofecoxib, vedoxoxib) (Valdecoxib and etolicob) and low-dose aminofolate, lefunomide; CiCleSonide; hydroxyl Chloroquine, & penicillamine, auranofin, or parenteral or oral gold preparations. 20 The present invention further relates to a compound of the present invention and a leuko diene biosynthesis inhibitor selected from the group consisting of a 5-lipoxygenase (5-10) inhibitor 62 200300083 玖, description of the invention, or 5-lipoxygenase activation Composition of protein (FLAP) antagonists: zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, N- (5-substituted) -thiophene-2-alkylsulfonamide, 2,6-di-tert-butylphenol hydrazone, methoxy 5-based tetrahydrofuran (such as Zeneca ZD-2138) , Compound SB-210661, 2-cyanonaphthalene compounds substituted with a pyrimidinyl group (such as L-739,010), 2-cyanophosphonium compounds (such as L-746,530), indpur and oxoline compounds (such as MK-591 , MK-886 and BAY X 1005). The present invention further relates to a compound of the present invention and a composition of 10 leukotrienes ltb4, LTC4, LTD4 and LTE4 receptor antagonists selected from the group consisting of phenothiazin-3-one (such as L-651,392) , Fluorene compounds (such as CGS-25019C), benzoethylenediamines (such as ontazolast), phenylweiimide amines (such as BILL 284/260), and compounds such as Zaflucas Zafirlukast, ablukast, montelukast 15, pranlukast, verlukast (MK-679), RG-12525 , Ro-245913, Iralukast (CGP 45715A) and BAY X 7195. The invention further relates to a composition of a compound of the invention and a PDE4 inhibitor (including an inhibitor of the isomeric form of PDE4D). 20 The present invention also relates to a compound of the present invention and an antihistamine H] receptor antagonists (including citirizine, loratadine, desloratadine, faso A combination of fexofenadine, astemizole, azelastine, and chlorpheniramine. 63 200300083 (ii) Description of the invention The present invention further relates to a compound of the present invention and a gastroprotective H2 receptor antagonist. The present invention also relates to a compound of the present invention and an α! And U 2 adrenal glands, which are also synergistic agents. Vasoconstrictive sympathomimetic agents (including cyclohexylpropyl 5-methylpyridine, stupid adrenaline, phenylpropanolamine , Methylephedrine test, chlorophyll hydrochloride iiL, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, bupropion hydrochloride and ethyl norepinephrine). The present invention further relates to a compound of the present invention and an anticholinergic functional preparation (including ipratropium bromide, tiotropium bromide, scopolamine bromide, 嚷 ° N-nitrogen leather and Tairen Composition of telepinepine). The present invention further relates to a compound of the present invention and a ^ 1 and ^ 4 adrenal receptor synergist (including metaisoproterenol, isoproterenol, isoproterenol, methamphetamine epinephrine , Butrepinephrine, formoterol, salmeter 0, meta-tert-butyl adrenaline 15, orciPrenMine, ditolyl alcohol mesylate and Pibuterol); or xanthanine (including theophylline and aminophylline); a combination of sodium cromoglycate or scopolamine receptor (Mi, M2, and M3) antagonists. The invention further relates to a composition of a compound of the invention and a class of insulin growth factor 2 type I (IGF-1) mimetics. The present invention further relates to a compound of the present invention and an inhaled glucocorticoid (including prednis, prednisolone, flunisolide, propionol, A composition of clodesamethasone propionate, budesonide, fretica propionate 646400083, fluticasone, and mometasone furoate. The present invention further relates to the present invention A compound of the invention in combination with: (a) a trypsin-like inhibitor; (b) a platelet activating factor (PAF) antagonist; (c) an interleukin-converting enzyme (ICE) inhibitor; (d) IMPDH inhibitors; 5 (e) adhesion molecule inhibitors (including VLA-4 antagonists); (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6-acid dehydrogenase inhibitors; ⑴ Kallikrein-B1 and B2 receptor antagonists; (j) anti-gout agents (such as colchicine); (k) yellow throat oxidase inhibitors (such as alligatorol); ⑴ diuretics (such as Via benzylflavan, sulfazone and bromobenzone); (m) growth hormone secretagogues 10 (η) transforming growth factor (TGF / 3); (0) platelet-derived growth factor (PDGF); (ρ) fibroblast growth factor (such as basic fibroblast growth factor (bFGF)); (q ) Granulocyte macrophage community stimulating factor (GM-CSF); Capsaicin cream; (s) Tachykinin NKil ^ NKs receptor antagonists selected from the group: NKP-608C, SB-233412 ( (15) talnetant) and D-4418; and (t) an elastase inhibitor selected from the group consisting of UT-77 and ZD-0892. The present invention further relates to a compound of the present invention and a matrix metalloproteinase (MMP) inhibitor composition, the matrix metalloproteinases are matrix lysins, collagenases, gelatinases, and aggrecanase; especially 20 collagenase-1 (MMP-1), collagenase- 2 (MMP-8), collagenase-3 (MMP-13), matrix lysin-1 (MMP-3), matrix lysin-2 (MMP-10), and matrix lysin-3 (MMP · 11). The compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable formulations for use in combination include standard non-steroids 65 200300083 玖DESCRIPTION OF THE INVENTION Anti-inflammatory drugs (hereafter referred to as NS AID), such as σ specific oxygen σ acetam, dichloramine phenylacetic acid, propionic acids (such as methacrylic acid, flubiprofen, fenprofen) , Ketophenylpropionate and ibuprofen), chloramates (such as mefenamic acid), indomethacin, suiindac, apazone, pyrazolinones (Such as benzozone), salicylates (such as aspirin), COX-2 inhibitors (such as cieecoxib, valdecoxib, rofocoxib) Rofecoxib and etoricoxib), analgesics and intra-articular therapies (such as corticosteroids and hyaluronic acid (such as hyalgan and synvisc)). 10 The compounds of the present invention can also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis Formula white, podophyllotoxin, paclitaxel, taxotere and farnesyl transferase inhibitors), VegF inhibitors, COX_2 inhibitors and antimetabolites (such as amine 15 mefonate anti-neoplastic Preparations, especially anti-mitotic drugs (including vinca alkaloids such as vinblastine and vinblastine). The compounds of the present invention may also be combined with antiviral agents such as Viracept, AZT, acidovir and famciclovir, and antiseptic compounds such as Vaiant) Combined 20 uses. The compounds of the invention can also be antagonized with cardiovascular preparations such as calcium channel blockers, lipid-lowering preparations such as statins, fibrates, blockers, ACE inhibitors, angiotensin receptors Agents and inhibitors of aggregation of small plates). 66 200300083 发明, Description of the invention The compounds of the present invention can also be combined with CNS preparations such as antidepressants (such as sertraline); Parkinson's disease drugs (such as (deprenyl), levodopa (L -dopa), Requip, Mirapex), MAOB inhibitors (such as selegine and rosagiline 5), comP inhibitors (such as Tasmar) ), A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, test synergists, dopamine synergists, and iT-element nitric oxide synthase inhibitors); and anti-Alzheimer's disease Drugs such as donepezil, 9-aminotetrahydroacridine, COX-2 inhibitors, (propentofylline) or (metryfonate) are used in combination. Compounds of the invention Also works with osteoporosis agents (such as roloxifene, droloxifene, lasofoxifene or fasomax) and immunosuppressants (such as FK-506, rapamycin, cyclosporin, azathioprine And aminomethylfolate) 15 in combination. [Embodiment 3 Detailed description of the preferred embodiment The compound of formula I can be prepared according to the following reaction scheme and discussion. A, X, Y, Z, η, q, s, t and R1 to R12 and reaction schemes and 20 The structural chemical formula I in the subsequent discussion is as defined above, unless otherwise stated. 67 200300083 玖, the first flowchart of the invention description

68 200300083 发明 、 Explanation of the invention Second flow chart

Y ^ COOH X,

69

XIII 200300083 发明 、 Explanation of the invention The third flowchart

70 200300083 发明, description of the invention

XVI Brother 4 Flowchart

71 200300083 发明, description of the invention 5th flowchart

72 200300083 (ii) Description of the invention The first scheme refers to the preparation of a compound of formula I. A compound of formula I in which A is-(OO) -NH- can be prepared from a compound of formula 11 by reacting with a compound of formula III in the presence of a base: H2N-R3 II! 5 Among them, L is a monohalo group or an anhydride leaving group having the chemical formula R- (〇〇) -〇- (where R is an optionally substituted alkyl or aryl group). Suitable tests include an excess of a compound of formula III, as well as triethylamine, diethylamine, σ, bismuth, sodium carbonate, tundo, and hunigs base, preferably triethylamine. The aforementioned reaction can be carried out without adding water or in the presence of a solvent. Suitable solvents include dichloromethane, tetrahydropyran and toluene, with dichloromethane being preferred. Alternatively, it can be in an aprotic solvent such as dichloromethane, a coupling agent such as 1- [3- (dimethylamino) propyl] ethylcarbodiimide (EDC) or Cyclohexylcarbodiimide (1 :(: :( :) and hydroxybenzotriazole hydrate 15 (H0Bt)) and a base (such as diisopropylethylamine (DIEA) or triethylamine) In the presence, by reacting with a compound of formula III, a compound of formula A is prepared from a compound of formula IV. The aforementioned reaction can be performed at a temperature of about 0t to 50t.丨 hours to 16 hours (as described by R. C. Larock in "Encyclopedia of Organic Transformation, Book B, pp. 20 972-976 (published by VCH Publishing in 1989)), where A is -NH- (OO )-Of the compound having the chemical formula can be obtained by combining with the compound of the formula VI (wherein L is a leaving group (#chloro, fluoro, bromo, iodo)) or a compound Chemical reaction of SR_ (c = 〇) _〇_ anhydride leaving group (where R is an optionally substituted alkyl or aryl group): 73 200300083 玖, Description of the invention

A R3 is prepared from a compound of formula V. The aforementioned reaction can be carried out in the presence of a suitable base. Suitable bases include an excess of a compound of formula V and triethylamine, diethylamine pyridine, sodium carbonate, pyridine and a Hunigs base, preferably triethylamine. The foregoing reaction may be carried out at a temperature of about 0 ° to 50 ° for about 10 minutes to 16 hours without adding water or in the presence of a solvent. Suitable solvents include digas methane, tetrahydrodiran and toluene, and digas methane is preferred. The compound of formula II can be prepared according to the method of the second scheme. 10 15 The compound of formula V can be prepared according to the method of the third scheme. The second flow chart refers to the preparation of a compound having a chemical formula with π, in which L is a leaving group and R1 is a nitrogen-linked (CVCW heterocyclic group. According to the method of the first flow chart, it will have the chemical formula 11 The compound in question is converted into a compound of formula I. Referring to the second scheme, in an alcohol solvent (such as methanol, ethanol, or n-butanol), a saponifying agent (such as with an aqueous base ( A reaction such as osmium hydroxide) prepares a compound of formula VI from a compound of chemical formula π. The aforementioned reaction can be performed at a temperature of about 0 to about one hour for about 1 to 24 hours. When deradicaling (such as tert-butylcool), a compound of formula 与 and an acid (such as hydrochloric acid) can be performed in a solvent (such as dihum ) Reaction for about 10 minutes to 6 hours to prepare a compound of formula IV. In which the L-leaving group (such as fluorenyloxy) and ^ -nitrogen-linked '74 20 200300083 玖, invention description C10) heterocyclic ring A compound of the formula „ It is prepared by a compound of one of the chemical formulas; it is reacted with a compound of one of the following chemical formulas under the conditions of reductive amination:

Wherein d is 1 to 8 ′ and any of the _CH2_ groups may be optionally substituted with 1 or 2 R9 substituents, and any of the _CH2_ groups may be optionally substituted 1 heteroatom substitution selected from _〇_, s (0) n4_NR10_ (where n is an integer from 0 to 2); or any single bond between any two -CHr groups may be optionally One double bond; W is > OO or >802; and each 12 is independently hydrogen, (Ci-C: 6) alkyl or halo. The reductive amination is preferably carried out at a pH between 6 and 8 and is typically carried out by a reducing agent such as sodium cyanoboronate gas or sodium diethoxylate monohydrogenate. The reaction is generally carried out in a protic solvent (such as methanol or ethanol) or a solvent mixture (such as digasmethane / methanol) at a temperature of about -78T: to 40t: for about} hours to 24 15 hours. (See A. Abdel_Magid, C. Maryanoff, K. Carson, Tetrahedron Lett, 34, 33, 5595-98 (1990), b). Other conditions involve the use of titanium isopropoxide and sodium cyanoborohydride (RJ Mattson et al. In J_ Org. Chem. (1990) No. 55 pp. 2552-4 e) or under dehydration conditions and subsequent Sub-20 amines are formed by reduction (eg, R · C · Larock in "Encyclopedia of Organic Transformation," B, p. 421 · 425 (VCH Publishing, 1989)). Optionally, it can be from the middle of the diazonium Product (derived from a compound of formula VII) to prepare a compound of formula II (where L is a leaving group (200300083 玖, description of the invention such as alkoxy) and Ri is a bridge in which the atom is nitrogen (Ci- Cig) heterocyclyl). In a solvent (such as glacial acetic acid) and at a temperature of about 0.00 to 30.0, by reacting a compound of formula VII with an acid (such as hydrochloric acid), then Diazo intermediates are prepared by treatment with sodium nitrite, and the reaction usually takes about 5 minutes to about 30 minutes to 3 hours. Under basic conditions, the above diazo intermediates and a compound of formula VIII ( Where 4 is 丨 to 8, and among them Any one of the -CHr groups may be optionally substituted with an R9 substituent, and any one of the -CH2- groups may be optionally substituted with one oxo group or one selected from · 0-, Heteroatom substitution of S (0) nS-NRi〇_ (where n is an integer from 0 to 2 10); or any single bond between any two -CH2- radicals may optionally be a double bond , W is > C = 〇4 >S〇2; and each L2 is independently an alkoxy or halo group) to prepare a compound of a chemical formula. The reaction typically uses sodium acetate as the base, and About 〇1 to 12〇. (: At one temperature, and the reaction usually takes about 1 hour to 24 hours. (See R.D. Carou et al. 15 in J. Med. Chem. (1983)) Issue 26, pp. 96-100). Alternatively, the skilled artisan will also understand one of the compounds of formula π (where R1 is a (Cl-Ci〇) heterocyclyl attached to the nitrogen), which can be obtained by It is prepared from a compound of formula VII (wherein L is a protecting group such as an alkoxy group) by standard synthetic methods; it is prepared by using two different conversion groups (20 as Alkylated or fluorinated) double ligand reagents:

L- (CH2) i-w, L2 IX where L is a leaving group such as a halogenated group; L2 is hydrogen, (Ci_c6) alkyl 76 200300083 玖, description of the invention 歹 工 基 (C ^ C6) alkoxy or Halo; \ ^ is > 〇〇 or >8〇2; d is 1 ^ 9, and any one of the -CH2- groups is optionally substituted with 1 or 2 substituents, and Wherein any one of the _CH2_ groups can be optionally substituted with a heteroatom selected from S (〇) n or -NR10- (where n is an integer of 0 to 2 or any two -CH2 · Any single bond between the groups may optionally be a double bond. Alternatively, a skilled artisan will also understand one of the compounds of the formula (where R1 is a (Ci_Cio) heterocyclic group attached to a nitrogen), It can be prepared by a standard synthetic method from a compound with a chemical town (wherein "is a protective group such as alkane 10); it is reacted with a liver reagent of one of the following chemical formula:

Wherein d is 1 to 9; and any one of the groups thereof may be optionally substituted by 1 or 2 R9 substituents, and any of the _CH2_ groups of 15 thereof may be selectively substituted by 1 A heteroatom substitution selected from -0-, (where n is an integer from 0 to 2); or any single bond between any two / ^-groups may optionally be a double bond. It can be in an aprotic solvent (such as dichloromethane), in an acid (a Fisher esterification), or a coupling agent (such as 1β [3- (dimethyl-20amino) propyl) ≫ 3-ethylcarbodiimide (EDC) or dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt)) and a base (such as diisopropylethyl In the presence of amines (DIEA or triethylamine), the chemical formula 77 200300083 玖, the description of the invention ROH (where R is optionally substituted (Cl-c4) alkyl or (C6_Cio) aryl ), And a compound of formula VII is prepared from a compound of formula XI. The reaction may be performed at a temperature of about 0.01 to 50. (: one temperature for about 1 to 16 hours (such as RC Larock in " Encyclopedia of Organic Transformations, Book B, pp. 972_976 (published by VCH Publishing Company in 1989). Compounds with chemical formulae VIII, IX, X & XI can be obtained commercially, or can be obtained by skilled artisans It is prepared by a well-known method. The flow chart of Di 3 refers to the preparation of a compound having the chemical formula ν, which is An intermediate product for preparing a compound having a chemical formula ν in the first flow chart. Referring to the third flow chart, a compound having a chemical formula V is prepared by the reduction of a compound having a chemical formula χπ. The reduction can be performed in about 丨To a pressure of 5 atmospheres and a temperature of about HTC to a temperature of about 15 ° C, using 15 catalysts such as palladium on carbon (Pd) in a suitable solvent (such as methanol, ethanol, tetrahydrocarbon, dihumane or ethyl acetate) / C), palladium on barium sulfate (pd / BaS04), platinum on carbon (Pt / C) or tris (triphenylphosphine) germanium chloride (Wilkinson catalyst), and hydrogen (rhenium?) Achieved this, as described by Paul Ryiander, Yu ,,, pp. 31_63 (published by the Academy of San Diego, American Academy of Music, Inc.).

) Q It is another effective procedure to use reagents such as ammonium formate and carbon in methanol under an inert environment (such as nitrogen or argon) and at reflux temperature. When R1 contains incompatible with the above hydrogenation conditions The other (applicable to thin-smoke or dentate-based) process is applicable to another procedure—a type of dissolved metal reduction. The compound of formula XII is treated with a metal such as zinc, tin or iron. The foregoing reaction may be performed at a temperature of about 0 ° C to 100 ° C for about 1 hour to 16 hours. As described in the second flow chart above, the conversion of a compound of formula VII to a compound of formula II is described in the second flowchart, which has its own formula XIII by reacting with a reagent of formula VIII, IX and X The compound of formula XII is prepared.

The starting material of formula XIII can be obtained commercially or known in the art. 10 The fourth scheme refers to another preparation of a compound of formula I.

Referring to the fourth scheme, a compound of formula I in which R1 is a (CkC ^ o) heterocyclyl group bonded to nitrogen can be prepared by an arylpalladium coupling reaction. Aryl is familiar to those skilled in the art of coupling reactions. A well-known coupling method (so-called Buchward & Hartwig condition), 15 involves the presence of a compound of formula XIV in the presence of a palladium (0) catalyst and a base (where L2 is chlorine, bromine, iodine, or trifluorofluorenylsulfonate (TfO)) and a compound of the formula WH (where the amidine is a hydrogen on a nitrogen ring atom) is coupled. Ibar (0) catalyst includes tris (diphenylmethyleneacetone) di (2) (Pd2 (dba) 3), di (diphenylmethyleneacetone) dipalladium (0) (Pd (dba) 2 ), Ethyl 20 palladium (Pd (OAc) 2) and a suitable ligand (such as a triarylphosphine ligand, tri (tert-butyl) phosphine, 1,1'-bis (biphenylphosphine) Group) ferrocene (DPPF), 2,2'-bis (biphenylphosphino) -1, Γ-binaphtyl (BINAP) or PHANEPHOS, most preferably tris (o-tolyl) phosphine). Suitable bases include potassium carbonate, potassium phosphate, carbonic acid, LiN (TMS) 2 or alcohol test (such as sodium benzyl alcohol, sodium ethoxide, 79 200300083), invention description terbutanol clock, and more specific _ sodium butoxide ). Suitable solvents include methylbenzene monoether solvents, preferably dihumane. The foregoing reaction may be performed at a temperature of about 1 to about ^ ° C for about 1 to 48 hours. These conditions are summarized in

Angew. Chem. Int. Ed. Engl. (1998) 37 (2046-2067) 5 In the second text, and is known to skilled artisans. The preferred Buchward condition is to use palladium acetate (Pd (〇Ac) 2) or tetrakis (triphenylphosphine) palladium (Pd (PPh3) 4) as the source of palladium. Suitable solvents include tetrahydrofuran, toluene, or similar solvents. The foregoing reaction can be performed at a temperature of about one to four hours, preferably about one hour to four hours, preferably two hours. Nickel catalysts such as 5-10 cyclic octylene nickel (Ni (cod)) are also suitable. Those skilled in the art Alternatively, compounds of formula I can be prepared according to the so-called Ullmann reaction, which is carried out in the presence of a suitable base or a catalyst by a compound of formula XIV (where l2 Is a halide) and a compound of formula ΛΛη (where η is a 気 15 on a nitrogen ring atom) is reacted. Suitable bases include alkali metal carbonates or hydroxide bases, preferably potassium carbonate Suitable catalysts include copper catalysts, preferably fine powdered bronze. Solvents suitable for use in the foregoing reactions include alcoholic or polar aprotic solvents such as N, N-dimethylformamide, ν, N- Dimethylacetamide or N-methylpyrrolidone (NMMP). The aforementioned reaction can be performed at a temperature between about 8 (rc to 20 180 C) for about 6 to 24 hours. Optionally, 'may By the so-called Suzuki coupling reaction, The compound of V (wherein L2 is a monoborate or dihydroxy butterfly acid) and Ri_H (wherein fluorene is a hydrogen atom on a nitrogen ring atom), a catalyst, a test and a dehydrating agent. Suitable boric acid Salts include 80 200300083 rhenium, invention description (HO) 2B-, 9-BBN, and calcined. Suitable catalysts include copper or Ibar (such as palladium acetate (Pd (OAc) 2, triphenylphosphine palladium or Pd (dppf ) Cl2), preferably copper (II) acetate. Suitable dehydrating agents include 4 angstrom molecular sieves. Suitable tests include tertiary amine bases such as triethylamine or pyridine, sodium carbonate, sodium ethoxide and phosphoric acid I 曱Suitable solvents include dichloromethane, dimethyl sulfoxide (DMSO) or

Tetrahydrofuran (THF). The foregoing reaction is typically carried out under an atmosphere of oxygen at a temperature of about 10 ° C to 50 ° C (preferably about 23 ° C) for about 6 to 72 hours. The palladium-catalyzed dihydroxyborate coupling is described in Miyaua, N., Yanagi, T., Suzuki, A. in Syn. Comm. (1988) No. 7 No. 10 10 p. 513 B. Alternatively, a compound of formula I can be prepared from a compound of formula XV or XVI via an intermediate product of formulas II and XII. The intermediate products of formulas II and XII can be converted into the compounds of formula I according to the methods of the flow charts 1 and 3, respectively. Similar to the coupling reaction described above for the conversion of 15 compounds of formula XIV to compounds of formula I

Therefore, the compounds of formula II and XII can be prepared from the compounds of formula XV or XVI, respectively. By the above-mentioned similar method for converting a compound of formula II to formula I and a compound of formula XII to formula I 20, a compound of formula XIV can be prepared from a compound of formula XV or XVI. The compounds of the formulae XV and XVI can be substituted commercially or they can be prepared by methods well known to the skilled artisan. The fifth scheme refers to another preparation of the compound of formula I. 81 200300083 发明 Description of the invention With reference to the fifth flowchart, a compound of formula I can be prepared from a compound of chemical sXVII, which is in the presence of an acid (such as hydrochloric acid) through reduction with tin; then By a so-called Sandmeyer reaction in which a diazo intermediate is prepared by treatment with sodium nitrite and then by quenching of cuprous dendritic materials such as cuprous chloride or cuprous bromide . Suitable solvents include alcohols, such as methanol and ethanol. The foregoing reaction is performed at a temperature of about -20 ° C to 0 ° C, and the reaction is generally performed for about 1 to 48 hours. 0 10

Compounds of chemical formula XVII (where R1 is a standard convertible group such as _NH2) ) Or a heterocyclyl). Methods for nucleophilic aromatic substitutions are summarized in

Belfield et. publishing).

The standard conversion method can be used to prepare a compound with the chemical formula χνπ of a standard convertible group, and prepare other compounds with the chemical formula χν_ 'MR1 series-a nitrogen-linked (Ci_Ci〇) heterocyclic group (containing i to 6 heteroatoms independently selected from _N ... N <, _NH_, _◦ •, and s (〇) n), wherein the (C〗 -C 丨.) heterocyclic group attached to the nitrogen is optionally Is substituted on any carbon atom capable of supporting additional substituents by i to 3 r 9 substituents per ring, and each R 9 is independently selected from the group consisting of: A, oxo, meridian, amine, Rhyme, (c 丨 _c4) alkyl, (Ci_C4) alkoxy, H〇2c_, r4r5n (〇2S) _, (C1_C4 forming group_ (〇2S) _NH_, (Ci_C4) xyl group_〇2s_ 82 200300083发明, description of the invention [(CVC4) alkyl group, r4r5n (c which, (C1_C4) alkyl group · N 基 ·, team_C4) alkyl group] 2 good, R4R5N (CH2) t_, (QCio) aryl group, (C3 -C8) cycloalkyl, (CVC10) heteroaryl, (Ci_Ci〇) heterocyclyl, (C6_CW aryl ... (3 c8)% alkyl_〇 ... (Ci_Ci.) Heteroaryl 〇 and heterocyclic · 〇_, where the (C1-C1G) heterocyclic group can also be optionally supported An additional substituent is substituted on any of the ring nitrogen atoms with 1 to 2 R1G substituents per ring, and each R10 is independently selected from the group consisting of: hydrogen, (Ci_C4) alkyl, (Cr c4) alkyl- ( 〇〇) _, (CVCi〇) aryl group, (C3_C8) cycloalkyl group, (Ci_c ^ heteroaryl group and (Cl_ClG) heterocyclic group; wherein R9 and R1G groups or substituents at any 10 15 of this (CVClG ) Aryl, (C3-C8) cycloalkyl, (Cl_ClG) heteroaryl, and (Ci-C1G) heteroalkyl 'may be optionally selected from 1 to 3 moieties per ring independently selected from Substitution: halo, hydroxyl, amine, _CN, (Ci_C4) alkyl, (cKc4) oxy, Cf3, CF3O ... (Ci-C4) fluorenyl_Li ... [(CVC4) alkyl] 2 -N-, (Cl-c4) ^ groups, (CVC4) alkyl groups-(s = 0) ... (CkC4) alkyl groups-(so2)-, (Cl_c4) alkyl groups-CKC = 0) _, T ai And (Cl_c4) alkyl- (〇〇)-. Compounds of formula XVIII can be commercially substituted, or can be prepared by methods known to skilled artisans. Alternatively, they can be similar to those described above. Method of Sandmeyer reaction 20 to prepare compounds of formula I and π from compounds of formula XX With a compound of Formula XXI can be substituted trade, or can be prepared by methods known to those of skill overripe. Compounds of formula I with basic properties can form a wide variety of different salts with a wide range of inorganic 83 200300083 发明, description of the invention and organic acids. Although the salt must be a pharmaceutically acceptable salt suitable for administration to animals, in practice, it is usually the first to isolate a pharmaceutically unacceptable salt form of a compound of the formula from the reaction mixture, and then borrow The treatment of a base reagent restores its 5 to a free base compound, and then converts the free base into a pharmaceutically acceptable acid addition salt. The base compounds of the present invention can be prepared in an aqueous solvent matrix or in a suitable organic solvent such as methanol or ethanol by treating the test compound with a substantial equivalent of the selected mineral or organic acid. Acid addition salts. Upon careful evaporation to remove the solvent, 10 the desired solid salts are obtained. The pharmaceutically acceptable acid addition salts used to prepare the base compounds of the present invention are those which form non-toxic acid addition salts, that is, salts containing a pharmaceutically acceptable anion, such as Gas, desert, iodide, nitrate, sulfate or bisulfate, phosphate or biphosphate, 15 acetate, lactate, citrate or acid citrate, tartrate or tartrate , Succinic acid salt, cis-butenedioate, trans-butenedioate, gluconate, gluconate, $ formate, methoxanthinate, and dibasic acid salt (ie U, -Methylene-bis- (2-acrylnaphthoate)). These compounds with acidic properties and chemical formulas (such as where r4 includes 20-nitrouretin or barbitan moiety) can form test salts with a variety of pharmaceutically acceptable cations. Examples of such salts include metal or soil metal salts, especially sodium and potassium salts. These salts can be prepared by conventional techniques. As the chemical test reagent for preparing the pharmaceutically acceptable salt test of the present invention, these are those which have the chemical formula ⑽ acidic compounds which form non-toxic 84 200300083 玖, description of the invention ㈣ salt test. These non-toxic sacrifice packs are derived from those that are pharmaceutically acceptable 2 :: ions (such as sodium, potassium, calcium and magnesium, etc.). By processing the corresponding acidic compound with an aqueous solution containing one of the desired musically acceptable cations, and then evaporating the resulting solution to dryness (preferably under reduced pressure), the #easy preparation of these Salt. Alternatively, it can also be prepared by mixing the lower alcohol burning solution of the acidic compound with the desired metal burning alcohol alkoxide, and then evaporating the resulting solution to dryness in the aforementioned manner. In either case

'Soils use stoichiometric amounts of reagents to ensure that the reaction is complete and to maximize product yield. The activity of the compound of the present invention in treating the above-mentioned different diseases can be measured according to one or more of the following analysis methods. In the analysis in the test tube described later, the IC5G of all the compounds of the present invention tested was lower than 1 #M. Pharmacological points; It is known that specific compounds (such as benzamyl benzamidine adenine nucleoside 15 glycoside dibasic acid (bbATP)) are equivalent agents of P2X7 receptors, and they are formed on the plasma membrane

Hole formation (Drug Development Research (1996), 37 (3), p. 126). Therefore, in the presence of ethidium bromide (a fluorescent DNA probe) ', when the receptor was activated with bbATP, an increase in the fluorescence of ethidium odorized intracellularly bound to DNA was observed. Alternatively, the ethidium bromide can be replaced with the propion dye 20 YRP0_i to detect the effect of absorbing the dye. The increase in fluorescence can be used as a measure of P2X7 receptor activation, and thus the effect of a compound on the P2X7 receptor can be quantified. In this way, the compounds of the present invention can be tested for their antagonist activity against P2X7 receptors. In a 96-bottom flat-bottomed microtiter m, 250 microliters of Test 85 200300083 was added. The test solution included 200 microliters of TIP-1 cell suspension (10 · 4M ethidium bromide) (2 · 5x106 cells / liter, better as described in the literature, pre-stimulated with a combination of LPS and TNF to promote crying performance), 25 microliters of high potassium and low sodium containing 10-5M bbATM Buffer 5 solution (10 Hepes, 150 mM potassium chloride, 5 mMD-glucose, and 1.0 ° /. Fetal bovine serum and pH 7.5) and containing 3 × 10 · 5M test compound (more preferably 5 × 10.4 · M and more lxl0-4M and more preferably 1x3M) in 25 microliters of high clock buffer solution. Cover the plate with a plastic plate and incubate at 37 hours. The reading of the Pingya was performed in a Perkin-Elmer fluorescent plate reader (excitation: 10 520 nm, emission: 595 nm, slit width: Ex 15 nm, Em 20 nm). . For comparison, bbATP (a P2X7 receptor equivalent) and 5-phosphate (a ρ2χ7 progenitor antagonist) were used as controls in the experiment. From the obtained readings, the piCw value of each test compound can be calculated, which is the negative logarithm of the concentration of the test compound required to reduce the activity of the mbbATP equivalent agent by 50% 15. In a similar manner, a compound of the invention can be tested for its antagonist activity against MX® receptors using cytokines as indicated readings. Using a lymphosphere separation matrix obtained from Organon Technica (Westchester, PA, USA), 20 blood collected from normal volunteers was separated in the presence of heparin. Collect the area containing the banded monocytes in the generated gradient, and take 10 ml of maintenance medium (RPMI 1640, 5% fetal bovine serum, 25 FPS, pH 7 and 10/0 Penicillin / Streptomycin ) To dilute and collect cells by centrifugation. The obtained cell pellet was suspended in 10 ml of a maintenance medium, and 86 200300083 玖, description of the invention The cell count was performed. In a general experiment, 2 x 105 monocytes were implanted in a total volume of 96 cells per square meter in a total volume of 01 ml. The monocytes were allowed to attach for 2 hours, after which the supernatant was discarded, the attached cells were washed twice, and then cultured in a maintenance medium at 37 C and 5% carbon dioxide overnight at 50 ng / lLPS (Angstroms) Escherichia coli (e.coh) serotype 055: B5; St. Louis Sigma Chemical Co., Missouri, USA Activated cultured monocytes. After 2 hours of incubation, the activation medium was removed and the cells were washed with 0.1 ml of Chase medium (RPMI 1640, 1% fetal bovine serum 10, 20 mM Hepes, 5 mM sodium carbonate, and pH 6 9). Two times, then add 0.1 ml of Chase medium containing a test agent, and incubate the plate for 30 minutes; analyze the concentration of each test agent in a triplicate tank. ATP (from a 100 mM stock solution at pH 7) was then added to reach a final concentration of 2 mM, and the plate was incubated for an additional 3 hours. 15 culture medium was collected, clarified by centrifugation, and its IL-1 $ content was measured by ELISA (R & D Systems, Minneapolis, Minnesota, USA). The composition of the present invention may be formulated in a conventional manner using one or more musically acceptable carriers. Therefore, the active compound of the present invention can be formulated for oral, buccal, intranasal, parenteral (such as intravenous, intramuscular or subcutaneous), local or rectal administration, or formulated for inhalation or blowing. In the form of administration. For oral administration, the pharmaceutical composition may be in the form of, for example, a lozenge or capsule, which is prepared in a conventional manner with pharmaceutically acceptable excipients 87 200300083 玖, the 'excipients such as binders described in the invention (Such as pre-gelatinized corn flour, polyethylene. More than propylene or cellulose propyl methyl cellulose), fillers (such as lactose, microcrystalline cellulose or calcium phosphate), lubricants (such as stearic acid Magnesium, talc or silicon oxide), disintegrating agent (such as horseshoe potato or rice flour with sodium acetate) or wetting agent (such as sodium lauryl sulfate) can be applied by methods well known in the art . Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions; or in the form of a dry product which is reconstituted with water or a suitable carrier before use. The liquid formulation can be prepared in a conventional manner with pharmaceutically acceptable excipients; excipients such as suspending agents (such as sorbitol 10 water, methyl cellulose or hydrogenated edible fats), emulsifiers (Such as lecithin or acacia), non-aqueous vehicles (such as almond oil, oleic esters, or ethyl alcohol), and preservatives (such as methyl or propyl p-hydroxybenzoate or sorbic acid). For buccal administration, the composition may be in the form of a lozenge or lozenge prepared in a conventional manner. 15 Compounds with the formula [] can also be formulated for continuous delivery according to methods known to skilled artisans. Examples of these formulations can be found in US Patent Nos. 3,538,214, 4,06〇, 598, 4 173 626, 3,119,742, and 3,492,397, all of which are incorporated herein by reference in their entirety. data. The active compounds of the present invention can be formulated for parenteral administration by injection, including the use of known catheterization techniques or perfusion. Formulations for injection can be presented in unit dosage forms with added preservatives, such as in ampoules or multi-dose containers. The composition may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain Formulation 88 200300083, a description of the invention such as a suspension of hydrazone, a stabilizer, and / or a dispersant. Alternatively, the active ingredient may be in the form of a powder to be reconstituted before use in a suitable carrier, such as sterile water that does not contain pyrogenic substances. The active compounds of the present invention may also be formulated for rectal administration, such as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa beans or other glycerol derivatives). 10 15 20 For intranasal administration by inhalation, the active compounds of the present invention can be easily rotated in the following forms: solutions; dried powder formulations; or from a squeezing spray that is squeezed or pumped by a patient Capacity "suspension; or from the use of a suitable propellant (such as two-gas difluoromethane, three-gas flumethane, two-gas fluorocarbons, seven carbon chain, carbon dioxide or other suitable gas) from a pressurized container Or—Aerosol spray in the form of a nebulizer. In the case of aerosol: 'a metered dose unit can be measured by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain A solution or suspension of the active compound. Capsules and clips (such as prepared from gelatin) for use in an aspirator or insufflator may be formulated to contain the compound of the present invention and a suitable powder base such as lactose or Starch). For oral, parenteral or buccal administration in general adults, Shuming's active compound is used to treat one of the above conditions (inflammation). The iron extraction dose is 01 to 2 per unit dose. 〇〇mg of active ingredient It can be administered, for example, 1 to 4 times a day. The compound of formula ⑴ and its pharmaceutically acceptable salts and solvates can be used in its own form, but it is usually administered in the form of a pharmaceutical composition, where Compounds / Salts / Solvator with Chemical Formula ⑴

89, 083 (ii) Description of the invention The adjuvant, diluent or carrier (combined ingredient) is combined with a pharmaceutically acceptable " Hai pharmaceutical composition preferably contains from 0.05 to 99. Depending on the mode of administration, the active ingredient weighs 1% and more preferably from 0.1 to 10%, and contains from 1 to 99.95% by weight and more preferably from 30 to 99 ^^ 0 One of the musically acceptable adjuvants, diluents, or carriers, the weight of 1% is based on the composition as a whole.

The formula I of an aerosol formulation for treating the above-mentioned conditions in an average adult is preferably such that an aerosol of each quantitative dose or, an inhaled dose, contains gang micrograms to 1,000 micrograms of the compound of the present invention. The total daily dose of aerosol will range from 10 micrograms to ίοquiji Xiyi fi a brother 芏 ιυ gram of dry circumference. The mother's day can be administered several times (for example 2, 3, 4 or 8 times), and each administration is for example 1, 2 or 3 doses. In general, the aerosol combination formula used to cure the above-mentioned conditions (such as adult aspiration distress symptoms) is preferably formulated in such a way that the aerosol in each quantitative dose or inhalant 1 "contains about micrograms to 100 micrograms of the compound of the invention 15. The total daily dose of the aerosol will be in the range of 100 micrograms to 10 milligrams.

. It can be administered several times a day (e.g. 2, 3, 4 or 8 times), with each administration e.g. i, 2 or 3 doses. The formulation method of the air service formula for treating the above-mentioned conditions (such as adult respiratory distress syndrome) in Syrian adults is preferably such that each quantitative dose or, 20 inhaled dose, aerosol contains about 20 micrograms to 1,000 micrograms Compounds of the invention. The total aerosol dose will range from 100 micrograms to 10 milligrams of p38 kinase inhibitor. It can be administered several times a day (e.g. 2, 3, 4 or 8 times), and each time e.g. 1, 2 or 3 doses. The present invention also covers 90 200300083, a prodrug comprising a compound of formula I, a pharmaceutical composition, and a method for treating and preventing a prodrug comprising a compound of formula I. Compounds of formula I with free amine, amido, hydroxyl or carboxyl groups can be converted into prodrugs. Prodrugs include monoamino acid residues or polyammonium chains with two or more (such as two, three, or four) 5 amino acid residues, via the free amine group of a compound of formula I, Hydroxyl or carboxyl peptide bonds are covalently linked. Amino acid residues include 20 naturally occurring amino acids (which are usually represented by three English letter symbols), and also include 4-hydroxyproline, hydroxylysine, demoic acid, isopropyl Dermoic acid, 3-Aminohistidine, pentylamine, yj-alanine, r-amino10 butyric acid, citrulline, cysteine, serine, ornithine and methylsulfide Glycine. Prodrugs also include compounds in which carbonates, carbamates, amidines, and alkyl esters are covalently bonded to the aforementioned substituents of compounds of formula I via the carbonyl carbon drug prodrug side chain. The following examples illustrate the preparation of the compounds of the present invention. The 15 melting points shown are uncorrected. NMR data are shown in ppm (d) and refer to gas-locked signals from a sample solvent (rat gas imitation (unless otherwise noted)). Mass spectral data were obtained from a Micromass ZMD APCI mass spectrometer equipped with Gilson gradient high performance liquid chromatography. The following solvents and gradients were used in the analysis. Solvent A: 98% water / 2% acetonitrile / 〇—〇〇〇 / 0carboxylic acid, and solvent B: 20 acetonitrile containing 0.005% formic acid. Typically, a gradient is performed from 95% of solvent A to 100% of solvent B over a period of about 4 minutes. The mass spectrum of the main elution components was then obtained in positive or negative ion mode with molecular weights ranging from 165 AMU to 1100 AMU. Specific optical rotation was measured using sodium D-line (5 nm) at room temperature. Commercially available reagents were used without further purification 91 200300083 发明, description of the invention. THF refers to tetrahydrofuran. Dmf refers to Ν, Ν · dimethylmethylamine. Chromatography refers to the use of 32 to 63 mm silicone gel under the conditions of nitrogen fortification (flash column chromatography). g / 胗 into the official column chromatography. Room temperature or ambient temperature refers to 20 to 25 ° C. In order to find the magnetic secret 丄 cubic a so as to achieve the maximum yield, all without 5 water reaction system Under a nitrogen ring culture> 'Brothers enter the 仃. Concentration under reduced pressure is only using a rotary evaporator.

Those of ordinary skill will understand that in some cases a protecting group may be required during preparation. After the target molecule is obtained, it can be prepared by methods familiar to those skilled in the art (by Greene and Wms, the second edition of the 10-Protection II Book of Organic Synthesis (Wiley Intersciences, 1991). Remove the protective group. 1st example 2-Gadi 5- (3,5-dioxo-4,5-difluorene-3H- "1.2,41 triazinyl-hexyl) -benzylamine

Α · (3 · Carboxy-4- 氱 -Mamo V3.5-Diargon fluorene hydrogen Hex-6-weilic acid

In a solution of mechanically stirred solution of 5-amino-2-chlorobenzoic acid ethyl ester (5.0 g '26.9 mol) on ice 92 200300083 发明, description of the invention, acetic acid (100 ml), Add 12N hydrochloric acid (7.5 strokes). After 30 minutes at room temperature, the reaction mixture was cooled to 10 ° C, and a solution of sodium nitrite in water (5 liters) was added dropwise (the rate of addition was such that the reaction temperature was maintained at 10). 〇 to 丨〗 ^). During this period 'the reaction was observed to change from purple to light brown. At 10. 〇 After stirring for 30 minutes, sodium acetate (5.4 g) and (3-ethoxycarbonyltrisyl-3-oxo-propionyl) aminoacetic acid ethyl vinegar (7.2 g ). After stirring at 10 for 20 minutes and then at room temperature for 1 hour, 2.2 g of sodium acetate was added. After stirring at the reflux temperature for 6 hours, the reaction mixture was cooled to room temperature and a 50% sulfuric acid aqueous solution (29 ml) was added. After the resulting mixture was allowed to fall for 2 hours at reflux temperature, the mixture was cooled to room temperature, diluted with water (135 liters), and filtered. Wash Shen Dianwu with water and dry in vacuum. The crude product was recrystallized from isopropyl ether to give 3.8 g (46%) of the title intermediate as an orange solid. Mass spectrum [M-1] ratio of 15: 310.1 and 312.1 of 3: 1; 4 NMR (500 MHz, CD30D) 5 7.64 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz , 1H), 8 · 14 (d, J = 2.6 Hz, 1H) 〇Hydroxy-5- (3,5-dichloro-4,5-dihydro-3H- "1,2,41 triazine -2-yl jasmine

2〇 2- (3-Weikyl-4-Ga-benzyl 5--oxo-2,3,4,5-tetrahydro- [1,2,4] triazine-6-metanoic acid (3 · 4 g) Suspension of one of the carbamic acid (2 ml) 93 200300083 玖, description of the invention, stirring at 175 ° C. After 20 hours, the resulting solution was cooled to room temperature, during which time a The precipitate was placed in ice water, stirred for 30 minutes, and filtered to give a yellow solid. The solid was dried in vacuo for 24 hours to give ^ g of the title intermediate. Mass spectrum [M-1] The ratio is 266.1 and 268.1 at 3: 1; NMR (500 MHz, CD3OD) 5 7.58 (s, 1H), 7.60 (d, Bu 8.8 Hz, 1H), 7.72 (dd, J: 2.6 and 8.8 Hz ), 8.09 (d, J = 2.6 Hz). Milk-5- (3,5-dioxo-4,5-dihydro-3Η · "1 · 2 · 41 triαtai-2-yl jasmine

Add 2_chloro-5- (3,5-dioxo-4,5_dihydro-3H- [1,2,4] triazin-2-yl) -benzoic acid (50 mg) to thionyl chloride ( 1 liter), and stirred at reflux temperature for 1 hour. The mixture was concentrated in vacuo to give 50 μg of the title intermediate as an amorphous amber solid, which was immediately used in the next 15 steps. Substitute 4,5-Di ^ ji: LL1 ^] triazine_2_, ^ (2-ethyl-hexylphenylhydrazone) in 2-ethylhexylamine (15 mg, 0.125 mmol) To one of the solutions in dichloroethane (1 ml) was added diisopropylethylamine resin (60 mg, 200.225 moles), followed by 2 'chloroform (3,5_dioxane). Generation -4,5_dichloro-3Η [1,2,4] monohept-2-yl) -chlorobenzylformate (21 mg, ο ·. "亳 mol) on 3 94 200300083 玖, Description of the invention: 1 A solution of a mixture of dichloroethane and tetrahydrodifuran (15 ml). The reaction mixture was shaken for 16 hours and filtered. The filtrate was treated with MP-carbonate resin and the resulting mixture was shaken for 3 hours. The mixture was filtered, and the resin was washed sequentially with dichloromethane and 9: 1 methanol / acetic acid followed by 5. The mixed filtrate was concentrated under reduced pressure to obtain the title compound as an amorphous solid. Mass spectrum [M- 1] The ratio is 3: 1 of 377.2 and 379.2; 4

NMR (500 MHz, CDC13) 5 0.92 (t, 3H), 0.96 (t, 3H), 1.26-1.66 (m, 9H), 3.46 (m, 2H), 6.26 (broad s, 1H), 7.51 (d, 1H), 7.59-7.62 (m, 2H), 7.94 (s, 1H), 8.72 (broad s, 10 1H). Examples 2 to 44 are shown in Table 1 and are synthesized in a manner similar to that outlined in Example 1D, by combining a suitable amine with hydrazine · 5_ (3,5_dioxo_ 4, 5-dihydro · 3- [1,2,4] triazin-2-yl) · benzylidene chloride was prepared by coupling. In these examples, the 'product was purified by preparative HPLC using Shimadsu LC-8A preparative grade liquid 15-phase chromatography. All end products are

Analysis was performed using LC / MS from Micromass ZMD LC / MS (ESI mode). The method used for HPLC mobile phase gradient change is as follows: Time (minutes) A% B% 0.00 95 5 1.0 80 20 2.3 50 50 3.7 0 100 3.7 95 5 Solvent A is 98% water + 2% acetonitrile + 0.01% formic acid. Solvent B was acetonitrile + 0.005% formic acid. 95 200300083 玖, Description of the invention Table 1 Example Structure Mass Spectrometry (ES +) Mass Spectrometry (ES-) LC retention time (minutes) 2 Λνχχ; «Χη〇η5 〇351.2 349.2 2.2 3 Ν ^ Υ0 V1 0 399.1 397.0 2.4 4 ηΛΦ N- V0 ν1 405.0 403.0 2.3 5 Ν ^ ν〇ν- 371.1 369.0 2.0 6 Ν ^ ν〇 V1 0 451.0 448.9 2.3 7 ^ 0 0, Vs 0 389.1 387.0 2.1

96 200300083 玖, Description of the invention Example Structure mass spectrum (ES +) Mass spectrum (ES-) LC retention time (minutes) 8 Ν ^ Υ〇V- 0 441.0 436.9 2.3 9 [ίη o ci Ν ^ ν ° V1 0 401.1 399.0 2.2 10 N ^ V〇V1 0 405.0 403.0 2.2 11 Η3〇 ^^, Λφ N-V0 V1 0 337.1 335.1 2.1 12 N-V0 νχ 0 389.1 387.0 2.0 13 0 447.1 445.0 2.4 14 ch3 rrNY0 V1 0 415.1 413.0 2.3

97 200300083 发明, Description of the invention Example Structure mass spectrometry (ES +) Mass spectrometry (ES ·) LC retention time (minutes) 15 CH, n, nY0V- 0 481.0 479.0 2.3 16 CH, / V1 o 379.2 377.1 2.7 17 αχΧ-ΝΛφ N ^ V〇V1 0 405.0 403.0 2.2 18 N ^ V〇V1 O 439.0 438.9 2.5 19 0 Cl N ^ V ° V1 0 351.2 349.1 2.3 20 N ^ Y〇V1 0 389.1 387.0 2.1

98 200300083 Example of the invention, Structure, Mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) 21 0 CI person 0 363.2 361.1 2.2 22 CI C, A 〇〇V1 0 441.0 439.0 2.4 23 〇γ% α 1 NV〇 V1 385.1 383.0 2.3 24 q. α human 0 V1 0 377.1 375.0 1.9 25 ηΑ 〇 ^ Ν ΟΗ CI 0 Η3. 3 421.7 419.8 2.0

99 200300083 发明, Description of the invention Example Structural mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) 26 hA, N CI 〇 375.6 373.7 2.4 27 hA, N Cl 0 0 421.9 419.6 2.1 28 hA, N Cl ο 375.8 373.8 2.4 29 HNis〇y 385.2 383.1 2.2 30 ι Λ 421.1 419.1 1.9 31 405.2 403.1 1.7 32 tS〇c ^ '429.2 427.1 2.0 100 200300083 玖, Description of invention Example Structural mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) ) 33 Ϊ 477.2 475.2 2.6 34 Chiral VocM 403.3 401.2 40.2. 2.6 35 Ah xxy 387.2 385.1 1.5 36 CO ci φχ VN'n -v 413.2 411.1 2.0 37 417.2 415.1 2.2 38 401.2 399.1 2.0 39 ch3 at HTO > 403.3 401.2 2.6

101 200300083 玖, Description of the invention Example Structural mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) 40 〇, 9 ^ 〇Φ ^ ° vn'n 0 439.3 437.2 2.6 41 hA Human N (fS H 0 outside 401.5 399.6 2.1 42 ηΛ In NA Cl 〇UvCH, 481.5 479.5 2.2 43 q ^ CHi Cl HN ^ ¢ ^ ° Vn'n -v 0 453.3 451.2 2.8 44 fP Txxy 425.3 423.2 2.5 45 510.1 508.1 2.4

102 200300083 玖, Description of the invention Example Structural mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) 46 Ηγγ 0 V-0 475.2 473.2 ------- 2.2 47-^ NV〇V1 0 429.5 427.5- — ~ 2.7 The 48th example ^ 1 ^ 1,5di_dioxotrifluoromethyl-phenyl) -ethyl 1 · benzate:

In 2-chloro_5 · (3,5-dioxo_4,5-dihydro-3H- [1,2,4] triazin-2-yl) -phenylarsinic acid (75 mg, 0.3 mmol) Ear), EDCI (60 g) and hydroxybenzotriazole hydrate (HOBt) (50 g) in a stirred solution of difluorenylfluorene (3 l), add 2- ( 2-trifluoromethylphenyl) ethylamine (53 mg, Q.3 10 pen moles). After 30 minutes, triethylamine (45 μl) was added. After 3 hours, the reaction mixture was diluted with ethyl acetate (75 ml) and washed sequentially with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in a vacuum to obtain 73 g of an amorphous solid. This solid was purified by silica gel chromatography (eluent with ethyl acetate / hexane of 1.1). 200300083 5 years, description of the invention, and then crystallization from isopropyl ether to obtain 36 mg of white The title compound in solid form. The dazzling point is 148-150 ° C; mass spectrum [M-1] 437.6; mass spectrum [M + 1] 439.9. The 49th to 50th cases are shown in Table 2 and are similar to those outlined in the 48th case. Synthesis by combining the appropriate amine with 2-Ga-5- (3,5-dioxo-4,5-dihydro_3H_ [1,2,4] triazin-2-yl) _benzoic acid Coupling and preparation. The final product was analyzed by LC / MS using Micromass ZMD LC / MS (ESI mode). The method used for hPLC mobile phase gradient change is as follows: -------- time (minutes) A% B% 0.00 95 5 1.0 ----- 80 20 2.3 --------_ 50 50 3.7 — ^ _ 0 100 3.7 95 5> Cereal Eight is 98% water + 2% acetonitrile + 0.01% formic acid. Solvent B was acetamidine + 0.005% formic acid. 104 200300083 玖, description of the invention Table 2 Example Structure Mass spectrum (ES +) Mass spectrum (ES-) LC retention time (minutes) 49 N ^ V〇 V7h 0 419.5 417.5 2.4 50 ηΛ, N φγ ^ Cl ο 379.4 377.4 1.6

The 51st case N-f2- (2-Phenylethyl 1--5- (3,5-digaso_4,5-diaza-31 ^-"1,2,41 5 triazine-2- ) -2 · fluorenyl-benzylamine

A. 2-Methyl-5- (3,5-digaso-4,5-dihydro-3H-``1,2,41 triazin-2-yl V behenic acid

105 200300083 发明. Description of the invention Dissolve 5-amino-2-chloro-benzoic acid methyl ester (3.5 g, 21.2 mmol) in glacial acetic acid (80 ml) and add 5.5 ml of concentrated hydrochloric acid. After stirring at ambient temperature for 30 minutes with an overhead stirrer, the mixture was cooled to 10 t 'and a solution of sodium nitrite (1.6 g) in water (4 ml) was added dropwise to make 5 The internal temperature is maintained below 15 ° C. During the addition, the reaction mixture changed from amber to cloudy orange. After 30 minutes, sodium acetate (3.8 g, 46.6 mmol) and ethyl (3-ethoxycarbonylamino-3-oxo-propanyl) carbamate (5.7 g, 23.3 亳 Mor). After 10 minutes' the reaction was warmed to ambient temperature. After 1 hour, 10 sodium acetate (1.7 g, 21.2 mmol) was added, and the reaction mixture was heated at reflux temperature. After 3 hours, the dark reddish brown mixture was treated with 50% sulfuric acid (23 strokes) and heated again at reflux temperature. After 2 hours, the mixture was concentrated under reduced pressure, and then water (200 ml) was added. After stirring for 30 minutes, the golden precipitate (3.5 g) was collected by filtration. The resulting solid was suspended in 3 liters of mercaptoacetic acid and stirred at 175 ° C. After 4 hours, the mixture was allowed to cool and stand for 16 hours. Dilute the mixture with water (100 liters) and mix! hour. #Release and force mouth to filter. Wash Shen Dianwu with water and dry in vacuum. The resulting brown solid was collected by filtration). Mass spectrum [M-1] 246.4. 20

g ^ _ > H2- (2-Gas-phenyl ^ Digassing_4 5_ Dikyu_3ΐ 11 ^ 41 Tris-2-yl) -2-methyl ^ pyridine Method, by 2-methyl_5_ (3,5_dioxo-4,5-a sl-3H- [1,2,4] difluoren-2-yl) _phenylarsinic acid and 2- ( The coupling of o-p-phenyl) ethylamine was used to prepare the title compound. The product is a colorless 106 200300083 发明, invention description oil. MS (ES +) 385 · 2; (ES0383 · 2; Lc retention time was 21 minutes (using the method outlined in LC / MS and the examples in Table I). Case 52? -Gas: Ν · ί2- (2 二 ^ 基 1-5- (4- 甲 1 土 5_ 二 气 代 ^ 5 hydrogen.

N- [2- (2-Gas-phenyl) _ethyl] · 5_ (3,5-dioxo_4,5-dihydro-3Η- [1,2,4] triazine- 2-yl) _benzidine (70 mg, 0173 mmol) in a stirred solution of dioxane (1.5 ml), methanol ⑺% (10 liters) was added, followed by addition (Trimethylsilyl) 20 M solution of diazomethane (0.35 liters). After 16 hours of incubation at ambient temperature, it was concentrated under reduced pressure. Purification was performed by silica gel chromatography (eluted with 2: 1 hexane / ethyl acetate) to obtain the title compound in the form of a white, non-Japanese shellfish as a white solid. Melting point is 161. 15 Mass spectrum (ES +) 419.2; (ES-) 417.1; LC retention time was 2.4 facets (using the method outlined in LC / MS and the examples in Table I). Case 53 200300083 发明, description of the invention

Ο CI

Chloride

pu in 2-chloro-5 · bromophenylarsinic acid (1.5 g, 6.3 mmol), EDCI (1.63 g 5,8.5 mmol) and HOBt (1.15 g, 8.5 mmol) in two To a stirred solution of methylformamidine (20 ml) was added 2- (2-airphenyl) ethylamine (1.06 ml, 7.5 mmol). After 15 minutes, triethylamine (1.18 ml, 8.5 mol) and dimethylformamidine (5 ml) were added. After 2 hours at ambient temperature, the mixture was diluted with ethyl acetate (50 ml) and washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate solution, water and brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.12 g of an amorphous solid. Mass spectrum (ES +) 374.6; (ES_) 372.2 〇 ·· Chloro-N- 『2- (2-chloro-benzylethyl 1-5- (2-oxo-1,1-benzyl-1-methylbenzyl) 15 amine Under a nitrogen atmosphere, 5-bromo-2-chloro · N- [2- (2 · chlorophenyl) -ethyl] • benzyl in an oven-dried round bottom flask equipped with a reflux condenser Sulfonamide (200 mg, 0.536 mmol), (5-valprolactam (106 mg, 1.07 mmol), bell carbonate (156 g, 1.13 mmol), dihumane (1 mg 200300083 发明, description of the invention

Liter, filled with nitrogen) and a mixture of one of copper (1) (5 mg) and heated in an oil bath at 120-125 ° C. After 21 hours, the mixture was cooled to room temperature, filtered through a silicone pad, and concentrated under reduced pressure to give 50 mg of a crude product. Purification was performed by preparative HPLC (preparative grade 5-phase chromatography using Shimadsu LC-8A), which was eluted with a gradient of one of 0.1% formic acid in acetonitrile to give 2.5 mg of colorless amorphous The title compound as a solid. MS (ES +) 391.6; LC residence time was 2.3 minutes (using the method outlined in LC / MS and the examples in Table I). Examples 54 to 57 are shown in Table 3, and are synthesized in a manner similar to that outlined in 10 of Example 53 by combining the appropriate amine with 5-bromo-2-chloro _ ^^ [2- ( It is prepared by coupling 2-chloro-phenyl) -ethyl] -benzamide. In some examples, the product was purified by preparative HPLC using Shimadsu LC-8A preparative liquid chromatography. The final product was analyzed by LC / MS using Micromass ZMD LC / MS (ESI mode). The method used for 15 degree change of HPLC mobile phase ladder is as follows: Time (minutes) A% B% 0.00 95 5 1.0 80 20 2.3 50 50 3.7 0 100 3.7 95 5

Solvent A was 98% water + 2% acetonitrile + 0.01% acetic acid. Solvent B was acetamidine + 0.005% formic acid. 109 200300083 发明, Description of the invention Table 3 Example Structural mass spectrometry (ES +) Mass spectrometry (ES-) LC retention time (minutes) 54 CC 1 ch3 417.7 2.3 55 Cl or ^ [X h3c ”434.3 2.1 56 cr 379.8 2.4 57 α; τ ° 457.1 2.8 Example 58 2-nitro-N- 『2- (2-gas-benzyl) ethyl 1-5-(5-gas-K5-dihydro-1,2,41-triazole _4_ group) -benzylamine 200300083 发明, description of the invention

N-N

-5-Molybdenylamino

In 5-amino-2-chloro-benzoic acid methyl ester hydrochloride (111 g, 50 mmol) and pyridine (0.79 g, 10.0 mmol) in anhydrous tetrahydro? To a stirred 0 ° C mixture in hexane (15 ml), phenyl chloroformate (0.95 g, 6.0¾ mole) was added. After warming to room temperature, the 3 reaction mixture 'was diluted with ethyl acetate (50 ml) and washed sequentially with 10% hydrochloric acid, water, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and purified by flash chromatography (10 eluting with 10% ethyl acetate in hexane) to give 0.8 g (53%) of a colorless solid. 4 NMR (300 MHz, DMSO-d6) 5 3.9 (s, 3H), 7.0 (br s5 1H), 7.18 (m, 2H), 7.4 (m, 3H), 7.6 (m, 1H), 7.9 (d, J = 2.5 Hz, 1H). Mass spectrum (M-H) ratio is 304 and 306 of 3: 1. 15 B. 1-methylamidino_4- (2-nitro-5-carbamoylmosyl) aminourea 111 200300083 玖, Description of the invention

p- ^ y = 〇 in 2-chloro-5-phenoxycarbonylamino · benzoic acid methyl ester (0.22 g, 0.72 pen moles) in one methylamine (1.4 ml) solution Formic acid was added formic acid (0.135 g, 3.15 mol). After stirring at room temperature for 20 hours, the reaction was partitioned between ethyl acetate and hydrochloric acid. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified on silica gel (eluted with 30% methanol in ethyl acetate) to give 2003 g (17%) of a colorless solid. Mass spectrum (M + Η) ratio of 3: 1 of 272 and 274. Ρ 二 2 · 乳 · 5_ (5_ ^ 代 -I, 5 · 二 氡-"1,2,4 ~ | Triseta

1-Methylfluorenyl-4- (2-chloro-5-carbonated methoxyphenyl) amino gland (0.03 g. 11¾ mole) in 1.0 M potassium hydroxide (0.44 Ml). Added 1 · 0Ν

Spectral (M-Η) ratio is 3: 1 to 238 and 240. A solution, heated at 80 ° C for 72 hours, and cooled to room temperature hydrochloric acid (0.8 ml), and the mixture was evaporated to dryness in a vacuum 112 200300083 玖, Description of the invention D · 2-乱 · Ν_ 『2- (2 -Disorder-epiyl) ethyl 1-5- (5 -Gas-1,5 -Difish,-"1 Triazole-4V benzamidine

At 2-chloro-5- (5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl) -benzoic acid (0.028 g, 0.117 mmol) in anhydrous N, To one of the solutions of N-dimethylformamide (4 ml) 5 was added 1-hydroxybenzotriazole (0.018 g, 0.14 mmol). After stirring at room temperature for 10 minutes, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0-025 g, 0.13 mmol) was added. After stirring at room temperature for 30 minutes, 2-chlorophenethylamine (0.018 g, 0.12 mol) and triethylamine (0.012 g, 0.12 mmol) were added, and the mixture was stirred at 10 room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed sequentially with water and brine, and dried over sodium sulfate. Removal of the solvent 'in vacuo followed by purification by reverse phase HPLC gave 0.042 g (10%) of the title compound as a colorless solid. NMR (300 MHz, CDC1J 5 (m5 2H), 3.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.60 15 (d, J = 7.9 Hz, 1H ), 7.76 (s, 1H), 7.78 (s, 1H), 8.43 (s,

1H) and 8.64 (m5 1H). Mass spectrum (M-H)] ratio of 375 to 377 at 3: 1. [Simplified illustration of the drawing] [Representative symbol table of the main components of the drawing] Yi 113

Claims (1)

2003. Scope of patent application 1. A compound of formula I: Where Α is-(C = 0) NH- or -ΝΗ (ΟΟ)-; X, Υ, and Z are = (CR6)-, = (CR7), and = (CR8)-; or, = (CR7) -And = (CR8)-; or qi CR6) _ ,; or one (CR6)-, = (CR7) -and; or = N ·, = (CR7) -and = N-; or ~ (CR)- , = N-and = N ·; 10 15 R is a (C ^ C ^) heterocyclic group bonded to nitrogen, which contains 1 to 6 heteroatoms selected from -N =, -N <, -NH_, · 〇-, and -S (0) n; The (Ci-Cw) heterocyclic group linked to nitrogen in fluorene is taken by at least one oxo group or one of these heteroatoms is _s (0) n (where 11 is 1 or 2); its fluorene and nitrogen The linked (Cl-CiG) heterocyclic group can also be optionally selected from 1 to 3 R9 groups per ring on any carbon atom capable of supporting additional substituents. Each R9 is independently selected from the group Substituents: hydrogen, halogenated L group, optionally substituted by one to three fluoro groups (Ci_c, elementary group h0- (cvc4) ^ group, optionally taken by an oxo group / 4 ( ^ C4moxy, H2C-, (CVC6) alkyl_0- (C = 〇) _ (2S) (C1_C4) alkyl- (〇2S) _NH-, (crc4) alkyl # 2S-[( C = 4 back group, R4R5N (㈣) _, RVN (CH2) r (CVCl〇) aryl, (C3-C8) cycloalkyl, (poriumCl0) heteroaryl, (C C10) heterocyclyl, (Cd ^ 10) square group-0_, (c3_c8) cycloalkyl-〇_, (C 114 20 300083), (C 114 20, application patent range c10) heterocubyl seven- and (Ci_CiG) heterocyclyl_〇 ·; The nitrogen-linked (CkC1g) heterocyclic group can also be optionally substituted on any ring nitrogen atom capable of supporting the additional substituent with 1 to 2 feet 10 groups per ring, each r1. Is independently selected from the group consisting of hydrogen, hydrogen, optionally substituted by 3 to 3 fluoro) alkyl, h0- (Ci-C4) alkyl, (cv C4) alkyl -(〇〇)., (CVC4) alkyl-_Kι〇) aryl, (c3-c8)% alkyl, (Ci_Cig) heteroaryl and heterocyclic group; wherein in the R # R1G substituent, Each of the aforementioned (C6_C1G) aryl group, (c3-c8)% alkyl group, (CVCi〇) heteroaryl group, and (c-Cl.heterocyclic group) may be optionally substituted on any ring carbon atom. The ring is partially selected from the group consisting of a dentyl group, a meridian group, an amine group, -CN, (Cl_c4) alkyl, (Ci_c4) alkoxy, -CF3, cF3 .... (Ci-C4 ) Burning base _, [(Ci_C4) Yuan base] 2 Good, (CiA) Burning base j, (CrC4) Burning base-(8 Which, (CVC4) Yuan _ (s〇2) ... Heart C4) Tongji Qi -(〇〇) _, formamyl and (CVC4) alkyl ^^ 〇) ·; η is an integer from 0 to 2; q is an integer from 0 or 2; S is an integer from 1 to 3; t is an integer from 0 to 3; 20 feet is chloro, bromo, (Cl-c4) alkyl R3 is selected from the group: (C4_Ci〇) Alkyl, (C3_Ci2 ^^-(CR > VV >) (c6-c10) ^ m. (CRnRl2v (CH2) _M ~) heterocyclyl- (CRYV and (Cl-c10) heteroaryl_ (CRnRl2) s) The (C4-C1Q) alkyl group can be selectively and independently substituted with one or more substituents selected from the group of 115 200300083 and patent applications: halo, via, -CN, (CVC4) (C1-C4) alkoxy, -CF3, CF30-, (CVC4) alkyl-S., (Ci-coalkyl) _ (s = 0) _, (Cl_c4) alkyl_ (s〇2 ) __ c0 (Ci_C4) alkyl, methylformyl, (Cl-C4) alkyl-((> 0) ·, (CVCi〇) aryl, (C3-C8) cycloalkyl, Cl-Cl〇) heteroaryl, (CVCi〇) heterocyclyl, (C6-C10) square group_〇_, (c3_c8) cycloalkenyl-〇 ·, (C ^ -C ^ o) heteroaryl_ 〇- and (CVC10) heterocyclyl-0 ·; wherein each of the R3 group members (ci-Ci〇) heterocyclyl- (CRUrAs- and (Ci_Ci〇) heteroaryl_ (cr11r12) s_) contains 1 to 3 heteroatoms independently selected from _〇_ and -s (0) n_; wherein the R3 group member (c3 -c12) cycloalkyl- (CR11R12) S_, (C6_Ci〇) aryl_ (CR R) q- (CH2)-, (Ci-Cio) heterocyclyl- (CRUR12) S_ and (Ci-cio) hetero Each of aryl- (CRUR) s- can be optionally substituted on each ring carbon atom capable of supporting an additional independent substituent by i to 4 substituents independently selected from the following groups per ring Replace: _ Daiji, Xiang Cio) aryl, -C10) heteroη "... 1G: ^ i_ (CRuR1s_ can optionally be selected from any of the aforementioned (c6_cycloalkyl, (CrCi〇) Heteroaryl and 116 200300083 each of the ring groups that can be applied for and patented can be optionally substituted on any ring carbon atom by each of j to 3 independently selected from the following groups: _generation group, Hydroxyl, amine, -CN, (CVC4) alkyl, (Cl_C4) alkoxy, -CF3, CF3〇-, (CVC4) alkyl-NH-, [(Cl-C4) alkyl] 2, ( CVC4) alkyl-S-, (CVC4) alkyl- (S = 0)-, (CrC ^) alkyl- (S02)-, (CkC #) alkyl-〇- (〇0)-, formazan And (Cl_c4) alkyl_ (c = 0) _; R4 and R5 are each independently selected from the group consisting of hydrogen, (Cl_C6) alkyl, HO- (C2-C6) alkyl and (c3-c8) Cycloalkyl, or R4 and R5 optionally form a 3- to 8-membered heterocyclic ring together with the nitrogen atom to which they are specifically attached; R6, R7, and R8 are each independently selected from the group consisting of hydrogen, halogen, cyano, Hydroxyl, (CkC6) alkyl optionally substituted with 1 to 4 chloro or fluoro groups and optionally substituted with 4 to 4 chloro or fluoro groups (CVC6) alkoxy; R11 and R12 are each independently selected from the group consisting of hydrogen, fluoro, cyano, meridian, -CF3, CF30-, (CKC6) alkyl, (C3-C8) cycloalkane (Ci-CJ alkyloxy, (c3-C8) cycloalkoxy, phenyl, (Ci-Ci〇) heteroaryl, and (cvcw heterocyclyl); wherein the (Ci-c: 6) alkyl, <: 3-(: 8) cycloalkyl, (CVC6) alkoxy, (C3-C8) cycloalkoxy, phenyl, (Ci-Cio) heteroaryl and (crC1G) heterocyclyl can be selected With 1 to 3 substituents independently selected from the group consisting of chloro, fluoro, cyano, hydroxy, -cf3, cf30-, (Ci_C4) alkyl-S-, (CVC4) Alkyl (S 〇) **, (Ci-C4) alkyl- (S02)-, (Ci-CJalkyl)-0- (〇0) _, methyl or (CVC4) alkyl- (〇0 )-; The premise is that when R3 is (C3-Ci2) cycloalkyl- (CRllR12) s_, 117 200300083, the scope of patent application for R11 and R12 is hydrogen, and 3 is 丨 or 2, then (Cs_Ci2) The cycloalkyl group must be other than the optionally substituted gold steel alkyl group; or a pharmaceutically acceptable salt or solvate thereof. Thereof, wherein X, Ya and z are 5 = (CR0l ·, = (CR7) - and = (CR8) -. 3. If the compound in the scope of patent application 1 or 2, where A is _ (C = 0) NH- 〇4. In the compound, the scope of patent application 3, wherein R3 is (C3_Ci2) cycloalkyl- (CRnR ] 2) s-; R " and Ri2 are each independently hydrogen or (Ci_C4) alk 10 group; ^ 1; and the (C3-C12) cycloalkyl- (CRnR12) s- system is selectively 3 to 3 substituents independently selected from the group consisting of hydrogen, halo, hydroxy, CN-, (CVC4) alkyl, (Cl-C4) alkoxy, oxo, -C02- (Cl_C4 ) Alkyl-, formamyl, (Cl-C4) alkyl- (c = o) _. 15 5. The compound according to item 4 of the patent application, wherein R 2 is chloro. 6. The compound according to item 5 of the patent application, wherein R6, R7 and R8 are each hydrogen. 7. The compound as claimed in item 6 of the scope of patent application, wherein R1 is ... Wherein R10 is selected from the group consisting of hydrogen, (Cl-C6) alkyl, HO- (C2-C6) alkyl, and (c3-c8) cycloalkyl. 118 200300083 The scope of application for patents The compounds in the first scope of the declared patents, wherein the compound having the chemical formula 丨 has the following chemical formula: Wherein R3 is optionally substituted (C3-Ci2) cycloalkyl_ (CR R) S-, wherein R11 and R12 are each independently hydrogen or (Ci_c4) alkyl, or at least one of R11 and Other than hydrogen or (Ci_C4) alkyl (more preferably, the ruler and ruler in CRur12 in which C is directly connected to the A group are each hydrogen); _substituted group, hydroxyl group, -CN, (CVC4) alkyl group, ( Cl-C4) alkoxy, (CVC4) alkyl-〇- (〇〇)-, fluorenyl, (Cl_c4) alkyl- (c = 0)-, (c6-c10) aryl, (c3- c8) cycloalkyl, (q-Cio) hetero Aryl, (CVC1 ()) heterocyclyl, (c6-c1 ()) aryl_0 ... (C3_C8) cycloalkyl-0 ·, (Ci-Cio) heteroaryl · 〇_ and (cvc10) hetero A cyclic group; each of the aforementioned (c6-c1 ()) aryl, (C3-C6) cycloalkyl, (Cl_Cl〇) heteroaryl, and (C1-C1G) heterocyclyl substituents, optionally Is substituted by i to 3 moieties independently selected from the following groups per ring i to 3 groups: CrC4) alkyl. 9. The compound according to item 1 of the scope of patent application, wherein the compound is selected from the group consisting of 2-chloro-N- [2- (2-chloro-phenyl) -ethyl] -5- (3,5 -Dioxo_4,5-Di119, patent application scope £ ^ · 3Η · [1,2,4] tris-2-yl) -benzamide; 2-chloro 5- (3,5 -Dioxo_4,5-dihydro-311- [1,2,4] triazin_2_yl) 1_ Ν · [2 · (2-fluoro-phenyl) -ethyl] -phenylhydrazone Amine; 2 · Chloro-5- (3,5-dioxo-4,5-dihydro-3 [-[1,2,4] trione_2_yl) _ Ν- (2,2-biphenyl -Ethyl) -benzimidamine; Ν- [2- (2-chloro-phenyl) -ethyl] -5- (3,5-dioxo_4,5-dichloro_3Η- [ 1,2,4] triazin-2-yl) -2 · fluorenyl-benzylamine; Ν- [2- (2-benzyloxy-phenyl) ethyl] -2 · chloro_5_ (3 , 5-Dioxo · • 4,5-Dihydro-3Η- [1,2,4] triazin-2 · yl) -benzamide; 2-chloro-5- (3,5-dioxo -4,5-dihydro-3fluorene- [1,2,4] triazine_2_yl) _N- (l-phenyl · cyclohexylmethyl) -benzidine; 2-chloro-5- (3,5-dioxo-4,5-dihydro-311- [1,2,4] tri-11-qin-2-yl) N- (l-p-tolyl-cyclohexylmethyl) -benzene Formamidine; 2-chloro-N_ [2- (2 · Ga-phenyl) -ethyl] -5- (4-methyl-3,5-di -4,5-dihydro-3 '-[1,2,4] triazin-2-yl) -benzamide; 2-chloro-5- (3,5-dioxo-4,5- Dihydro-3Η- [1,2,4] triazin_2_yl) _ Ν_ [2- (2 • trifluoromethyl-phenyl) -ethyl] -benzamide; and 2.chloro- Ν- [2- (2-chloro-phenyl) -ethyl] -5- (3-oxo-2,3-dibenzo [1,4] thien-4-yl) -benzidine . ⑺ · A pharmaceutical composition for treating a disease regulated by P2X? In a mammal, which comprises an effective amount of the compound according to any one of claims i to 9 and a pharmaceutically acceptable Carrier. 200300083 Lu, (1), the designated representative of the case is: Figure _ (2), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that can best show the characteristics of the invention: 4