TWI291960B - Pyrimidine compounds of formula (ι),and pharmaceutical composition having cell-cycle inhibitory activity comprising the - Google Patents

Description

1291960 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed A7 B7 V. Description of the Invention (1) The present invention relates to a pyrimidine derivative or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, which has cell cycle inhibitory activity and It can be used for anti-cell proliferation (such as anti-cancer) activity and thus can be used to treat human or animal body. The invention also relates to a method of producing the pyrimidine derivative, a pharmaceutical composition comprising the derivative, and the use thereof for the manufacture of a medicament having an anti-cell proliferation effect on a warm-blooded animal such as a human. The intracellular protein family known as cyclin plays a central role in the cell cycle. Close control of the synthesis and degradation of cyclins causes fluctuations in their performance during cell cycling. Cyclins bind to cyclosporin-related serine/tyrosine kinases (CDKs) and their combination is required for the activity of intracellular CDK (such as CDK1, CDK2, CDK4 and/or CDK6). Although the precise details of how these factors bind to regulate CDK activity are unknown, the balance between the two shows whether cells evolve through the cell cycle. Recent studies focusing on oncogenes and tumor suppressor genes have identified the regulation of entry into the cell 彳 shield as the primary control point for mitogenesis in tumors. Furthermore, CDKs appear to be downstream of several oncogene signaling pathways. Modulation of CDK activity by up-regulating cyclins and/or deletion of endogenous inhibitors appears to be an important axis between the mitogenic signal pathway and tumor cell proliferation. According to this, it has been recognized that cell cycle kinases, especially CDK2, CDK4 and/or CDK6 inhibitors (which are manipulated in the S-phase, G1-s phase and G1_s phase, respectively) should be selective inhibitors of cell proliferation. Such as mammalian cancer cell growth inhibitors. The present invention is based on the discovery that a pyrimidine compound unexpectedly inhibits cell cycle kinase effects and exhibits selectivity for CDK2, CDK4 and CDK6, and thus has I if ϋ ϋ · ϋ n I n ϋ — Bi — Bi J , a 1 ϋ ϋ (Please read the back of the note first and then fill in the book) ί«· -4 -

1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 V. Invention Description (2) It has anti-cell proliferation properties. This property is produced by μ (4),,,. It can be used to treat and abnormal cell cycle % and cell proliferation, such as diseases, such as; (peripheral tumor and leukemia), fiber proliferation and differentiation disorders, cognac, wind Thirsty ' ^ rheumatism is inflammation, Kaposi's sclerosis, blood stasis, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial vasospasm, autoimmune disease, acute and chronic inflammation, bone disease and retinal tube Proliferative eye disease. Accordingly, the present invention provides a compound of formula (I): Η

Wherein: the ring is an imidazo[i,2a]pyridin-3-yl or pyrrole[2,3a]pyridine-3-yl; R2 is attached to the carbocyclic ring and is selected from the group consisting of halogen, nitro, cyano, hydroxy, Trifluoromethyl, difluoromethoxy, amine, carboxyl, aminemethanyl, thiol, amine acid, C1-6fe, c2-6 alkenyl, C2-6 block, Ci-6 alkoxy, Cm decyl, Cm alkoxy, N-CCw alkyl)amine, ν, Ν-Κμalkyl) 2 amine, Cm alkanoyl, Ν-βκ alkyl)amine carbhydryl, t ^N-CCk alkyl;) 2 urethane group, CU6 alkyl S(0)a wherein a is 0 to 2, Cm alkoxycarbonyl, (Cw alkyl)amine sulfonyl, fluorene, fluorene-((^ _1 2 alkyl) 2 amine sulfonyl, phenyl, heterocyclic, phenylthio or (heterocyclyl)thio, *(:μ6 alkyl, C2-6 alkenyl, C2-6 alkyne 1111 — — — — — — I— ^« — — — — — — — (Please read the notes on the back and fill out this page) 1 2 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Description of Invention (3) Any of phenyl, phenyl or heterocyclic groups Optionally substituted on the carbon by one or more G; and if the heterocyclic group contains a _NH- moiety, the nitrogen atom may optionally be substituted with a group selected from Q; m is 0-5; wherein R2 may be the same or different ; R is halogen, nitro, cyano, light, trifluoromethyl, trimethoxy, amine, thiol, amine carbhydryl, thiol, amine fluorenyl, c1-3 Base, C2_3 alkenyl, C2-3 alkynyl, Ci-3 alkoxy, C.3 alkyl fluorenyl, Ν-β decyl) amine, hydrazine, Ν-β decyl) 2 amine, Cw alkane Mercaptoamine, Ν-β Ηalkyl)amine carbhydryl, hydrazine, Ν-β υalkyl) 2 amine carbhydryl, alkyl S(0)a wherein a is 0 to 2, alkyl) amine sulfonium Or an alkyl) 2 amine sulfonyl group; wherein any of the Cu alkyl group, the Cu alkyl group, the C2-3 alkenyl group or the C2.3 ruthen group may be substituted on the carbon by one or more J as appropriate; 0 to 2, wherein R1 may be the same or different; a cyclic phenyl group is a phenyl group or a phenyl group fused to a C5_7 cycloalkyl ring, and R is a halogen, a nitro group, a gas group, a rosin group, an amine group, a thiol group. , Aminomethyl, thiol, sulfonyl, C2.6 alkenyl or C2.6 alkynyl; p is 〇_4; wherein R3 may be the same or different; R4 is AE-based; The middle A is selected from the group consisting of Cw alkyl, phenyl, heterocyclic, C3-8 cycloalkyl, phenyl Cw alkyl, (heterocyclyl) Cw alkyl or C3.8 cycloalkylcycloalkyl; 6 alkyl, phenyl, heterocyclic, C3.8 cycloalkyl, phenyl Cw alkyl, (heterocyclyl)Ci-6 alkyl or C3-8 cycloalkyl Cw cycloalkyl can be viewed on carbon as appropriate One or more D substitutions; and if the heterocyclic group contains a -NH- moiety, the nitrogen atom may optionally be substituted with a group selected from R; _^_ -6-___ This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) ilm^----113⁄4 (Please read the note on the back and fill out this page) Order---- -L · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 V , invention description (4) E is a chemical bond or -〇-, -c(0)-, -〇C(0)-, -0C(0)-, -N(Ra)C(0)-, -C( 0) N(Ra)-, -N(Ra)-, -S(0)r-, -S02N(Ra)- or -N(Ra)S02-; wherein R is hydrogen or optionally one or more D substituted C κ alkyl and r is 0 - 2 ; D is independently selected from oxo, arginyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, amine Formyl, thiol, amine Acid group, C!-6 alkyl group, C2.6 alkenyl group, C2-6 alkynyl group, Cm alkoxy group, Cm alkyl group, Cm alkoxy group, N-(CU6 alkyl) amine group, anthracene, Ν-Νκ alkyl)2 amine group, Cw alkanoguanidino group, alkyl)amine carbhydryl group, hydrazine, Ν-βκ alkyl) 2 amine carbhydryl group, Cy alkyl S(0)a wherein a is 0 To 2, C _6 alkoxycarbonyl, Cm alkoxycarbonylamino, benzyloxycarbonylamino, N-(Cm alkyl)amine sulfonyl and N,N-(Cw alkyl) 2 amine sulfonyl Wherein Cm alkyl, C2_6 fluorenyl, (: 2_6 alkynyl or phenyl optionally substituted by one or more K on carbon; q is 0 · 2; wherein R4 may be the same or different; +q$5 ; G, J and κ are independently selected from i, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amine, carboxyl, amide, thiol, sulfonate Mercapto, methyl, ethyl, methoxy, ethoxy, ethoxylated, ethoxylated, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N _ethylamine, etidamine, N-methylamine, mercapto, N-ethylamine, mercapto, N,N-dimethylamine, mercapto, N,N-diethylamine Base, N-methyl-N-ethyl month; Base, methylthio, ethylthio, methyl sulfonyl, ethyl sulfonyl, methanesulfonyl, ethanesulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylamine continued Sulfhydryl, N-ethylamine hydrazino, hydrazine, hydrazine dimethylamine hydrazino, hydrazine, hydrazine diethylamine sulfonyl or fluorenyl-methyl-hydrazine-ethylamine sulfonyl; And the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) —-l·—*--------------- order-------- -· (Please read the notes on the back and fill out this page) Bu· 1291960 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (5) Q and R are independently selected from CM alkyl, <^ _4 alkyl fluorenyl, CM alkyl sulfonyl, C! _ 4 oxycarbonyl, amine methyl, N-(CM alkyl) amine carbaryl, N, N- (C1 < 4: Fe) amine Mercapto, benzyl, benzyloxycarbonyl, benzhydryl and phenylsulfonyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. For the avoidance of doubt, "wherein any Cm alkyl group is substituted as appropriate, the term and other such terms are also intended to be substituted as appropriate on other bases containing a C1-6 alkyl group, such as CK6 alkoxy, Cw. Alkyl fluorenyl, Cm alkoxycarbonyl, alkyl)amino, hydrazine, hydrazine-((^_6 alkyl) 2 amine, alkanoguanidino, alkyl)aminocarboxamidine, N,N-(Cl -6 alkyl) 2 aminocarboxamyl, C w alkyl S(0)a wherein a is 〇 to 2, CU6 alkoxycarbonyl, Cm alkoxycarbonyl, N·(C^alkyl)amine sulfonate Mercapto or hydrazine, hydrazine-(<:μ6 alkyl) 2 amine sulfonyl. In this specification, "alkyl, containing both straight-chain and branched alkyl groups, but related to individual alkyl groups such as" The propyl group only contains a linear chain. For example, "c κ alkyl, including C^4 基, Cu, Cufe, propyl, isopropyl, and t-butyl. However, regarding individual alkyl groups such as "propyl," Chains and related individual branched chains such as "isopropyl", especially only branched chains. Similar notation is also used for other groups, such as "phenyl Cl_6 alkyl, containing phenyl CM alkyl, benzene Base, i _ phenylethyl and 2-phenylethyl. "Halogen," means fluoro, chloro, bromo and iodo. When the substituent is optionally selected from "one or more" groups, it is understood that this definition encompasses all substituents selected from the indicated groups or selected from the group Two or more substituents. ''Heterocyclyl, which is 4-12 atoms and at least one atom selected from nitrogen, sulfur or oxygen and is saturated or partially saturated with a carbon or nitrogen bond unless otherwise stated. 1 ϋ ϋ ϋ a^i I i·— tat ϋ 1 1 m ·ϋ 1-1 _0, I m —κ mmmmt I (Please read the notes on the back and fill out this page) -8-

129 ^6ί)ΐ7386 Patent Application Replacement Page (May 96) V. Inventive Note (6) and or unsaturated single or double ring, in which _CHr is based on the sinking-C(〇)_, The ring nitrogen atom may optionally carry a C).6 alkyl group and form a quaternary compound or a ring nitrogen and/or a sulfur atom which may optionally be oxidized to form an N-oxide or S-oxide. Examples of 'hetero-based' and suitable groups are P-based, hexahydro-p-precipitate, p-predated, pyranyl, pyrrolyl, isothiophene, fluorenyl, quinolinyl, pyrenyl , 1,3 -winter-oxo-substituted hexyl group, · P-plugin, hexahydro-P ratio P well base, pr-sudden bite base, P-rhodium-based base, sulfur-P base, p-P Linke, high hexahydrogen p ratio p, well, 3,5-dihydrohexahydropyridyl, tetrahydropyranyl, imidazolyl, pyrimidinyl, 峨p well, tower p, hetero-ruthenyl, N _ methyl p ratio p group, 4 - p ratio ketone group, 1-isoquinolinone group, 2-oxopyrrolidine group, 4-oxazolone group, pyridine-N_ emulsion and p-quinion -N-oxide. Preferred "heterocyclyl" is a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms and at least one atom selected from nitrogen, sulfur or oxygen and, unless otherwise stated, bonded by carbon or nitrogen. Wherein the _CHr group may be substituted by C(0)_, and the ring nitrogen atom may optionally carry a Ci 6 fe group and form a quaternary compound or a ring nitrogen and/or a sulfur atom may be oxidized to form an N-oxide or S-oxide. The phenyl group fused to the Cw cycloalkyl ring is preferably a staging group or a tetrap-lining group. "Cw alkoxycarbonyl, an example is ethoxycarbonyl. Examples of "Ci 6 alkoxycarbonyl" include alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n- and tert-butoxycarbonyl." Cw alkoxy, comprising Gw alkoxy, methoxy, ethoxy and propoxy. Examples of the "Cw alkanoyl group" include a Cw alkanoamine group, a formamidine group, an amine acetate group, and a acrylamide group. "Cufe-based S(0)a wherein & is 〇 to 2, and examples include Cw sulfonyl sulfhydryl, Cl.3 alkyl S(0)a, methylthio, ethylthio, decylsulfinyl Ethylsulfinyl, methanesulfonyl and ethylsulfonyl. "Cw alkane-9 - This paper scale applies to Chinese national standards (C weep s) A4 gauge (210X297 mm) 1291960 A7 B7 V. DESCRIPTION OF THE INVENTION (7) The base ''example includes a CM alkyl group, a Ci. 3 alkyl group, a propyl group, and an ethyl group. Examples of the "N-Cm alkylamino group" include an alkyl group, an amino group, a methylamino group and an ethylamine group. Examples of the alkyl"2 amine group" include anthracene, Ν-βυalkyl)2 amine group, di-anthracene-methylamino group, bis(indenyl-ethyl)amino group, and oxime-ethyl-anthracene-methylamino group. Examples of "C2.6 alkenyl" are C2.3 alkenyl, vinyl, allyl and 1-propenyl. Examples of "C2.6 alkynyl" are C2.3 alkynyl, ethynyl, 1 propyne And 2-propynyl. Examples of "N-(C^alkyl)aminesulfonyl" are N-CC^alkyl)aminesulfonyl, N-(methyl)aminesulfonyl and N-( Ethyl) sulfonyl group. "Ν-βκ alkyl" 2 amine sulfonyl group, examples are alkyl) 2 amine sulfonyl, N,N-(dimethyl)amine sulfonyl and N-( Methyl)-N-(ethyl)amine sulfonyl. Examples of "N^Cw alkyl)aminocarboxamyl" are N-(Cw alkyl)aminecarbamyl, N-(Cm alkyl)aminecarbamyl, methylaminocarbonyl and ethylaminocarbonyl. "Alkyl" 2 amine methyl hydrazino, an example being hydrazine, fluorenyl- fluorenyl) 2 amine carbhydryl, N,N-(Cm alkyl)amine carbhydryl, dimethylaminocarbonyl and methyl Aminocarbonyl. "C 5-7 cycloalkyl ring, examples are cyclopropyl and cyclohexyl. Examples of "(heterocyclyl)(^.6 alkyl) include pyridylmethyl, 3-morpholinylpropyl and 2-pyrimidin-2-ylethyl. Examples of "(heterocyclyl)thio" include thiophene Alkylthio and pyridylthio. "C3-8 cycloalkyl, examples include cyclopropyl and cyclohexyl. Examples of "Cw cycloalkyl Cm cycloalkyl" include cyclopropylmethyl and 2-cyclohexyl Examples of "C κ alkoxycarbonylamino" include a methoxycarbonylamino group and a third butoxycarbonylamine group. Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, those of the compounds of the invention which are sufficiently basic. a salt, for example, an acid addition salt with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or malic acid. Further, a suitable medicine of the compound of the present invention which is sufficiently acidic can be used - 10- This paper scale has passed the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ilr!h------Φ (please read the notes on the back and fill out this page) Order---- ----- Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed 1291960

The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints accepting salts as alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or organic bases which provide physiologically acceptable cations. A salt, for example, a salt formed with methylamine, dimethylamine, trimethylamine, hexahydropyridine, morpholine or tris-(2-hydroxyethyl)amine. The compound of the formula (1) can be administered as a prodrug, which is cleaved in the human or animal body to obtain a compound of the formula (I). Examples of prodrugs include in vivo hydrolysable compounds of formula (1). In vivo hydrolysable esters of compounds of formula (I) containing a carboxyl group or a hydroxyl group are, for example, pharmaceutically acceptable for hydrolysis to the original acid or alcohol in the human or animal body. Sour vinegar. Suitable pharmaceutically acceptable esters of tetamine include Cm alkoxymethyl esters such as methoxyacetic acid, C κ decyloxymethyl esters such as trimethyl ethinyl methyl ester, self-grown vinegar, and a 8-ring burning An oxycarbonyloxy Cm alkyl ester such as 1-cyclohexylcarbonyloxyethyl ester, hydrazine, 3 • dioxanthene-2-one methyl ester such as 5-methyl-1,3-dioxolane Alkene-2-keto-methyl ketone; and C!6 oxycarbonyloxyethyl ester such as 1-methoxycarbonyloxyethyl ester and which can be formed on any of the carboxyl groups of the compound of the present invention. The in vivo hydrolysable ester of the compound of formula (I) containing a hydroxy group comprises an inorganic ester such as decanoic acid and a related compound of the ruthenium ketone and the hydrolytic cleavage of the ester in vivo to obtain the original thiol group. An example of or - S oxy ke vine contains ethoxy methoxy methoxy | 2 2 _ dimethyl propyl methoxy methoxy methoxy. The in vivo hydrolysable ester is selected from the group consisting of a thiol group, a benzamyl group, a phenethyl group and a substituted phenethyl group, an alkoxycarbonyl group (obtaining an alkyl carbonate), a dialkylamino group Dialkylaminoethyl)-N-alkylaminocarbazinyl (obtaining urethane), dialkylaminoethyl and thioglycolyl. Examples of the substituent of the benzoic acid group include the 3- or 4-position of the benzylidene ring via a methylene group bonded to the 3- or 4-position of the benzoyl ring. The paper size is applicable to the China National Standard (CNS) A4 specification ( 210 X 297 mm) :___C___:______I ________------- (Please read the notes on the back and fill out this page) 1291960 A7 V. INSTRUCTIONS (9) Base and hexahydropyrrole. - - -------f (Please read the notes on the back and fill out this page) Some compounds of formula (1) may have a palm center and/or geometric isomerization center (E- and Z-isomers) It is to be understood that the invention encompasses all such optical, non-stereoisomers and geometric isomers with CDK inhibitory activity. The present invention relates to compounds of formula (1) which possess any and all transmutation of CDK inhibitory activity. It is also understood that certain compounds of formula (I) may exhibit both solvated and non-solvated states, such as hydrated states. It is to be understood that the invention encompasses all such solvated compounds with CDK inhibitory activity. Another object of the present invention is to provide a compound of the formula (I) (as described above), wherein: the Intellectual Property Intelligence Bureau employee consumption cooperative prints a ring A for miso and [1, 2a]p ratio D 3 · base or p ratio p幷[2,3a]p is more than a 3-amino group; R2 is attached to a carbocyclic ring and is selected from the group consisting of _, nitro, cyano, hydroxy, trifluoromethyl, difluoromethyl lactyl, amine, Alkyl, amine, mercapto, thiol, amine decyl, Ci.6 alkyl, c2-6 alkenyl, c2-6 alkynyl, Ck alkoxy, Cm decyl, Cy alkoxy, N-Ww Alkyl)amino, ν, Ν-Κμalkyl) 2 amine, CM succinyl, NJCm alkyl) amine carbaryl, hydrazine, Ν-βα alkyl) 2 amine carbaryl, Cw alkyl S(0)a wherein & is 〇 to 2, Cw alkoxycarbonyl, fluorenyl) fluorenyl and n,N-(Ck alkyl) 2 amine fluorenyl; m is 0 - 5; wherein R2 R1 may be the same or different; R1 is halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, aminemethanyl, thiol, sulfonyl, Cl_3 alkyl , C2_3 fluorenyl, C2_3 alkynyl, Cl_3 alkoxy, Cl_3 alkyl fluorenyl, alkyl) amine, hydrazine, Ν-β decyl) 2 amine, Cl_3 alkane Amine, Ν_(<^3垸-12- Μ氏张尺钱财关家标准(C'NS) A4 specification (210 X 297 public)! 291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. INSTRUCTION DESCRIPTION (10) Aminomethylmercapto, N,N-(Cwalkyl)2aminecarboxamidine, Cu alkyl S(0)j, a is 0 to 2, N-fw alkyl) Aminesulfonyl or anthracene, Ν-βυalkyl)2 sulfonyl; η is 0 to 2, wherein R1 may be the same or different; Β is phenyl or phenyl fused to a C5_7 cycloalkyl ring; R3 is halogen, nitro, cyano, hydroxy, amine, carboxyl, amide, thiol, sulfonyl, C2_6 alkenyl or c2_6 alkynyl; p is 〇·4; wherein R3 may be the same or R is an A_E- group; wherein A is substituted on the carbon by one or more D and is selected from (: μ6 alkyl, phenyl, heterocyclic, phenyl Cw alkyl or (heterocyclyl) ) <^_6 alkyl; E is a chemical bond or -〇-, -C(0)-, -0C(0)-, -〇C(0)-, -N(Ra)C(0)-, - C(0)N(Ra)-, -N(Ra)-, -S(0)r·, -S02N(Ra)· or -N(Ra)S02-;

Ra is hydrogen or, as the case may be, one or more D substituted Cm alkyl and r is 〇_2; D is independently selected from oxo, _, nitro, cyano, thio, trifluoromethyl, Fluoromethoxy, amine, ruthenium, amine carbhydryl, thiol, amine sulfhydryl, C!-6 alkyl, C2-6 fluorenyl, C2_6 alkynyl, Cm alkoxy, Cm alkanoyl, Cm alkoxy group, N-(C!-6 alkyl)amino group, fluorene, fluorenyl-fluorenylalkyl) 2 amine group, C "6-pyroguanamine group, hydrazine (C-based) amine-based base, hydrazine - (C!_6 alkyl) 2 Aminomethyl thiol, C _ 6 alkyl S(0)a wherein a is 0 to 2, Ck alkoxycarbonyl, (Cm alkyl) aminoxasulfonyl and alkyl) 2 Aminesulfonyl; and q is 0-2; wherein R4 may be the same or different; and wherein p+qs5; or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo - 13- This paper scale applies to Chinese national standards ( CNS)A4 specification (210 X 297 mm) ---------------------Book---------· (Please read the note on the back first)再?? Then fill out this page} 1291960 A7 B7 V. INSTRUCTIONS (11) Preferably, R1, R2, r3, r4, η, m, p, q, ring A and ring B are as follows. Any of the foregoing or later The scope of the patent application or the specific example. The ring A of the present invention is preferably imidazolium [l, 2a] pyridin-3-yl. The ring A of the present invention is preferably pyrazol [2, 3a] pyridine - 3-Based. Preferably R2 is attached to the ring carbon and is selected from the group consisting of halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, aminemethanyl, amine sulfonyl , Cw alkyl, C2_3 alkenyl, Cw alkoxy, Cm alkanoyl, Cy alkoxy, alkyl)amino, alkyl) 2 amine, Cw alkanoyl, Ν-β decyl Aminomethyl hydrazino, hydrazine, Ν-β decyl) 2 amine carbaryl, CK3 alkyl S(0)a wherein a is 0 to 2, N-CCu alkyl) sulfonamide and N, N-( CK3 alkyl)2amine is a fluorenyl group. More preferably, the R2 is attached to a ring carbon and is a Cu alkyl group. The extra R2 is attached to a ring carbon and is a methyl group. In another object of the present invention, a preferred R2 is attached. Attached to the ring carbon and selected from the group consisting of halogen, acetyl, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, amine carbaryl, thiol, sulfonyl, C!_3 Alkyl, C2_3 alkenyl, <32_3 block, Cu alkoxy, Ci.3 quilt, Cu calcined, N-CCu) Base, hydrazine, Ν-βυalkyl) 2 amine group, Cw alkanoguanidino group, N-CCu alkyl) amine carbhydryl group, hydrazine, Ν-β υ alkyl) 2 amine carbhydryl group, Cu alkyl S ( 0) a wherein a is 0 to 2, Cu alkoxycarbonyl, alkyl) sulfonyl, fluorene, Ν-β decyl) 2 amine continuation of Si, phenyl, heterocyclic, phenylthio or (hetero a sulfhydryl group; wherein any of c 悦 基, C 2-3 %, C 2-3, 冬, or hetero basal may be substituted on the carbon by one or more G; The ring base contains · ΝΗ - part of the -14 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ' : {Please read the back note and fill out this page) ---- ----订--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291960 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed B7 V. Invention description (12) Nitrogen atom can be selected as appropriate Substituted from the base of Q. In another object of the invention, more preferably R2 is attached to the ring carbon and is selected from the group consisting of halogen, cyano, C _6 alkyl, Cm alkoxy, Cw alkyl s(〇) a wherein a is 0, phenyl, a phenylthio or (heterocyclyl)thio group; wherein any of an alkyl group, a phenyl group or a heterocyclic group may be optionally substituted on the carbon by one or more G, wherein g is selected from the group consisting of a hydroxyl group and a dimethylamino group . In another object of the invention, particularly preferred R2 is attached to the ring carbon and is selected from the group consisting of bromine, cyano, methyl, methoxy, ethylthio, 2-hydroxyethylthio, 2-dimethylaminoethylthio , phenyl, phenylthio or p-seceno-2-ylthio. In another object of the invention, more preferably R2 is attached to the ring carbon and is selected from the group consisting of bromine, cyano, methyl, methoxy, ethylthio, 2-hydroxyethylthio or 2-dimethylaminoethylsulfide base. In another object of the invention, particularly preferred R2 is attached to the ring carbon and is selected from the group consisting of 2 • hydroxyethylthio. In still another object of the present invention, preferably R2 is attached to the ring carbon and is selected from the group consisting of fluorine, gas, bromine, cyano, methyl, methoxy, ethylthio, 2'-thioethylthio or 2? Aminoethylthio group. Preferably m is 0 - 2 ; wherein R2 may be the same or different. In one object of the present invention, it is preferred that m is ruthenium. In another object of the present invention, preferably m is 1. In still another object of the present invention, preferably 42; wherein Han 2 may be the same or different. Further, in the present invention, it is preferred that r2 is attached to the ring carbon and is selected from the group consisting of gas, gas, / odorant cyanomethyl, methoxy, ethylthio, 2-methylthiol or dimethylamino. Ethylthio and hydrazine are 0_2; wherein R2 may be the same or different. -15- 'Paper ruler money country national standard (CNS$ii7210 X 297 mm) MM w MB * I ϋ 1 ϋ βϋ^dJ ϋ ϋ n ϋ ϋ II (Please read the back note and fill out this page) 1291960 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (13) Preferably R2 is attached to a ring carbon and is selected from the group consisting of bromine, cyano, methyl, methoxy, ethylthio, 2-hydroxyl Ethylthio or 2-dimethylaminoethylthio and m is 0 - 2; wherein R2 may be the same or different. Preferably, ring A and (R2)m form an imidazolium pyridine-3-yl group, pyrrole ruthenium [2,3a]p is more than yttrium-3-yl, 2-methyl imipen[i,2a]p -3 -yl, 2-methylmethyl sulfoxime]pyridine-3-yl or 2,5-dimethylimidazo[1,2&]pyridin-3-yl. In another object of the present invention, ring A is preferred to form imidazolium [ija] pyridin-3-yl, pyrrole [2,3a]pyridin-3-yl, 2-methylimidazolium [ija]pyridine-3 -yl, 2-methylpyrazolium]pyridin-3-yl, 2,5-dimethylimidazo[l,2a]p is more than -3--3-yl, 6-phenyl imipo[l , 2a]p is more than -3-yl, 2-methyl-6-methoxy imizan [l, 2a]p is more than -3-yl, 5-bromo π π[i, 2a] pyridine - 3-yl, 5-phenylthioimidazo[i,2a]pyridin-3-yl, 5-ethylthiomime[l,2a]pyridin-3-yl, 5-(2-hydroxyethylthio) Imidazolium with pyridin-3-yl, 5-p-cephen-2-ylthiomidine [i,2a]pyridin-3-yl, 5-cyanoimin [1,2a] Pyridin-3-yl or 5-(2-dimethylaminoethylthio)mizone[1,2&]indole-3-yl. In another object of the present invention, it is preferred that ring A and (R2)m form an imidazolium n, 2a] pyridin-3-yl or 5-(2.light-ethylthio)imidazolium [l,2a]pyridine. _ 3 _ base. Preferably, η is 0 or 1 and when η is 1, preferably R1 is attached to the 5_ position of the pyrimidine ring. Better η is 0. Preferably, R1 is halogen or Cw alkyl S(0)a wherein a is 0; wherein the Cl3 alkyl group may be substituted on the carbon by one or more J as appropriate; wherein j is a light group. More preferably, R1 is bromine or 2-hydroxyethylthio. • 16- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) - — — ^ — — Γ — — — — — -------- (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 --------————__B7_ V. Invention Description (14) Especially Rl is Creek or 2 The hydroxyethylthio group and η are 0-1. Preferably, the ring is phenyl or indanyl. Better % Β is winter base or printed with Qiao-based. In particular, the ring is phenyl. Preferably, R3 is a halogen or an amine sulfonyl group. More preferably, R3 is a fluorine, gas, bromine or amine cross. In particular, 疋R is a milk or amine continuation group. More particularly, R3 is an amine continuation base. Preferably, ρ is 0-2; wherein R3 may be the same or different. Preferably, p is a hydrazine in one of the objects of the present invention. Another object of the present invention is preferably 1). In still another object of the invention, preferably p is 2; wherein R3 may be the same or different. Preferably, R 舄 fluorine, gas, bromine or amine contiguous group; and p is 1. In still another object of the invention, when ring B is phenyl and p is 1, preferably R3 is attached to the position between the -NH- moiety of formula (I). Preferably Ra is hydrogen. Preferably, E is -NHSOr 〇 preferably R4 is a group of A-Ε·; wherein the oxime is optionally substituted on the carbon by one or more d and is selected from the group consisting of cM alkyl, phenyl, heterocyclic or phenyl 0 M base; E system chemical bond or · 〇., -c (0) _, -N (Ra) C (0) -, -S (0) r or N (Ra) SOr; where Ra is hydrogen, A Or an ethyl group and r is 0-2; D is an oxo group, a cyano group, a hydroxyl group, an amine group, an acid group, an amine methyl group, an amine sulfhydryl group, a Cm alkyl group, a C2.3 fluorenyl group, a C2_3 alkyne Base, CN3 alkoxy, q.3 alkane-17- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the phonetic on the back? Please fill out this page)

1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 V. Description of invention (15) Base, N-(C 〖·3 tiger base) amine group, n, n_(Ci•alkyl) 2 amine group, a·; Amidino group, N-(Ci-3 alkyl)amine carbenyl, n,n_(Ci-2alkylaminecarbamyl, alkyl S(〇)a wherein a is 〇 to 2, Ν· ( Cm alkyl) sulfonamide or N,N_ & More preferably, R4 is a group of AE-; wherein A is optionally substituted on the carbon by one or more D and is selected from the group consisting of c(mono)alkyl, phenyl, heterocyclyl or phenyl (:M alkyl; E-system chemical bond Or _〇_, _c(〇)_4-S(〇)r_; wherein ^ is 〇_2; D is hydroxy or hydrazine, Ν-β fluorenyl) 2 amine group. In particular, R4 is methyl, ethyl, methoxy, methylthio, methylsulfonyl, acetyl, 3-hydrazine, hydrazine-dimethylamino-2-hydroxypropoxy, 2-hydrazine, hydrazine- Ethylaminoethoxy, benzyloxy, anilinosulfonyl, pyrimidine-2-aminosulfonyl, phenoxy, 3,5-dioxohexahydropyridine . In another object of the invention, preferably R4 is a group of A-E_; wherein A is selected from the group consisting of Cw alkyl, phenyl, heterocyclic, Cm cycloalkyl, phenyl cμ alkyl, (heterocyclyl) a calcinyl or CM cycloalkyl C 6 alkyl group; wherein Ci6 alkyl, phenyl, heterocyclic, Cm cycloalkyl, phenyl C* alkyl, (heterocyclyl)alkyl or Cm cycloalkyl Cm The cycloalkyl group may be optionally substituted on the carbon with one or more d; and if the heterocyclic ring contains a -NH-based moiety, the nitrogen may optionally be substituted with a group selected; the E-system chemical bond or -〇-, -c (0) _, -Ν(Ι^)(:(〇)-, or _N(Ra)S〇r •, where Ra is hydrogen or Cl6 alkyl and 4〇·2; D is independently selected from hydroxyl group, Amine, Cl.6 alkoxy, N-(Ci6 alkyl)amine, N,N-(Cy alkylh amine, Cl-6 alkoxycarbonylamino or methoxycarbonyl-18) Use Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 --B7 V. INSTRUCTIONS (16) Amines; any Cy alkyl group may be substituted by one or more κ on carbon; K is selected from hydroxy or Diethylamine; and R is a Cw alkyl group. In another object of the present invention, preferably R4 is a group of A_E_; wherein A is selected from the group consisting of methyl, ethyl, propyl, pentyl, phenyl, pyrimidinyl, 3,5-diindanylpyridinyl, Cyclopropyl, benzyl, pyrrolidine 丨 基-ylethyl, hexafluent ρ bite · 1 · yl ethyl, p y y decyl ethyl, 3 · (2 · oxo p than Luodian _ 1-based)propyl, 3-imidazolium-1-ylpropyl, 2- morpholinoethyl, 3- morpholylpropyl, 2-anisin-4-ylethyl, 2-hexahydro-p ratio Cultivated 1-ylethyl, 3-hexahydropyridin-1 propylpropyl or cyclopropylmethyl; wherein hydrazine may be substituted on carbon by one or more D; and pyrrolidine-2 in it The base, imidazole-4-yl or hexahydropyridinyl-1 may be substituted on the nitrogen by a group selected from the group consisting of r; E-system chemical bond or _〇_, -c(0)·, _N(Ra)C (0)-, _S(0)r- or N(Ra)SOr; wherein Ra is hydrogen or cy-charged and r is 0-2; D-system is selected from the group consisting of a trans group, an amine group, a methoxy group, and a Amino, ethylamino, isopropylamino, hydrazine, hydrazine dimethylamino, N,N-diethylamino, butyloxycarbonylamino or benzyloxycarbonylamino; methyl, ethyl Any of isopropyl or tert-butyl can be viewed on carbon The case is substituted with one or more K; the K group is selected from a hydroxyl group or a diethylamine group; and R is a methyl group. In another object of the present invention, preferably R4 is methyl, ethyl, methoxy, methylthio, ethyl hydrazino, benzyloxy, methylsulfonyl, N,N•diethylaminoethoxy. , 3-N,N-monomethylamino-2-pyridyloxy, phenoxy, N-methylamine _ -19- This paper scale has been used in the National Standard of T (CNS) A4 specification (210 X 297 mm) -----r-------·! I Book·!----- (Please read the notes on the back and fill out this page) 1291960 A7 B7 Ministry of Economic Affairs Intellectual Property Office Printed by the employee consumption cooperatives. V. Description of the invention (17) Formyl, N,N-dimethylamine, mercapto, N-(3-amido-1-ylpropyl)amine, mercapto, N-[ 3-(2-oxopyrrolidin-1-yl)propyl]aminecarbamyl, 3,5-dihydrohexahydropyridin-1 -ylsulfonyl, N-cyclopropylaminesulfonyl, N- Cyclopropylmethylamine turmeric, anilino fluorenyl, N-feed-2-ylamine hydrazino, N-methylamine sulfonyl, N-propylamine sulfonyl, N-( 2-methoxyethyl)amine sulfonyl, N-(2-methylaminoethyl)amine sulfonyl, N-(2-isopropylaminoethyl)amine, N-(2- Dimethylaminoethyl)amine fluorenyl, N-(2-diethylamino) Amine, N-[2_(ethylethylamino)ethyl]amine, N-[2-(diethylaminoethyl)ethyl]aminesulfonyl, ν·(pyrrole Acridine-1·ylethyl)amine cross-branched, N-[2-(l-methyl-p-r-decyl-ethyl)ethyl]amine fluorenyl, Ν-(2-ΤΤhydrogen ρ ratio淀-1-ylethyl)amine fluorenyl, Ν-(2-hexahydrop ratio 1 (1 well-1-ylethyl)amine sulfonyl, fluorenyl-(2-morpholinoethyl)amine Sulfonyl, fluorenyl-(2-imidazol-4-ylethyl)amine sulfonyl, fluorenyl-(3-hydroxypropyl)amine sulfonyl, fluorene-(2,3-dihydroxypropyl)amine sulfonate Anthracenyl, fluorenyl-(3-methoxypropyl)amine sulfonyl, fluorenyl-(3-aminopropyl)amine sulfonyl, fluorenyl-(3-methylaminopropyl)amine sulfonyl, Ν-(3-dimethylaminopropyl)amine sulfonyl, fluorenyl-(3-diethylaminopropyl)amine sulfonyl, fluorenyl-(3-isopropylaminopropyl)amine sulfonyl, Ν-(3-t-butoxycarbonylaminopropyl)aminesulfonyl, fluorenyl-(3-benzyloxycarbonylaminopropyl)amine sulfonyl, fluorene-[3-(2-oxo) Ρρ比哈丁-1-yl)propyl]amine continuation base, Ν-(3-anlinylpropyl)amine sulfonyl, Ν-[3-(4-methylhexahydropyrazine-1 -propyl) propyl sulfonyl Ν-(3-Imidazolyl-1-yl)amine sulfonyl or fluorenyl (5-hydroxypentyl)amine sulfonyl. In another object of the invention, R4 is preferably Ν-methylamine sulfonyl , Ν-(2-methoxyethyl)amine sulfonyl, Ν-(2-methylaminoethyl)amine sulfonyl, Ν· (2-di-20- (please read the back note) Fill in this page again)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Ministry of Public Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291960 A7 __ B7 V. Inventions (18) Methylaminoethyl) Aminesulfonyl, N -(3-methoxypropyl)aminesulfonyl, N-(3-dimethylaminopropyl)aminesulfonyl or N-(3-isopropylaminopropyl)aminesulfonyl. Preferably R4 is methyl, ethyl, methoxy, methylthio, ethyl hydrazino, benzyloxy, methylsulfonyl, N,N-diethylaminoethoxy, 3_N,N-dimethyl Amino-2-hydroxypropyloxy, phenoxy, N-methylaminecarbamyl, N,N-dimethylaminecarbamyl, N-(3-imidazolyl-1-ylpropyl)amine A Sulfhydryl, N-[3-(2-oxopyrrolidin-1-yl)propyl]amine,carboxylidene, 3,5-dihydrohexahydropyridin-1-ylsulfonyl, N-cyclopropyl Aminesulfonyl, N-cyclopropylmethylamine sulfonyl, anilinosulfonyl, N-pyrimidin-2-ylsulfonyl, N-methylaminesulfonyl, N-propylamine Indenyl, N-(2-methoxyethyl)amine sulfonyl, N-(2-methylaminoethyl)amine, N-(2-isopropylaminoethyl)amine, N-(2-dimethylaminoethyl)amine sulfonyl, N-(2-diethylaminoethyl)amine sulfonyl, N.[2-(hydroxyethylamino)ethyl]amine sulfonate Mercapto, Ν·[2·(diethylaminoethyl)ethyl]amine sulfonyl, Ν-(pyrrolidin-1-ylethyl)amine sulfonyl, Ν-[2-(1 - A Pyryryryl-2-yl)ethyl]amine sulfonyl, fluorenyl-(2-hexapyridine-1-enylethyl)amine turmeric, Ν-(2- Ττ rat-violet ethyl)amine aryl, Ν-(2 ·morpholinylethyl)amine sulfonyl, N·(2-imidazol-4-ylethyl)amine sulfonyl, N-(3 -hydroxypropyl)aminesulfonyl, N-(2,3-dihydroxypropyl)aminesulfonyl, N-(3-methoxypropyl)aminesulfonyl, N-(3-amino Propyl) sulfonyl, N-(3.methylaminopropyl)amine sulfonyl, N-(3-dimethylaminopropyl)amine sulfonyl, N-(3 ·diethylamino Propyl)aminesulfonyl, N-(3-isopropylaminopropyl)aminesulfonyl, N.(3-butoxycarbonylaminopropyl)aminesulfonyl, N-(3-benzene Methoxycarbonylaminopropyl)amine sulfonyl, N_[ 3-(2-oxopyridinidine--21- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ϋ Li I ϋ IBBi ϋ 11 n ϋ ϋ 1 ϋ · ϋ ϋ · 言 (Please read the note on the back and fill out this page) _ 1291960 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (19 ) 1 -yl)propyl]amine sulfonyl, N-(3 ·morpholinylpropyl)amine sulfonyl, N-[3-(4-methylhexahydropyrazine-1 yl)propyl Aminesulfonyl, N-(3-imidazole-1 - propyl)aminesulfonyl or N-(5-hydroxypentyl)aminesulfonyl; and q is 1. Preferably q is 0-1. In one object of the invention, q is zero. In another object of the invention, q is one. In still another object of the invention, when ring B is phenyl and q is 1, preferably R4 is attached to the para position of the -NH- moiety of formula (I). Preferably, ring B, (R3)p and (R4)q form a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-phenylene group, a tris-phenyl group, 4--phenylphenyl, 3-bromophenyl, 3-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 -Methylthiophenyl, 4·methylthiophenyl, 4-methyldecylphenyl, 3-amine hydrazino, 4-amine decylphenyl, 3-ethylindolyl, 3,4- a class of i-winter, 3-disorder-4-gas phenyl, 2- gas-4-methylphenyl, 4-(3-N,N-dimethylamino- 2-#-based Propyl)phenyl, 4-phenyloxyphenyl, 4-anilinosulfonylphenyl, 4-(4-pyrimidin-2-ylsulfonyl)phenyl, 4-phenoxybenzene Base, 4·(2-Ν,Ν·diethylaminoethoxy)phenyl, 4-(3,5-dihydrohexahydropyridin-1·ylsulfonyl)phenyl or indanyl. In another object of the invention, more preferably, ring B, (R3)p& (11) forms a phenyl group, a 2-phenylene group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 3-phenylene group, and 3 - bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-methylthiophenyl, 3-ethenylphenyl, 3-ethylphenyl, 3-amine styrene benzene , 4-fluorophenyl, 4-oxophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-amine decylphenyl, 3-methyl-4-amine sulfonylbenzene Base, 4-(N-methylaminemethanyl)phenyl, -22- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 丨 — -- ------鮝-------- Order 1 (please read the note on the back and fill out this page) -------.% 1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 _____B7____ V. Invention description ( 2〇) Dimethylamine-mercapto)phenyl, 4-methylthiophenyl, 4-methylsulfonylphenyl, 4-(N-methylamine fluorenyl)phenyl, 4- (N -propylamine hydrazino)phenyl, 3-chloro-4-(N-propylaminesulfonyl)phenyl, 4-(N,N-diethylaminoethoxy)phenyl, 4- Benzyloxyphenyl, 4-phenoxyphenyl, 4- (N_ Cyclopropylamine sulfonyl)phenyl, 4-(N-cyclopropylmethylaminesulfonyl)phenyl, 4-(3,5-dioxin) Phenyl, 4-anilinyl contigyl phenyl, 4-(N-bromo-2-ylaminosulfonyl)phenyl, 4-[N-(2-methoxyethyl)amine sulfonate Thiol] phenyl, 3-ox-4_[N-(2-methoxyethyl)amine sulfonyl]phenyl, 3·methyl• 4 - [ N-(2-methoxyethyl) Aminesulfonyl]phenyl, 4-[N-(3-diethylaminopropyl)aminesulfonyl]phenyl, {N-[2-(l-methylpyrrolidin-2-yl)ethyl Aminosulfonyl}phenyl, 3-chloro-4-fluorophenyl, 3,4-dichlorophenyl, 2-chloro-4-methylphenyl, 4-(3-N,N-di Methylamino-2-hydroxypropoxy)phenyl, 4-[N-(3-hydroxypropyl)aminesulfonyl]phenyl, 4-{N-[3-(2-oxopyrrolidine-1 -yl)propyl]aminesulfonyl}phenyl, 4-[^4-(5-hydroxypentyl)aminesulfonyl]phenyl, 4-[indolyl(3-methoxypropyl)amine Sulfhydryl]phenyl, indole-5-ylamino, 4-[indolyl-(3-isopropylaminopropyl)aminesulfonyl]phenyl, 4-[indole-(2-isopropylamino) Acesulfonyl]phenyl, 4 · [Ν-(3 -imidazolyl-1-ylpropyl)amine Sulfhydryl]phenyl, 4_[Ν-(3-dimethylaminopropyl)aminesulfonyl]phenyl, 4-[indolyl(3-morpholinylpropyl)aminesulfonyl]phenyl , 3-methyl-4-[indolyl-(3-morpholinylpropyl)aminesulfonyl]phenyl, 4-[[3-(3-aminopropyl)aminesulfonyl]phenyl, 4- {Ν-[2-(Hydroxyethylamino)ethyl]amine sulfonyl}phenyl, 4-[Ν-(2-imidazolyl-4-ylethyl)amine sulfonyl]phenyl, 4-[ Ν-(3-methylaminopropyl)aminesulfonyl]phenyl, 4-[Ν-(2-hexahydropyrazine-1-ylethyl)amine sulfonyl]phenyl, 4 - [Ν - [3 - (4-methylhexahydropyrazine-1 -yl)propyl]amine sulfonyl]benzene___-23-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) --------------------- Order --------- (Please read the notes on the back and fill out this page) 1291960 A7 B7___ V , invention description (21) group, 4-[N-(2,3-dihydroxypropyl)amine sulfonyl]phenyl, -imidazolidinyl-1-ylpropyl)aminomethyl]phenyl, 4- [N-[2-(diethylaminoethyl)ethyl]aminesulfonyl]phenyl, 4-[N-[3-(2-oxopyrrolidine)-yl)propyl]amine A Thiol]phenyl, 4-[N-(2-dimethylamino) Ethyl)aminesulfonyl]phenyl, 4-[N-(2-morpholinylethyl)aminesulfonyl]phenyl, 3-methyl-4-[N-(2-norlinyl) Acesulfonyl]phenyl, 4-[N-(pyrrolidin-1-ylethyl)amine-methylmethyl]phenyl, 4-[N-(2-methylaminoethyl)aminesulfonate Phenyl, 4_[Ν·(2-hexahydropyridin-1-ylethyl)amine sulfonyl]phenyl, 4-[[Ν(2-diethylaminoethyl)amine sulfonyl] Phenyl, 4-[indolyl-(3-tert-butoxycarbonylaminopropyl)aminesulfonyl]phenyl, 4-[indolyl-(3-benzyloxycarbonylaminopropyl)amine sulfonyl Phenyl or 4-[indo-(3-diethylaminopropyl)amine sulfonyl]phenyl. In another object of the invention, the cycloheptyl, (R3)p(R4)q is formed to form 4-amine sulfonylphenyl, 4-(N-methylaminesulfonyl)phenyl, 4-[N -(2-methoxyethyl)aminesulfonyl]phenyl, 4-[N-(3-methoxypropyl)aminesulfonyl]phenyl, 4-[N_(3-isopropylaminopropyl) Acesulfonyl]phenyl, 4-[N-(3-dimethylaminopropyl)aminesulfonyl]phenyl, 4-[N-(2-dimethylaminoethyl)amine sulfonate Mercapto] phenyl or 4-[N-(2-methylaminoethyl)amine sulfonyl]phenyl. Accordingly, it is an object of the invention to provide a compound of the above formula (I) wherein: ring A is imidazolium [l,2a]pyridine-3-yl or pyrrole[2,3a]pyridine-3-yl; R2 is attached to the carbocyclic ring And selected from the group consisting of halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, amine mercapto, amine sulfonyl, Cw alkyl, C2-3, Ci_3 ^oxy, Ci_3 calcined base, Ci.3 calcined base, N-* (Cw alkyl) amine, hydrazine, Ν-β decyl) 2 amine, Cw alkanoamine, alkyl) amine Methyl hydrazide, hydrazine, hydrazine-β-decylalkyl) 2 amine carbaryl, Cw alkyl 8 (0\--24- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm 1 (please First read the notes on the back and then fill out this page) f ^? 111111 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291960 A7 B7___ V. Invention Description (22) where a is 0 to 2, N- (Cufe-based) amine continued Sulfhydryl and N,N-(Cu)-based 2 amine acid groups; (Please read the back of the note and fill out this page) m is 〇-2; where R2 may be the same or different; η is 0; Is phenyl or indane, R3 is halogen or amine sulfonyl; R4 is Α-Ε- Wherein hydrazine is substituted on carbon by one or more D and is selected from the group consisting of cM alkyl, phenyl, heterocyclic or phenyl CM alkyl; E is a chemical bond or -〇-, -C(O) -, -N(Ra)C(0)-, _S(0)r- or N(Ra)S02-; wherein Ra is hydrogen, methyl or ethyl; ρ is 0-2; wherein R3 may be the same or different D is an oxo group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an amine carbenyl group, an amine sulfonate group, a Ci_3:fe group, a C2-3 fluorenyl group, a C2_3 block group, an oxy group, a Ci_3 succinic acid , N-CCyalkyl)amino, anthracene, Ν-βυalkyl) 2 amine, CN3 alkanoyl, N-fw alkyl) amidyl, N,N-(C!_2 alkyl 2Aminomercapto, Cw alkyl S(0)a wherein a is 0 to 2, alkyl)amine sulfonyl or fluorene, Ν-β fluorenyl) 2 amine contig; q is 〇-1; R4 may be the same or different; the Intellectual Property Intelligence Bureau employee consumption cooperative prints or its pharmaceutically acceptable salt or in vivo hydrolysable ester. Therefore, another object of the present invention is to provide a compound of the above formula wherein: ring A is imidazolium [l, 2a] pyridin-3-yl or pyrrole [2,3a]pyridine-3-yl; R2 is attached to the carbocyclic ring and Cw alkyl; m is 0 - 2 ; where R2 may be the same or different; -25- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291960

5. Description of the invention (23) η马ο ; Β is phenyl or indole _5_ group; R3 is fluorine, chlorine, bromine or amine sulfonyl; ρ is 0 - 2; wherein R3 may be the same or different; R4 is methyl, ethyl, methoxy, methylthio, methylsulfonyl, ethyl, 3-indole, fluorenyl-dimethylamino 2-hydroxypropyloxy, 2-indole, hydrazine Ethylaminoethoxy, benzyloxy, anilinoyl fluorenyl, pyridinium-2-aminodiazonyl, phenoxy, 3,5-dihydrohexahydropyridin-1 -ylsulfonyl q is 0-1; wherein R4 may be the same or different; or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester. Therefore, a further object of the present invention is to provide a compound of the above formula (1) wherein: ring A and (R2)m form an imidazolium [i, 2a] pyridin-3-yl, pyrrole [2,3a] apurinyl- 3-yl, 2-methylimidazolium [l,2a]pyridin-3-yl, 2-methylpyrrole[2,3a]pyridin-3-yl or 2,5-dimethylimidazolium [l, 2a] pyridin-3-yl; η is 0; fluorene, (R3)p and (R4)q form phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-d-phenyl, 2- Chlorophenyl, 3-oxophenyl, 4-oxophenyl, 3-bromophenyl, 3-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 3-methoxyphenyl , 4-methoxyphenyl, 3-methylthiophenyl, 4·methylthiophenyl, 4-methylsulfonylphenyl, 3-amine phenyl, 4-amine benzene Base, 3-ethoxyphenyl, 3,4-diphenyl, 3-chloro-4-fluorophenyl, 2-nitro-4-methylphenyl, 4-(3-N, N_ Methylamino-2-hydroxypropoxy)phenyl, 4-benzyloxyphenyl, 4-anilinohydrophenyl, 4-(4-indolyl-2-carboxylic acid) Phenyl, 4-phenoxyphenyl, 4-(2-N,N-diethylaminoethoxy)phenyl, 4-(3,5- -26 - paper scale for China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page)

[291960

5. Description of the invention (24) Dihydrohexahydropyridin-1-ylsulfonyl)phenyl or indanyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Therefore, still another object of the present invention is to provide a compound of the above formula (I): wherein ring A is imipen[1,2a]pyridin-3-yl or pyrrole[2,3a]pyridine-3-yl; R1 is _ Or C10 alkyl S(0)a wherein α is oxime; wherein the C3-3 alkyl group may be substituted on the carbon by one or more j; wherein j is a hydroxyl group; η is 0-1; R2 is attached to the carbocyclic ring and is selected From halogen, cyano, Cm alkyl, Ci 6 alkoxy, Cw pit S(0)a wherein a is hydrazine, phenyl, phenylthio or (heterocyclyl)thio; wherein alkyl, phenyl Or a heterocyclic group may be substituted on the carbon, optionally with one or more hydrazines; wherein G is selected from the group consisting of light and dimethylamino; m is 0 - 2; wherein R2 may be the same or different; ring B is phenyl or R-5 is a fluorine, chlorine, bromine or sulfonyl group; p is 0-1; R4 is an AE- group; wherein A is selected from a group, a phenyl group, a heterocyclic group, a phenyl group, a pyridyl group, a (heterocyclyl) Cm alkyl group or a Gw cycloalkylcycloalkyl group; the oxime group, a phenyl group, a heterocyclic group, a Cw cycloalkyl group, a phenyl Cl-6 alkyl group, (heterocyclyl)Ci6 alkyl or C3·8 cyclic Cw cyclodecyl may be substituted on the carbon by one or more D as appropriate; Where the ring group contains a -NH- moiety, the nitrogen may optionally be substituted with a substituent selected from R; E is a chemical bond or _〇_, -C(0)_, -N(Ra)C(0)-, _s(〇 v or -N(Ra)SOr ; where Ra is hydrogen or alkyl and r is 〇·2 ; -27- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the back first) Note: Please fill out this page) ϋ I _1 ϋ I eamr ϋ One, I n 1 ϋ -ϋ ι Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Five DESCRIPTION OF THE INVENTION (25) D is independently selected from the group consisting of a hydroxyl group, an amine group, a Cl_6 alkoxy group, an N-((^-6 alkyl)amino group, an anthracene, a fluorene-(<^_6 alkyl) 2 amine group, a Cl_6 An alkoxycarbonylamino group or a benzyloxycarbonylamino group; wherein the Cm alkyl group may be optionally substituted with one or more K on the carbon; K is selected from a hydroxyl group or a diethylamino group; and R is a Cw alkyl group; q is 0 1 ; or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo. Therefore, a further object of the present invention is to provide a compound of the above formula (I) wherein: ring A is a miso [1, 2 a ] p ratio _ 3 - group; η is 0; ring Β is phenyl; R3 is Sulfhydryl; Ρ is 0 -1 ; R4 is Ν-methylamine sulfonyl, Ν_(2-methoxyethyl)amine sulfonyl, Ν-(2-methylaminoethyl)amine sulfonate , Ν-(2-dimethylaminoethyl)amine sulfonyl, Ν·(3-methoxypropyl)amine sulfonyl, Ν-(3-dimethylaminopropyl)amine sulfonate Or a hydrazone-(3-isopropylaminopropyl)amine continuation base; and q is 0·1; or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester. In another object of the invention, preferred compounds of the invention may be any of the compounds 丨_38 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. In another object of the invention, preferred compounds of the invention may be any of the compounds of Examples 1-98, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. In still another object of the present invention, the preferred compound of the present invention can be Example 7, -28 - (please read the note on the back side and then fill out this page) f tl —.—m〆_ This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1291960 A7 B7______ V. Description of the invention (26) Any of the compounds 39, 40, 52, 53, 55, 65, 68 and 86 or their pharmaceutically acceptable salts or in vivo Hydrolyzed ester. A preferred object of the invention is a compound of formula (1) or a pharmaceutically acceptable salt thereof. Another object of the invention is to provide a process for the preparation of a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein R1, R2, R3, R4, ring A, ring B are unless otherwise indicated , m, p, q & n as defined by the formula (1) ^) include: a) make the pyrimidine of formula (II): Γ% first read the back, note the matter and fill this page)

I I I I ---

Order ----------. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, where L is a substitutable group; reacts with the amine of formula (m):

b) The pyrimidine of formula (IV): -29- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 Α7 Β7 V. Instructions (27)

, (IV) and formula (VM complex reaction:

(Please read the notes on the back and then fill out this page) where one of the oxime and Q is a substitutable X and the other is a metal reagent Y; or c) a compound of formula (VI):

(VI) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, and the compound of formula (VII):

Where 115 is (: 1.6 alkyl and R6 is hydrogen or R1; -30- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) such as chlorine, stone or trifluoro 1291960 A7

V. INSTRUCTIONS (28) and subsequently if desired: 1) converting a compound of formula (I) to another compound of formula (1); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof . L is a substitutable group, and suitably L is, for example, a γ or a fluorenyloxy group, a bromine, a methanesulfonyloxy group or a toluene-4 sulfonyloxy group. The suitable substitutable group X of the earth is, for example, a sulfonyl or a sulfonyl group, for example, a thiol group. Suitable metal groups γ are, for example, copper, lithium, organoboron reagents such as -BCOPr1) 2 or -B(Et) 2 or organotin compounds such as SnBu 3 , organic ruthenium compounds such as Si(Me)F 2 , organozirconium compounds such as sink 13 Organic compound such as

AlEh, an organomagnesium compound such as MgBr, an organozinc compound such as ha or an organic mercury compound such as HgBr. The specific reaction conditions of the above reaction are as follows. a) The pyrimidine of formula (II) and the amine of formula (111) can be reacted together as follows: i) in a suitable solvent such as a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon = toluene, N-methylpyrrole In the presence of a pyridine, optionally in the presence of a suitable acid such as a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) and at a temperature of from 〇 ° C to reflux (preferably at reflux temperature); Or u) in standard Buchwald conditions (see, for example, Journal of the American Chemical Society 'Π8, 7215; Journal of the American Chemical Society, η9, material 5; Journal of Organic Chemistry, 62, 1568 and 6066), for example, in the presence of palladium acetate In a suitable solvent = aromatic solvent such as toluene, benzene or xylene, with a suitable base such as inorganic such as stone, or organic test such as third butanol, in a suitable ligand such as 2 2, cone (diphenyl) Phosphine)-1,1 in the presence of hydrazine and at a temperature of 25 to 8 〇X: (please read the notes on the back and fill out this page)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives -31 - 1291960 A7 V. INSTRUCTIONS (29) The pyrimidine of formula (II) can be prepared according to reaction scheme I (V)

Μ (Ila)

Cross-coupling conditions (ΪΙΙ) Reaction Scheme I wherein one of Μ and Q is a substitutable group x as defined above and the other is a metal reagent Y as defined above. Crosslinking coupling conditions are known to the skilled artisan. Suitable conditions include, for example, those listed in b) below. When ring A is imidazolium [i, 2a] pyridin-3-yl, the compound of formula (II) can also be prepared according to Reaction Scheme II: K is a suitable leaving group (for example Cm alkoxy), R6 is as defined above , y is 0-4, R7 is hydrogen or R2; q is a suitable leaving group (e.g., alkoxy) and R5 is as defined above. When ring A is pyrazolium [2,3a]pyridin-3-yl, the compound of formula (II) can also be prepared according to reaction scheme III: 〇 H h . (R2) n N

K IK.--------------------------- (Please read the details on the back and fill in the book again) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed (Mb) or

R7 醯化条件 Ε^Ο,ΊΉΡ

Δ -32- This paper size applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1291960 Δ7 A7 B7 V. Description of invention (30)

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

ΒαΟΗ, Δ reaction diagram II

Η20 Δ i) 1 cut person niq Na〇Me -33-

(Ilj) Δ

, R6, Q (please read the notes on the back and fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)) 1291960 A7 -- B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (31)

SMe

BuOE, Δ reaction diagram in . wherein R5, R6 and R7 are as defined above. Compounds of formula (Ilf) or (Ilk) may be further modified to obtain compounds of formula (IIn): (11〇 (Ilk)

(Ilm) Reaction Scheme IV It is well known to those skilled in the art that the compound of formula (IIn) can be modified by standard functional group modification reactions known in the art to obtain L wherein the leaving group is a gas such as gas, bromine, toluenesulfonyl and methylsulfonium. a compound of formula (II). The compounds of the formulae (Ila), (lib), (lie), (lid), (Ilh), (111) and (ΙΠ) are commercially available compounds or are known to the literature or can be prepared by standard methods known in the art. . b) Compounds of formula (IV) and (V) can be reacted under standard cross-coupling conditions. Its -34- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) iLLIIl·------ (Please read the note on the back and fill out this page) Order ·-- m· 1291960

BRIEF DESCRIPTION OF THE INVENTION (32) Examples are catalysts such as ruthenium (triphenylphosphine) palladium (ruthenium), vaporized palladium (π), palladium bromide (U), nickel (II) vapor, and nickel bromide (11). Or in the presence of gasified bis(triphenylphosphine)nickel (π) in a suitable inert solvent or diluent such as tetrahydrofuran, hydrazine, 'dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene In the presence of methanol or ethanol. This reaction is more effective in the presence of a suitable base such as sodium carbonate or potassium carbonate, pyridine, 4-methylamino or morpholine, and preferably at a temperature of, for example, 1 Torr to 25 ° C, preferably 60 to 120 °. C is carried out. The compound of formula (IV) can be prepared according to reaction scheme v. · Conditions for Process a) (Ha) (HI) (IV) Ministry of Economic Affairs Intellectual Property Office Employees' Cooperatives Print Reaction Chart V Compounds of formula (V) are commercially available compounds or known to the literature or may be borrowed from this technique Prepared by standard methods. The compounds of the formulae (VI) and (VII) can be reacted together in a suitable solvent such as N-methylpyrrolidone or butanol at a temperature of 100.20 ° C, preferably 150-170 ° C. The reaction is preferably carried out in the presence of a suitable base such as sodium methoxide or potassium carbonate. The compounds of formula (VI) and (VII) are commercially available compounds or are known to the literature or they may be prepared by standard methods known in the art, or the compounds of formula (VII) may be similar to the aforementioned pairs (Ilf) and (Ilk). The method is prepared. It is to be understood that certain of the various ring substituents of the compounds of the present invention can be introduced by standard aromatic substitution reactions or by customary functional group modification reactions which are produced separately from each other before or after the foregoing reaction, and are therefore included in the object of the process of the present invention. The reaction and the modification reaction include, for example, introduction of a substituent by an aromatic substitution reaction, reduction of a substituent, crystallization of a 5-alkyl group, and oxidation of a substituent. The reagents and reaction conditions for this procedure are well known to the chemical industry. Specific examples of aromatic substitution reactions include

(Please read the note on the back? Please fill out this page again)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 __ B7 V. INSTRUCTIONS (33) Introduce nitro group with concentrated nitric acid, using, for example, sulfhydryl _ and Lewis acid (such as Ilu, I) under Friedel Crafts conditions The acid group is introduced, and the alkyl group is introduced under the conditions of Friedel Crafts using a burnt-based halogen and a Lewis acid (such as aluminum tri-aluminum), and a halogen group is introduced. Specific examples of the modification reaction include hydrogenation of a nitro group to an amine group by, for example, catalytic hydrogenation with a nickel catalyst or heating and stirring treatment with iron in the presence of hydrochloric acid; oxidation of an alkylthio group to an alkylsulfinyl group or an alkylsulfonyl group. It is to be understood that in some of the foregoing reactions, any active group that protects the compound is desired. Suitable methods for protection and protection are known to those skilled in the art. Conventional protecting groups can be used according to standard procedures (see, for example, T. W. Green, Organic Synthetic Protecting Group, Johll & Sons, 1991). Therefore, if the reactant contains, for example, an amine group, a complex group or a radical group, it needs to be protected in some of the aforementioned reactions. Suitable protecting groups for the amine or amine group are, for example, a saccharide group such as a mercapto group such as an ethenyl group, a oxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarboxy group, an arylmethoxycarbonyl group such as benzyloxy. A carbonyl group or an aryl group such as a benzyl group. The deprotection conditions for the above protecting groups may vary depending on the protecting group selected. Thus, for example, a stilbene group such as an alkanoyl group or an alkoxycarbonyl group or an aryl fluorenyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. Alternatively, a mercapto group such as a third butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or citric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be, for example, a catalyst such as The carbon is hydrogenated or removed by treatment with a Lewis acid such as bis(trifluoroacetic acid) boron. Other suitable protecting groups for the primary amine are, for example, sulfhydryl groups which may be removed by treatment with an alkylamine such as dimethylaminopropylamine or with a hydrazine. Suitable protecting groups for the stalk base are, for example, sulfhydryl groups such as an anthracenyl group such as an ethenyl group, an aryl group such as a benzamidine group, or an arylmethyl group such as a benzyl group. The above protection base -36- (please read the notes on the back and fill out this page)

*· ), / y Z K 1υ μ ί Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1291960

DESCRIPTION OF THE INVENTION (34 The conditions for detachment vary depending on the protecting group selected. Thus, for example, a sulfhydryl group such as a aryl or aryl group can be removed by treatment with a metal hydroxide such as propylene or sodium hydroxide. An arylmethyl group such as a phenylhydrazine group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. Suitable protecting groups for the carboxyl group are, for example, esterifying groups such as those which can be removed, for example, by hydrolysis with a base such as sodium hydroxide. Or, for example, the third butyl group may be removed by acetic acid such as an organic acid such as trifluoroacetic acid, or the benzyl group may be removed, for example, by hydrogenation on a catalyst such as palladium-carbon. The protecting group may be synthesized at any stage. The compounds of the present invention have anti-cell proliferative activity, such as anti-cancer activity, which is believed to be derived from the CDK inhibitory activity of the compound. The properties can be determined by the following procedure. Evaluation. The following abbreviations are used for the analysis: - HEPES is N-[2 _hydroxyethyl]hexahydropyrazine_N'_ [2_ethanesulfonic acid] DTT is dithiothreitol PMSF is phenylsulfonylsulfonium fluoride This compound was used in an in vitro kinase assay in a 96-well format dish using scintillation proximity analysis (Scin Tillation proximity Assay) (SPA_ derived from the eight-body) test to measure the amount of [r-33-P]-adenine triphosphate incorporation into the test matrix (GST_retinal blastoma protein; GST-Rb). The test compound (diluted to the correct concentration with DMSO and water) was placed in each well, and roscovitine was placed in the control well as an inhibitor control group or DMSO as a positive control group. ___-37- This paper scale applies to Chinese national standards. (CNS) A4 size (210 X 297 mm) (Please read the notes on the back and fill out this page)

1291960 A7 _B7____ V. INSTRUCTIONS (35) (Please read the phonetic transcription on the back side and then fill out this page) Add about 0.2 μl of CDK2/cycline E fraction diluted in 25 μl of incubation buffer to each well. Purified enzyme (depending on enzyme activity) followed by addition of 20 μl of GST-Rb/ATP/ATP3 3 mixture (containing 0 · 5 μg GST-Rb and 0·2 μΜ ATP and 0·14 μ (: ί [ r -3 3-P]-adenosine triphosphate in incubation buffer), and the resulting mixture was gently shaken and then incubated at room temperature for 60 minutes. Then add 150 μL of (0.8 mg/well protein A-) to each well. PVT SPA beads (Amersham), 20 pM/well anti-glutathione transferase, rabbit IgG (from Molecular Probes), 6 ImM EDTA and 5 OmM HEPES pH 7·5 (containing 0.05% sodium azide) 150 μl of stop solution. The plate is sealed with Topseal-S disc sealant, placed for 2 hours and then rotated for 2 minutes at 2500, 111, 1124\8. The plate is read on each hole in Ding (^〇〇11]11: Take 30 seconds. The incubation buffer used to dilute the enzyme and matrix mixture contains 50 mM HEPES pH 7.5, 10 mM MnCl2, 1 mM DTT, ΙΟΟμΜ sodium vanadate, 100 μ Μ NaF, lOmM sodium glyceryl phosphate, BSA (final 1 mg/ml). Tested by the Ministry of Economics, Intellectual Property Office, Staff Consumer Cooperative, printed this analysis using only partial retinoblastoma protein (Science, March 13, 1987; 235 (4794): 1394-1399; Lee WH·, Bookstein R·, Hong F·, Young LJ·, Shew JY·, Lee Ε·Υ·), fused to GST tag. Encoding amino acid 379-928 PCR of the retinoblastoma gene (derived from retinoblastoma plastid ATCC pLRbRNL) and sequenced into the pGEX 2 T fusion vector (Smith DB and Johnson, KS gene 67, 31 (1988); The tac promoter for performance, for any large-38-^ paper scale applicable to China National Standard (CNS) A4 specification (210>< 297 mm) A7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291960 ___B7___ V. Description of the Invention (36) The internal lac Iq gene of the Enterobacteriaceae host, and the coding gene for thrombin cleavage - available from Pharmacia Biotechnology, was used to amplify the amino acid 792-928. This sequence was re-sorted to pGEX 2 T. The resulting retinoblastoma 792-928 sequence was expressed in E. coli (BL21 (DE3) pLysS cells) using standard burst expression techniques and purified as follows. 0 E. coli paste was resuspended in 10 ml/g NETN buffer (50 mM Tris) pH 7·5, 120 mM NaCl, 1 mM EDTA, 0.5% ν/ν NP_40, 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and 1 μg/ml pepstat) and each 100 ml homogenized sound vibration 2 X 45 seconds. After centrifugation, the supernatant was loaded onto a 10 ml glutathione agarose column (Pharmacia Biotech, Hert, UK) and washed with NETN buffer. Protein washed with kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and 1 μg/ml pepstatin) Dilute with 50 mM reduced glutathione kinase buffer. GST-Rb (792-927) fractions were collected and buffered for kinase dialysis overnight. The final product was analyzed by sodium dodecyl sulfate (SDS) PAGE (polyacrylamide gel) using an 8-16% Tris-glycine gel (Novex, Chicago, USA).

CDK2 and cyclin E use HeLa cells and activated T cell mRNA as a template for reverse transcriptase-PCR to separate CDK2 and cyclin E from the open reading frame and to the insect expression vector PVL1393 (from Invitrogen 1995 green number V1392) -20). Then CDK2 and Cyclin E are in the insect SF21 cell system (derived from the autumn night snail moth ovary -39- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back first) Fill in this page)

1291960 A7 B7 V. INSTRUCTIONS (37) Secondary performance in the tissue of the planted grassworm (Spodoptera Frugiperda cells) [using the standard virus Baculogold co-infection technique]. (Please read the note on the back of the page and then fill out this page.) Alizarin E/CDK2 Manufacturing Example The following examples are provided for SF2 1 cells with double infection M0I3 for each of the cyclic E and CDK2 viruses (at TC100 + 10% FBS ( Details of the manufacture of cyclin E/CDK2 in TCS) + 0.2% Pluronic). SF21 cells grown to 2.33 X 106 cells/ml in tumbling flask medium were inoculated with a 10x500 ml roller bottle at 0.2X10E6 cells/ml. The roller bottle was incubated at 28 °C on a roll assembly. After 3 days (72 hours), the calculated cells and 2 bottles averaged 1.86 X 10E6 cells/ml (99% survival). The medium was then infected with each virus with a double virus of MOI 3. The virus was mixed before adding to the medium and the medium was transferred back to a 2 8 °C rolling device. After 2 days (48 hours), 5 liters of medium was collected. The total number of cells received was 1.58 X 10E6 cells/ml (99% viable). The cells were spun in a Heraeus Omnifuge 2.0 RS at 2500 rpm for 30 minutes at 4 °C in a 250 ml batch. Discard the supernatant. Part of CDK2 and cyclin E co-purification Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed SF2 1 cells resuspended in lysis buffer (50 mM Tris pH 8.2, 10 mM MgCl2, 1 mM DTT, 1 mM glyceryl phosphate, 〇·1 mM Sodium orthovanadate, 0 · 1 mM NaF, 1 mM PMSF, 1 μg/ml leupeptin and 1 μg/ml aprotinin) and homogenized for 2 minutes in a 10 mL Dounce homogenizer. After centrifugation, the supernatant is loaded onto a Poros HQ/M 1.4/100 anion exchange column (PE-40-) This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 Δ7 Α7 Β7 V. Description of the Invention (38) (Please read the notes on the back and fill out this page) System, Hertford, UK). The initial gradient of 0 - 1 M NaCl (performed in the dissolution buffer minus the protease inhibitor) was co-dissolved with CDK2 and cyclin E for 20 minutes. Co-dissolution was observed by Western blotting using anti-CDK2 and anti-cycline E antibodies (Santa Cruz Biotechnology, California, US). Similarly, the architecture design can be used to obtain analysis of CDK4 and CDK6. CDK2 (EMBL Registry No. X62071) and Cyclin A or E (see EMBL Accession No. M73812) can be used together, and the details of this analysis are contained in PCT International Bulletin No. W0 99/21845, the relevant biochemical and biological assessment paragraphs For reference herein, although the pharmacological activity of the compound of the formula (1) varies depending on the structure, the activity of the compound of the formula (1) usually has an IC5G concentration or a dose of 250 μM to 1 nM and proves to be 0 when tested in the above in vitro assay, Example 1 1 The CDK2 inhibitory activity was measured by Ι(:5〇=0·19μΜ and Example 12 (Ι5〇=0·17μΜ. The in vivo activity of the compound of the present invention can be measured by standard techniques such as measuring cell growth inhibition and evaluating cells. Toxicity analysis. The Department of Economic Intelligence's Intellectual Property Office employee consumption cooperative prints cell growth inhibition by Sulforhodamine B (SRB), a protein dyed fluorescent dye to stain cells and thus obtain a predicted amount of protein in the hole (ie, cells) (See Boyd, MR (1989) NCI Preclinical Antitumor Drug Discovery Screening, Prin. Prac Oncol 10: 1-12). The following details are used to measure cell growth inhibition. - The cells are plated in a suitable medium of 100 ml volume in a 96-well plate; the medium for MCF-7, SK-UT-1B and SK-UT-1 is Dubeck-modified Eagle's medium. The cells are attached overnight and then added to 1 % DMSO (v/v) Maximum Concentration -41 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 B7

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. 5. Various inhibitor compounds in the description of the invention (39). The control plate was analyzed to obtain cell sputum before administration. The cells were incubated for 3 days at 37 ° C (5% CO 2 ). After three days, TCA was added to the dish to a final concentration of 16% (v/v). The plate was then incubated at 4 °C for 1 hour, and the supernatant and tray were removed and washed with tap water. After drying, 100 ml of SRB dye (〇·4% SRB in 1% acetic acid) was added for 3 minutes at 37 Torr. Excess SRB was removed and the dish was washed in 1% acetic acid. The SRB bound to the protein was dissolved in 10 mM Tris pH 7.5 and shaken at room temperature for 3 minutes. The 〇Ds was read at 540 nm and the concentration of the self-inhibitor versus absorbance half-log plot was determined as the inhibitor concentration that caused 50% inhibition of growth. The concentration of the compound which lowers the optical density to a density lower than that at the start of the cell experiment on the disk gives cytotoxicity. Typical IC5 〇値 of the compounds of the invention tested in the SRB assay ranged from j mM to 1 nM. Another object according to the invention is to provide a pharmaceutical composition comprising a pyrimidine derivative of the formula (I) as defined above, or a pharmaceutically acceptable or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable diluent or carrier. According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable or in vivo hydrolysable ester thereof, as hereinbefore defined, and a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral administration, such as a lozenge or capsule, suitable for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or irrigation/main) such as sterile solutions, suspensions or emulsions. It is suitable for local administration such as ointment or cypress, suitable for rectal fungus such as test. Generally, the above compositions can be prepared in a conventional manner using conventional excipients. I «^1 n· 1 n mm— n ϋ n · w mm mm mm 喔 mm am μη mm (Please read the notes on the back and fill out this page again) -42·

Ϊ291960

V. Description of invention (4〇) The Intellectual Property Office of the Intellectual Property Bureau of the Ministry of Economic Affairs prints the compound of formula (I). The compound is generally administered to a warm-blooded animal in the range of 5-5 mg per square meter of animal area, that is, about 01-100. Mg/kg, and this generally provides a therapeutically effective amount. A unit dosage form such as a troche or capsule usually contains, for example, 丨250 mg of the active ingredient. It is better to use a daily dose of b5 〇 mg / kg. However, the daily dose will vary with the host to be treated, the particular route of administration, and the severity of the condition being treated. Accordingly, the optimum dosage can be determined by the physician treating the particular patient. A further object according to the invention is to provide the use of a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for the treatment of a human or animal method. It has been found that a compound of the present invention or a pharmaceutically acceptable salt thereof or in vivo hydrolyzable is an effective cell cycle inhibitor (anti-cell proliferation agent) whose properties are derived from its CDK inhibitory properties. The compounds according to the invention are contemplated for use in the treatment of a disease or medical condition modulated only by CDK enzymes, and the compound and the compound produce a CDK inhibitory effect in a warm-blooded animal in need of such treatment. The compounds of the present invention therefore provide a method of treating malignant cell proliferation characterized by inhibition of CDK enzyme, i.e., the compound can be used to produce an anti-proliferative effect modulated only by or in part by CDK inhibition. The compounds of the invention are expected to possess a wide range of anti-cancer properties, as CDKs are associated with many common human salts such as leukemia and breast cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer, bladder cancer, pancreatic and ovarian cancer. It is therefore expected that the compounds of the invention will have anticancer activity against these cancers. Furthermore, it is expected that the compounds of the present invention are provided against leukemia, lymphoid malignant and solid tumors such as carcinomas in tissues and sarcomas such as liver, kidney, prostate and pancreas. In particular, the compounds of the invention are expected to advantageously alleviate major and recurrent solid swellings such as colon, breast, prostate, lung and skin - 43 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please first Read the note on the back? Then fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 __ B7 V. Invention Description (41) Growth of the tumor. More particularly, the compounds of the invention, or pharmaceutically acceptable cancers or in vivo hydrolysable esters thereof, are expected to inhibit the growth of major and recurrent solid tumors associated with CDKs, particularly tumor growth and expansion associated with CDKs, including, for example, certain Tumors of the colon, breast, prostate, lung, vagina and skin 0 It is also expected that the compounds of the invention will carry activity against other cell proliferative diseases of a wide range of other disease states, including leukemia, fibroproliferation and differentiation disorders, cognac, rheumatism Arthritis, Kaposi's sclerosis, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, bone disease, and retinal vascular proliferation. Thus according to the present invention there is provided a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above, for use as a medicament; and a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof or hydrolyzable in vivo Esters are used in the manufacture of medicines for producing cell cycle inhibition (anti-cell proliferation) effects in warm-blooded animals such as humans. In particular, by inhibiting the action of CDK2, CDK4 and/or CDK6, especially CDK2, prevention of entry or development via s phase produces an inhibitory effect. According to another feature of the invention, there is provided a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in the treatment of cancer (solid tumors and leukemia), fibroproliferation and differentiation disorders, dryness, rheumatism Medical use of arthritis, Kaposi's cirrhosis, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, bone disease and retinal tube proliferation . Therefore, according to the present invention, a warm-blooded animal such as a human in need of such treatment is provided - 44- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note first and then fill out this page) )

1291960

DESCRIPTION OF THE INVENTION A method for inhibiting the effect of cell cycle inhibition (anti-cell proliferation) comprises administering to the animal a chemically deliberate compound. In particular, the inhibition is effected by inhibiting the action of Cdk2, CDK4 and/or CDK6, especially CDK2, or by the development of 8-phase. As stated, the size of the dose required to treat or prevent a particular cell proliferative disorder will vary with the host to be treated, the route of administration, and the severity of the condition to be treated. The unit dose can be, for example, M 〇〇 mg/kg, preferably mg/kg. The CDK inhibitory activity as described herein may be treated alone or in addition to the compounds of the invention in one or more other substances and/or treatments. This combination therapy can be achieved by administering the individual compounds of the treatment simultaneously, sequentially or separately. In the field of medical oncology, normal operating systems use a combination of different treatments to treat patients with cancer. In addition to the cell cycle inhibition therapy defined above, the other components of this combination therapy may be: surgery, radiation therapy or chemotherapy. This chemotherapy may comprise three main classes of therapeutic agents: (1) other cell cycle inhibitors with the same or no ketone mechanism as defined above; (ii) cytostatic agents such as antiestrogens (eg tamoxim (tam) 〇xifen), toremifene > raloxifene, droloxifene, 〇 〇 〇 xy fene, progesterone With ethyl salt), aromatase inhibitors (such as amine scavenger (anastr〇z〇le), letrazole, voraz〇ie, its exemestane), anti-pregnancy _ , anti-androgen (such as flutamide, niluta-45- this paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 mm) " — — — ^----- -- (Please read the notes on the back and fill out this page) Order -------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 B7 V. Invention Description (43) (Please read the back Precautions fill in this page) (nilutamide), bicalutamide, propylene progesterone acetate, LHRH agonists and antagonists (if Goserelin acetate, luprolide, testosterone 5 from-dihydroreductase inhibitors (eg non-sodium), anti-invasive agents (eg metalloproteinase inhibitors such as horsepower) (marimastat and urokinase plasminogen activator receptor function) and growth factor regulatory inhibitors (this growth factor comprises, for example, platelet-derived growth factor and hepatocyte growth factor. This inhibitor comprises growth factor antibody, growth factor Receptor antibody, tyrosine kinase inhibitor and serine/threonine kinase inhibitor; and Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed (iii) anti-proliferative/anti-tumor drugs and their combinations, if used In the field of medical oncology, such as antimetabolites (such as antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenine analogs, cytosine arabinose); antitumor antibiotics (such as anthracycline) Such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin C, dactinomycin, radiance Mithramycin; platinum derivatives (such as cisplatin, carboplatin); alkylating agents (such as nitrogen mustard, melphalan, chlorambucil) , busulphan, cyclophosphamide, ifosfamide, nitrosourea, thiotepa; anti-mitotic agents (such as vinca sulphate such as Changchun new test and plum-like pine Such as the yew test, it is taxotere; topoisomerase inhibitors (such as epipodophyllotoxins such as etoposide and teniposide, arsacrine) ), Topotecan (topotecan). In accordance with the purpose of the present invention, a pharmaceutical combination is provided -46 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 1291960

5. Description of the invention (44), comprising a compound of formula (1) as defined above and other anti-tumor substances as defined above for use in the combined treatment of cancer. In addition to its therapeutic use, the compound of formula (1) or its pharmaceutically acceptable f-salt can also be used as a development and in vitro evaluation of the effects of inhibitors of cell cycle activity in experimental animals such as sera, dogs, rabbits, monkeys, rats and rats. A pharmacological tool standardized in the body system as part of the study of new therapeutic drugs. The other therapeutic compositions, processes, methods, uses, and pharmaceutical manufacturing characteristics described above can also be applied to other and preferred embodiments of the compounds described herein. EXAMPLES The invention will now be illustrated by the following non-limiting examples, wherein unless otherwise indicated: (1) The temperature is in degrees Celsius (°c); the operating system is carried out at room temperature or ambient temperature, i.e., at a temperature of about 18-25 ° C; The organic solvent is dehydrated with anhydrous magnesium sulfate; the solvent is evaporated using a rotary evaporator at a reduced pressure (600-4000 Pascal; 4.5-30 mmHg) bath temperature of 60 ° C; (iii) Chromatography means fast on the silicone Chromatography; thin layer chromatography (TLC) is performed on the crushed rubber sheet; and the crushed B〇nd Elut column represents a column containing 1 g or 20 g of 40 μm particle size gel, and the tannin is contained in 6〇. The milliliter can be discarded in the syringe and supported by the porous disk 'from the Varian trade name "Mega Bond Elut SI" in the port city of California, USA, "Mega Bond Elut" as the trademark; (iv) the usual reaction process by TLC tracking and reaction time is only used (v) The final product has satisfactory proton nuclear magnetic resonance (Nmr) spectroscopy and/or mass spectrometry data; -47- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please Read the phonetic on the back? Please fill out this page again)

1291960 A7 B7 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing Methyl Ethyl Group; V. Description of Invention (45) (vi) The yield is for illustrative purposes only and may not be obtained through hard work; if more substances are needed Repeated preparation; (vii) The primary identification of protons when providing NMR data is expressed in parts per million (ppm) relative to the internal standard tetramethyl ruthenium (TMS), using the dimethylated dimethyl amide (DMSO-dd is tested as a solvent at 3 〇〇mHz unless otherwise stated; (viii) chemical symbols have their general meaning; SI units and symbols are used; (ix) solvent ratio is volume·volume (v/v); And (X) mass spectrometry is performed using a direct exposure probe in a chemical ionization (CI) mode with electron energy at 70 volts; the ionization shown is by electron impact (EI), fast atom bombardment (FAB) Or electrospray (Esp); expressed in m/z ;; usually only ions of major mass are reported; (xi) compounds containing asymmetrically substituted carbon and/or sulfur atoms are not resolved unless otherwise stated; (xii) When the synthesis is described as similar to the previous examples, the amount used is the foregoing The molar equivalents used in the examples; (xvi) the following abbreviations are used: NMP 1 -methyl-2 _ p is the same as p; DMF N,N-dimethylformamide; DMFDMA N, N·2 Methylformamide DMSO dimethyl sulfoxide; THF tetrahydrofuran; and EA elemental analysis. Example 1 -48- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm (please read the back of the note first) Please fill out this page again) Order: 1291960 A7 B7 V. Description of invention (46) g-(3-Chloroanilino)-4 - (2 ·methylimidazole # n,2alpyridine-ϋ The bite will be hydrogenated under nitrogen Steel (236 mg of 60% mineral oil suspension, 5 9 mmol) was added to a NMP (10 mL) / guest solution containing 3- aniline (496 mL, 4.7 mmol). Mix for 3 〇 minutes, and add (2-methyl sulphate and [1,2a] p than -3-yl)-2·methylthio p-precipitate (method ι) (6 〇〇 gram A solution of '2.3 millimolars' of NMP (2 ml). The mixture was heated at 15 Torr for 3 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined extracts were dehydrated and evaporated. The volatiles were removed, and the residue was dissolved in ethyl ethionate/hexol (1:1) and purified by chromatography with the polarity increasing to ethyl acetate/methanol (9 7:3). The purified product was acetic acid and The desired compound (1 · 5 9 mg, 21 %) was obtained by hexanes, </ RTI> </ br> </ br> </ br> </ br> </ br> Dd, 1H), 7.42 (dd, 1H), 7.59-7.64 (m, 2H), 8·02 (s, 1H), 8.55 (d, 1H), 9.72 (d, 1H), 9.84 (s, 1H) Example 2 - 1 2 (Please read the notes on the back and fill out this page) Order---------· The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints the steps of repeating example 1, and uses appropriate Starting material, the following compound 0 was prepared as an example compound NMR m/z [ΜΗΓ 2 2- (4-aminosulfonylanilino(2-methylimidazolium [l,2a]pyridine-3-yl)pyrimidine 2.64 (s , 3H), 7.05 (dd, 1H), 7.15-7.20 (m, 3H), 7.44 (dd, 1H), 7.64 (d, 1H), 7.74 (d, 2H), 7.92 (d, 2H), 8.68 (d, 1H), 9.75 (d, 1H) 381 -49- This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1291960 A7 B7 V. Description of Invention (47) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 31 2-anilino-4-(2-methylimidazolium [l,2a]pyridine-3- Pyrimidine 2.64 (s, 3H), 6.92-7.00 (m, 2H), 7.08 (d, 1H), 7.30 (dd, 1H), 7·40 (dd, 1H), 7·60 (d, 1H) , 7.72 (d, 2H), 8.50 (d, 1H), 9.60 (s, 1H), 9.75 (d, 1H) 302 4 2-(4 · milylamine)-4-(2-methylimidazolium) [l,2a]pyridin-3-yl)pyrazine 2.75 (s,3H), 6.82 (dd,1H), 7.01 (d,1H), 7.22 (br s, 1H),7·30 (m,3H) , 7.60 (m, 2H), 8.47 (d, 1H), 9.53 (d, 1H) 336 51 2-(3-anilino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 7.02 (d,1H), 7.12 (dd,1H), 7.30 (dd,1H), 7.42 (d,1H), 7.50 (dd,1H), 7.60 (d,1H), 7.75 (d,1H),8.00 (s,1H), 8.48 (d,1H), 8.61 (s,1H), 9.82 (s,1H) 322 61 2-(3,4-diacetylamino)-4-(isoxazole) , 2a]pyridin-3-yl)pyrimidine 7.15 (dd,1H), 7.50 (dd, 2H), 7.58 (d,1H), 7.65 (dd, 1H), 7.78 (d,lH), 8.22 (d, 1H) ),8. 50 (d,1H), 8.62 (s, 1H), 9.95 (s,1H) 7 2-(4-Aminesulfonylanilino)-4-(imidazolium [l,2a]pyridin-3-yl) Pyrimidine 7.20 (d, 3H), 7.55 (d, 2H), 8.80 (d, 3H), 8.95 (d, 2H), 8.50 (d, 1H), 8.68 (s, 1H), 10.05 (s, 1H), 10.10 (d,1H) 367 -50- —^---------------Book---------. (Please read the notes on the back and fill out this page. ) mg This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 A7 B7 V. Invention description (48) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 81 2-(3 - gas - 4-Az-anilino)-4-(isoxazole[1,2a]pyridin-3-yl)pyrimidine 7.14 (dd,1H),7.32-7.55 (m, 3H), 7.60 (dd,1H), 7.78 ( d, 1H), 8.10 (dd, 1H), 8.48 (d, 1H), 8.62 (s, 1H), 9.82 (s, 1H) 340 9 2-(2-anilino)-4-(taste spit) [l,2a]pyridin-3-yl)pyrimidine 7.08 (dd,1H), 7.17 (d,1H), 7.37 (m,2H), 7.48 (dd,1H), 7.51 (br s,1H), 7.62 ( d, 1H), 7.76 (d, 1H), 8.30 (s, 1H), 8.40 (m, 1H), 9.81 (d, 1H), 9.94 (dd, 1H) 322 10 2-(2- -4-methylanilino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 2.38 (s,3H), 6.91 (dd,1H), 7.14 (d,lH), 7.28 (br s, 1H), 7.38 (m, 2H), 7.61 (s, 1H), 7.73 (d, 1H), 8.16 (d, 1H), 8.28 (s, 1H), 8.40 (d, 1H), 9.78 (d ,1H) 336 II1 2-[4·(3,5-dihydrohexahydropyridin-1-yl)amine cross-branched oxime]-4-(isoxazole[l,2a]pyridin-3-yl Pyrimidines 4.87 (s, 2H), 5·20 (s, 4H), 7.16 (dd, 1H), 7·51 (d5 2H), 7.75 (d, 1H), 7.83 (d, 2H), 7.98 (d , 2H), 8.50 (d, 1H), 8.64 (s, 1H) 439 12 1,2 2-[4-(2-diethylaminoethoxy)anilino]-4-(imidazolium) , 2a] pyridin-3-yl) shouting 0.98 (t, 6H), 2.50-2.62 (m, 4H), 2.78-2.82 (m, 2H), 4.00 (t, 2H), 6.84 (dd, 2H) , 7.08 (dd,1H), 7.38 (d,1H), 7.48 (dd,1H), 7.60 (s,2H), 7.75 (d,1H), 8.38 (d,1H), 8.59 (s, 1H), 9.42 (s, 1H) 403 1 Replace sodium hydride with sodium bis(trimethyldecyl) decylamine (1 M in THF). -51 - II卜—i------- (Please read the note on the back and fill out this page) 11111111 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 - - -__B7___ V. Inventive Note (49) 2 The product was purified by chromatography and purified by dichloromethane/methanol (1 〇〇: 〇 to 80:20), with diethyl ether and hexanes, and collected by filtration. . (Please read the precautions on the back and then fill out this page.) Example 1 3 U 4 · (3 - Dimethylamine. 碁--2 · Hydroxypropoxy) Aniline 4 _ (Azlactone 幷 um p 3-(3-dimethyl)-2-dimethylamino-2-carbopropoxy)aniline (497 mg, 1.76 mmol) (Method 11) and cyanamide (185 mg, 4.4 mmol) The mixture of NMP (1 ml) of the ear was heated at 160 ° C for 30 minutes. Then add 3-(3-methylaminoprop-2-en-diindole) imidazolium [l,2a]pyridine (method 5) (400 mg, 1.76 mmol) and sodium methoxide (183 mg, 3.5 mmol) 1) Butanol (1 ml) mixture, and the mixture was heated under reflux for 3 hours. The mixture was cooled and the residue was purified EtOAcjjjjjjjj NMR: 2.35 (s, 6H), 2·40-2·63 (m, 2H), 3.82-4.02 (m, 3H), 6.90 (d, 2H), 7.06 (dd, 1H), 7.30 (d5 1H) , 7.50 (dd, 1H), 7.59 (s, 2H), 7.74 (d, 1H), 8.38 (d, 1H), 8·58 (s, 1H), 9.42 (s, 1H); m/z : 405 [MH]+. fjiXAzll- Repeat the steps of Example 13 and use the appropriate starting materials to prepare the following compounds. 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed -52- ί Paper Scale Applicable to China National Standard (CNS) A4 Specification (210x297 public 1291960 A7 ____ — B7 V. DESCRIPTION OF THE INVENTION (50) Example compound NMR m/z [MH] + 141 2-[4-(3-dimethylamino-2-hydroxypropanyl)anilino]-4-(2-A The base ρ is more than [2,3a] p than the -3-yl). 2.20 (s, 6H), 2, 26-2·45 (m, 2H), 2.65 (S, 3H), 3.80-3.95 (m,3H), 4.80 (s,1H),6·88 (d,2H), 7.00 (d,2H),7·38 (dd,lH),7·60 (d,2H),8.38 (d , 1H), 8.44 (d, lH), 8.65 (d, 1H), 9.21 is, 1H) 419 152 2·[4-(3-dimethylamino-2-pyridyloxy)anilino]- 4-(2-methylimidazolium [l,2a]pyridin-3-yl)pyrimidine 2.63 (s,3H),2·80 (s,6H), 3.12-3.26 (m,2H), 4.27 (br s ,1H),5·93 (br s,1H), 6.90-7.04 (m,4H), 7.40 (t, 1H), 7.60 (dd,2H), 8.45 (d, 1H), 9045 (s, 1H) , 9·73 (d, 1H) 419 1 product was purified by chromatography with di-methane/hexane (1 ··丨And the polarity is increased to di-methane/methanol/triethylamine (96:4:0.5). The product was purified by chromatography, eluted with dioxane/methanol/triethylamine (96:4: EtOAc) and recrystallised from acetonitrile/methanol. EXAMPLES 1 6 - 3 6 The following examples were prepared, purified and characterized by the following general procedure: Sodium bis(trimethyldecyl) decylamine (2.05 mL of 1 THF in THF, 2.05 mmol) under nitrogen. Add to a solution containing aniline (丨.65 mmoler rnmp (1.5 ml). The mixture was stirred at ambient temperature for 3 minutes, and added with 4-(imidazolium [l,2a]pyridin-3-yl) -2 -Methylthiopyrimidine (Method 4) (200 mg, 0.83 mmol) of NMP solution. The reaction mixture was heated at 150 ° C for 2.5 hours. The solvent and volatiles were removed by evaporation. Acetic acid ------53- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). - ί·. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291960 A7 B7 V. Invention Description (51) (Please read the note on the back and fill out this page) Ethyl ester, followed by ethyl acetate/methanol (9 7 : 3), finally purified by elution with ethyl acetate/methanol (97:3). The reaction product was made on a 46 mm X 10 cm Hichrom RPB 100A column. Water / acetonitrile / formic acid (9 5 : 5 : 〇 · 1 total 1 · 5 minutes ' followed by 10 minutes gradient to 5 : 9 5 : 0.1) at a flow rate of 1 · 0 ml / min and example compound HPLC retention time (minutes) m/z [MH] + 16 2·anilino-4-(imidazolium[1,2a]pyridin-3-yl)pyrimidine 7.26 288 17 2-(2-fluoroanilino)-4-(imidazolium) , 2a]pyridin-3-yl)pyrimidine 7.26 306 18 2·(3-bromoanilino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 8.30 368 19 2-(3-Fluoroaniline 4-(imidazolium [l,2alpyridin-3-yl)pyrimidine 7.70 306 20 2-(3-methoxyanilino)-4-(imidazolium [l,2a]pyridin-3-yl) Pyrimidine 7.39 318 21 2-(3-methylthioanilino)-4-(imibulin [1,2a] p ratio-3-yl) pyrimidine 7.98 334 22 2-(3-ethylmercaptophenyl) -4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 7.13 330 23 2-(3-ethylanilino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 8.11 316 24 2-(4-Fluoroanilino)-4-(imidazolium [1,2a]pyridin-3-yl)pyrimidine 7.47 306 25 2-(4-anilinoyl)-4-(imidazo[1, 2a]pyridin-3-yl)pyrimidine 8.15 322 26 2-(4-methoxyanilino)-4-(imidazolium) 2a]pyridin-3-yl) 口密盐7.02 318 27 2-(4-Benzyloxyanilino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 8.65 394 28 2-[ 4-(anilinosulfonyl)anilino]-4-(imidazolium[l,2a]pyridin-3-yl)p-dense 7.79 443 29 2-(4-methanesulfonylanilino)·4 -(Imidazolium [l,2a]pyridin-3-yl)pyrimidine 6.84 366 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing 54- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1291960 A7 B7 V. Description of the invention (52) 30 2-(4-Methylthioanilino)-4-(imidazolium [l,2a]pyridin-3-yl) Methylate 7.89 334 31 2-(4-A Benzylamino)-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 7.65 302 32 2_(3-Aminesulfonylanilino)-4_(imidazolium [1,2&amp;]pyridine-3 -yl)pyrimidine 6.30 367 33 2-[4-(pyrimidin-2-ylaminosulfonyl)anilino]-4-(imidazolium [1,2a]p is more than -3-dimidine 6.72 445 34 2-((phenoxyanilino)_4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 8.86 380 35 2-(3-methylanilino)-4_(imibroid[l,2a] P-precipitate-3-yl) melamine 7.63 3 02 36 2-Indan-5-ylamino)-4-(imidazolium [1,2a]pyridin-3-yl)pyrimidine 8.20 328 (Read the back of the note first? Please fill out this page again. Example 3 7 1 2 (3-anilino)-4-(2,5-dimethylimidazolium n, 2alpyridine-3 _) Pyrimidine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 2-Methylthio-4-(2,5-dimethylimidazo[i,2a]pyridin-3-yl)pyrimidine (Method 14) (200 mg, 0.74 mmol) under nitrogen Add to a solution of 3-chloroaniline (0.16 mL, 1.48 mmol) and sodium hydride (60 mg, 148 mmol) in NMP (1 mL). The mixture was heated at 〇5 ° C for 4 hours and cooled. The crude reaction mixture was loaded on a B〇nd Elut column to remove NMP by elution with methylene chloride, followed by elution with dichloromethane/methanol/methylamine (75:2:5) to dissolve the product. The product was purified by ethyl acetate / hexane (8:2) NMR: 2.27 (s, 3H), 2.61 (s, 3H), 7.01 (d, 1 Η), 7·12 (d, 1H), 7.30 (m, 2H), 7.56 (d, 1H), 7.62 (d, 1H), 8.57 (d, 1H), 9.41 (s, 1H), 9.83 (s, 1H); m/z: 350[MH]+〇' -55- 1291960 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative V. Inventive Note (53) Example 3 8 The procedure of Example 3 7 was repeated, and the following compound was prepared using the appropriate starting material. Example compound NMR m/z [MH] + 38 2-(3-chloroanilino)-4-(2-methyl. oxime [2,3 a] p-precipitate-3-yl) p-precipitated 2.64 ( s, 3H), 6.95-7.03 (m, 2H), 7.17 (d, 1H), 7.32 (d, 1H), 7.44 (dd, 1H), 7.58-7.64 (m, 2H), 8.04 (s, 1H) , 8.57 (d, 1H), 9·72 (d, 1H), 9.84 (s, 1H) 336 Example 3 9 丨4-(N-methylamine sulfonyl)aniline 1 - 4-(imidazolium H, 2al Pyridine-3-yl)pyrimidine under nitrogen to add toluene (4 ml) to hydrazine (diphenylideneacetone) di-free (0) (24 mg, 0.026 亳 mol), 2, 2f-double (two Phenylphosphine)-1,1,binaphthyl (21 mg, 0.034 mmol), 2-chloro-4-(imidazolium [l,2a]pyridin-3-yl) orally (Method 20; 150 Mg, 〇_652 mmol) and 4-(methylamine sulfonyl) aniline (Method 2 3; 135 mg, 0.725 mmol). The reaction flask was vented and filled with nitrogen and sodium tributoxide (140 mg, 1.46 mmol) was added. The reaction flask was re-plated and refilled with nitrogen. The mixture was heated at 1 〇 〇 °C for 3 hours and allowed to cool. The mixture was diluted with B-B, and washed with water. The organic phase is separated and the volatiles are removed by dehydration and evaporation. The residue was purified by chromatography eluting with ethyl acetate / methanol (1 〇〇: 〇 至 。 。 。 。 。 。 。 。 。). NMR: 2.42 (d, 3H), 7.25-7.10 (m, 2H), 7.52-7.45 (m, 2H), 7.79-7.70 (m, 3H), 7.98 (d, 2H), 8.50 (d5 iH) , 8 62 (s, -56- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------ΦΚ,-------- (Please read the back first Note: Please fill out this page again) Book 1291960 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print A7 B7_ V. Invention Description (54) 1H); m/z: 381 [MH]+. Example 4 0 - 4 4 The procedure of Example 39 was repeated and the following compound was prepared using the appropriate starting material. Example compound NMR m/z [MH] + SM 401 2-{4-[N-(2-methoxyethyl)amine continued SS-phenyl]anilinyl}-4-(imidazolium [l,2a]pyridine- 3 · Base) shouting 2.90 (q, 2H), 3.18 (s, 3H), 3.28-3.30 (m, 2H), 7.16 (dd, 1H), 7.48-7.54 (m, 3H), 7.71-7, 80 (m,3H), 7.95 (d,2H), 8.50 (d,1H), 8.62 (s, 1H) 425 Meth 24 412 2_[4-(N-propylaminesulfonyl)anilino]-4- (Imidazolium [1,2 a] p is more than -3 -yl) p-dense 0.80 (t, 3H), 1.34-1.42 (m, 2H), 2.65-2.75 (m, 2H), 7·15 (dd , 1H), 7.17 (dd, 1H), 7.55-7.48 (m, 2H), 7.70-7.79 (m, 3H), 7.95 (d, 2H), 8.50 (d, 1H), 8.63 (s, 1H) 409 Meth 25 42 2-[4-(N-Cyclopropylamine sulfonyl)anilino]-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 0.00-0.05 (m, 2H), 0.09 · 0.12 (m5 2H)? 1.70-1.75 (m, 1H), 6.79 (dd, 1H), 7.10-7.15 (m, 2H), 7.32-7.42 (m, 4H), 7.60 (d, 2H), 8.12 ( d,lH), 8.28 (s, 1H), 9.74 (s,1H), 9.75 (s,1H) 405 [MH]' Meth 26 43 2-[4-(N,N-dimethylaminecarbamyl) Anilino]-4-(imidazolium [l,2a]pyridin-3-yl) p-density 2.98 (s? 6H)? 7.10 (dd? 1H)? 7.3.8-7.50 (m? 3H)? 7.72-7.82 (m?3H)? 8.45 (d,1H), 8.61 (s,1H), 9.82 ( s,1H) 359 -57- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) —:—*--------------- Order--- ------^^9-. (Please read the back note 咅3 and then fill out this page) I» 1291960

V. Description of the invention (55) 443 2·[4·(Ν-Methylamine decyl) arginyl]-4-(味幷[1,2&amp;]? 2.78 (d, 3H), 7.15 (dd, 1H), 7.43 (d, 1H), 7·50 (dd, 1H), 7.75-7.82 (m, 5H), 8.24 (d, 1H), 8.48 (d, lH), 8.62 (s, 1H), 9·90 (s, 1H) 345 The product was purified by chromatography with ethyl acetate (7 〇: 3 〇) and polarity increased to (〇:丨〇〇). . The product was purified by chromatography eluting with hexane/ethyl acetate (5 EtOAc: EtOAc) The product was purified by chromatography eluting with hexane/ethyl acetate (8 〇: 2 〇) and polarity to ethyl acetate/methanol (90:1 〇). Example 4 5H4_『N-(3-hydroxy-propyl, amine 碏醯芄 里 n n 岫 岫 ( ( (Please read the back of the note and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed acridine -3 -yl)pyrimidine 2-anilino-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine (Example 16; 100 mg, 0.347 mmol) was dissolved in sulfoxide (4 The mixture was cooled to 5 ° C in ML). Gas sulfonic acid (6 ml, 0.90 mmol) was added and the mixture was stirred at 5 ° C for 30 minutes, then warmed to ambient temperature and stirred for 60 minutes. The mixture was then heated under reflux for 90 minutes. The volatiles were removed by evaporation and the residue was azeotroped with toluene. 3-Aminopropanol (3 ml) was added to the residue, and the mixture was stirred at ambient temperature for 30 min. The mixture was purified by chromatography with hexane/ethyl acetate (5:50) and EtOAc (MeOH:MeOH) NMR: 1.45-1.56 (m, 2H), 2.79 (q, 2H), 3.35 (q, 2H), 4·39 (t, 1H), 7.15 (dd, 1H), 7.31 (t, 1H), 7.45- 7.54 (m, 2H), 7.70-7.79 (m, 3H), 7.95 (d, 2H), 8_50 (d, 1H), 8.62 (s, -58- This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) Order 1291960 A7 B7 V. Description of invention (56) 1H); m/z: 423 [Μ-ΗΓ. Example 4 6 5 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The procedure of Example 4 5 was repeated and the following compounds were prepared using the appropriate starting materials. Example compound NMR m/z [MH] + 46 2-{4-[N-(3-cyclopropylmethyl)aminesulfonyl]anilino}-4-(imidazolium[1,2a]p ratio bite -3-yl)p bite 0.00-0.04 (m, 2H), 0.25-0.32 (m? 2H), 0.70-0.78 (m, 1H), 2.60 (t, 2H), 7.10 (dd, 1H), 7.28 -7.42 (m, 3H),7·68_7·75(ιη, 3H), 7.87 (d,2H), 8.42 (d,1H), 8.60 (s,1H) 421 47 2-{4-[N-( 5-hydroxypentyl)amine sulfonyl]anilino}-4-(imidazolium[1,2a]p is more than -3-dimonide 1.18-1.40 (m? 8H), 2.70 (t, 2H)5 4.25 (br s, 1H), 7.15 (dd, 1H), 7.48-7.52 (m, 2H), 7.70-7.78 (m, 3H), 7.95 (d, 2H), 8.50 (d, 1H), 8.62 (s ,1H) 453 48 2-(4-{Ν-[2-(1-methylpyrrolidin-2-yl)ethyl]amine sulfonyl}anilino)-4-(imidazolium [l,2a] Pyridine-3-yl) Shouting 1.18-1.25 (m? 2H)? 1.48-1.58 (m, 2H), 1.60-1.70 (m, 1H), 1.90-2.00 (m, 2H)? 2.10 (s? 3H) 2.70-2.85 (m, 4H), 7.15 (dd, 1H), 7.40 (s, 1H), 7.48-7.53 (m, 2H), 7.70-7.80 (m, 3H), 7.95 (d, 2H), 8.50 (d,1H),8.63 (s,1H) 476 [MH]' -59- This paper scale applies to Chinese national standards CNS) A4 size (210 X 297 mm) (Please read the back of the precautions to fill out this page) -------- --------- 1291960 A7 Order

V. INSTRUCTIONS (57) 49 2-{4-[N-(3-Diethylaminopropyl)aminesulfonyl]anilino}-4-(imidazolium[1,2a]p than lake-3 -Base) p-density 0.86 (t,6H), 1.42 (q, 2H), 2.30 (q, 4H), 2.38- 2.42 (m, 2H), 2.75 (q, 2H)? 7.15 (dd5 1H)5 7.42 7.55 (m, 2H), 7.70-7.80 (m5 3H), 7.95 (d, 2H), 8.50 (d, 1H), 8.65 (s '1H) 480 50 1 ±, 2-{4-[N- (2-Isopropylaminoethyl)aminesulfonyl]anilino}-4-(imidazolium[1,2a]p is more than -3-yl). 0.87 (s, 3H), 0.90 (s, 3H) ), 2.46-2.50 (m, 2H), 2.58 (q, 2H), 2.80 (t, ' 2H), 7.18 (dd, lH) 57.48-7.52 (m, 2H), 7.70-7.80 (m, 3H), 7.95 (d,2H), 8.50 (d,1H), 8.62 (S:1H) 452 1 product was eluted with hexane/ethyl acetate (7 〇: 3 〇) and polarity increased to (〇:丨〇〇) Chromatography purification. 2. The product was purified by chromatography with hexane/ethyl acetate (50:50) and polarity added to ethyl acetate/methanol (9 5:5). 3 The product was purified by chromatography with hexane/ethyl acetate (8 〇: 2 〇) and polarity added to ethyl acetate/methanol (90:1 〇). Example 5 1 [ 3 - (2-oxo-purine m)-propyl-supplemented 4-(imidazolium n.2alpyridin-3-yl)pyrimidine 2-anilino-4-(imidazolium[l,2a] Pyridin-3-yl)pyrimidine (Example 16; 1 〇〇 克 ' 0.347 mmol) was dissolved in sulfoxide (3 mL) and the mixture was cooled to 5 °C. Gas sulfonic acid (0 〇 6 ml, 〇. 90 mmol) was added and the mixture was stirred at 5 ° C for 30 minutes, then warmed to ambient temperature and stirred for 6 〇 minutes. The mixture was heated under reflux for 90 minutes. Evaporation to remove volatiles and residues of total toluene _ -60- This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 public f &quot; (please read the back note before filling this page) •丨! I ! 丨 丨 丨 丨 丨 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 129 129 129 129 129 129 -----B7 V. Inventive Note (58) Boiling. Add pyridine (3 ml) and 3-(2-oxopyrrolidin-1-yl)propylamine (3 ml) to the residue to make the mixture The mixture was stirred for 1 hour at ambient temperature. The mixture was purified by chromatography eluting with hexane/ethyl acetate (50:50) and polarity to ethyl acetate/methanol (80:20) to afford 60 mg (3 6%). NMR··1·51- 1.60 (m, 2Η), 1·80-1·90 (m, 2H), 2·13 (t, 2H), 2.70 (t, 2H), 3.10 (t, 2H), 3.20 (t, 2H), 7·16 (dd, 1Η), 7·48·7·55 (m, 2H), 7.70-7.80 (m, 3H), 7.95 (d, 2H), 8.50 (d, 1H) ), 8.62 (s, 1H); m/z: 492 [MH]+. Example 5 2 - 7 0 .. ^ --------^--- ------^ (Please read the notes on the back and fill out this page.) Repeat the procedure in Example 4 5 and prepare the following compounded Yang using the appropriate starting materials. Example Compound ~ NMR m/z [MH1 + 52 2-{4-[N-(3-methoxypropyl)aminesulfonyl]anilino}-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 1.55-1.62 (m, 2H), 2.75- 2.81 (m, 2H), 3.12 (s, 3H), 3.23-3.28 (m, 2h), 7.15 (dd, 1H), 7.38 (t, '1H), 7.55 (m, 2H), 7·;〇· 7.80 (m,3H), 7.96 (d, 2H), 8.50 (d,1H),8·6'2 439 53 2-{4-[N_(3-isopropylaminopropyl)amine Sulfhydryl]anilino}-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 1·48 (t,2H), 1.88 (d, 6H), 2.42 (t, 2Η), 2· 5'9 (m,1H), 2.79 (t,2H), 7.15 (dd,lH), 7.48.7,55 (m,2H), 7.70-7.80 (m,3H),7.95 (d,2H), 8.50 (d9 1HL 8.62 (s.lH) 466

X 10 (2 grids 4

1291960 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (59 ) 54 2-{4-[N_(3-Imidazol-1-ylpropyl)aminesulfonyl]anilino}-4- (Imidazolium [l, 2a]pyridine-3_yl;) Pyrimidine 1.80 (m, 2H), 2.70 (q, 2H)? 3.94 (t? 2H), 6.82 (s, 1H), 7·08 (s, 1H) ), 7.14 (dd, 1H)? 7.48-7.52 (m, 4H), 7.70 (d, 2H), 7.78 (d, 1H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 473 [M-Η]- 551 2-{4-[N-(3-Dimethylaminopropyl)aminesulfonyl]anilino}-4-(imidazolium [l,2a]pyridine-3 -yl)pyrimidines 1·48 (m, 2H), 2.02 (s, 6H), 2.12 (t, 2H), 2.78 (t, 2H), 7.15 (dd, 1H), 7.38 (s, 1H), 7.48- 7.57 (m, 2H), 7.72 (d, 2H), 7.78 (d, 1H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 452 56 2-{4-[N -(3-morpholinylpropyl)aminesulfonyl]anilino}-4-(imidazolium[1,2a]pyridin-3-yl)pyrimidine 1.52 (t? 2H)? 2.18-2.22 (m,6H ), 2.78 (t, 2H), 3.43-3.48 (m, 4H), 7.15 (dd, 1H), 7.38 (s, 1H), 7.48-7.55 (m, 2H), 7.74 (d, 2H), 7.78 ( d,1H), 7.98 (d5 2H), 8.50 (d, 1H ), 8.62 (s, 1H) 494 571 2-{4-[N-(3-Aminopropyl)amine sulfonyl]anilino}-4-(imidazolium [1,2a] p than lake-3 -based) p-precipitate 1.38-1.45 (m, 4H), 2.79 (t, 2H), 7.15 (dd, 1H), 7.48-7.56 (m? 2H)? 7.60-7.64 (m, 1H), 7.72 (d , 2H), 7.79 (d, 1H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 424 581 2_(4-{N-[2-(2-hydroxyethylamino) Ethyl]amine sulfonyl}anilino)-4-(imidazolium [l,2a]pyridin-3-yl)p-dense 2.75 (t,2H), 2.86-2.90 (m,2H),3.54 (t, 2H), 3.60 (t, 2H), 7.08 (d, 2H), 7.18 (dd, lH), 7.42-7.55 (m, 2H), 7.75-7.80 (m, 3H), 8.00 (d, 2H) ), 8.52 (d,1H), 8.62 (s, 1H) 454 -62- (Please read the note on the back and fill out this page) — — — — — — — — — This paper scale applies to the Chinese National Standard (CNS) ) A4 size (210 X 297 mm) 1291960 A7 _B7 V. Description of invention (6Q) 592 2-{4_[N-(2-imidazol-4-ylethyl)amine printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Continuation of fluorenyl]aniline}-4_(imidazolium[l,2a]pyridin-3-yl)p-dense 3.10 (t,2H), 3.95 (t, 2 H), 7.10 (d, 2H), 7·40 (s? 2Η)? 7.50 (d9 2Η) 5 7.58 (d, 2Η), 7.69 (d, 2H), 7.75 (d, 1H), 8.45 ( d,1H)5 8.60 (s,1H), 8.79 (s,1H),9.75 (s,1H),10.1 (s,1H) 601 2-{4-[N-(3-methylaminopropyl) Aminesulfonyl]anilino-4-(imidazo[l,2a]pyridin-3-yl)pyrimidine 1.70- 1.78 (m? 2H)? 2.66 (s,3H), 2.90 (t,2H), 3.00 ( t,2H),7.08 (d,2H), 7.18 (t,1H), 7.44 (d,2H),7.51 (m,1H), 7.70- 7.80 (m,3H), 8.02 (d,1H),8.52 (d,1H), 8.63 (s,1H) 436 611 2-{4-[N-(2-hexahydropyrazine-1·ylethyl)amine aryl] anilino}-4-(imidazolium) [l, 2a] pyridin-3-yl) shouting 2.30 (t, 2H), 2.40-2.43 (m, 4H), 2.59 (t, 2H), 2.83-2.90 (m, 4H), 7.18 (dd, 1Η),7·49-7·55 (m, 2H), 7.68 (d, 2H), 7.78 (d, 1H), 8.02 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 621 2-{4_[N-[3-(4-methylhexahydropyrazine-1 -yl)propyl]aminesulfonyl]anilinyl}-4_(imidazolium[1,2a]p than lake- 3-based) p-dense 1.49 (m, 2H), 2.10 (s, 3H), 2.15-2.25 (m, 8H), 2.78 (q, 2H), 3.25-3 .29 (m, 2H), 7.18 (dd, 1H), 7.40 (dd? 1H), 7.50 (d? 2H)? 7.75 (d? 2H)? 8.80 (d, 1H), 7.95 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 507 (Please read the note on the back first? Please fill out this page again. -63- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 Δ7 Α7 Β7 V. Invention description (61) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 631 2-{4-[Ν-[2-(2·diethylaminoethylamino)ethyl]aminesulfonyl]anilinyl}-4-(imidazolium [l,2a]pyridin-3-yl) Pyrimidine 0.93 (t,6H), 2.40-2.58 (m,4H), 2.62 (t,2H), 2.84 (t, 2H)? 3.20-3.40 (m,4H), 7.10 (d,1H), 7.18 (dd , 1H), 7.42-7.50 (m, 3H), 7.72-7.80 (m, 3H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 509 641 2-{4-[ Ν·(2,3-Dihydroxypropyl)aminesulfonyl]anilino}-4-(imidazolium[l,2a]pyridin-3-yl)~dense 2.66 (m,1H), 2.86 (m , 1H), 3.21-3.30 (m, 2H), 3.46 (m, 1H), 4·49 (t, 1H), 4.70 (d, 1H), 7.18 (dd, 1H), 7.24 (dd, 1H), 7.48-7.52 (m? 2H)? 7.70-7.80 (m, 3H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 441 65 2-{4-[Ν·(2 - dimethylaminoethyl)amine sulfonyl]anilino}-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 2.08 (s,6H), 2.24 (t, 2H), 2.82 (t, 2H), 1.7 (dd, 1H), 7.30 (s, 1H), 7.44 - 7.54 (m, 2H), 7.70 - 7.80 (m, 3H), 7.95 (d, 2H) ), 8.50 (d,1H), 8.63 (s, 1H) 438 66 2_{4-[N-(2-morpholinoethyl)aminesulfonyl]anilinyl}-4-(imidazolium [l, 2a]pyridin-3-yl)pyrimidine 2.34-2.45 (m, 6H)? 2.87-2.95 (m5 2H)? 3.46-3.60 (m,4H), 7.09 (d,2H), 7.18 (dd? 1H), 7.42 -7.50 (m,3H),7·74·7·80 (m, 2H), 7.98 (d,2H), 8.50 (d,1H), 8.62 (s,1H) 478 [M-Η]- 67 2 -{4-[N-(2-Pyrrolidin-1-ylethyl)amine sulfonyl]anilino}-4-(imidazolium[l,2a]pyridin-3-yl)p-dense 1.64-1.74 (m? 4H), 2.52-2.64 (m, 6H)5 2.87-2.92 (m, 2H), 7.18 (dd, 1Η), 7·44-7·54 (m, 3H), 7.72-7.80 (m, 3H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 464 -64- (Please read the note on the back and fill out this page) _1 I ϋ ϋ ϋ 1_ 1 _1 BBBBi · ϋ ϋ ^1 i·, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 B7 V. Description of invention (62 68 2-{4-[N-(2-Methylamino) Ethyl) sulfonyl]aniline 4-(Imidazolium[1,2a]pyridin-3-yl)pyrimidine 2.61-2.64 (m,2H), 2.68 (s,3H), 2.90 (t,2H), 7.18 (dd, 1H)? 7.48- 7.58 (m, 2H), 7.68-7.78 (m, 4H), 7.95 (d, 1H), 8.00 (d, 1H), 8.51 (d, 2H), 8.64 (s, 1H) 424 69 2-{4- [N-(2-Hexahydropyridin-1-ylethyl)amine sulfonyl]anilino}-4-(imidazo[l,2a]pyridin-3-yl)pyrimidine 1.28-1.40 (m? 2H) 1.40-1.58 (m, 4H), 2.20-2.50 (m, 6H), 2.84-2.92 (m, 2H), 7.18 (dd, 1H), 7.48-7.53 (d, 2H), 7.72-7.80 (m, 3H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H) 478 70 2-{4-[N-(2-diethylaminoethyl)amine sulfonyl]aniline }-4-(Imidazolium[l,2a]pyridin-3-yl)p-dense 0.86 (t,6H),2.32-2.42 (m,6H), 2.79 (t,2H), 7.18 (dd,1H) , 7.23 (s, 1Η), 7·48-7·52 (m, 2H), 7.70-7.80 (m, 3H), 7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s5 1H) 466 The product was purified by chromatography eluting with ethyl acetate/methanol (100:0) and polarity to (70:30). (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs. 2 The product was not separated by chromatography, but was dispersed in dichloromethane and methanol and separated from the reaction mixture. Example 7 1 2 - { 4 - Γ N-(3 -imidazolyl-1-ylpropyl)aminecarboxylidene 1-anilinoindol-4-(4-imidazolium f 1,2a~|p-precipitate-3 -yl) Toluene (1 〇 ml) was added to 2-amino-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine under a nitrogen atmosphere (Method 22; 200 mg, 0.95 mmol) , 1-[3-(4.bromobenzylideneamino)propyl]imidazole (Method 27; 350 mg, 1.14 mmol), hydrazine (diphenylmethyleneacetone) dipalladium (0) (43 Mg, 0.047 mmol, and 2,2'-bis (diphenylphosphine (28 mg, 0.046 mmol). -65- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297) &quot; — 1291960 A7 B7 H,---·---------- (Please read the notes on the back and fill out this page) V. Invention description (63) Add second-di Sodium alkoxide (218 mg, 0.0023 mmol), the reaction mixture was washed well with nitrogen and heated at 1 ° C for 24 hours. The volatiles were removed by evaporation and hexane / ethyl acetate (5 0 : 5 0 ) And the polarity is increased to ethyl acetate/methanol (9 5 : 5 ), and the solution is purified by chromatography to obtain the target compound 9 9克 (24%). NMR: 1.90-2.00 (m, 2H), 3.22 (q, 2H), 4.02 (t, 2H), 6·86 (s, 1H), 7.16 (dd, 1Η), 7.21. s,1Η),7·42_7·55 (m,2Η),6·80 (s,3Η), 7·78 (d,1H),7.83 (s,4H),8.38 (t,1H),8.48 ( d,1H), 8.62 (s, 1H), 9.92 (s,1H); m/z: 439 [MH]+o Example 7 2 - 7 4 fReconstruction Example 7 1炙Step, and use appropriate Starting materials, the following compounds were prepared. Example compound NMR m/z [ΜΗΓ SM 721 2- (4-{N-[3_(2-oxopyrrolidin-1-yl)propyl]aminoindenyl}anilinyl) -4-(imidazolium [l,2a]pyridine-3-yl)pyrimidine 1.70 (quin, 2H), 1.90 (quin, 2H), 2·21 (t, 2H), 3.18-3.24 (m, 4H), 3.30-3.38 (m, 2H), 7.15 (dd, 1H), 7.42-7.52 (m, 2H), 7.78 (d, 1H), 7.82 (s, 4H), 8.27 (t, 1H), 8.49 (d, 1H), 8.62 (s, 1H), 9.90 (s, 1H) 456 Meth 28 732 2-{3-Ga-4-[N-(2-methoxyethyl)amine continuation] - 4 - (isoxazole [l, 2a] pyridin-3-yl) pyrimidine 3.00 (q, 2H), 3.12 (s, 3H), 3.25-3.30 (m, 2H), 7.18 (dd, 1H), 7.50 -7.58 (m, 2H), 7.68 (t, 1H) 7.75-7.80 (m, 2H), 7.87 (s, 1H), 8.22 (s, 1H), 8.55 (d, 1H), 8.64 is, 1H) 459 66- This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 mm) IIIII Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives! 291960 A7 B7 V. Inventions (64) 743 2-[3-Chloro-4-(N-propylamine sulphate) 80 (t,3H), 1.38 (m, 443 yl) anilino]-4_(imidazo[l,2a] 2 Η), 2.79 (q, 2H), 7.18 smectin-3 -yl)p-dense ( Dd,1Η), 7.48-7.55 (m, 2H), 7.66 (dd, 1H), 7·78 (dd 2H), 7.92 (d, 1H), 8·25 (s5 1H), 8.55 (UH), 8.68 (s, 1H), 10.10 (d, 1H) 5 10.26 (s, 1H) The reaction was purified by heating at 100 C for 48 hours and eluting with dichloromethane/methanol (9 ο: 1 ο). Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperative 2, starting with 2,4·dichloro-1-(2-methoxyethylaminesulfonyl)benzene (Method 29). Starting from 2,4-dioxa·1-(1-propylamine thio)benzene (Method 3〇) Example 7 5 (3-methyl-4-amine hydrazinyl)-4 - (唆弁 唆弁 i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i Pyridin-3-yl)pyrimidine (Example 35; 80 mg, 0.266 mmol) gave the title compound (6 mg, 17%). NMR: 2.60 (s, 3H), 6.95-7.20 (m, 4H), 7.46-7.50 (m, 2Η), 7·70-7·80 (m, 4H), 8·50 (d, 1H), 8.62 (s, 1H), 9.87 (s, 1H); m/z : 381 [MH]+. Example 7 6 - 7 8 Repeat Example 7 5 Steps Using the appropriate starting materials, prepare the following compounds: -67- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) (Please read the notes on the back and fill out this page) ----Book---- 1291960 A7 B7 V. Description of Invention (65) Example compound NMR m/z [ΜΗΓ 76 2-{3-methyl -4-[N-(2-methoxyethyl)amine sulfonyl]anilino} - 4 -(imixo[1,2 a ]p-precipitate-3-yl)p-dense 2.55 (s , 3H), 2.91 (q, 2H), 3.11 (s, 3H), 3 .22 (t,2H), 7.12 (dd,1H),7.44-7.55 (m, 3H), 7.74-7.80 (m,4H), 8.50 (d,1H), 8.62 (s,1H), 9.98 (s , 1H) 439 77 2-{3-methyl-4-[N_(3-morpholinopropyl)aminesulfonyl]anilino}-4-(imidazolium [l,2a]pyridin-3-yl ) p-precipitate 1.49 (m? 2H), 2.13-2.20 (m5 4H), 3.24-3.32 (m? 2H), 2.58 (s, 3H)5 2.80 (t, 2H), 3.42-3.48 (m? 4H) 7.12 (dd, 1H), 7.48-7.53 (m, 2H), 7.75-7.80 (m, 4H), 8.50 (d, 1H), 8.62 (s, 1H) 508 78 2-{3-methyl-4_ [N-(2-morpholinoethyl)amine]]anilinyl}-4-(imidazolium[l,2a]pyridin-3-yl)pyrimidine 2.18-2.21 (m? 4H)? 2.30-3.38 (m, 2H), 2.59 (s, 3H), 2.87 (t5 2H), 3.42-3.48 (m5 4H), 7.12 (dd, lH), 7.42-7.55 (m, 3H), 7.75-7.80 (m, 4H) ), 8.50 (d, 1H), 8.62 (s, lH), 9.98 (s, 1H) 494 Example 7 9 (Please read the note on the back and then fill out this page) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing Bromine -2 - (4-Amine-nonylanilino)-4 -(imidazole # [~i, 2alpyridine-3 - a) pyrimidine rabbit as described in Example 4 5, but treated with 2 Μ ethanol ammonia 2 - aniline -5 _澳_ 4_ (Mi wei [l, 2a]p than -3-yl) shouting (example 97; 73 mg, 〇 2 mmol) 'obtained target compound (1 8 mg, 2 1 %). NMR: 7 12 (dd, 1H), 7.19 (s, 2H), 7.53 (dd, 2H), 7.72 (d5 2H), 7.79 (d5 1H), 7·84 (d, 2H), 8.76 (s ,1H),8·78 (s,1H),9.62 (s,1H&gt;; m/z: 445 -68 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public f &quot; 1291960 A7 B7 V. INSTRUCTIONS (66) [MH], EXAMPLE 8 0 - 8 1 Repeat the procedure of step 7 9 Using the appropriate starting materials, prepare the following Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing 0, Example Compound NMR m /z [ΜΗΓ 80 5-bromo-2-{4-[indolyl-(2-methoxyethyl)amine] anilide 4-(imidazo[1,2a]pyridin-3-yl) P-precipitate 2.90 (m, 2H), 3.18 (s, 3H), 3.28 (q, 2H), 7.10 (dd, 1H), 7.48-7.58 (m, 2H), 7.70 (d, 2H), 7.79 (d ,1H),7.86 (d, 2H), 8.76 (s,1H), 8.78 (s, 1H), 9.60 id,1H) 503 81 5-bromo-2-{4-[N-(2-dimethylamine) Alkyl sulfonyl]anilino}-4-(imidazolium [l,2a]pyridin-3-yl)pyrimidine 2, 〇6 (s,6H), 2.25 (t,2H), 2.82 (t , 2H), 7.15 (dd, 1H), 7.30 (s, 1H), 7.55 (dd, lH), 7.72 (d, 2H ), 7.80 (d, 1H), 7.90 (d, 2H), 8.75 (s, 1H), 9.80 (s, 1H), 9.65 (d, lH), 10.28 (s, 1H) 516 821 5-bromo-2 -{4-[N-(3-Dimethylaminopropyl)amine hydrazino]anilino}-4-(Mis(R)[l,2a]p-precipitate-3-yl)p-dense 1.70- 1.80 (m5 2H)? 1.87-1.98 (m, 2H), 2.62 (d, 6H), 2.79 (q, 2H), 7.12 (dd, 1H), 7.55 (dd, 1H), 7.59 (dd, 1H), 7.70 (d, 2H), 7.79 (d, 1H), 7.90 (d, 2H), 8.78 (s, 1H), 8.79 (s, 1H), 9.64 (d, 1H)? 10.32 (s, 1H) 530 Purification by chromatography was carried out by means of the pit/acetic acid b (50:50) and the polarity was increased to ethyl acetate/methanol (7〇: 30). Ϊ 1183 (Please read the notes on the back and fill out this page)

- I ϋ ϋ ·ϋ ϋ ϋ 1 ·ϋ ^1 I «· _ -69- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 V. Description of invention (67 base ethyl The phenylamino-4-bromoimidazolium and the "l,2alpyridin-3-yl)pyrimidine were treated with 2-methoxyethylamine under the conditions described in Example 51. 5-bromoimidazo[i,2a]pyridin-3-yl)pyrimidine (Example 98; 70 mg, 0.23⁄4 mol) gave the title compound 23 mg (25%). Nmr: 2.90 (q, 2H), 3.18 (s, 3H), 3.26-3.29 (m, -2H), 7·49-7·54 (m, 2H), 7.60 (dd, lH), 7.74-7.78 ( m, 3H), 7.90 (d, lH), 8.54 (d, 1H), 8.62 (s, 1H); m/z: 503 [MH]+. Example 8 4 oxyethyl)amine sulfonate m 1 anilino}} 4 f 5 -1 thio-mi 幷 幷 "l, 2a&quot;|p than bite-3-based V-dense sodium hydride (80 mg 60% mineral oil suspension (2.0 mmol) was added to thiophenol (0.102 liter, !· 〇 mmol) dissolved in NMP (4 ml) and the mixture was stirred; mix for 30 minutes. Add 2 - {4-[Ν·(2-methoxyethyl)amine hydrazinyl]anilinyl} - 4 - (5-bromomethanone [1,2a]) dissolved in NMP (1 ml) ρ is more than 3-aminopyrimidine (Example 83; 100 mg, 0.19 mmol) and the mixture was heated at i50 ° C for 18 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dehydrated and evaporated to remove volatiles. The residue was partitioned with diethyl ether and filtered to give the title compound 20 mg (20%). NMR: 2·85 (q, 2H), 3.15 (s, 3H), 3.24 (q, 2H), 7.10-7.30 (m, 5H), 7·38 (d5 1H), 7·46 (dd5 1H), 7.52 (d,1H), 7.75 (d,2H), 7.79 (d,1H), 7.92 (d,2H), 8.54 (d,lH),8.66 (s,1H); m/z: 533 [MH] , Example 8 5 - 8 8 -70- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) -ir!r------ψί, {Please read the note on the back first Fill in this page}

ϋ ϋ ϋ ϋ I^OJa I ϋ I ϋ II Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 1291960 _B7 V. Invention Description (68) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Repeated Example 8 4 Steps and Use The following compounds were prepared as appropriate starting compounds. Example compound NMR m/z [MH] + 851 2·{4-[Ν-(2-methoxyethyl)aminesulfonyl]anilino-4- 4- - Ethylthioimidazolium [1,2a]pyridin-3-yl)pyrimidine 1.18 (t,3H), 2.84-2.95 (m, 4H), 3.18 (s, 3H), 3.26-3.30 (m, 2H), 7.49-7.58 (m,3H), 7.71-7.79 (m,4H), 7.90 (d, 2H), 8.50-8.55 (m,1H), 8.60 (s,1H),8.89 (s,1H) 485 861 2 -{4-[N-(2-methoxyethyl)aminesulfonyl]anilinobu 4_(5-(2-hydroxyethylthio)imidazolium [l,2a]pyridin-3-yl)pyrimidine 2.90 (t,2H), 3.05 (t,2H), 3.20 (s,3H),3·32 (t,2H), 3.60 (q,2H),5.00 (t,1H), 7.45 (dd,1H) , 7.50 (d, 1H), 7.58 (d, 1H), 7.70-7.79 (m, 3H), 7.95 (d, 2H), 8.50 (d, 1H), 8.59 (s, 1H), 9.95 (s, 1H), 10.05 (s, 1H) 501 872 2-{4-[N-(2-A Ethyl ethyl) sulfonyl]anilino}-4-[5-decenoxyl-2-ylthio)imidazolium [l,2a]pyridin-3-yl)pyrimidine 2.90 (m, 2H), 3.15 (s,3H), 3.24 (q,2H),7.08-7.10 (m, 1H), 7.32 (d,1H),7·42 (d, 1H), 7.50 (d,1H), 7.70-7.80 (m , 4H), 7.94 (d, 2H), 8.52 (d, 1H), 8.63 (s, 1H) 539 883 2-{4-[Ν-(2·methoxyethyl)aminesulfonyl]anilinyl }-4-[5-(2-Dimethylaminoethylthio)imidazolium [l,2a]pyridin-3-yl)pyrimidine 2.15 (s,6H), 2.40-2.50 (m, 2H), 2.90 ( q, 2H), 3.09 (t, 2H), 3.20 (s, 3H), 3.28-3.32 (m, 2H), 7.48-7.58 (m, 3H), 7.72-7.80 (m, 3H), 7.95 (d, 2H), 8.51 (d, 1H), 8.60 (s, 1H), 9.90 (s, 1H), 10.11 (s, lH) 528 -71 - (Please read the note on the back and fill out this page) if port, — — — — — — — — — r· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 B7 V. Description of invention (69) 1 Product by ethyl acetate/methanol (100 :0) and the polarity is increased to (95: 5) dissolution and chromatographic purification. The product was purified by chromatography eluting with ethyl acetate. 3 The product was purified by chromatography using ethyl acetate/methanol (1 〇〇: 〇) and the polarity was increased to (7 〇: 3 〇). Example 8 9 gjLiA_-"N-(2-methoxyethyl)amine sulfonyl phenylamino 4"5-cyanoimidazolium "1,2alpyridin-3-yl, pyrimidine-containing 2-{4 -[N-(2-methoxyethyl)amine hydrazino]anilino-4-(5•bromoimidazolium [l,2a]pyridin-3-yl)pyrimidine (Example 83; 87 mg, 0.17 m Mohr), tetraethylammonium cyanide (27 mg, 0.17 mmol), diphenylphosphinoferrocene (23 mg, 0.03 mmol), copper cyanide (1) (62 mg, 0.7 m) Mol) and hydrazine (dibenzylideneacetone) dipalladium (yttrium) (7 mg, 0.008 mol) anhydrous diazane (6 ml) was flushed with nitrogen and heated at reflux for 48 h, evaporated The residue was purified by chromatography eluting with hexane/ethyl acetate (5: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: (q, 2H), 3.15 (s, 3H), 3.25-3.30 (m, 2H), 7.42 (dd5 1H), 7.58 (d, 1H), 7.72_7.78 (m, 3H), 7.90-7.98 (m , 3H), 8.59 (d5 1H), 8.40 (s, 1H), 10.23 (s, 1H), 10.53 (s, 1H); m/z: 447 [Μ·Η]_ 〇 Example 9 0 -丨N- (3-trimethylamine Aminosulfonyl 1anilinyl b 4 _ (5 _ bromidazolium "l, 2al pyridine-3 _ a) azinc as described in Example 4 5, but treated with 3-dimethylaminopropylamine 2-anilino-72- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) « — — — — — — I — I· . Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291960 A7

V. INSTRUCTIONS (70) -4-(5-Xi Mijun幷[i,2a]p is more than -3-yl) shouting (example 98; 200 g, 0.52 mol) to obtain the target compound ( 92 grams, 34%). Nmr: (Please read the notes on the back and fill out this page) 1.48-1.58 (m, 2H), 2.10 (s, 6H), 2.20-2.28 (m, 2H), 2.72-2.80 (m, 2H), 7 · 08 (d, 1H), 7.40-7.48 (m, 2H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.71-7.78 (m, 3H), 7.90 (d, 2H), 8.55 (d , 1H), 8.64 (s, 1H); m/z: 530 [MH]+. Example 9 1 L(2-hydroxyethylthio)·2-{4-ΓΝ-(2-methoxyethyl)amine sulfonyl 1 phenylamino 丨· 4 -(米峻幷丨l,2a~ l·Bistidine·3-yl)pyrimidine r· Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed sodium strontium (1,58 mg of 60% mineral oil suspension, 4.0 mmol) added to NMP ( 4 ml) of 2-hydrogenthioethanol (0.139 ml, 2.0 mmol) was stirred for 30 minutes. Add 5-bromo-2-{4-[N-(2-methoxyethyl)aminesulfonyl]anilino}-4-(imidazo[1,2&amp; dissolved in NMP (1 mL) Pyridine-3-ylpyrimidine (Example 80; 100 mg, 0.19 mmol), and the mixture was heated at 120 °C for 3 hours. The mixture was allowed to cool, diluted for a long time, neutralized with 2 EtOAc, and extracted with ethyl acetate. The extract was washed with water and brine, and the volatiles were removed by dehydration and evaporation. The residue was purified by chromatography eluting with EtOAc/EtOAc (EtOAc) NMR: 2.85-2.98 (m, 4 Η), 3.15 (s, 3H), 3.24-3.30 (m, 2H), 3·51 (q, 2H), 4.82 (t, 1H), 7.10 (dd, 1H), 7.45-7.54 (m, 2H), 7.70 (d, 2H), 7·78 (d, 1H), 7.90 (d, 2H), 8.70 (s, 1H), 8.85 (s, 1H), 9.72 (d, 1H), 10.18 (s, 1H); m/z: 501 [MH]+ 〇 Example 9 2 -73- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7 -____B7__ V. INSTRUCTIONS INSTRUCTIONS (71) 2_-{4-『N-(3 -Tertiary carbonylamino)propylamine 1aminesulfonyl}anilino 4 ·(Mijun幷n, 2a~l·pyridine -3 -yl)pyrimidine (please read the note on the back and then fill out this page) 2-anilino-4-(imidazo[l,2a]pyridin-3-yl)pyrimidine (Example 16; 290 mg, 1.0 Millions were dissolved in sulfoxide (6 mL) and the mixture was cooled to 〇 °C. Gassulfonic acid (0.266 ml, 4.0 mmol) was added slowly and the mixture was stirred at 〇 °C for 30 minutes, allowed to warm to ambient temperature and stirred for 2 hours, then heated to reflux for 1 hour. The volatiles were removed by evaporation. The residue was dissolved in anhydrous p. (5 mL). EtOAc (EtOAc: EtOAc (EtOAc) , 10 mmol of pyridine (10 ml) and cooled to 〇 ° C under nitrogen. The mixture was stirred at 0 ° C for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation and the residue was azeotroped with water. The residue was taken up in water and filtered, and purified by chromatography eluting with methylene chloride/methanol (9 5: 5) and polarity to (90:10) to afford 207 mg (40%) of the desired compound. NMR: 1.30 (s, 9H), 1.50 (quin, 2H), 2.67 (m, 2H), 2.85 (m, 2 H), 7.38 (m, 2H), 7.58 (d, 1H), 7.68 (d, 1H) ), 7.70 (d, 2H), 7·89 (d, 1H), 7.95 (d, 2H), 8.58 (d, 1H), 8.80 (s, 10 lH); .m/z: 524 [MH]+ . Example 9 3 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1t_{4-『3_(Benzyloxycarbonylamino)propyl)aminesulfonyl 1 phenylamino-4- 4-imidazolium, 2alpyridin-3-yl)pyrimidine was treated as described in Example 9.2. 2. Anilino-4 -(imidazo[l,2a]pyridin-3-yl)pyrimidine (Example 16; 290 mg, 1.0 mmol) And 3-(benzyloxycarbonylamino)propylamine (0.294 ml, 1.2 mmol) gave the title compound 212 mg (3 8%). NMR: 1.50 (quin, 2H), 2.70 (q, 2H), 2.98 (dd, 2 H), __-74- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (72 4.98 (s? 2H)? 7.12-7.15 (m? 4H)? 7.18 (t? 2H)? 7.19 (t5 1H)? 7.75 (d, 2H ), 7.79 (d, 1H), 7.90 (d, 2H), 8.50 (d, 1H), 8.60 (s, 1H); m/z: 558 [MH]+ 〇 instance 9 4 two [i _ (2 — Methylaminoethyl ketone ^ ) aniline ^ _ phenyl syrup spit "i, 2al 庐 ratio 1- 3 - ) 3-(3-dimethylaminopropyl-2-ene-1-yl)-6 _Phenyl imidazolium [1,24 pyrimidine (Method 38; 50 gram, 〇17 mmol) was added to 4-(2-diethylaminoethoxy)phenyl hydrazine (Method 42; 60 亳)克, 〇19 mmol) and sodium methoxide (1 1 gram, 0.21 Torr) in n-butanol (1.5 liters) solution, the mixture was heated at 115 ° C for 15 hours. And the residue was purified by chromatography eluting with hexane/ethyl &amp; L ethyl ester (50:50) and polarity to ethyl acetate/methanol (8 〇:2 〇) to yield to the target compound (5 亳克, 6%). NMR: 1.07 (t, 6H), 2.64 (q, 4H), 2.92 (t, 2H), 4.10 (t, 2H), 6·98 (d, 2H), 7.08 (m, 2H) ), 7.15 (d, 1H), 7.37-7.60 (m, 4H), 7.70 (d, 2H), 7.92 (s, 1H), 8.30 (s, 1H), 8.35 (d, 1H), 9.80 (d, 1H); m/z: 479 [MH]+ 0 Example 9 5 4-(6-f-oxy-2-yylpyridinium njaipyridinyl v 2 _ r4 _amine-l-phenylanilide) 3-(3·monomethylaminopropan-2-ylindole-1·indenyl)_2-methylmethoxyimidazolium [l,2a]pyrimidine (Method 39; 862 mg, 3.51 mmol) was added to 4-amine was continued in a solution of carbaryl (Method 41; 1.5 g, 7.03⁄4 mol) and methanol steel (758 mg, 14 mmol) in n-butanol (4 mL). - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the phonetic on the back? Please fill out this page again)

1291960 A7 V. INSTRUCTIONS (73) (Please read the note on the back first? Then fill in this page) Heat 2 4 hours. The mixture was cooled, and the obtained precipitate was collected by filtration, and purified by chromatography eluting with ethylbenzene/ethyl acetate (5:50) and polarity to ethyl acetate/methanol (9 〇: 1 〇) to obtain the target compound. . NMR: 2.60 〇, 3H), 3.88 (s, 3H), 6.70 (dd, 1H), 7.03 (d, 1H), 7.12 (d, 1H), 7·18 (s, 2H), 7.75 (d, 2Η) ), 7.90 (d, 2Η), 8.52 (d, 1Η), 9.68 (d, 1Η), 9·97 (s, 1H); m/z: 411 [MH]+ 〇 Example 9 6 (3-aniline) 4-(pyrazole # π , 2alpyridine-3-yl)pyrimidine Anhydrous n-butanol (6.0 ml) was added to 3-(3-dimethylaminoprop-2-en-1-yl)-2 -methylpyrazol [2,3 a]pyridine (method 18; 180 mg, 0.84 mmol), 3- gas phenyl hydrazine (142 mg, 〇·84 mmol) and sodium hydride (67 mg) 60% mineral oil dispersion, ι·67 mmol, and the mixture was heated under nitrogen at i25 ° C for 7 hours. The volatiles were removed by evaporation, and the residue was crystallised from mixture of diethyl ether and distilled water. The title compound (78 mg, 29%) was obtained. 7.60 (d, 2H), 8.08 (s, 1H), 8.43 (d, 1H), 8.70 (d, 1H), 8.82 (d, 2H), 9·68 (s, 1H); m/z: 322 [ MH]+. Example 9 7 Ministry of Economics Production Bureau employee consumption cooperative printed 2 · Anilino-5 -bromo-4 · (imidazolium 1,2al pyridin-3-yl) pyrimidine treated as described in Example 7 1 2-amino-5-bromo-4 -(Imidazo[1,2&amp;]pyridin-3-yl)-salt (Method 31; 200 mg, 0.67 mmol) and bromobenzene (〇·〇 8 mL, 0.76 mmol), and hexane /ethyl acetate (5 〇: 5 〇) and the polarity is increased to (0: 100) dissolution and the product is purified by chromatography to obtain the target compound. NMR: 76- Table paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 V. Invention description (74) 6.98-7.10 (m, 2H), 7.30 (dd, 2H), 7.50 (dd, 1H), 7 collapse (d , 2H), 7.78 (d, 1H), 8.64 (s, 2H), 8.72 (s, 1H), 9 (d, ih), 9.82 (s, 1H). 5, Example 9 8 base-4 - (5 - bromoimidazolium, 2al pyridine &amp; treatment of 2-amino-4-(5-bromoimidazolium n,2a)pyridin-3-yl) as described in Example 71 (Method 35; 1.0 g, 3.4 m Mohr) and bromobenzene (4 36 ml, 4·1 亳mol) and borrowed ethyl acetate/methanol (9 8 : 2 ) Increasing polarity to (90:10) and purified by chromatography eluting product was the target compound 7〇 mg (6〇 / square. NMR: 7.00 (dd, 1H), 7.30-7.40 (m, 4H), 7 59 (d, 1H), 7.65-7.75 (m, 3H), 8.42 (d, 1H), 8.60 (s, 1H) , 9·7〇(s, 1H); m/z: 364 [MH]_. Preparation of the starting materials The starting materials of the above examples are either commercially available or prepared from known materials by standard methods. For example, the following reactions are illustrative, but are not intended to limit the preparation of some of the materials used in the above reactions. Method 1 Methyl hydrazine "l, 2al exo-k disease-3-yl" di-j-dimethylthiopyrimidine under nitrogen will contain 3-(3-dimethylaminopropan-2-indole-1- 2-methylimidazolium [l,2a]pyridine (method 2) (20 g, 87 mmol), thiourea (6.52 g, 86 mmol) and sodium methoxide (1·19)克, 22 mmol) of butanol (220 ml) was heated at 85 °C for 2 hours. Add methyl iodide (2 mL, 32 mmol). The mixture was heated at 85 ° C for an additional hour. And the volatiles were removed by evaporation. The residue was taken from ethyl acetate/methanol (1 〇〇: 〇 and polarity increased to 97 ··**: :------------ (please read the back) Note: Please fill out this page) Order---------- -77 1291960

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives. V. Description of the invention (?5) Separation and purification by chromatography to obtain the target compound (16 g, 7丨%). NMR: 2.59 (s, 1H), 2.62 (s, 3H), 7. 1 〇 (dd, 1H), 7.40 (dd, 1H), 7.42 (d, 1H), 7.63 (d, 1H), 8.62 (s, 1H), 9.54 (d, 1H), m/z: 257 [MH]+. Method 2

Lii3_dimethylaminopropane-2-ene-〗-_芊&gt; 2 -Methylimidazole #"1 · 2 alpyridine under nitrogen" 3 - ethyl hydrazino _ 2 · methyl imi 1,2 a]pyridine (method 3) (40 g of '0.23 mol) and DMFDMA (200 ml) were heated under reflux for 4 days. The volatiles were removed by evaporation. 21 g, 40%). NMR: 2.64 (s, 3H), 3.29 (s, όΗ), 5·50 (d, 1H), 7.00 (dd, 1H), 7.38 (dd, 1H), 7.54 (d, 1H), 7.70 (d,1H), 9.55 (d,1H), m/z: 230 [MH]+. Method 3 Acetyl-2-methylimidazolium "1.2 &amp; 1 pyridinium containing 2-amine A mixture of pyridine (60 g, 0.64 mol) and 3- gas-2,4-pentanedione (101.4 g, 0.75 mol) in diethyl ether (450 ml) and THF (750 ml) The mixture was allowed to stand at ambient temperature for 8 hours. The solvent was removed by evaporation, and the residue was purified by chromatography eluting with di-methane/hexane (1:1) and polarity to dioxin/methanol (9 8:2). The purified product was taken up in hexane to give the title compound (46.2 g, 40%). NMR: 2.55 (s, 3H), 2.68 (s) 3H), 7.15 (dd, lH), 7.56 (dd, 1H), 7·64 (d, 1H), 9.58 (d5 1H), m/z: 175 [MH]+. Method 4 (Imidazolium 1,2 Alpyridine-3 ·yl)-2-methylthiopyrimidine-78- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) (please read the notes on the back? )

I 1 n ϋ ϋ * mmmK 1_1 ϋ ϋ -ϋ I 1291960 A7 B7 V. Inventive Note (76) It is known that 3-(3-·-methylaminopropan-2-fine '-l-fluorenyl) taste η幷[1 2a]p is more positive than the mixture (method 5) (0.90 g ' 4.23⁄4 mol), sulphur (〇 · 32 g, 4.2 mmol) and sodium methoxide (0.34 g, 6.3 mmol) The butanol (1 ml) mixture was heated at 8 5 C for 2 hours. The mixture was cooled to 3 ° C, and methyl hydrazine (〇. 6 mL) 9.6 mM was added dropwise for 3 hours. The volatiles were removed by evaporation. EtOAcqqqqqqqq NMR: 2.61 (s, 3H), 7.22 (dd, 1H), 7.54 (dd, 1H), 7.72 (d, 1H), 7.77 (d5 1H), 8.56 (d, 1H), 8.66 (s, 1H) ), 9.83 (d, 1H); m/z: 243 [MH] + oxime method 5 h (3-dimethylaminoprop-2-en-2-yl)-2-methylimidazolium π. 2 Alpyridine A mixture of crude 3-acetylimidazolium [l,2a]pyridine (Method 6) (3.3 g, 19.1 mmol) and DMFDMA (40 mL) was heated under reflux for 6 hrs. The mixture was allowed to cool, the volatiles were removed by evaporation, and the residue was evaporated with hot acetic acid. The solid product was collected by filtration to give the title compound 2.29 g, 52%. NMR: 2.90 (br s, 3H), 3.10 (br s, 3H), 5.81 (d, 1H), 7_09 (dd, 1H), 7.42 (dd, 1H), 7·65 (d, 1H), 7.70 ( d, 1H), 8.43 (s, 1H), 9.72 (d, 1H); m/z: 216 [MH]+. Method 6 3 -Ethyl imidazolium, 2 alpyridine A small amount of aluminum chloride (20.4 g, 153.2 mmol) was added to the imidazo[1,2 a]pyridine (8.9) cooled at 5 °C. Gram, 75.7 millimoles) in a solution of di-methane (150 ml). The mixture was allowed to warm to ambient temperature and stirred for one hour, then heated to reflux. Then add acetic anhydride slowly in 30 minutes (5 · 1 milligrams of paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) --- -----Order-------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed-79- _ 1291960 A7

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives. V. Inventions (77) liter, 53.93⁄4 mol) and reflux heating the mixture for 9 〇 minutes. The reaction mixture was allowed to cool. The solvent was removed by evaporation and ice/water was added to the residue. The aqueous mixture was made alkaline with a 2 Torr aqueous solution of sodium hydroxide and extracted with ethyl acetate. The combined extracts were dehydrated and the volatiles were evaporated to give a brown oil. The oil was shown to contain about 35 % of the target compound, the balance being imidazolium [丨, 2 a] pyridinium. This mixture can be used directly without purification. NMR: 2.57 〇, 3 Η), 7.22 (dd, 1 Η), 7.61 (dd, 1 Η), 7.79 (d, 1 Η), 8.60 (s, 1 Η), 9.52 (d, 1H). Method 7 - (3,5_ 〃 〃 处 比 比 -1- 基 基 基 ) 横 横 -1- -1- 横 横 横 氢气 氢气 氢气 氢气 氢气 氢气 氢气 氢气 氢气 续 续 续 续 续 续 续 续 续 续 续 续 续 续 续 续 续Mercapto 4-nitrobenzene (Method 8) (500 mg, 1.82 mmol) and 1% palladium-carbon catalyst (150 mg) in ethanol (25 mL) and ethyl acetate (25 mL) The solution was 3 hours. The catalyst was removed by filtration through diatomaceous earth, and the filter pad was washed with ethanol and ethyl acetate. The volatiles were removed from the filtrate by evaporation, and the residue was crystallised from diethyl ether and hexane to afford the title compound (395 mg, 88 &lt; NMR·_4_90(s, 2H), 5.10 (s, 4H), 6.02 (s, 2H), 6.58 (d, 2H), 7.50 (d, 2H). Method 8 (3,5 · Dihydrohexahydropyridin-1-yl)sulfonyl-4 · Nitrophenyl 4-nitrobenzenesulfonamide (2.02 g, 10 mmol) was added to contain 1,3 , a solution of 5-trioxane (1.96 g, 20 mmol) in acetic acid (5 mL). The mixture was stirred for 5 minutes and methanesulfonic acid (1 mL) was slowly added. The mixture was further stirred at 35 ° C for 20 minutes and cooled to 〇 ° C, washed with water and twice with 5% aqueous sodium hydrogen carbonate solution, then evaporated and evaporated to remove volatiles. Residues from B-80- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -ΛΨ-------- — — — — — 1291960 A7 V. INSTRUCTION DESCRIPTION (78) Recrystallization from the alcohol gave the title compound (955 mg, 35%). NMR: 4 87 (s, 2H), 5.30 (s, 4H), 8.20 (d, 2H), 8.42 (d, 2H). Diethylaminoethoxy) hydrazine is stirred under hydrogen pressure with 4-(2-diethylaminoethoxy)_ 1 nitrobenzene (method 10) (1.0 g, 4.23⁄4 mol) And 1 〇% palladium-carbon catalyst (2 〇〇 mg) mixture of ethanol (30 liters) for 3 hours. The catalyst was removed by filtration through Shixiazao soil, and the filter pad was washed with methanol. The volatiles were removed from the filtrate to give the title compound (400 mg, 46%). M/z: 209 [MH]+. Method 1 0 (2-diethylaminoethane group)_ 1 _Nanmo Moshui (8 ml) and xylene (35 ml) were added to sodium 4-nitrobenzene oxide (1 〇.5 g, 65 mmol, a mixture of 2-(diethylamino)ethyl chloride hydrochloride (8.6 g, 5 mmol) and potassium carbonate (10.4 g, 75 mmol), the mixture was refluxed Heat for 2 hours. The Dinsdaker device is then installed and the water removed. The organic solution was allowed to cool to ambient temperature and allowed to stand for 18 hours. The solution was decanted from the solidified column and the volatiles were evaporated to give the title compound (8.0 g, 52%). NMR: 0.90 (t, 6H), 2.50 (q, 2H) 2.89 (t5 2H), 4.15 (t, 2H), 7.15 (d, 2H), 8.18 (d, 2H); m/z: 239 [MH] +. Method 1 1 4 - "3 - (N,N-Dimethyl)amino-2-hydroxypropane 1 Benzene 3-N,N-Dimethylamino-2-hydroxy-3-(4- Nitrophenoxy)propane (Method 12) (3.75 g) is dissolved in ethanol (40 liters). Under nitrogen pressure, 1 〇 0 /. -81 - Private paper scale is applicable to China National Standard (CNS) A4 specification. (210 x 297 mm) (Please read the note on the back and fill out this page) | Install---- 1111111 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 B7 V. Description of Invention (79) Palladium-Carbon (0.4 g). Nitrogen was replaced by hydrogen, and the reaction mixture was stirred overnight. The catalyst was removed by filtration through Shixia, and the filtrate was evaporated to dryness. The residue was dissolved in diethyl ether containing a small amount of isopropanol and hydrogen chloride was added. Solution (1 Μ ether solution, 16 liters). Ethyl ether was evaporated and the solid residue was suspended in isopropanol. The mixture was heated on a steam bath for a few minutes and then cooled to ambient temperature. The powder was washed with isopropyl alcohol, diethyl ether and dried (3 〇 4 g, 72.4%). NMR: 2.80 (s, 6 Η), 3.15 (m, 2 Η), 3·88 (m, 2 Η), 4 .25 (m,1H), 5.93 (br S,1H),6.88 (m,4H); m/z 211 [ΜΗ]+; EA CUH18N202.1.6 HC1 Computation: C; 49.2, Η; 7·4, 10.4, Cl; 21.7%: measured 値: C; 49.2, H; 7.2, N; 10.1; C1; 191〇/〇. Method 1 2 Amine 碁 基 nitro 苽 argon, and will be 1- ( 4-Nitrophenoxy)-2,3-epoxypropane (Method 13) (4.3 g) was dissolved in methanol (30 mL) and DMF (10 mL). 17 liters), and the mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in saturated aqueous hydrogen carbonate and ethyl acetate. The ethyl acetate layer was separated and washed twice with saturated brine. Dehydrated with anhydrous sodium sulfate, filtered and evaporated to give crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssss (m, 1H), 4.00 (m, 3H), 7.00 (d, 2H), 8.20 (d, 2H); m/z 241 [MH]+. Method 1 3 Blocks oxy)-2,3_ Ring^ ^ 1-(Nitrophenoxy)-2,3-epoxypropane by means of 21^11_2}1〇11§1^, etc. (Please read the note on the back first) Fill in this page) Order--------- I·· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-82- 1291960 A7 B7 V. Invention Description (80) Human Synthetic Communication (1994), 24 Prepared by a similar method as described on pages 833-839. iu-IL------Φ loading (please read the notes on the back and fill out this page) 4_Nitrophenol (4.0g), anhydrous potassium carbonate (8.0g) and tetrabutylammonium bromide (0.4 g) mixed with epibromohydrin (1 〇 ml). The reaction mixture was at 1 Torr. (: heating for 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered, filtered, evaporated to dryness, and the residue was twice distilled with toluene. Ethanol (丨〇0/〇): purified by elution with dichloromethane, and evaporated to crystallize (4·36 g, 77.7%). NMR (CDCl3)·· 2.78 (m, lH), 2.95 (m, 1H) , 3·38 (m, 1H), 4.02 (dd, 1H), 4.38 (dd, 1H), 7.00 (d, 2H), 8.20 (d5 2H); m/z 196 [MH]+. Method 1 4 ( 2,5 _Dimethylfuranthene, 2 alpyridin-3-ylpyrimidine I·. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 3 _(3-dimethylaminoprop-2-ene-1 - mercapto)-2,5-dimethylimidazo[1,2 a] p ratio bite (method 15) (3.50 g, 14.4 mmol), thiourea (1.09 g, 14.4 mmol) and methanol A mixture of sodium (1.01 g, 18.7 mmol) was heated in '5 5 C for 2 hours in butanol (50 liters). The mixture was cooled to 30 ° C and potassium moth (1.8 ml, 28.8) was added dropwise. Milligram), the mixture was stirred for additional 3 hours. The volatiles were removed by evaporation and the residue was taken from ethyl acetate / methanol ( 1 〇〇:0 and the polarity was increased to 97: 3) The title compound (2.37 g, 61%) was obtained by chromatography. NMR: 2.41 (s, 3H), 2.60 (s, 3H), 2·70 ( s,10 3H), 7.56 (d,1H), 7.88 (d,1H),7_92 (d,1H),8·81 (d,1H),9.39 (s,1H); m/z: 271 [MH ]+〇Method 1 5 3 - (3 -Dimethylaminoprop-2-en-1-ylindenyl)-2,5-dimethylimidazo[1, 2 al -83 - This paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291960 A7 --______B7____ V. Description of Invention (81 ) Containing 3-ethoxycarbonyl-2,5-dimethyl A solution of the imidazolium [1,2a]pyridine (method 16) (3.60 g, 19.1 mmol) in DMF DMA (20 mL) was warmed to reflux for 60 hours. The mixture was cooled and evaporated to remove solvent. The solid was collected by filtration and dried to give title compound (3.61 g, 84%). NMR: 2.30 (s? 3H)? 2.62 (s? 3H)? 2.90 (br s? 3H)? 3.10 (br s? 3H) , 5.48 (d, 1H), 7.22 (dd5 1H), 7.44 (d, 1H), 7·68 (d5 1H), 9_39 (dd, 1H) 0 Method 1 6 1 - B Acid-based-2,5-dimethyl succinyl sulphate f 1,2 a Add 3-oxo-2,4-pentanedione (6.5 ml, 54.4 mmol) to the 2-amino group- 4-Methyl p was mixed with a solution of dec. (5.00 g, 46.3 mmol) and EtOAc (EtOAc) (EtOAc). The reaction mixture was cooled and the solvent was removed by evaporation. The resulting solid residue was dispersed in hot hexane. Filtration, collection and dehydration gave the title compound (3 · 69 g, 43%). NMR: 2.35 (s, 3H), 2.75 (s, 3H), 7.41 (dd5 1H), 7.57 (d, 1H) 9.40 (d, 1H); m/z: 189 [MH]+. Method 1 7 4 · (2-methylpyrazolium "2,3 alpyridin-3-yl-V 2 -methyl" will contain 3-(3 · dimethylaminoprop-2-ene) under nitrogen i _ 醯 ) ) _ 2 _ 甲 甲 azole 幷 [2, 3a] pyridine (method 18) (3.89 g, 17 亳 Mo Er), sulfur urinary urine (1.27 g, 17 mmol) and sodium methoxide (0.929 a mixture of butyl alcohol (45 ml) in butyl alcohol (45 ml) was heated at 85 ° C for 2 hours. Add the iodine clock (1 〇 5 ml, 1 7 mmol). The mixture was heated at 85 ° C for an additional 2 hours. Evaporation removal wave -84- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note before filling this page) | Fog — — — — — — — 1291960 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (82) Hair, residue by ethyl acetate/methanol (1 〇〇: 〇 and polarity increased to 9 7 : 3 ) Dissolution and chromatography Purification gave the title compound (3.1 g, EtOAc): </RTI> </ RTI> </ RTI> 2.58 (s5 1H), 2.68 (s, 3H), 7.04 (dd5 1H), 7.39 (dd, 1H), 7.48 (d, 1H), 8.35 (d,1H), 8.50 (d,1H), 8.72 (d,1H); m/z: 257 [M H]+〇 method 1 8 3-(3---fe-propyl-propyl-2)-women-1-bristyl)-2-methyl p is more than 2,3 a] p ratio under nitrogen, 3-Ethyl-2-methylpyrazol[2,3 a]pyridine (Method 19) (2 g, 11.5 mmol) and 〇^«^ 八 (10 mL) at 11 〇. The mixture was heated for 48 hours. The volatiles were evaporated, evaporated, evaporated, evaporated, evaporated, evaporated ,1H), 6.95 (dd,1H), 7.38 (dd,1H), 7.62 (d,1H),8·10 (d,1H),8·62 (d,1H); m/z: 230 [MH ]+. Method 1 9 3 -Ethyl 2 -methyl p is more than 2,3 al p than water containing 1-aminopyridine iodine (26.9 g, 0.12 mol) (336 ml) The solution was first added with potassium carbonate (53.8 g, 0.39 mol), followed by the addition of a mixture of 2,4-pentamethylenediamine (24.8 g '0.25 m) as it was heated at 80 °C for 2 hours to make it; Allow to stand at ambient temperature for 18 hours. Add water and extract the characters with ethyl acetate. The combined extracts were dehydrated and evaporated to remove volatiles. The residue was recrystallized from hexane and the product was collected by filtration. The solvent is removed from the filtrate by evaporation and added to the insoluble residue from recrystallization. The crude product was produced by Yangshao-fluoromethane/hexane (1··1) and the polarity was increased to dichloromethane/methanol (9 7 V separation and purification by chromatography. The product was dispersed in hexane and added. The Chinese Standard (CNS) A4 specification (210 X 297 mm) is applied to the -85- table paper scale obtained by crystallization, called &amp; % Dan (please read the note on the back and fill out this page) | ------------------------------------------------------------------------------------- , 7, 09 (dd, 1H), 7·55 (dd, 1H), 8.12 (d, 1Η), 8.72 (d, 1H); m/z: 175 [MH]+. Method 20 2 - gas · 4 · (imidazolium, 2 al pyridine 3 -yl) pyrimidine under nitrogen, suspended in phosphorus helium (200 ml) and pentachlorinated scale (ii g, 53%) of 2-hydroxy-4 (Imidazolium [1,2 a]pyridin-3-yl)pyran (Method 21; 9.92 g, 46%). The suspension was heated under reflux for 24 hours. Evaporation was carried out to remove excess phosphorus helium, and ice water was added, and 2 Μ The mixture is neutralized with an aqueous solution of sodium hydroxide. The aqueous mixture is extracted with acetic acid to dehydrate and evaporate to obtain a mesh. The standard compound is 7.42 g (69%). NMR: 7.15 (dd, 1 Η), 7.59 (dd, 1 Η), 7.80 (d, 1H), 8.05 (d, 1H), 8.64 (d, 1H), 8.79 ( s,1H),9.72 (d, 1H); m/z: 231 [MH] + oxime method 2 1 2 -hydroxyl 4 -(imidazolium, 2 al pyridine _ 3 - some V sputum at 60 ° C Next, a solution of sodium nitrate (11 〇 4 g, 〇16 mol) dissolved in water (100 ml) was added to 2-amino-4-(imidazole) dissolved in 70% acetic acid (300 ml). [l,2a]pyridin-3-yl)pyrimidine (Method 22; 11.27 g, 0.053 mol). The mixture was heated at 60 ° C for 3 hours, allowed to cool and neutralized with 5 NaOH aqueous sodium hydroxide. The resulting precipitate was collected by filtration, washed rapidly with cold water and dried in vacuo to give the title compound 9 95 g (89%) NMR: 6.98 (d, 1H), 7.12 (dd, 1H), 7.55 (dd,1H), 7.80 (d,1H), 7.82 (d,1H), 8.70 (s,1H); m/z: 213 [MH]+. Method 2 2 —— -86 - This paper size applies to China National Standard (CNS) A4 specification (210 x 297 public f) HIIL------ (Please read the back note first and then fill out this page) — — — — — — — Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1291960 Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Cooperatives, Printing A7 V. Inventions (84) 2·Amino-4 (GM squatting syndrome will contain 3-(3_ Dimethylaminopropion-2-en-an-1-aryl)mijun and n, 2a air enthalpy (method 5; 20 g, 0.093 mol), sodium methoxide (2 〇 gram, 〇 372 mol) and The mixture of hydrazine hydrochloride (22.09 g, 233. 233 mol) of n-butanol (15 ml) and methanol (1000 ml) was heated under reflux for 6 hours. The obtained solution and the insoluble matter were poured out, and the volatiles were removed by evaporation, and the residue was purified by chromatography eluting with methylene chloride/methanol (97:3) to give the title compound 13* (67% "nmr: 6 78 (s, 1H), 7.15-7.05 (m, 2H), 7.45 (dd, 2H), 7.70 (d, 1H), 8.20 (d, 1H)? 8.50 (s? 1H)5 10.15 (d? 1H); m/z : 212 [MH]+o Method 2 3 4-(N-Methylamine sulfonyl) oxime neck Add methylamine (3 ml of 3 3 〇/〇 ethanol solution) to fluorinated sulfonamide (200 耄) Gram, 1.13⁄4 mol), followed by the addition of triethylamine (〇 159 ml, !) millimolar), the mixture was heated at 80 ° C for 6 hours, then stirred at ambient temperature for 8 hours. Evaporation to remove volatiles The residue was azeotroped with toluene to give the title compound (160 mg, 76%). NMR: 2.30 (s, 3H), 5.85 (s, 2H), 6.60 (d, 2 Η), 7. 39 (d, 2H); m/z: 187 [ΜΗ]+. Method 2 4 ULN-(2-methoxyethyl)amine sulfonyl)aniline will contain 2-methoxyethylamine (859 mg, η·4 Milligram), fluorinated aniline (1.0 g, 5.71 mmol) and triethylamine (1.72 g, 22.9 mmol) n-butanol mixture heated under reflux 1 8 Time. The mixture was allowed to cool and evaporated to remove the volatiles. The residue was purified by chromatography eluting with ethyl acetate/hexane (5:50) and polarity to (7 〇: 30) to give the title compound (86 〇 mg, 87 - the paper size is applicable to the Chinese national standard (CNS) A4 specification (21〇X 297 mm)

---.---.------ (Please read the notes on the back and fill out this page) Order---------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 A7 B7 V. INSTRUCTIONS (85) 65%) NMR NMR·· 2.78 (q, 2H), 3.15 (s5 3H), 3.25 (t5 2H), 5.87 (s, 2H), 6.58 (d, 2H), 7.10 ( t, 1H), 7.40 (d, 2H); m/z: 231 [MH]+. Method 2 5 - 2 6 The following compounds were prepared using the procedure of Method 2 4 . Methods Compound name NMR m/z 25 4-(N-propylaminesulfonyl)aniline 0.78 (t5 3H), 1.40 -1.25 (m, 2H), 2.60 (q, 2H), 5.84 (s, 2H), 6.59 (d,2H),7·00 (UH),7.39 (d,2H) 26 4-(N-cyclopropylaminesulfonyl)aniline 0.01-0.15 (m5 4H), 1.70- 1 ·75 (m , 1H), 5.60 (s, 2H), 6.30 (d, 2H), 7.05 (s, 1H), 7.10 rd, 2H) 211 [MH]. Method 27 1 _Γ3-(4-bromobenzylidene Amino group &gt; propyl 1 M 4 Add 1-(3-aminopropyl)imidazole (2.39 ml, 〇.〇2 mol) to 4-bromobenzoic acid (4·0 g, 0.018 mol) In a solution of ethanol (250 ml), the mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation, and the residue was burned with a gas / a gas (5 0 : 50) and the polarity increased to a gas. /Methanol (8 〇: 2 〇) Dissolution and purification by chromatography to the target compound. NMR: 1.95 (m 2 Η) 3.20 (q, 2H), 4.0 (t, 2H), 6.87 (s, 1H), 7.19 ( s,1H), 7.64 (d, 2H), 7.68 (s,1H), 7.78 (d,2H), 8.58 (t,1H); m/z: 308 [MH]+0 Method 2 8 1-丨3 -(4-bromobenzylideneamino)propyl i-2•oxo a contig Treatment of 1-(3-aminopropyl)_ 2 oxopropyrrolidine (3·07 ml '14 mmol) as described in Method 2 7 gave the title compound. nmr: 1.68 (quin, _ - 88- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) IL___~____________ (Please read the note on the back and fill out this page) II 爹OJ mmamm n ϋ * 1291960 A7

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (86) 2H), 1.90 (quin, 2H), 2.0 (t5 2Η), 3·15-3·22 (m, 4H), 3·29- 3·33 (m, 2H), 7.64 (d, 2H), 7·78 (d, 2H), 8.48 (t, 1H). Method 2 9 Chloro-1-(2-methoxyethylamine sulfonate)benzene will be dissolved in n-butanol (10 ml) of 2,4-dichlorobenzenesulfonyl chloride <5 mg, 2 A mixture of 1-methoxyl and 2-methoxyethylamine (230 mg, 3.1 mmol) was heated under reflux for 1 hour. The volatiles were removed by evaporation, and the residue was purified by chromatography eluting with EtOAc (EtOAc) NMR: 3. 〇4 (t, 2H), 3.08 (s, 3H), 3.22 (t5 2H), 7.60 (dd, 1H), 7.82 (d, 1H), 7.92 (d, 1H), 8.0 (s, 1H); m/z: 282 [MH]-. Method 3 0 foot, 4 - a milk · 1_ (1-propylamine continuation base) benzene; spring in the positive butanol (103⁄4 liters) of 2,4_dichlorobenzene horizontal g stupid (5 〇〇 A mixture of milligrams, 2·1 Amol) and 1-propylamine (0.2 mL, 2.4 mmol) was heated under reflux for 48 hours. The volatiles were removed by evaporation. NMR: 0.78 (t, 3 Η), 1.35 (q, 2H), 2.79 (t, 2H), 7.60 (dd, 1H), 7.84 (d, 1H), 7.92 (d5 2H). Method 3 1 5 -Bromo-4 -(imidazolium "K 2 alpyridine · 3 -yl) sulfonate Bromine (54 liters, 0.0011 moles) was added dropwise at ambient temperature to 2-amino-containing 4- (Imidazolium [l52a]pyridine-3-(yl)pyrimidine (Method 22; 2 (10) mg, 〇95 mmol) in acetic acid (4 mL). The mixture was heated at 65 ° C for 9 Torr and allowed to cool. The resulting precipitate was collected by filtration, washed with hexane and dehydrated, _____ _ - 89 - paper size national standard (CNS) A4 size (210 X 297 mm) --*- ---Γ ---1------ Pack---- (Please read the notes on the back and fill out this page) 1111111 1291960 Β7 V. Inventive Note (87) Obtain the target compound. NMR: 7_44 (dd, 1H), 7·9〇·8·〇〇 (m, 2H), 8·59 (s, 1H), 8.99 (s, 1H), 9.78 (d, 1H); m/z : 290 [MH]+. (Please read the notes on the back and fill out this page) Method 3 2 5 -Bromoimidazolium . 2 al pyridine containing diethyl acetoacetate (50 ml, 0.332 mol) of 2 4 (143 ml) A solution of water (85 ml) and concentrated hydrochloric acid (5 ml) was heated under reflux for 3 min to allow the mixture to cool. Add bicarbonate steel (53 g), then add a solution containing 5 · bromo-2-aminopyridine (30 g, 0.174 mol) in dioxane (230 ml) and water (85 ml). Heat under reflux for 24 hours. The mixture was cooled, poured into water and acidified with 2 HCl. The mixture was washed with ethyl acetate and the aqueous layer was purified with 2 aqueous sodium hydroxide. The aqueous mixture was extracted with ethyl acetate. The extracts were combined, dehydrated, and evaporated to remove volatiles. The residue was purified by chromatography eluting with hexane/ethyl acetate (50:50) and polarity to (2 5 ··50) to afford 20 g (59%) of the desired compound. NMR: 7.30 (dd, 1 Η), 7.54 (d, 1H), 7.59 (s, 1H), 7.90 (s, 1H), 8.89 (S, 1H); m/z: 197 [MH]+. Method 3 3 3 - Ethyl-5 - bromopyrazine, 2 ah Bishui Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed a small part of gasified aluminum (10.2 g, 77 mmol) in 1〇 Add to a solution of 5 · bromoimidazolium [1,2 a]pyridine (Method 3 2; 5.0 g, 26 mmol) in hexanes (1 mL). The mixture was heated under reflux and acetonitrile (2.54 mL, 3 όm) was added over 15 min. The mixture was heated under reflux for 24 hours, cooled to hydrazine, and then additional aluminum chloride (1 〇 2 g, 77 </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> followed by the addition of acetonitrile (3.26 mL). Mixture reflow heating 24 small -90- This paper scale is applicable to China National Standard (CNS) A4 specification (21〇χ 297 mm) 1291960 A7 B7 V. Invention description (88) (Please read the back of the note? On this page) then 'evaporate to remove volatiles. Ice water was added, and the mixture was purified with aq. The extract was washed with water, dehydrated, and evaporated to give the title compound (4.0 g). NMR: 2.58 (s, 3 Η), 7.74-7.82 (m, 2 Η), 8.62 (s, 1 Η), 9.62 (s5 1H); m/z: 241 [MH]+. Method 3 4 hbromo-3 - (3-dimethylaminopropan-2-en-1-indolyl) imidazolium "1,2 alpyridine 3-ethylindolyl-5-bromoimidazolium [1,2 a]pyridine (method 3 3; 4.0 g) was dissolved in DMF EtOAc (EtOAc)EtOAc. Excess DMFDMA was removed by evaporation. The residue was crystallised eluted eluted eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut d,1Η), 7.58 (dd,1H),7·64 (d,1H), 7.70 (s,1H),8.44 (s,IH),9.90 (s,1H); m/z: 294 [MH] +. Method 3 5 % 2 -Amino-4-(5-bromoimidazolium, 2 alpyridine-3yl)pyrimidine Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed to make 5-Bromo·3 - (3 - Dimethylaminoprop-2-en-1-yl-imidazolium [1,2a]pyridine (Method 34; 2.5 g, 8.5 mmol), hydrazine hydrochloride (2.01 g, 2 1 mmol) A mixture of n-butanol (140 ml) and methanol (45 ml) of sodium methoxide (1.83 g, 34 mmol) was heated under reflux for 18 hours. The volatiles were removed by evaporation. (9 5 : 5 ) Dissolution and purification by chromatography to give the desired compound (1.1 g (45%). NMR: 6.86 (s, 2H), 7.12 (d, 1H), 7.57 (dd, 1H), 7.68 (d, 1 Η) ), 8.22 (d, 1H), 8.51 (s, 1H); m/z: 290 [MH] + 〇-91 - This paper scale applies to Chinese national standards (CN S) A4 size (210 X 297 mm) A7 1291960 B7 ___ V. Description of invention (89) Method 3 6 L-phenylimidazole #丨1 h ;| Adjacent to 2-amino-4 as described in Method 32 -Phenylpyridine (0-90 g, 5.29 mmol) gave the title compound: KMR: 7.07 (d, 1 Η), 7.35-7.53 (m, 4H), 7.59 (s5 1H), 7.64 (d, 2H) ), 7.83 (s, 1H), 8·18 (d, 1H); m/z: 195 [MH], method 3 7 3 - bromo-6 - stupid amide 幷 "i, 2 ahh will contain bromine ( A solution of 0. 24 ml, 4.6 mmol (water) (1 ml) was added to ethanol containing 6-phenyl imizone [i, 2a] pyridine (method 36; 0.85 g, 4.88 mmol). In a solution of 5 ml), the mixture was stirred for 1 hour in the dark. The mixture was basified with aqueous sodium bicarbonate and extracted with di-methane. The extract was evaporated to remove solvent. The title compound was obtained. NMR: 7.38-7.56 (m, 4H), 7.77 (s, 1H), 7.83 (d, 2H), 7.96 (s, 1H), 8.39 (d, 1H); m/z: 273 [MH ]+. Method 3 8 3 : (3 -Dimethylaminoprop-2-enyl-1 醯-yl-v 6 -phenylimidazolium 1,2 alpyridine under nitrogen) will be phenyl magnesium (2.7 liters 1M THF solution) was added to a solution of 3- odor-6 phenyl imidon [1,2 a] pyridine (method 3 7 ; 〇 48 g, 丨76 mmol) in THF, and the mixture was heated under reflux for 2 hours. The mixture was cooled to 0 C and N. methoxymethylacetamide (3 mL, 2.64 mmol) was added dropwise. The mixture was warmed to ambient temperature and stirred for 18 hr. Wash with aqueous sodium bicarbonate, then wash and dehydrate with brine, remove volatiles by evaporation. Residue dissolved in DMFDMA (swell) __ - 92 - P-sheet scale applicable to China National Standard (CNS) A4 size (210 X 297 mm) ----^~ (Please read the note on the back first? Then fill in this page) - Install -------- Book i:------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291960 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Inventive Note (9Q), the mixture was heated under nitrogen for 60 hours. Excess DMFDMA was removed, the residue was taken up in EtOAc (EtOAc) elute ), 7.38-7.58 (m, 4H), 7.67 (d5 1H), 7.86 (d, 2H), 8.00 (s, 1H), 8.48 (s, 1H), 9·76 (d, 1H); m/z : 292 [MH]+ 〇 Method 3 9 3-(3 -Dimethylaminoprop-2-en-1-yl)-2-methyl-6_A gas π 幷 "1,2 al Pyridine will contain 3-ethylindolyl-6-methoxy-2-methylphenoxypurine [1,2 a] p ratio (method 40; 1.49 g, 7.3 mmol) and toluenesulfonic acid (5 mg) The DMFDMA (25 ml) was heated under reflux for 20 h. EtOAc (EtOAc): 3.82 (s, 3H), 5.44 (d, 1H), 6.69 (dd, 1H), 6.97 (d, 1H), 7.65 (d5 1H), 9.21 (d5 1H); m/z: 260 [ΜΗ] Method 4 0 3 -Ethyl-6-methoxy-2-methylmiridine, 2 ap is added to the solution containing 3·chloroethane oxime (2.86 ml) in THF (6 ml) 2-amino-4-A Pyridine (2.71 g, 21.8 mmol) of THF (14 milliliters) was added and the mixture was stirred at ambient temperature 30 minutes, followed by stirring for 3 hours at reflux. The solvent was removed by evaporation and the residue was purified eluting eluting eluting eluting eluting eluting 47%). NMR: 2.05 (s,3H), 2.63 (s,3H),3_86 (s,3H)5 6_83 (dd,1H),7.07 (d,1H),9.20 (d5 -93 - This paper scale applies to Chinese national standards (CNS) A4 size (210 x 297 mm) ---^ - 1·1 ! ! ! ! ! ! 丨丨丨 I 丨 II (Please read the note on the back and fill out this page) 1291960 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 Β7 V. Invention description (91) !Η); m/z: 205 [MH]+ Axillary-amine sia-based phenyl laurel is dissolved in ethanol (60 ml) and A mixture of sulfonanilide (2 g, 0.166 mol) and benzylthiocyanylguanamine (34 g, 0.33 mol) in concentrated hydrochloric acid (li ml) was heated in a steam bath until solvent evaporated. Water was added and the mixture was heated under reflux for 5 minutes. Sodium hydroxide (丨 4 · 4 g) was added and the mixture was heated under reflux. The mixture was allowed to cool, the pH was adjusted to 2 with hydrochloric acid, and the precipitated solid was removed by filtration. The filtrate was neutralized and the solvent was removed by evaporation. The residue was recrystallized from water to give a crude target compound. m/z: 215 [MH]+. Method 42 4-(2-Methylaminoethane) phenyl veins are dissolved in water (1 ml) of 3,5-dimethylpyrazole formazan nitrate (〇·2 g, 13⁄4 mol) A mixture of 4-(2·diethylaminoethoxy)aniline (method 9; gram, 48 mmol) was heated under reflux for 3 hours. The solvent was removed by evaporation, the residue was crystalljjjjjjjj NMR: 0.98 (t, 6H), 2.57 (q9 4H)? 2.79 (t? 2H), 4.00 (t5 2H)? 6.99 (d, 2H), 7.15 (d, 2H); m/z: 251 [MH] + 〇Example 9 9 The following is a representative formulation for the treatment or prevention of a compound of formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester (hereinafter referred to as a compound hydrazine) for human use: 94- _ *_ J ^· i_i i_·— n ϋ tmf l an · ·ϋ l ϋ 1 ϋ mmmat ^ ^ 1··· Βϋ 1 ^1 (Please read the note on the back and fill out this page) / y ζ X lu ζ i Η - 1/ ο Ν 1 V 卞1291960 A7 B7 V. INSTRUCTIONS (92) (a): Lozenges I mg/ingot compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5 % w/v cream) 2.25 Magnesium stearate 3.0 (b): Lozenges II mg/ingot compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyethyl gamma phloprofenone (5% w/v cream) 2.25 Magnesium stearate 3.0 (c): lozenge III mg/ingot compound X 1.0 lactose Ph.Eur 93.25 croscarmellose sodium 4.0 corn house powder paste (5% w/ v cream) 0.75 magnesium stearate 1.0 ---.---~------ loaded -------- -------- (Please read the note on the back of the note 2 and then fill out this page) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives (d): Capsules mg / capsule compound X 10 Lactose Ph.Eur 488.5 Stearin Magnesium 1.5 - 95- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291960 A7

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

(Please read the notes on the back and fill out this page)

The degree of application applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm - loaded -------- ordered - I I .

Claims (1)

1291960 Brother Patent Application No. 08$117386 Chinese _ j Please replace the patent scope too. Patent scope ι· A compound of formula (1)·· Η (R1), D Λ (I) wherein: % 八 is imidazo[l52a]pyridyl or pyrrolo[2,3 is pyridine _3 _ group; R2 is attached to the carbocyclic ring and is selected from the group consisting of a cyano group, a cyano group, and a C 丨6 alkyl group. , C丨·6 alkoxy, Cw alkyl s(0)a wherein 3 is fluorene, phenyl, phenylthio or (heterocyclylthio; wherein phenyl or heterocyclic is optionally present) Substituted by one or more G on carbon; m is 0 - 2 ; wherein R 2 may be the same or different; may be a sail of a4°; wherein any C-group may be substituted by one or more Js in the slave η is 0 to 1; 裱18 is phenyl or phenyl fused to the CW cycloalkyl ring; R3 is halogen or amine sulfonyl; ρ is 0 - 2; wherein r 3 may be the same or different; R 4 is Α-Ε-based; wherein lanthanide is selected from Cw alkyl, phenyl, heterocyclic, C38 naphthene paper scale itifl + ® standard (CNS) A4 specification (21GX〗 97^' '---- ——____ ABCD 1291960 VI. Patent application range: alkyl, phenyl, heterocyclic, CS_8 cycloalkyl, phenyl Cm alkyl, (heterocyclyl) Cu alkyl or C3·8 cycloalkyl Cl·6 alkane The base may be substituted on the carbon by one or more D as appropriate, and if the heterocyclic group is contained In the NH part, the nitrogen atom may be optionally substituted with a group selected from R; ·, E is a chemical bond or -〇-, _c(〇)...·Ν(γ)(:(〇)-, or -N( Ra)SCV; wherein Ra is hydrogen or Ci6 alkyl and "is 〇_2; D is independently selected from a group, an amine group, a alkoxy group, a NU group) amine group, N,N-(Cl.6 alkane a base of an amine, a Ci. 6 alkoxycarbonylamino group and a benzyloxycarbonylamino group, wherein any of C 1-6 alkyl or phenyl may be substituted on the carbon by one or more K; q is 0 - 1, G, J and K are independently selected from a # group, a dimethylamino group or a diethylamino group; R is selected from a CM alkyl group; and wherein the heterocyclic group is selected from pyrimidinyl, 3,5-di a group consisting of hexahydropyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, imidazolyl, morpholinyl, hexahydropyridyl, guanidine, and thiophene; or its pharmaceutical acceptability Salt 2. A compound of the formula (I) according to the scope of claim 1 wherein R1 is bromine or 2-3⁄4 ethylthio group and η is 〇-1; or a pharmaceutically acceptable salt thereof. A compound of the formula (1) according to any one of claims 1 to 2, wherein the cyclic oxime is imidazo[l,2a]pyridin a pyridine-3-yl group; or a pharmaceutically acceptable salt thereof. 4. According to the formula of any one of claims j to 2, the paper scale standard _71^ sees the grid (21〇x -29?7 mm) A BCD 1291960 VI. In the scope of patent application, V is attached to ring carbon and is selected from the group consisting of Dun, Chlorine, Bromine, Cyano, Methyl, Methoxy Ethylthio, 2-Hydroxyethylidene Or 2-dimethylaminoethylthio and (5) are 0-2; wherein R2 may be the same or different; or a pharmaceutically acceptable salt thereof. 5. The compound of the formula (1) according to any one of claims 1 to 2 wherein R is a murine, chloro, m- or amine acid group; and p is 1; or a pharmaceutically acceptable salt thereof. 6. A compound of the formula (1) according to any one of claims 1 to 2, wherein R is methyl, ethyl, methoxy, methylthio, ethyl benzyl, benzyloxy, methylsulfonate Mercapto, N,N-diethylaminoethoxy, 3-N,N-dimethylamino-2-hydroxypropoxy, phenoxy, N-methylaminecarbamyl, N,N- Dimethylamine A, Azyl, N-(3-imidazol-1-ylpropyl)amine, M-N-[3-(2-oxopyrrolidin-1-yl)propyl]aminocarbazide , 3,5-dihexahydropyrazine-1 -ylsulfonyl, N-cyclopropylamine sulfonyl, N-cyclopropylmethylamine sulfonate, anilino-transverse base, N-call -2-2-ylamine acid group, N-methylamine sulfonyl group, N-propylamine sulfonyl group, N-(2-methoxyethyl)amine sulfonate, N-(2-A Aminoethyl)amine sulfonyl, N-(2-isopropylaminoethyl)amine sulfonyl, N-(2-dimethylaminoethyl)amine sulfonyl, N-(2-di-B Aminoethyl)amine sulfonyl, N-[2-(hydroxyethylamino)ethyl]amine sulfonyl, N-[2-(diethylaminoethyl)ethyl]amine sulfonyl, N-(pyrrolidin-1-ylethyl)amine sulfonyl, N-[2-(1-methylpyrrolidin-2-yl) Amine sulfonyl, N-(2-hexahydropyridin-1-ylethyl)amine sulfonyl, 1^(2-point gas-pyridyl-1 -ylethyl)amine continuation base, N - (2 -morphinylethyl)amine oxime, N-(2-imidazol-4-ylethyl)amine sulfonyl, N-(3-hydroxypropyl) This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) !29196〇, patent application range AB c D Amine, mercapto, N-(2,3-dihydroxypropyl)amine sulfonyl, N-(3-methoxy Propyl sulfonyl, N-(3-aminopropyl)amine sulfonyl, N-(3-hydrazinopropyl)amine sulfonyl, N-(3-dimethylaminopropyl Aminesulfonyl, N-(diethylaminopropyl)amine sulfonyl, N-(3-isopropylaminopropyl)amine sulfonyl, N-(3-butoxycarbonylamino) Propyl)amine sulfonyl, · methoxycarbonylaminopropyl)amine hydrazino, hydrazine-[ 3 - (2-oxo hydrazide ρ 呢 · 1 -yl)propyl]amine sulfonate Sulfhydryl, (3-morpholinylpropyl)amine sulfonyl, 1 [3-(4-methylhexahydropyrazine)-yl]propyl]sulfonyl, Ν· (3 _ -1-ylpropyl)aminesulfonyl or fluorenyl-(5-hydroxypentyl)amine sulfonyl; 1; or a pharmaceutically acceptable salt. A compound of the formula (1) according to any one of claims 1 to 2, wherein the ring B is a phenyl group; or a pharmaceutically acceptable salt thereof. 8. According to the scope of the patent application! A compound of the formula (1) selected from the group consisting of: 2-(4-aminesulfonylanilinoimidazo[n,2a]pyridine-3-yl)pyrimidine; 2-[4-(N-methylaminesulfonyl) Aniline] 4((imidazo-n,2a)pyridin-3-yl)-bito; 2 - {4-[N-(2-methoxyethyl)aminesulfonyl]anilino-4-(imidazole) And [l,2a]pyridin-3-yl)pyrimidine; 2-{4-[N-(3-methoxypropyl)aminesulfonyl]anilinoimidazo[l,2a]pyridin-3-yl Pyrimidine; 2 - { 4 - [ N-(3-isopropylaminopropyl)amine sulfonyl]anilino-4-imidazole !291960, the scope of patent application And [l,2a]pyridin-3-yl)pyrimidine; 2-{4-[N-(3-dimethylaminopropyl)aminesulfonyl]anilino}_4·(imidazo[l,2a] Pyridin-3-yl)pyrimidine; 2 - { 4 -[ N-(2-dimethylaminoethyl)amine sulfonyl]anilino-4-decapyrazolo[l,2a]pyridin-3-yl) Pyrimidine; 2 { 4 - [ N- (2-methylaminoethyl)amine aryl] anilinoyl 4-(mi-di[l,2a]pyridin-3-yl)pyrimidine; or { 4 - [ N-(2-methoxyethyl)amine sulfonyl]anilino-4-[5-(2-hydroxyethylthio)imidazo[l52a]pyridine-3-yl]pyrimidine; or pharmaceutically acceptable Salt. A pharmaceutical composition having a cell cycle inhibitory activity, which comprises a compound of the formula (1) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or Excipient. The compound of the formula (1) according to any one of the claims 1 to 2, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a cancer (solid tumor, leukemia), fibroproliferation and differentiation disorder, Cognac, rheumatoid arthritis] Kaposi's sclerosis, hemangioma, acute and chronic kidney disease, arteries: tumor, arteriosclerosis, arterial stenosis, autoimmune disease, acute and L-induced inflammation, bone disease and retinal tube proliferation Eye disease drug. U. The compound of the formula (1) according to any one of the claims of the present invention, or a pharmaceutically acceptable salt thereof, for use in the production of cell cycle inhibition in a warm-blooded animal (] 4 human) Cell proliferation) drugs. 12. 々a According to any one of the formula (1) of the patent scope of the invention, the compound of the formula (1), the medicinal salt of the sauce, which is used for the manufacture of c d κ to suppress the paper scale A BCD 1291960 ----- VI. Drugs that apply for the scope of patents. 13. The use of any one of items i to 2 of the patent application or a pharmaceutically acceptable salt thereof for use in the manufacture of: j: a mouthpiece. Agriculture, medicine for treating cancer 14. According to any one of items i to 2 of the patent application scope ^ - ^ -X ^ ^ Compound of formula (I), it: t: , which is used for manufacturing for treatment Drugs for leukemia, cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, pancreatic cancer, and ovarian cancer. Μ 腺 腺 、 膀胱 膀胱 膀胱 · · · · · · · 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 And cancers in the pancreas and sarcoma. 、· According to the formula (1) of the scope of the patent application, (1) the character, or its pharmaceutically acceptable salt, is used to manufacture 2, room, prostate, lung, vagina and skin. The main and second drugs. Recurrent pericardial sputum. According to the formula (1) of any of the patent applications, (1) an antibody, or a pharmaceutically acceptable salt thereof, for use in manufacturing, oral CDKs, tumor growth and proliferation (. Especially the colon gland, lung, vagina and skin tumors) of the main: heart: tumor drugs. ^ ; This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)