TWI327146B - Pyrimidine derivatives for inhibition of cell proliferation - Google Patents

Description

1327146 A7 B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to a pyrimidine derivative, or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof, which has cell cycle inhibitory activity and can be used for its anti-cell proliferation (eg, Anti-cancer) activity and thus useful in therapeutic methods in humans or animals. The present invention also relates to a method for producing the pyrimidine derivative, a pharmaceutical composition comprising the same, and use thereof for the manufacture of a medicament for producing an anti-cell proliferation effect in a warm-blooded animal such as a human. An intracellular protein family called eye lins plays an important role in the cell cycle. The synthesis and degradation of the transcellular cells are tightly controlled and thus the amount of expression changes during the cell cycle. The binding of transgenic cells to the transcellular cells associated with serine/threonine kinases (CDKs) and their association is required for intracellular CDK (such as CDK1, CDK2, CDK4 and/or CDK6) activities. Although the precise details of how these factors bind to regulate CDK activity are not known, the balance between the two determines whether cells evolve through the cell cycle. Recent focus on studies of oncogenes and tumor suppressor genes has identified entry into cell cycle regulation as the primary control point for mitosis in tumors. Furthermore, CDKs appear to be downstream of several oncogene signaling pathways. Upregulation of cell transfected cells and/or deletion of endogenous inhibitors without modulation of CDK activity appears to be an important major axis between the mitogenic signaling pathway and tumor cell proliferation. Accordingly, inhibitors of cell cycle kinases, particularly CDK2, CDK4 and/or CDK6, which operate in the S-phase, G1-S and G1-S phases, respectively, will be valuable for cell proliferation selective inhibition. Agents, such as growth inhibitors of mammalian cancer cells. The present invention is based on the discovery that a pyrimidine compound unexpectedly inhibits the effects of cyclin kinase and exhibits selectivity for CDK2, CDK4 and CDK6, and thus the -4- paper scale applies to the China National Standard (CNS) A4 specification (210 X 297). Mm) H·.' Binding

1327146 A7 ------B7 V. INSTRUCTIONS (2) With anti-cell proliferative activity "This property is expected to have therapeutic and abnormal cell cycle and cell proliferation-related disease states such as cancer (solid cancer and white blood cancer), fiber Parent cell proliferation and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis 'arterial reocclusion, autoimmune disease, acute and chronic inflammation, bone disease And the value of eye diseases with retinal vascular hyperplasia. Accordingly, the present invention provides a compound of formula (I):

One or more of X1, X2, X3 and X4 are nitrogen and the other is CR5 wherein R5 may be the same or different; R1 is halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl , Aminomethyl sulfhydryl, Argon thiol, Amine sulfonyl, Cyclo, C2, 6 -5- 伥 伥 度 通用 中 aa aa aa aa aa ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 1327146 A7 ____ B7 V. INSTRUCTIONS (3) Abasium, C2.6 alkynyl, CV6 alkoxy, Ci-6 alkanoyl, N-(Ct.6 alkyl)amine, hydrazine, Ν-γ decane Amino group, C, .6 alkylalkylamino group, Ν-((^-6 alkyl)aminomethyl fluorenyl, hydrazine, hydrazine-CCm alkyl) 2 aminomethyl fluorenyl, CN6 alkyl S (0) a wherein a is 〇 to 2, alkyl)amine sulfonyl or fluorene, Ν-γ^alkyl) 2 amine aryl; wherein R1 may optionally be substituted on the carbon by one or more R6 R2 and R5 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, trimethyl fluorenyl, trifluoromethoxy, amine, carboxyl, aminomethyl thiol, thiol, sulfonyl (V6 alkyl, C2_6 fluorenyl, C2.6 alkynyl, C, .6 alkoxy, Cyalkyl fluorenyl, Cl 6 alkyl fluorenyloxy, N-(CV6 alkyl) amine, hydrazine , ΙνΚΟ^ alkyl) 2 amino, Cw alkyl fluorenyl, NdCw alkyl) aminomethyl fluorenyl, hydrazine, fluorene-π "alkyl) 2 aminomethyl fluorenyl, Cw alkyl S (0) a wherein a is 0 to 2, Cn6 alkoxycarbonyl, N-((V6 alkyl)aminesulfonyl, N,N-((V6 alkyl) 2 aminesulfonyl, phenyl, heterocyclic, a phenylthio or (heterocyclyl)thio group; wherein any R 2 or R 5 may be optionally substituted on the carbon atom with one or more R 7 ; and if the heterocyclic group contains a -NH- group, the nitrogen may be optionally Finely selected from the group of R8; η is 0 to 2, wherein R1 may be the same or different; R3 is halogen, nitro, hydroxy, amine, carboxyl, aminomethylguanidino, thiol, amine sulfhydryl, C2 .6 fluorenyl or C2.6 block; p is 0-4; wherein R3 may be the same or different; R4 is a group of AE-; wherein A is selected from Cm alkyl, phenyl, heterocyclic, C3-8 a cycloalkyl group, a stupidyl C 6 alkyl group, a (heterocyclyl) Cw alkyl group or a C 3-8 cycloalkylalkyl group; wherein a is optionally substituted on the carbon atom with one or more R 9; and wherein the heterocyclic group -6 - This paper wave scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7__ _ V. Inventive Note (4) In the case of -NH- group, the nitrogen may be selected from the group of RlQ instead of 'E is a chemical bond or -0-, <(0)-, -0〇(0)-, - (:(0)0-, ->^(113)(:(0)-, -C(0)N(Ra)-, -N(Ra)_, -S(〇)a-, -S02N (Ra)- or -N(Ra)S02- : wherein Ci is hydrogen or, as the case may be, one or more RM substituted Ci·6 alkyl groups and a is 0-2; R9 is independently selected from oxo, halogen , nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino 'carboxy' aminocarboxamidine, hydrocarbyl, sulfonyl, Cw alkyl, C2.6 alkenyl, C2.6 alkynyl, C, -6 alkoxy, CU6 alkyl fluorenyl, Cw alkyl decyloxy, alkyl) amine, N,N-(CV6 alkyl) 2 amine, Cw alkyl decyl amine , N-fw alkyl)aminomercapto, anthracene, Ν-γ^alkyl) 2 aminocarboxamyl, CV6 alkyl S(0)a wherein a is 0 to 2 'Cw alkoxycarbonyl a Cb6 alkoxycarbonylamino group, a decyloxycarbonylamino group, an NJCw alkyl)aminesulfonyl group and an alkyl)2aminesulfonyl group; wherein R9 may be optionally substituted on the carbon by one or more R12; Is 0-2; wherein R4 may be the same or different; and wherein p + q <5; R6, R7, R11 and R12 are independent From halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amine, carboxyl, aminomethyl sulfhydryl, thiol, sulfonyl, methyl, ethyl methoxy , ethoxy, ethoxylated, methylamino, ethylamino, di-amino, diethylamino, N-methyl-N-ethylamine. ethoxylated, N-methylamine Base methyl sulfhydryl, N-ethylaminocarbamyl, N,N-dimethylaminocarbamimidyl, N,N-diethylaminocarbamimidyl, N-methyl-N·ethyl Aminomethylmercapto, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarboxy, N-methylamine continuation base, N-ethyl amide acid group, N, N- This paper scale is applicable to China National Standard (CMS) A4 specification (21〇x 297 mm) 1327146 A7 _ B7 ____ V. Invention Description (5) dimethylamine sulfonyl, hydrazine, hydrazine-diethylamine sulfonyl or N-methyl-N-ethylamine sulfonyl; and R8 and R1Q are independently selected from C, .4 alkane Base, CV4 alkyl fluorenyl group, C -4-alkylsulfonyl group, C, _4 alkoxycarbonyl group, aminomethyl fluorenyl group, N-(Cu 4 alkyl) aminocarbamyl group, hydrazine, Ν^ Alkylmethylmercapto, fluorenyl, benzyloxycarbonyl, benzhydryl, and phenylsulfonyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Another object of the present invention Provided is a compound of the formula (1) as defined above, wherein the oxime is selected from the group consisting of Cw alkyl, phenyl, heterocyclyl 'C3-8 cycloalkyl, phenylalkyl, (heterocyclyl)alkyl or C3.8 cycloalkyl Cw alkyl; wherein A may be optionally substituted on the carbon with one or more R9; and if the heterocycle contains a -NH- group, the nitrogen may optionally be substituted with a group selected from R1(). In the present specification, "alkyl" includes a straight-chain or branched alkyl group but represents an individual group such as "propyl", and is specifically only a linear state. For example, "Cw alkyl" includes a Cm alkyl group, a Cw alkyl group. , propyl, isopropyl and tert-butyl. However, individual groups such as "propyl" are only specified as straight-chain and individual branched-chain alkyl groups such as "isopropyl" are only specific as branched chains. Similar transformations are also applied to other groups, such as "phenyl Cm" The base " contains phenyl fluorenyl 4-alkyl, decyl, 1-phenylethyl and 2-phenylethyl. "Halogen" for fluorine, chlorine, bromine and iodine. - When the substitution system is selected from "one or more" as appropriate, it is to be understood that this definition contains all selected from specific groups or selected from one or two specific All substituents "heterocyclyl" are saturated, partially saturated or unsaturated, mono or bicyclic rings containing from 4 to 12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen unless otherwise stated Otherwise, it can be bonded via carbon or nitrogen, where -CHr group can be used as the case -8 - This paper wave scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

1327146 A7 ___B7__ V. DESCRIPTION OF THE INVENTION (6) The -c(0)-based substitution and the ring sulfur atom may be oxidized to an S-oxide. Examples and preferred groups of M heterocyclic groups are morpholinyl, piperidinyl, pyridyl, pyranyl, fluorenyl, isoindole, fluorenyl, "quinandyl, thiophene , 1,3 - benzodioxolane, <> sputum bite, brigade base, blow bite base, p than bite base ' 吗 基 基 base, 〇 bilolyl, Shouting wells, 3,5-dioxohexidinyl, tetrahydropyranyl, imidazolyl, pyrimidinyl, pyridinyl, tartar, iso-oxime, 4-p ketone, 1-isoindole quinone, 2-u thiol and 4-pyrazolone. Further examples and preferred groups of M heterocyclic group are morpholinyl, piperidine, butyl group, P-pyridyl group, P-l- yl, P-based, iso-beta, af丨Sulfhydryl, quinuclidyl, pyrenyl, 1,3-benzodioxan, α-sedazyl, arsenic, yttrium, V» plug bite, 7 洛洛基, sulfur? Linji, (Τ 洛 σ σ 林 、, 啩 啩 、 高, 高piperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyridyl, pyridinyl, fluorenyl, isoindole An oxazolyl, 4-acridinone, 1-iso-17 quinolinone, 2- ρ-barulone and 4-cerine group, especially morphine, ρ-pyrazolyl and pyrrolidinyl. Preferred "heterocyclyl" is a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms, at least one of which is selected from nitrogen, sulfur or oxygen' unless otherwise stated, otherwise it may pass through carbon Or a nitrogen bond, wherein the _Ch2- group can be oxidized to the s_ oxide by the -c(o)-yl substitution and the ring sulfur atom as appropriate. "Ci·6虎-基基基•' is ethoxylated Examples of "C!·6 aerobic carbon-based oxime include methoxy group, ethoxycarbonyl, positive- and - Butoxycarbonyl. "〇16 alkoxy" Examples include methoxy, ethoxy and propoxy. "cl6 alkyl amidino group, • contains amylamine, ethyl amine and polypropylene Amine. "C|.6 alkyl s(〇)a where a is 0 to 2" Examples include methylthio, ethylthio, methylsulfinyl, ethyl-9- This paper scale applies China Garden Standard (CNS) A4 specification (210X297 mm) 1327146 A7 B7 V. Description of invention (7 sulfinyl, methylsulfonyl and ethylsulfonyl. "C|-6 垸 基 quot Examples include propyl ketone and ethyl ketone. "N-CCw alkyl)amino group" Examples include methylamino and ethylamino. "Ν,Ν-βυalkyl)2 amine group" Di-N-methylamino, bis-(indolyl)amino and fluorenyl-ethyl-hydrazine-methylamino. Examples of 匸2-6 fluorenyl are vinyl, allyl and 1 - Examples of "C2-6 alkynyl" "C2-6 alkynyl" are an ethyl group, a 1-propyl block group and a 2-propyl block group. An example of a "Ν-βυ alkylalkylamine sulfonyl group is Ν-( Methyl) sulfonamide and Ν-(ethyl)amine sulfonyl. Alkyl)2amines Sulfonyl" Examples are N,N-(dimethyl)amine sulfonyl and N-(methyl)-N-(ethyl)amine sulfonyl. Examples of "N-CCm alkyl)amine mercapto" are methylaminocarbonyl and ethylaminocarbonyl. "N'Nd^alkyl)2aminocarboxamyl" Examples are dimethylamino carbon groups And methylethylaminocarbonyl.,, C3_8 cycloalkyl" Examples are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "(Heterocyclyl)Ci 6 alkyl•, examples include p Than methyl group, 3- linylpropyl group and 2-f-densyl-2-ylethyl group. "(Heterocyclyl)thio group" Examples include pyridylthio group, 3-morpholinyl sulfur And 2-pyrimidin-2-ylthio. "Cw cycloalkyl Cl.6 alkyl" Examples are cyclopropylethyl, cyclobutylf-, 2-cyclopropylpropyl and cyclohexylethyl Phenyl-alkyl, examples are non-ethyl, benzyl and 2-phenylpropyl. Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic 'For example, with an inorganic acid or an organic acid, for example, a di-acid, a phosphoric acid, a trifluoroacetic acid, a citric acid or a maleic acid, an acid addition salt. Further, a salt which is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, Alkali soil = With an organic test that can provide physiologically acceptable cations, such as with a guanamine, dimethylamine, ", or thiophene ethylamine", the paper scale is suitable for the material: (CNS) a visual 1327146 A7 B7 V. INSTRUCTIONS (Salt of 8) The in vivo hydrolysable ester of the compound of the formula (I) containing a carboxyl group or a hydroxyl group is, for example, a pharmaceutically acceptable vinegar which is hydrolyzable in human or animal body to produce a crude acid or an alcohol. The pharmaceutically acceptable ester of a carboxyl group comprises a C,6 alkoxymethyl ester such as methoxymethyl ester, C, 6 alkyl alkoxymethyl methyl ester such as trimethylacetoxymethyl, and hydrazine Stearic ester, Cw cycloalkoxycarbonyloxy (^.6 alkyl ester such as i • cyclohexylcarbonyloxyethyl ester; 1,3-dioxol-2-ketomethyl ester such as 5_ Methyl-1,3-oxo-2-indenylmethyl vinegar; and Cw alkoxycarbonyloxyethyl ester such as 1-methoxycarbonyloxyethyl ester and which can be used in the compound of the present invention Formed on any of the bases. The in vivo hydrolysable ester of the compound of formula (I) containing a hydroxyl group comprises inorganic esters such as squaric acid esters and α-glycosyloxyl esters and esters which are hydrolyzed in vivo to obtain cleavage. Phase The compound α-glycine acylate is exemplified by an ethoxylated methoxy methoxy ester and a 2,2-dimethylpropoxy methoxy methoxy ester. The in vivo hydrolyzable vinegar forming group of the hydroxy group comprises hydrazine. Stuffed base, benzamidine, phenylethylhydrazine and substituted benzamidine and phenethyl, alkoxycarbonyl (obtained alkyl carbonate), dialkylaminocarbamyl and anthracene -(Dialkylaminoethylaminoaminocarbazinyl group (obtaining urethane), dialkylaminoethyl fluorenyl group and carboxyethyl fluorenyl group. Examples of substituents on benzamidine group include ring nitrogen The atom is bonded to the 3 or 4-position morpholine and bridging base of the benzamidine ring via a methyl bond. Some of the compounds of formula (I) may have a palm center and/or a geometrically isomeric center (Ε- and Ζ-isomers), and it is understood that the invention encompasses all such optical, non-corresponding isoforms with CDK inhibitory activity. And geometric isomers. The present invention relates to any and all transmutation forms with CDK inhibitory activity -11 - This paper scale applies to the Ten Country Standard (CNS) Α4 specification (210X29? mm)

1327146

(i) a compound. In particular, those who know that it is known that the R4 is hydrogen, and the imidazole rings depicted by the formula (I) can be mutually changed. It is also necessary to understand that a certain servant of formula (I) can be present in both solvated and unsolvated states such as hydrated state. It is to be understood that the present invention is intended to cover all of the solvated states with CDK inhibitory activity. The variable group is preferably as follows. This variable base may use any definition, patent application scope or the foregoing or following definitions as appropriate. In one aspect of the invention, it is preferred that the ring VIII is a group of formula (IA). In another aspect of the invention, it is preferred that the ring VIII is a group of formula (IB). Preferably, one of X1, X2, X3 and X4 is nitrogen and the other is CR5 wherein R5 may be the same or different. In one aspect of the invention, it is preferred that the hydrazine is nitrogen and the other is CR5 wherein R5 may be the same or different. In another aspect of the invention, preferably X2 is nitrogen and the other is CR5 wherein R5 may be the same or different. In another aspect of the invention, preferably X3 is nitrogen and the other is CR5 wherein R5 may be the same or different. In another aspect of the invention, preferably X4 is nitrogen and the other is CR5 wherein R5 may be the same or different. Preferably, R1 is halo or alkyl s(0)a wherein a is 0; wherein R1 may optionally be substituted on the indole via one or more R6; wherein R6 is a trans-group. More preferably, R1 is bromine or 2-hydroxyethylthio. Preferably, R1 is bromo or 2-hydroxyethylthio and n is hydrazine-1. Preferably R2 is hydrogen. -12- This paper size applies to China National Standard (CNS) Α 4 specifications (210X297 mm)

1327146

In another aspect of the invention, preferably the r2 is selected from the group consisting of hydrogen, C, -6 alkyl or alkyl) 2 amine groups. In another aspect of the invention, preferably r2 is selected from the group consisting of hydrogen, methyl, ethyl or N,N-dimethylamino. Preferably R5 is hydrogen. In another aspect of the invention, preferably R5 is selected from the group consisting of argon, Ci-6, or CV6, wherein R5 is optionally substituted on the carbon with one or more R7, wherein R7 is selected from halo. In another aspect of the invention, more preferably R5 is selected from the group consisting of hydrogen, methyl, methoxy or 2,2,2-diethoxy. In another aspect of the invention, preferably η is 2, wherein R1 may be the same or different. In another aspect of the invention, preferably η is 1. In another aspect of the invention, preferably η is zero. Preferably R3 is an amine sulfonyl group. In another aspect of the invention, it is preferred that R3 is an amine sulfonyl group or a halogen. In another aspect of the invention, more preferably R3 is sulfonamide or fluoro. Preferably ρ is 0 or 1. Preferably, R4 is fluorene-fluorene-based; wherein the lanthanide is selected from C, -6 alkyl; wherein hydrazine is optionally substituted on the carbon by one or more R9; E is -N(Ra)C(0)-, - S(0)a-, -S02N(Ra)- or -N(Ra)S02-; wherein Ra is hydrogen or C, _6 alkyl and a is 0-2; R9 is independently selected from Cu alkoxy and ISKNdCw Base) 2 amine groups. Better R4 is AE-based; among them - 13- This paper scale is 'Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of invention (11) A is selected from thiol , Ethyl or propyl; wherein A is optionally substituted on the carbon by one or more R 9; E is -S(0)a- or -NHS02-; R9 is independently selected from methoxy and N,N- Methylamino group. In particular R4*N-(2-dimethylaminoethyl)amine sulfonyl, N-(2-methoxyethyl)amine sulfonyl, N-methylamine sulfonyl or N-(3 -Dimethylaminopropyl)amine continuation base. In another aspect of the invention, preferably R4 is AE-group; wherein A is selected from C -6 alkyl, C 3-8 cycloalkyl, (heterocyclyl) Ci 6 alkyl or c 3 8 cycloalkyl C, -6 alkyl; wherein A is precipitated on carbon by one or more sizing 9; E is -N(Ra)S02- '· wherein Ra is hydrogen or C^6 alkyl; R9 is independently selected from hydroxy , Cw alkyl, C2.6 alkenyl, c2-6, CU6 methoxy, N,N-(Ci.6 alkyl) 2 amine or (^·6 alkyl s(0)a where a In another aspect of the invention, <better R4 is AE-group; wherein A is selected from the group consisting of methyl 'ethyl, propyl, isopropyl, tert-butyl' cyclopropyl, cyclobutyl, chlorene Alkyl, pyrrolidin-1-ylethyl, pyrazole-1-ylethyl or cyclopropylmethyl; wherein A may be substituted on the warm one or more R9; E is -N(Ra) S02-; wherein Ra is hydrogen or methyl; R9 is independently selected from thio, methyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, N,N-dimethylamino or Sulfur. In another aspect of the invention, particularly preferred R4 is N-methylamine sulfonyl, N-cyclopropylmethylamine sulfonyl, N-ethylamine sulfonyl, N-propylamine Base, N- -14- Ben Zhang scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 ____B7 V. Description of invention (12) Allylamine sulfonyl, N-2-propynyl sulfonyl, N -cyclobutylamine sulfonyl, N-t-butylamine sulfonyl, N-cyclopropylamine sulfonyl, N-(2-dimethylaminoethyl)amine sulfonyl, N-( 2-methoxyethyl)amine sulfonyl, pyrazol-1-ylethyl)amine sulfonyl, N-methyl-N-(2-methoxyethyl)amine, N- (l-cyclopropylethyl)aminesulfonyl, N-(3-dimethylaminopropyl)aminesulfonyl, N-(3-Tethoxypropyl)aminesulfonyl, Ν·( 3-hydroxy-2-#-ylmethylpropan-2-yl)amine continuation base, Ν-(1,3-di-propylpropan-2-yl)amine, Ν-(3 -?&lt ;»Linyl-2-methylpropan-2-yl)amine cross-branched, N-(l,3-dimethoxypropan-2-yl)amine sulfonyl, N-(l,3-di Ethoxypropan-2-yl)amine sulfonyl, N-(l-methoxypropan-2-yl)amine sulfonyl, fluorenyl-(1·ethoxypropan-2-yl)amine sulfonate , N-(l-hydroxypropan-2-yl)amine sulfonyl, fluorenyl-(3-methylthio-2-methylpropan-2-yl)amine hydrazino, Ν-(3-ρ ratio Octo-1-yl-2-methylpropanoid -2-yl) oxime, Ν-(3-methoxy-2-methylpropan-2-yl)amine, ν-(2-methoxy-2-methylpropyl) Aminesulfonyl, ν-(1-propoxypropan-2-yl)amine or hydrazine-(3-hydroxy-2-methylpropan-2-yl)amine sulfonyl. Preferably q is 0 or 1. Preferably, p + q is 1 or 2. Better p + q is 1. Particularly preferred p + q is 1 and the R3 or R4 group is in the para position of the anilino group. In another aspect of the invention, preferably p + q is deuterium, 1 or 2; wherein R3 may be the same or different and R4 may be the same or different. Therefore, in a further object of the present invention, there is provided a compound of the formula (1) (as described above), wherein: Ring A is of the formula (IA); -15- The paper size is applicable to the National Standard (CNS) A4 specification (210X297) PCT) 1^27146

DESCRIPTION OF THE INVENTION One of χΙ, X2, X3 and X4 is nitrogen and others are CH; η is 〇; R2 is hydrogen; R is an amine continuation; P is 0 or 1; R4 is N-(2-dimethylamino) Ethyl) sulfonyl, n-(2-methoxyethyl)amine, Ν·methylamine sulfonyl or N-(3-dimethylaminopropyl)amine sulfonyl; q is hydrazine or 1; p+q is 1 and the r3 or r4 group is in the para position of the anilino group; or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester β; thus another object of the present invention is to provide a formula ()) (as above) a compound wherein: % 八 is a formula (18) (as described above); one of χ1, X2, X3 and X4 is nitrogen and the other is CR5; wherein R5 may be the same or different; η is 〇 ; R 2 is selected from hydrogen, C 6 alkyl or alkyl) 2 amine; R 5 is selected from hydrogen, C i. 6 entertainment: or CI 6 alkoxy, wherein R 5 may optionally be on the carbon via one or more R 7 Substituent; wherein R7 is selected from dentate; R3 is sulfonyl or halogen; p is 0 or 1; R4 is AE· group; wherein A is selected from Cm alkyl, C3.8 cycloalkyl' (heterocycle Base) Ci 6 alkyl or c3 8 -16- This paper wave scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public) 1327146 A7 B7 V. INSTRUCTIONS (14) 'Cycloalkyl C μalkyl; wherein A may be substituted on the carbon by one or more sizing 9; E is -N(Ra)S02-; wherein Ra is hydrogen or Cm alkyl; R9 is independently selected from hydroxy, Cw alkyl, C2.6 alkenyl, C2-6 alkyl, C|-6 alkoxy, fluorene, fluorene-((ν6 alkyl) 2 amine or (V6 alkyl) S(0)a wherein a is oxime; q is 0 or 1; p+q is 0, 1 or 2; wherein R3 may be the same or different and R4 may be the same or different; or a pharmaceutically acceptable salt or body thereof Hydrolyzable ester. Thus, in another object of the invention, there is provided a compound of formula (1) (as described above) wherein: ring A is of formula (IA) (as described above); one of hydrazine, X2, X3 and hydrazine 4 is gas and Others are CR5; wherein r5 may be the same or different; η is 0; R2 is selected from hydrogen, methyl, ethyl or hydrazine, hydrazine-dimethylamino; R5 is selected from hydrogen, methyl, methoxy or 2 , 2,2-trifluoroethoxy; R3 is sulfonyl or fluoro; ρ is 0 or 1; R4 is Ν-methylamine sulfonyl, Ν-cyclopropylmethylamine sulfonyl, hydrazine -ethylamine sulfonyl, fluorenyl-propylamine sulfonyl, fluorenyl-allylamine sulfonyl, fluoren-2-propynyl sulfonyl, fluorenyl-cyclobutyl Sulfonyl, hydrazine-t-butylamine sulfonyl, fluorenyl-cyclopropylamine sulfonyl, fluorenyl-(2-dimethylaminoethyl)amine sulfonyl, fluorene-(2-methoxy Ethyl) sulfonyl, fluorenyl-(2-pyrazol-1-ylethyl)amine sulfonyl, fluorenyl-methyl-hydrazine-(2-methoxyethyl)amine sulfonyl, N- (l-cyclopropylethyl-7- This paper scale applies to Chinese National Standard (CNS) Α4 specification (21〇x 297 mm) 1327146 A7 Description of the invention) Amine thiol, N-(3-di-famine Propyl sulfonyl, hydrazine _(3_τ oxypropyl)amine sulfonyl sulfonyl, hydrazine-(3-hydroxy-2-hydroxymethylpropan-2-yl)amine sulfonate N-(l,3 - propylidene-2-yl)amine, Ν-(3·?β-linyl-2-methylpropyl.2-yl)amine sulfonyl, Ν-(1,3-dimethoxy Amidyl sulfonyl N(l,3 -monoethylpropylpropan-2-yl)amine aryl, Ν-(ι_methoxyprop-2-yl)amine fluorenyl, N- (l-ethoxypropan-2-yl)amine continuation base, Ν-(ι-pyridyl-2-yl)amine sulfonyl, Ν-(3-methylthio-2-methylprop-2- _ ) 胺 胺 Ν Ν, Ν-(3-pyrrolidinyl) Amidoxime , Ν-(2-decyloxy-2-methylpropyl)amine, N-(l-propyllacyl-2-yl)amine, or ν·(3·经基·2 _Methylpropan-2-yl)amine sulfonyl; q is hydrazine or 1; p+q is hydrazine, 1 or 2; wherein r3 may be the same or different, the same or different; or a pharmaceutically acceptable salt thereof or Hydrolyzed vinegar in the body. In another object of the present invention, preferred compounds of the present invention are any of the exemplified compounds or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof. In another object of the present invention, the preferred compounds of the present invention are Examples 7, 27, 29 '39, 41, 42, 46 '63, 64 or 66 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. A preferred object of the invention is related to the compound of formula (1) or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein the process is as defined (wherein each substituent is as defined in formula (I), unless otherwise There are instructions) The following steps: -18- The paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1327146 A7 B7 V. Invention description (16) a) Make the following formula (11) π close attack :

Wherein L is a replaceable group; reacts with an amine of formula (ΙΠ):

b) making the pyrimidine of formula (IV):

Reacts with the compound of formula (V):

(V) -19- This paper size is applicable to National Standard (CMS) of National Standard (CMS) A4 Specification (210X 297 mm) 1327146 A7 B7 V. Description of Invention (17) One of Μ and Q is a replaceable base X and the other For the metal reagent Y; or c) to make the compound of formula (VI):

Reaction with a compound of formula (VII):

Wherein R 5 is alkyl and R 6 is hydrogen or R 1 ; d) an amine compound of formula (VIII):

Nh2 reacts with compound of formula (IX): -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of invention (18)

Wherein E is a substitutable group; and if desired: i) converting a compound of formula (I) to another compound of formula (1); ii) removing any protecting group; iii) forming a pharmaceutically acceptable salt or a hydrolyzable vinegar in vivo . L is a substitutable group. Suitable L group is, for example, a halogen, methylthio or sulfonyloxy group such as chlorine, bromine, methanesulfonyloxy or toluene-4-sulfonyloxy. E is a substitutable group, and a suitable E group is, for example, a pixel or a sulfonyloxy group such as chlorine, bromine, iodine or trifluoromethanesulfonyloxy. Suitable substitutable groups X are, for example, dentate or sulfonyl, for example, chloroform or trifluoromethylsulfonyl. Suitable metal reagents Y are, for example, copper, money, organoboron reagents such as Β(〇Η)2, -B(〇pri)2! _B(Et)2, or organotin compounds such as SnBu3, organic hair 2 compounds such as Si ( Me) F2, organic # compound such as ZrC丨3, organoaluminum compound such as AIEh, organomagnesium compound such as MgBr, organozinc compound such as ruthenium or organic compound such as HgBr. The specific conditions of the above reaction are as follows. a) The pyrimidine of formula (II) and the amine of formula (III) can be reacted together: i) in a suitable solvent such as a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon such as toluene or N-methyl-rhopyridine In the presence of 'as appropriate, in the appropriate acid such as inorganic acid-21 - this paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) 1327146 A7 B7 V. Description of invention (19) such as hydrochloric acid or sulfuric acid, Or in the presence of an organic acid such as acetic acid or formic acid (or suitable Lewis acid) and at a temperature in the range of o °c to reflux, preferably at a reflux temperature; or η) under standard Buchwald conditions (see, for example, American Chemical Society Journal, 118, 7215, Journal of the American Chemical Society, 119, 51; Journal of Organic Chemistry, 62, 1568 and 6066), for example, in the presence of palladium acetate in a suitable solvent such as an aromatic solvent such as toluene, benzene or xylene, with a suitable base such as an inorganic base Such as cesium carbonate or an organic base such as potassium t-butoxide, in the presence of a suitable ligand such as 2,2, bis(diphenylphosphonium)-1,1'- hydrazine and in the art to seven Temperature range. The pyrimidine of formula (II) can be prepared according to the following reaction scheme: (V)

L Cross-coupling conditions (III) (Ha) wherein one of Μ and Q is a substitutable group X as defined above and the other is a metal reagent 上述 as defined above. The conditions for cross coupling are well known to those skilled in the art. Suitable conditions include, for example, those described in b) below. When ring A is a group of formula (IA) and L is a methylthio group, the compound of formula (II) can also be prepared according to the following reaction scheme: 22- This paper scale applies Ten National Standards (CNS) A4 Specification (21〇x 297 mm) 1327146 A7 B7 V. Description of Invention (2〇

(Ilh) rJkxrTT NaOMe (Hg)

BuOH, DK is a suitable leaving group (for example, an alkyloxy group), R5 and R6 are as defined above, and Q is a suitable leaving group (for example, (^.6 alkoxy). When ring A is of formula (IB) When the base and L are methylthio groups, the compound of formula (II) can also be prepared according to the following reaction diagram: -23- This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1327146 A7B7

This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1327146 A7 B7 V. Description of invention (22) Modification by standard functional group modification, where L is a leaving group such as gas, bromine or toluene A compound of formula (II) which is sulfonyl and methylsulfonyl. The compounds of the formulae (Ila), (lib), (lie), (lid), (Ili) and (Ilj) are commercially available compounds or are known to the literature or can be prepared by standard methods known in the art. b) The compound of formula (IV) and the compound of formula (V) can be reacted together under standard cross-coupling conditions. Examples thereof are catalysts such as metal catalysts such as ruthenium (triphenylphosphine) palladium (0), vaporized palladium (II), palladium (II) bromide, nickel (II) vapor, nickel (II) bromide or Gasification of bis(triphenylphosphine) nickel (II) in the presence of a suitable inert solvent or diluent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene In the presence of methanol or ethanol, react together. The reaction is preferably carried out in the presence of a suitable base such as sodium carbonate or potassium carbonate, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine and preferably at a temperature of, for example, 10 to 250 ° C, preferably 60 to 120. The range of °C is carried out. The compound of formula (IV) can be prepared according to the following reaction formula: (Ha) + (ΙΠ) as the method ^ (IV) The compound of formula (V) is a commercially available compound or is known to the literature or may be known by the art. Method preparation. c) The compound of the formula (VI) and the compound of the formula (VII) can be reacted in a suitable solvent such as hydrazine-methylpyrrolidine or butanol at a temperature ranging from 100 to 200 ° C, preferably from 150 to 170 ° C. together. The reaction is preferably carried out in the presence of a room 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 may be prepared by standard methods known in the art, or the compounds of formula (VII) may be applied to Chinese national standards by similar -25-sheet scales ( CNS) A4 size (21〇x 297 mm)

Binding

Line 1327146 A7

The method of the above formula (Ilf) and (Ilk) produces β d) the guanamine compound of the formula (VIII) and the compound of the formula (ι) can be reacted under standard Buchwald conditions as in the above method a (ii). The compound of the formula (VIII) can be produced as described above. The compound of formula (IX) is a commercially available compound or is known to the literature or can be prepared by standard methods known in the art. It will be appreciated that certain of the various ring substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions or by conventional functional group modifications after the above reactions or simultaneously and are therefore included in the process of the invention. This reaction and modification include, for example, a substituent introduction by an aromatic substitution reaction, a substituent reduction reaction, a substituent alkylation reaction, and a substituent oxidation reaction. The reagents and reaction conditions for this procedure are well known in the chemical arts. Specific examples of the aromatic substitution reaction include introduction of a nitro group using concentrated nitric acid, introduction of a brewing base under conditions of Friedei Craft using, for example, fluorenyl painting and Lewis acid (e.g., a gasified chain); Keenan and Lewis acid (such as aluminum trioxide) are introduced into the alkyl group under the conditions of Friedel Craft; and the halogen group is introduced. Specific examples of the modification reaction include reduction of a nitro group to an amine group by catalytic hydrogenation, for example, with a nickel catalyst or heat treatment in the presence of iron in the presence of hydrochloric acid; oxidation of an alkylthio group to an alkylsulfinyl group or a condensate . It is also important to understand that in some of the reactions described herein, it may be necessary/need to protect any sensitive groups in the compound. Appropriate protection methods are known to those skilled in the art when the protective reaction is necessary or necessary. The conventional protecting group can be used according to standard procedures (see T. W. Green, Organic Synthetic Protective Group, John Wiley and Sons' 1991). Therefore, if the reactants contain such as 'amine, carboxyl or hydroxy-26- this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of the invention (24 basis, It is preferred to protect the group in the foregoing reaction. Suitable protecting groups for the amine group or the amine group are, for example, a brewing group such as an alkyl group such as an ethyl ketone group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a third butoxycarbonyl group. An arylmethoxycarbonyl group such as an oxime oxycarbonyl group or an aryl fluorenyl group such as a benzylidene group. The deprotection conditions of the above protecting group must be changed depending on the choice of the protecting group. Thus, for example, a fluorenyl group such as an alkyl fluorenyl group or an alkoxycarbonyl group is used. Or an aryl group can be removed, for example, by hydrolysis, such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, a mercapto group such as a third butoxycarbonyl group can be, for example, a suitable acid such as hydrochloric acid, acid or Removal by treatment with phosphoric acid or trifluoroformic acid, and arylmethoxycarbonyl such as methoxycarbonyl can be treated, for example, by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid such as hexafluoroacetate. Removal. Another suitable protecting group for the primary amine group is an example. The brewing group can be removed by, for example, a guanamine such as dimethylaminopropylamine or by treatment with a hydrazine. Suitable protecting groups for the radical are, for example, anthracenyl such as decyl such as ethyl hydrazino, aryl fluorenyl such as benzoyl. A mercapto or arylmethyl group such as a fluorenyl group. The deprotection conditions of the above protecting groups will vary depending on the choice of protecting group. Thus, for example, an anthracenyl group such as an alkanoyl group or an aryl group can be, for example, a suitable base such as an alkali metal hydrogen. The oxide, such as lithium hydroxide or sodium hydroxide, is removed by hydrolysis. Further, an arylmethyl group such as a fluorenyl group can be removed by, for example, hydrogenation over a catalyst such as saturated/ruthenium. Suitable protecting groups for the group are, for example, esterification groups. The methyl group may be removed by hydrolysis, for example, with a base such as sodium hydroxide or may be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or may be, for example, a catalyst such as palladium on carbon. The hydrogenation-removed sulfhydryl group can be used at any convenient stage during the synthesis.

1327146 A7 B7 V. INSTRUCTIONS (25) Surgical removal. As described above, the compound defined in the method of the present invention has an anti-cell proliferative activity such as an anti-cancer activity, which is believed to be derived from the CDK inhibitory activity of the compound. These properties can be evaluated using, for example, the following procedures: The following abbreviations are used for the analysis: HEPES is N-[2-hydroxyethyl] piperene ethanesulfonic acid] DTT is dithiothreitol PMSF is phenylmethylsulfonium fluorolate The test for the measurement of [γ-33-P]-adenine triphosphate incorporation into the test substance (GST-retinoma protein; the in vitro kinase assay in a 96-well format using scintillation proximity analysis (SPA-from Amersham); GST-Rb). The test compound (diluted to the correct concentration in DMSO and water) was placed in each well, and Rocsovitine was placed as the inhibitor control group or DMSO as the control group in the control group. Approximately 0.2 μl of CDK2/Cytotransferase E partially purified enzyme (depending on enzyme activity) was diluted in 25 μl of incubation buffer and added to each well followed by 20 μl of GST-Rb/ATP/ATP33 mixture (0.55 μg of GST-Rb and 0.2 μΜ of ATP and 0.14 μM [γ-33-Ρ]-gland: y: triphosphate incubation buffer) and the resulting mixture was gently shaken and then incubated at room temperature for 60 minutes. Next, 150 μl of (0.8 mg/hole protein A-PVT SPA beads (Amersham)), 2ΟρΜ/hole anti-chitin glucosamine transferase, rabbit IgG (from Molecular Probes) '61 were added to each well. 150 liters of stop solution of mM EDTA and 50 mM HEPES pH 7.5 with 0.05% sodium azide. -28- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 _ B7 V. Description of invention (26)

The pan was sealed with a Topseal-S pan seal and allowed to stand for 2 hours followed by 2500 rpm at 1124 xg for 5 minutes. The disk reads 3 seconds per hole on the Top count. The incubation buffer used to dilute the enzyme and substrate mixture contains 5 mM HEPES pH 7.5, 10 mM MnCl2, 1 mM DTT, 1 〇〇μΜ DTT, 100 μM sodium vanadate, 100 pM NaF, 10 mM sodium glyceryl sulphate, bsA (1 mg/ml final). Test Subjects In this analysis, only partial retinoblastoma proteins were used (Science, March 13, 1988; 235 (4794): 1394-1399; Lee WH, Bookstein R., Hong F., Young LJ, Shew JY , Lee EY), merged into the GST tag. PCR was performed on the retinoblastoma gene encoding amino acid 379-928 (derived from retinoblastoma plastid ATCC pLRbRNL), and the sequence was cloned into the pGEX 2 butyl fusion vector (811^1:11〇.8.) 〇11113〇11,1^.8. Gene 67, 31 (1988); it contains the tac promoter for evoked expression, the internal Iq gene for any E. coli host, and the coding region for thrombin cleavage - available from Pharmacia Biotech) It is used to amplify the amino acid 792-928. This sequence was again selected for implantation in pGEX 2T. The resulting retinoblastoma 792-928 sequence was expressed in E. coli (BL21 (DE3) pLysS cells) using standard induction performance techniques, followed by purification as follows. The E. coli syrup was resuspended in 10 ml/g NETN buffer (50 mM Tris pH 7.5 '120 mM NaCl ' 1 mM EDTA ' 0.5% v/v NP-40 , 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and 1 μg/ml aprotinin) and 1×45 sec per 1 ml of homogenate. After centrifugation, the supernatant was loaded on a 10 ml glutathione agarose column (Pharmacia -29 - this paper scale applies to national standard (CNS) A4 size (21〇x 297 mm) 1327146 A7 B7 V. Invention Description (27)

Biotech, Herts, UK), and BNET NET buffer wash; strip. After washing with kinase buffer (50 mM HEPES pH 7.5 'H) mM MgCl2 '1 mM DTT, 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and i μg/ml aprotinin) The protein was lysed in a kinase buffer with 50 mM reduced glutathione. The fractions containing GST-Rb (792-927) were collected and dialyzed against kinase buffer overnight. The final product was analyzed by sodium dodecyl sulfate (SDS) PAGE (polyacrylamide gel) using an 8-16% Tris-glycine gel (Novex, San Diego, USA).

CDK2 and cytosine E were ligated into the CDK2 open reading frame and transposon E using HeLa cells and activated T cell mRNA as a template by reverse transcriptase-PCR and cloned into the insect expression vector pVL1393 (from Invitrogen 1995 catalog number: V1392-20) » CDK2 and cytosine E are subsequently expressed in the insect SF21 cell system (Spodoptera Frugiperda cells from the ovary tissue of the larvae of the autumn scorpion - commercially available) [using the standard virus Baculogold co-infection technique]. Manufacture Examples of Cytosine E/CDK2 The following examples are provided in SF21 cells (in TC 1000/〇+10% FBS(TCS) + 0.2% Pluronic) with double-infection of MOI 3 for each of the transmembrane and CDK2 viruses. Details of the transmembrane E/CDK2. SF21 cells grown to 2.33 x 106 cells/ml in roller spinner flasks were used to incubate 10/500 ml roller spinner flasks at 0.2\10 £6 cells/ml. The roller was incubated on a 28 ° C roll rig. After 3 days (72 hours), the counted cells and the average from 2 bottles were found to be 1.86 X 10E6 cells/ml (99% viable). The culture was then applied to the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) for each virus M0I 3 -30- paper wave scale.

Binding

K- 1327146 A7 B7 V. Double virus infection of invention (28). The viruses were mixed together and added to the medium, and the cultures were returned to a 28 °C roller rig. After 2 days (48 hours) of infection, 5 liters of culture was collected. The total number of cells received was 1.58 X 10E6 cells/ml (99% viable). Cells were spun in a 250 ml batch for 30 minutes at 2500 rpm and 4eC on Heraeus Omnifuge 2.0 RS. Discard the supernatant.

Partial co-purification of Cdk2 and transmembrane E

Sf21 cells were resuspended in lysis buffer (50 mM Tris pH 8.2, 10 mMMgCl2, 1 mMDTT, 10 mM glyceryl citrate, 0.1 mM sodium o-vanadate, 0.1 mM NaF, 0.1 mM PMSF, 1 μg /ml aprotinin and 1 μg/ml aprotin) were homogenized for 2 minutes in a 10 ml Dounce homogenizer. After centrifugation, the supernatant is loaded to? 〇1*〇5 11 (^/cm 1.4/100 anion exchange column (PE biochemical system, Hertford, UK). Cdk2 and transposon E at the beginning with a 0-1M NaCl gradient (in lysis buffer minus The co-dissolution of the deprotease inhibitors was carried out in 20 column volumes. The co-dissolution was examined by Western blotting using both anti-Cdk2 and anti-transferase E antibodies (Santa Cruz Biotech, Inc., California, USA). The framework can be designed to assess the inhibition of CDK4 and CDK6. CDK2 (EMBL accession number X62071) can be used with either transposon A or transputin E (see EMBL accession number M738 12) and further analysis of this Details are found in PCT International Patent No. WO 99/21845, the relevant biochemical and biological evaluation paragraphs, which are incorporated herein by reference. Although the pharmacological properties of the compounds of formula (I) vary with the structure, it is usually -31 - the paper scale applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1327146

The activity of the compound of formula (1) can be demonstrated by IC5G concentration or dose in the range of 250 μΜ to 1 nM. The in vivo activity of the compounds of the invention can be assessed by standard techniques, such as by measuring cell growth inhibition and assessing cytotoxicity. Cell growth inhibition can be measured by staining Sulforhodamine B (SRB), a fluorescein that can stain color proteins, and thus can estimate the amount of protein (ie, cells) in the hole (see Boyd, MR (1989) NCI preclinical Anti-tumor drug discovery screening status, Prin. prac 〇nc〇l 1〇: Bu 12). Therefore, the following details were provided to measure cell growth inhibition: Cells were plated in a suitable medium in a 96-well dish based on a 96-well dish; the medium was modified by Dulbecker of MCF-7, SK-UT-1B and SK-UT-1. Eagle's medium. The cells were allowed to attach overnight, and then the inhibitor compound was added at various concentrations up to a concentration of 1% DMS0 (v/v). The control plate was analyzed to obtain the cell value before treatment. The cells were incubated for 3 days at 37 ° C (5% CO 2 ). Three days later, TCA was added to the dish to a final concentration of 16% (v/v). The plate was incubated at 4 ° C for 1 hour. The supernatant was removed and the pan was washed with tap water. After drying, 100 ml of SRB dye (0.4% SRB in 1% acetic acid) was added at 37 ° C for 30 minutes. 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 30 minutes. The ODs were read at 540 nm and the inhibitor concentration of the 50% inhibition of growth was determined from the semi-log plot of absorbance versus absorbance. The concentration of the compound which lowers the optical density to a level lower than that obtained on the plate at the beginning of the cell experiment is the cytotoxic value. Typical ic5 values for the compounds of the invention when tested in the SRB assay ranged from 1 mM to 1 nM. -32- This paper scale applies to National Standard (CNS) A4 specification (210; &lt; 297 mm), Description of the Invention (3) - According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a medicament An acceptable diluent or carrier. The composition may be in a form suitable for oral administration such as a lozenge or capsule, parenteral = drug (including intravenous, subcutaneous, intramuscular (four), intravascular or perfusion) aseptic hardening, suspension Liquid or emulsion, topical ointment or cream, or suppository for rectal administration. Usually, the above composition can be prepared by a conventional method using a conventional excipient. The compound of formula (1) is generally administered to a warm-blooded animal at a unit dose of an area per square meter of animal. A range of 5-5000 mg, i.e., about 11 mg/kg, and generally provides a therapeutically effective dose. Unit dosage forms such as lozenges or capsules will usually contain, for example, 1-250 mg of the active ingredient. 〇mg / = kg. However, the daily dose will necessarily vary with the host treated, the specific route of administration and the severity of the disease to be treated. Accordingly, the optimal dose can be determined by the physician for a particular patient. According to another object of the present invention, there is provided a use of a compound of the above formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in a method of treating a human or animal body. The compound or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester is an effective cell cycle inhibitor (anti-cell proliferation agent) derived from its CDK inhibitory property. Accordingly, the compound of the present invention is expected to be useful for treatment. A disease or medical condition that is only partially or partially regulated by CDK enzymes, that is, the compound can be used to produce a CDK inhibitory effect in a warm-blooded animal in need of such treatment. Thus, the compound of the present invention provides a therapeutic malignant cell 1327146 A7 ----B7 _ 5. The method of the invention (31), characterized by the inhibition of CDK enzyme, that is, the compound can be used to produce an anti-proliferative effect which is only regulated by or partially inhibited by CDKs. The compound of the present invention is expected to have a wide range Antitumor properties due to many common human cancers such as white blood and breast cancer, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary Cancer is associated. It is therefore expected that the compounds of the invention will possess anticancer activity against such cancers. Furthermore, it is expected that the compounds of the invention will carry solid tumors against white blood cancer, lymphoid malignancies and tissues such as liver, kidney, prostate and pancreas Such as carcinomas and sarcomas. In particular, the compounds of the invention are expected to advantageously slow the growth of primary and recurrent solid tumors such as the colon, breast, prostate 'lung and skin. More particularly, the compound of the invention or its pharmaceutically acceptable form Salts or in vivo hydrolysable esters are expected to inhibit the growth of such primary and recurrent solid tumors associated with CDKs, particularly the growth and spread of such tumors that are significantly associated with CDKs, including, for example, the colon, breast, prostate, lung , certain tumors of the vagina and the skin. It is also expected that the compound of the present invention will have activity against other cell proliferative diseases' in a wide range and his disease state includes white blood cancer, fibroblast proliferation and differentiation disorders, psoriasis, rheumatoid joints. Inflammation, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial reocclusion, self Immune diseases' acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation of. According to the invention, this object provides a compound of the formula (I), 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 in vivo hydrolysable esters for the production of cell cycle inhibition in warm-blooded animals such as humans (anti-34- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1327146 A7 B7 V. Description of the invention (32) Cell proliferation) The medical use of the effect. In particular, inhibition of CDK2, CDK4 and/or CDK6, especially CDK2, by S phase avoids entry or development and produces an inhibitory effect. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above for use in the manufacture of a medicament for the treatment of cancer (solid and white blood cells), fibroblast proliferation and differentiation Barriers, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial reocclusion, autoimmune disease, acute and chronic inflammation, bone disease and retinal blood vessels Proliferative eye disease, especially for the treatment of cancer. In accordance with the present invention, there is provided a method of producing a cell cycle inhibition (anti-cell proliferation) effect in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to the animal an effective amount of a compound as defined above. In particular, the inhibitory effect is produced by inhibiting CDK2, CDK4 and/or CDK6, especially CDK2, by s phase, thereby avoiding entry or development. According to another feature of the present invention, there is provided a method for treating cancer (solid cancer and white blood cancer), fibroblast proliferation and differentiation disorder, psoriasis, rheumatoid arthritis, Kaposi's sarcoma for a warm-blooded animal to be treated, such as a human. , hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial reocclusion, autoimmune disease, acute and chronic inflammation, bone disease, and eye diseases associated with retinal vascular hyperplasia, including administering to the animal An effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above. In particular, it provides a treatment for cancer in warm-blooded animals such as humans in need of this treatment. -35- This paper scale applies to national standard (CNS) A4 specification (210 X 297 mm). V. Description of invention (33) Method 'includes An effective amount of a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above, is administered to the animal. A further object of the present invention is to provide a pharmaceutical composition comprising the aforementioned definition = a compound of formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable diluent or carrier, which can be used in a warm-blooded animal such as a human. Produces a cell cycle inhibition (anti-cell proliferation) effect. A further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable diluent or carrier, which is useful for warming Blood animals such as humans treat cancer (solid ~ cancer and white blood cancer), fibroblast proliferation and differentiation disorders, cowhide rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and It f kidney disease, arterial atherosclerosis , arteriosclerosis, arterial reocclusion autoimmune disease, chronic inflammation, bone disease and eye diseases with retinal vascular hyperplasia. Further, the present invention is to provide a pharmaceutical composition comprising the above definition <Formula (1), or a pharmaceutical or a hydrolyzable ester thereof, and a pharmaceutically acceptable salt or a carrier, and the blood can be warmed Treating cancer in animals such as humans. The invention furthermore aims to provide the use of a compound of formula (1), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester, as defined above for the production of a cell cycle inhibition (anti-cell proliferation) effect in a warm-blooded animal such as a human. A further object of the present invention is to provide a compound of the formula (1) as defined above or a pharmaceutically acceptable salt thereof or a hydrolyzable in vivo for use in a warm-blooded animal such as a human cancer (solid cancer and white blood cancer), fibroblast proliferation and differentiation. Obstacle -36- x 297 mm) Paper size towel g @家标准(CNS) A4 gauge 1327146 A7 ------- B7 V. Description of invention (34) Pipi, rheumatoid arthritis, Kaposi Sarcoma, hemangioma, acute and chronic kidney disease, atheroma, arteriosclerosis, arterial reocclusion, autoimmune disease, acute and chronic inflammation, bone disease, and the use of eye diseases with retinal vascular hyperplasia. A further object of the invention is the use of a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above for the treatment of cancer in a warm-blooded animal such as a human. Avoiding the entry of cells into DNA synthesis by inhibiting the basic S-phase initiation activity, such as CDK2 inhibition, can also be used to avoid the toxicity of normal cells in the body to be subjected to circulating specific pharmaceutical agents. The inhibition of CDK2 or 4 will avoid the development of cell cycle in normal cells, which limits the toxicity of circulating specific pharmaceutical agents in s phase, G2 or mitosis. This protection can result in avoiding normal hair loss associated with the agents. Accordingly, a further object of the present invention is to provide a compound of the above formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as a cytoprotective agent. Therefore, a further object of the present invention is to provide a compound of the above formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof for use in avoiding hair falling due to treatment of a malignant condition with a pharmaceutical agent. Examples of medical agents known to treat malignant conditions that cause hair loss include a burning agent such as ifosamide and cyclophosphamide; an antimetabolite such as methotrexate 5-fluorouracil, odd Gemcitabine and cytarabine; vinca alkaloids and analogues such as Changchun new Changchunling 'vindesine, vinorelbine ___·37· paper ruler ^Home Standard (CNS) Α4 Specifications (2ι〇χ297 mm)---- 1327146 A7 __B7 V. Description of Invention (35); ziXaneS (such as paeUtaxei) and Dohitashi ( Docetaxel); oxidant isomerase I inhibitors such as irint〇tecan and topotecan; cytotoxic antibiotics such as doxorubicin, daun〇rubicin , mitoxantrone 'actinomycin-D and mitomycin; and other such as etoposide and tretinoin. Another object of the invention is that the compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, can be administered with one or more of the above-mentioned pharmaceutical agents. In this case, the compound of formula (I) can be administered in a systemic or non-systemic manner. In particular, the compounds of formula (I) of the present invention may be administered by non-systemic administration, such as topical administration. It is therefore a further feature of the present invention to provide a method of preventing hair loss during treatment of one or more malignant conditions in a warm-blooded animal such as a human by a pharmaceutical agent, comprising administering to the animal an effective amount of a compound of formula (1) or its pharmaceutical acceptability. Salt or in vivo hydrolyzable ester. Another feature of the present invention is to provide a method for preventing hair loss during treatment of one or more malignant conditions in a warm-blooded animal such as a human by a pharmaceutical agent, comprising administering to the animal an effective amount of a compound of the formula (1), simultaneously or sequentially or separately A pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof and an effective amount of the pharmaceutical agent. According to another feature of the present invention, there is provided a pharmaceutical composition for preventing hair loss caused by treating a medical condition with one or more malignant conditions, comprising a compound of the formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof A pharmaceutically acceptable diluent or carrier. According to another feature of the invention, there is provided a kit comprising a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and known to cause hair-38-this paper scale to be applicable to Chinese national standards (CNS&gt;A#Specifications (plus X Migong Chu) V. Invention Description (36 i drop to treat malignant conditions of medical agents.,: Γ本-invention - another purpose, is to provide - a set of kits, including: A compound of the formula (1) or a pharmaceutically acceptable salt thereof or a salt thereof which is known to cause hair loss to treat a malignant disease C) containing the first and second dosage forms. The compound of the formula (1) or its medical- or multi-dilute r-hydrolyzed vinegar is used for the manufacture of a medicine which can avoid the use of a medical agent for treating hair loss caused by a sexual condition. Treatment: According to the system, it is provided to prevent hair from falling. Combination or its pharmaceutical humans to administer an effective amount of the compound of formula (1). The topical salt or in vivo hydrolysable ester, depending on the situation and medicine can be :::::: or combined *, and simultaneously, sequentially or separately &amp; a therapeutic agent for the treatment of malignant conditions. The dose required for cell proliferative diseases. Single::: (4) The host, the route of administration, and the severity of the disease to be treated, and the range of the amount of sputum is, for example, 1 〇〇 mg/kg, preferably (4) mg ^ the CDK defined above. Inhibitory activity

It can contain other substances SI I IS tumor = two depending on =: = = other components are achieved. The hanging operation system uses a combination of different types to the treatment to treat cancer patients. In the field of medical oncology, in addition to the above definition -39 : 297 mm) Paper wave scale phase t S S stock (CNS) 1327146 A7 B7

Other components of the combination therapy may be: surgery, radiation therapy or chemotherapy. This chemotherapy can cover three therapeutic agents: (1) other cell cycle inhibitors that act on the same or different mechanisms as defined above; (π) cytokines such as antiestrogens (eg tamoxifen, toremidine) (toremifene), raloxifene, dro丨oxifene, iodoxyfene, progesterone (eg megestrol acetate), family enzyme inhibitors (eg Anastrozole, otazozie, verazolium (v〇raz〇丨 hook, exemestane) 'antiprogesterone' antiandrogen (eg flumeamide) ), niiutamide, bicalutamide, cypr〇ter〇ne acetate, LHRH agonists and antagonists (eg, Ossin acetate) (g〇serelin acetate), ulprolide, quercetin 5α; inhibitor of dihydrogen reductase (eg, finasteride), anti-invasive agent (eg, metalloproteinase inhibitors such as horsepower) Marimastat and urokinase fibrin prolase activator receptor function Inhibitors and growth factor function inhibitors (such growth factors include, for example, platelet-derived growth factors and hepatocyte growth factors, which include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, and serine /threonine kinase inhibitors; and (πι) anti-growth/anti-tumor drugs and combinations thereof, which can be used in medical oncology, such as antimetabolites such as antifolates such as methotrexate, fluoropyrimidine such as 5_ Fluorouracil, purine and adenosine analogues, cytosine arabinose; antitumor antibiotics (eg, cyclins such as dosolubine, daun〇mycin, AI-40-1327146 A7 B7 , invention instructions (38 lupirin (epirubicin, and idarubicin, mitomycin-C, dactinomycin, mitrefinmycin); platinum derivatives (such as Shunqi Ammonia platinum, carbon gas carboplatin; alkylating agent (eg, nitrogen mustard, melphalan, chlorambucil, busulphan' ring Phosphonium, acesulfame, nitrogen urea Thietepa; anti-mitotic agents (eg, vinca alkaloids such as vincristine and cedar-like cedar, taxotere); tau-isomerase inhibitors (eg, sneaky Epipodophyllotoxins such as etoposide and teniposide, amsacrine, t〇p〇tecan. According to the present invention, there is provided a pharmaceutical product comprising the compound of the formula (1) as defined above and other anti-tumor agents as defined above for use in combination therapy for cancer. In addition to its therapeutic use, the compounds of formula (I) and their pharmaceutically acceptable salts can also be used as a developmental in vivo and in vitro test system and standardized pharmacological tools for evaluation in experimental animals such as cats, dogs, rabbits, monkeys, mice and The inhibitory effect of cell cycle activity in mice as part of the search for novel therapeutic agents. Other and preferred embodiments of the compounds described herein may also be employed in the other pharmaceutical compositions, processes, methods, uses, and pharmaceutical manufacturing features described above. EXAMPLES The invention is illustrated by the following non-limiting examples, wherein unless otherwise indicated: (1) The temperature is in degrees Celsius (.〇; the operating conditions are carried out at room temperature or ambient temperature', ie in the range of 18-25 °C: - -41 - This paper wave scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1327146 A7 B7 V. INSTRUCTIONS (39) (u) The organic solution was dehydrated with anhydrous magnesium sulfate; the solvent was evaporated using a rotary evaporator under reduced pressure (600-4000 Pascal; 4.5-30 mm Hg) at a bath temperature of 60. (3); (111) chromatography means rapid chromatography on tannin; thin layer chromatography (TLC) is carried out on silica gel; wherein the amine *is〇lute column represents 1 μg of 4 μm particle size. The column of NH2 SPE adsorbent, which is contained in the 6〇ml discardable needle quotient and is supported by the porous plate “from 1ST, Mid Glamorgan trade name &quot;Isolute NH2”, &quot;Isolute” (iv) Generally, the reaction process is illustrated by TLc and the reaction time is only indicated; (v) the final product has satisfactory proton nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry data; (VI) the yield is only used for Explain and may not be available through diligent process development; if necessary, more materials can be prepared repeatedly; (vii) provide NMR data, the data is mainly to diagnose the proton 5 value relative to tetramethyl decane as an internal standard (TMS) per million parts (ppm), using deuterated dimethyl hydrazine (DMS〇_d6) as a solvent at 3 〇〇 MHz unless otherwise stated; (viu) chemical symbol has General meaning; use SI units and symbols; (ix) solvent ratio is volume: volume (v/v); and (X) The lineage is performed using a direct exposure probe in a chemical ionization (ci) mode of 70 eV; the ionization shown is by electron impact (EI), fast atomic bombardment (FAB) or electrospray (ESP); m/z meter: In general, only the ions showing the parent mass are listed; (xi) Unless otherwise stated, the carbon and/or sulfur atom containing the asymmetric substitution - 42 - This paper scale applies to the China® standard (CNS) ) A4 size (21〇x 297 public) 1327146

5. Description of the Invention The compound is unresolved; (xii) When the synthesis is described as being similar to the previous examples, the amount used is the millimolar ratio equivalent to the one used in the example; then (xvi) uses the following abbreviations: DMF N , N-dimethylformamide; DMFDMA N,N-dimethylformamide dimethylethenyl; DMSO dimethyl hydrazine; and THF tetrahydrofuran. Example 1 2-(4-Amine-n-nonylanilino)-4_(imidazolium)-pyrimidinium sulfonium chloride (4 ml) followed by DMF (5 μL) added to 2_ under nitrogen (4_sulfonylanilino)-4-(imidazo[i,2a]pyridin-3-yl)-pyroline (method 4; 75 fae '0.2 04 mmol) and the mixture was disturbed at ambient temperature 48 hours. The volatiles were removed by evaporation and MeOH (6 mL, 7M solution) was added to the residue under nitrogen and the mixture was stirred at ambient temperature for one hour. Evaporation to remove volatiles and residues by preparative HPLC (on Gilson, 1 &quot; C18 column buffer with 0.01% TFA buffer / water 5% to 50% in 1 〇 minutes gradient elution and 50% to 95% Purification by dissolution in 3.5 minutes). The title compound (17 mg, 23%) was obtained as a white solid. NMR: 7.20 (s, 2H), 7.60 (d, 1H), 7.72 (d, 2H), 7.95 (d) , 2H), 8.18 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H), 9.28 (s, 1H), l〇.〇i (S) 1H), 10.20 (s, 1H); m/z : 368 [MH]+. Example 2 2-(4-{N-丨2-(Dimethylamino)ethylimidosulfonylguanidino)-4-&lt;Ί斗和-43- This paper scale applies to Chinese National Standard (CNS) ) Α4 size (210 X 297 mm) 1327146 A7 B7 V. Description of invention (41) "l, 2a" pyridin-3-yl) pyrimidine 2-(4-cylaminophenyl)_4_(imidazo[ Ija] pyridinyl pyrimidine (method 4; 67 mg, 0.181 mmol) dissolved in acetonitrile (丨 ml) and cyclobutane ((ml) and stirred in nitrogen. Phosphorus (67 μl, 〇 added) 724 mmol) and N,N-dimethylacetamide (1 〇 microliter). The reaction mixture was heated under reflux for 3 ' minutes. The volatiles were removed by cooling and evaporation. Amine (252 μl '1.81 mmol) and 1 丨-dimethylethyldiamine (40 μl '0.362 mmol) in methanol (2 mL) without water. The mixture was placed at ambient temperature for 30 minutes. Then dichloromethane (15 ml) and water (15 ml) were added. The aqueous layer was separated and adjusted to pH 9 by careful addition of 2M aqueous sodium hydroxide. The precipitate was collected by filtration to water (2×15 ml) and diethyl ether. 3 XI 5 ml) Washing and dehydration with phosphorus pentoxide for 16 hours to give the title compound (16 mg, 20%). NMR: 2.1 (s, 6H), 2.3 (t, 2H), 2.8 (t, 2H), 7.3 ( Br s, 1H), 7.5 (d, 1H), 7.75 (d, 2H), 7.95 (d, 2H), 8.2 (d, 1H), 8,6 (d, 1H), 8.8 (d, 1H), 8.8 (s, 1H), 9.3 (s, 1H), 9.95 (d, 1H), 10.2 (s, 1H): m/z : 440 [MH]+. Example 3 2-{4-[N-(2 -Methoxyethyl)amines, 1 aniline oxime _4·(imipid 丨i, 2a) 匕 g well-3 - base) shouting bit sulfoxide (6 ml) and DMF (10 Microliter) was added to 2-(4-thinylanilide)-4-(imidazo[1,2a]pyramino-3-yl)pyrimidine under nitrogen (Method 4; 1 10 mg '0.299 mmol) The neutralized mixture was stirred at ambient temperature for 12 hours. The volatiles were removed by evaporation and the residue was placed under nitrogen. EtOAc (EtOAc) (EtOAc) And mixture -44 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) binding

1327146 A7 B7 V. INSTRUCTIONS (42) Stirring at ambient temperature for 3 hours. Evaporation to remove volatiles and residue by column chromatography with di-methane/methanol (100: 〇 polarity increased to 95:5) The title compound (6 mg, 5%). NMR: 2.9 (t, 2H), 3.2 (s, 3H), 3.4 (t, 2H), 7.5 (t, 1H), 7.7 (d, 1H), 7.8 (d, 2H) 7.95 (d, 2H), 8.2 (d, 1H), 8.6 (d, 1H), 8.9 (s, 1H), 9.3 (s, 1H), 10.0 (d, 1H), 10.2 ( s, 1H) ; m/z : 426 [MH]+. Example 4 methoxyethyl)amine sulfonyl 1 amine 丨-4-(imidazole # n.2al忒嗓-3-yl) π 2-[4-sulfonylanilino]-4-(imidazo[1,23]pyrimidin-3-yl)pyrimidine (Method 8; 180 mg of 〇_49 mmol) dissolved in acetonitrile (1 mL) Ring-butyl (1 ml) and agitated "addition of phosphonium chloride (13 6 μl, 1.46 mmol) and hydrazine, hydrazine-dimethylacetamide (1.8 μl). The reaction mixture was stirred at ambient temperature for 4 hours and then heated under reflux for 3 Torr, cooled and evaporated to remove volatiles. The resulting solution was placed under nitrogen and a solution of 2-methoxyethylamine (85 μL, 0.978 mmol), triethylamine (204 mL, 1.47 mmol) in methanol (5 mL) Stir at temperature for 1 hour. The resulting solid was collected by filtration, washed with EtOAc (3.times.20 mL) and dehydrated to afford the title compound (89 mg &apos; 43%). NMR: 2.9 (dd, 1 Η), 3.08 (m, 2 Η), 3.18 (s, 3 Η), 3.3 (t, 2H), 7.56 (d, 1H), 7.77 (d, 2H), 7.98 (d, 2H) , 8.6 (d, 1H), 8.86 (dd, 1H), 8.98 (s, 1H), 10.3 (s, 1H) 10.54 (s, 1H) ; m/z : 426 [MH]+. Example 5 2-(4-Amine Resinylanilide)-4-(Miso and 丨l, 2b)^g Well-3-Base) Call this -45 - Common Paper China National Standard (CNS) A4 Present (21〇x 297 public)

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1327146 A7 B7, invention description (43) 2_anilino_4_(imidazo[l,2b]indol-3-yl)pyrimidine (Example 10; 100 mg '0.347 mmol) dissolved in sulfinium chloride (2 〇 ml) and the solution was stirred and cooled to 0 ° C ° chlorosulfonic acid (92 μl, 1.39 mmol) and the reaction was stirred at 0 ° C for 30 minutes and then stirred at ambient temperature for 丨 hours and finally at 8 (rc was heated for 90 minutes. The mixture was cooled and evaporated to remove the volatiles. 2M methanolic ammonia (6.0 mL) was added to the residue and the mixture was stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation and added to the residue. Distilled water and the mixture were stirred for 30 minutes. The precipitate was collected by filtration, washed with water and then evaporated. 81 mg, 64%) NMR: 7.1 (s, 2H), 7.45 (d, lh), 7.8 (d, 2H), 8.03 (m, 3H), 8.32 (d, 1H), 8.64 (m, 2H) , 8.8 (d, 1H); 10.05 (s, 1H); m/z: 368 [MH]+. Example 6 2-[4-iy-methylaminesulfonyl)anilino-4- 4-imidazolium Benz-3-yl) 2-anilino-4-(imidazo[l,2b]indol-3-yl)pyrimidine (Example 1; 100 mg, 0.347 mmol) was treated as described in Example 5, The crude <RTI ID=0.0></RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; NMR: 2.4 (d, 3H), 7.16 (q, 1H), 7.45 (dd, 1H), 7.75 (d, 2), 8.07 (m, 3H), 8.33 (d, 1H), 8.67 (m, 2H), 8.8 (d, 1H); 10.11 (s, 1H) ; m/z : 380 [M-Η]·. -46 - This paper size applies _ National Standard (CNS) A4 specification (21〇Χ 297 public)

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1327146 A7 B7 V. INSTRUCTIONS (44) Example 7 2-{4-[N-_(U-oxyethyl)amine sulfonyl]anilino-4-(imidazolium)^ 嗒耕-3- Pyrimidine 2-anilino-4-(imidazo[丨,%嗒耕_3_yl)pyrimidine (Example 1〇; 1〇〇mg, 0.347 mmol) was treated as described in Example 5 to obtain crude The sulfonium sulfonate was treated with a solution of 2- methoxyethylamine (0 452 mL) MeOH (1 mL). NMR (DMSO d6 + d4 acetic acid): 2.87 (t, 2H), 3.15 (s, 3H), 3.27 (t, 2H), 7.4 (dd, 1H), 7.74 (d, 2H), 8.05 (m, 3H) , 8.3 (d, 1H), 8·64 (m, 2H), 8_76. (d, 1H). m/z : 424 [Μ·Η]. Example 8 2-[4-(N-(_3_-Dimethylaminopropyl)amine fluorenyl)anthracene (furan arsenic &lt;1,2bl嗒-3-yl)pyrimidine 2-anilino-4 - (Imidazoxan, 2b) 嗒 _3_ yl) pyrimidine (Example 1 〇; 1 〇〇 mg, 0.347 mmol) was treated by the method described in Example 5 to obtain a crude sulphur mole, which was 3 - 1 Treatment with a solution of methylaminopropylamine (87 μL), dimethylethylamine (2 16 mL) in methanol (4.0 mL). The volatiles were removed by evaporation, distilled water was added to the residue, and the mixture was removed for 30 minutes. After collecting the Shen Dian's washed and dehydrated with distilled water. The crude product was dissolved in DMF and purified on a column of 10 g of the amine base 4, 111 pre-equilibrated with methanol. The product was dissolved in methanol, and the purified product was crystallised from ethyl ether/ethyl acetate (yield: EtOAc). NMR: 1.48 (m, 2H), 2. 〇3 (s, ^), 2.13 (t, 2H), 2.75 (t, 2H), 7.33 (s, 1H), 7.45 (dd, 1H), 7.73 -47 - The paper size is the common Chinese national standard (CMS) A4 specification (210 x 297 mm) 1327146 A7 B7 V. Description of invention (45 (d, 2H), 8.07 (m, 3H), 8.33 (d, 1H), 8.65 (s, 1H), 8.68 (d, 1H), 8.8 (d, 1H), 10.11 (s, 1H) ; m/z : 451 [MH]' » Example 9 g_-anilino-4-(imidazolium) [l,2al pyridin-3-yl)pyrimidine-methylaminopropan-2-indole-1-aryl)mipron [1,2a] 峨 well (method 3; 400 mg, 1.85 mmol), Phenylhydrazine bicarbonate (365 mg, 丨.85 mmol) and sodium methoxide (199 mg, 3.7 mmol) dissolved in anhydrous dimethyl ethanoamine (15 ml) and mixture at 160 ° C and nitrogen Heat under reflux for 2 hours. The reaction mixture was cooled with &lt;RTI ID=0.0&gt;&gt;&gt; The ice was melted and the aqueous solution was extracted with a second gas (2×20 mL). The combined extracts were dried <jjjjjjjjjjj NMR: 7.0 (t, 1H), 7.35 (t, 2H), 7.48 (d, 1H), 7.75 (d, 2H), 8.1 (d, 1H), 8.52 (d, 1H), 8.88 (s, 1H) , 9.21 (s, 1H), 9.86 (s, 1H), 9.98 (d, 1H) ; m/z : 299 [MH]+. Example 10 2-anilino-4-(imixo[l,2bl^&lt;4-3-yl)# ate 3-(3-dimethylaminoprop-2-en-1-yl)imidazolium [i, 2b] ploughing (method 17; 600 mg ' 2.78 mmol), phenyl hydrazine bicarbonate (6 〇 3 mg, 3 〇 6 mM) and sodium methoxide (300 mg, 5.56 mmol) It was suspended in anhydrous dimethyl ethanoamine (25 ml) under nitrogen and the mixture was at 16 Torr. 〇 Heat and mix for 2 hours. The reaction was then stirred at room temperature for 20 hours followed by the addition of phenylhydrazine hydrogencarbonate (27 3 mg) and sodium methoxide (150 mg) and the reaction was taken at 16 Torr. (: Heated for 2 hours. The reaction was cooled to ambient temperature and acetic acid (0.5 ml) was added and evaporated. -48- This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm)

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1327146 A7 ___B7 V. Description of invention (46) In addition to volatiles. Water was added to the residue and the resulting suspension was stirred for 30 minutes. The product was collected by filtration <RTI ID=0.0>: </RTI> NMR: 6.96 (t, 1H), 7.33 (m, 2H), 7.42 (dd, 1H), 7.85 (d, 2H), 7.97 (d, 1H), 8.30 (d, 1H), 8.55 (s, 1H) , 8.61 (d, 1H), 8.77 (d, 1H), 9.63 (s, 1H). m/z : 289 [MH]+. Example 11 2 -anilino-4_(taste and n,2a~|〇^--3-yl) shouted 3-(3-dimethylaminoprop-2-en-1-yl)imidazo[ l,2a]pyrimidine (Method 7; 450 mg of <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The main component (70%) in an isomeric mixture of 1,2a]pyrimidin-2-yl)pyrimidine (392 mg, 65%). NMR: 7.0 (t, 1H), 7.26 (dd, 1H), 7.34 (t, 2H), 7.73 (d, 2H), 8.46 (d, 1H), 8.69 (dd, 1H), 8.76 (s, 1H) , 9.67 (s, 1H), 10.38 (d, 1H) » Example 12 2-(2-Fluoroanilino)-4-(imipo-oxime, 2b), 荅·» well-3-yl) shout 3-(3.Dimethylaminoprop-2-en-1-yl-1-imidazolyl)imidazo[ub]pyrene (Method 17; 1.0 g, 4.63 mmol), 2-fluorophenylhydrazine hydrogencarbonate ( Method 25; 1.1 g of '5.09 mmoles) and sodium methoxide (550 mg, 10.2 mmol) were suspended in DMA (42 ml) and the mixture was stirred and stirred at i4 〇eC for 5.5 hours. The mixture was cooled to ambient temperature and then acetic acid (0.33 mL) was added and evaporated to remove the volatiles. The residue was taken up in EtOAcqqqqqqqli NMR: 7.13 (m, 1H), 7.2 (m, 2H), 7.4 (dd, 1H), 7.93 (m, 2H), 8.8 (d, 1H), -49- The wood paper scale applies to the Chinese National Standard (CNS) ) A4 size (210x 297 mm) 1327146

8-43 (s, 1H), 8.58 (d, 1H), 8.77 (d, 1H), 9.05 (s, 1H) ; m/z : 307 [MH]+. Example 1 3 Anilino-4-(2-y-imidazolium n, 2 bl-indolidin-3-yl)pyrimidine 3-(3-dimethylaminopropan-2-ylidene-1-indenyl)imidazo[丨二闪塔耕 (method 18 '1.5 g ' 6.523⁄4 mol), phenyl hydrazine bicarbonate (丨.41 g, 7.1? millimolar) and methanol (704 mg, 13.04 mmol) suspended in Dimethyl ethanoamine (62 ml) and the mixture were stirred at 16 (TCh for 25 hours). The mixture was cooled and phenyl hydrazine bicarbonate (642 mg, 3.25 mmol) and sodium methoxide (352 mg, 6.52) were added. The mixture was heated for an additional 2 hours. The mixture was cooled to ambient temperature and acetic acid (116 mL) was added and evaporated to remove volatiles. The title compound (785 mg, 40%) was obtained. 1H), 7.76 (d, 2H), 7.83 (d, 1H), 8.15 (d, 1H), 8.58 (d, 1H), 8.65 (d, 1H), 9.5 (s, 1H) ; m/z : 303 [MH]+ 〇 Example 14-19 The method described in Example 13 was prepared as follows Example compound NMR M/z 141 2-anilino 4-(2-ethylimidazo[1,2b]physin-3-yl)"mididine 1.27 (t, 3H), 3.27 (q, 2H ), 6.93 (t, 1H), 7.27 (m, 2H), 7.36 (dd, 1H), 7.73 (m, 3H), 8.17 (d, 1H), 8.57 (d, 1H), 8.65 (d, 1H) , 9.48 (s, 1H) 317 [MH]+ -50- This paper wave scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----

Binding

1327146 A7 B7 152 2-anilino 4-(2-dimethylaminoimidazo[l,2b]indol-3-yl)pyrimidine 2.98 (s, 6H), 6.93 (t, 1H), 7.25 (m, 3H), 7.57 (d, 1H), 7.9 (m, 3H), 8.45 (d, 1H), 8.52 (d, 1H), 9.55 (s, 1H) 332 [MH]+ 16 2-anilinyl 4-( 5-methoxyimidazo[1,2b], -3-yl) succinimide 4.1 (s, 3H), 6.95 (t, 1H), 7.22 (d, 1H), 7.32 (t, 2H), 7.82 (d, 2H), 8.0 (d, 2H), 8.18 (d, 1H), 8.40 (s, 1H), 8.60 (d, 1H), 9.60 (s, 1H) 319 [MH]+ 17 2-aniline 4-(5-(2,2,2-trifluoroethoxy)imidazo[l,2b]indole-3-yl), 5.81 (q, 2H), 6.95 (t, 1H), 7.22 (d, 1H), 7.32 (t, 2H), 7.82 (d, 2H), 7.92 (d, 1H), 8.26 (d, 1H), 8.42 (s, 1H), 8.61 (d, 1H), 9.6 (s, 1H) 387 [MH]+ 18 2-anilino 4_(6,7-dimethylimidazo[l,2b]indol-3-yl)pyrimidine 2.39 (s, 3H), 2.58 (s, 3H), 6.95 (t, 1H), 7.34 (t, 2H), 7.88 (d, 2H), 7.92 (d, 1H), 8.45 (s, 1H), 8.58 (m, 2H), 9.58 (s, 1H) 317 [MH]+ 19 2-anilino 4-(6-methylimidazo[1,2b]indol-3-yl)pyrimidine 2.45 (s, 3H), 6.96 (t, 1H), 7.32 (t , 2H), 7.87 (d, 2H), 7.92 (d, 1H), 8.08 (s, 1H), 8.48 (s, 1H), 8.58 (d, 1H), 9.48 (s, 1H) 303 [MH] + 1 by chromatography eluting with dichloromethane/methanol (98.5: 1.5), NMR: V. (48); m/z: 2 was purified by chromatography eluting with dichloromethane/methanol (98:2). Example 20 2-{2-Ga-4-" (2-methyl-based ethyl) sulfonamide, a 1-methylamino}-4-(imidazo-"l,2bl嗒-3-yl)pyrimidine gas Sulfonic acid (109 μl, 1.64 mmol) added to 2-(2-fluoroanilino)-4- -51 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1327146 Inventive Note (49) (Taste and [l, 2b] indol-3-yl) pyrimidine (Example 12; 13 mg, 〇41 mmol) of sulfite (2.6 mL) was cooled to it In the stirred solution, the reaction was stirred for 5 minutes at 〇C' followed by heating at 90 °C for 80 minutes, and the volatiles were removed by cooling and evaporation. To the residue was added 2-methoxyethylamine (〇 75 mL, 858 s. Mol) sterol (2.0 ml) and the mixture was stirred at ambient temperature for 2 。 minutes. Lose volatiles were removed and water was added to the residue and the mixture was mixed for 3 minutes. The precipitate was collected by filtration, washed with water and dehydrated. The title compound ( 217 mg, 86%). NMR: 2.94 (t, 2H), 3.17 (s, 3H), 3.28 (t, 2H), 7.43 (dd, 1H), 7.65 (dd, 3H), 8.06 (d, 1H), 8.32 (d, 1H), 8.41 (t, 1H), 8.5 5 (s, 1H), 8.66 (d, 1H), 8.78 (d, 1H), 9.45 (s, 1H) ; m/z : 444 [MH]+. Example 2 1 2-(2-Fluoro-4- Aminesulfonylanilino)-4-(imidazolium, 2 bl., 3-yl)pyrimidine 2-(2-fluoroanilino)-4-(imiphtho[1,2b]taghu-3 - base) shouted (Example 12; 175 mg, 0, 572 mmol). NMR: 7.33 (s, 2H), 7.45 (dd, 1H), 7.67 (m, 2H), 8.07 (d, 1H), 8.33 (m, 2H), 8.53 (s, 1H), 8.66 (d, 1H ), 8_8 (d, 1H), 9.45 (s, 1H); m/z: 386 [MH]+. Examples 22-26 The following compounds were prepared by the method described in Example 2 1. -52- This paper scale applies to China Standard (CNS) A4 size (210X297 mm) 1327146 A7 B7 V. Description of the invention (5〇) Example compound NMR M/z 22' 2-(4-Aminesulfonylanilino)-4-(2-methyl Imidazo[1,2b]indole-3-yl) σ-dense 2.82 (s,3H), 7.13 (s,2H), 7.37 (dd, 1H), 7.73 (d, 2H), 7.9 (d, 1H) ), 7.97 (d, 2H), 8.16 (d, 1H), 8.65 (m, 2H), 9.97 (s, 1H) 380 [MH] 232 2-(4-amine Nonylanilino)-4-(2-ethylimidazo[l,2b]indole-3-yl) p-bite 1.30 (t, 3H), 3.27 (q, 2H), 7.13 (s, 2H) , 7.38 (dd, 1H), 7.73 (d, 2H), 7.87 (d, 1H), 7.95 (d, 2H), 8.2 (d, 1H), 8.65 (m, 2H), 9.97 (s, 1H) 396 [MHf 243 2-(4-Aminesulfonylanilino)-4-(5-methoxyimidazo[1,2b]indole-3-yl)π-dense 4.19 (s, 3H), 7.09 ( d, 1H), 7.13 (s, 2H), 7.78 (d, 2H), 8.0 (d, 2H), 8.06 (d, 1H), 8.2 (d, 1H), 8.43 (s, 1H), 8.68 (d , 1H) 398 [MHf 254 2-(4-Amine anilinyl)-4-(5-(2,2,2-trifluoroethoxy)imidazo[l,2b]嗒耕-3- Pyrimidine 5.2 (q, 2H), 7.15(s, 2H), 7.24 (d, 1H), 7.78 (d, 2H), 7.98 (d, 2H), 8.02 (d, 1H), 8.3 (d, 1H ), 8.5 (s, 1H), 8.7 (d, 1H), 10.04 (s, 1H) 466 [MH]+ 26 2-(4-Aminesulfonylanilide)-4-(6,7-dimethyl Imidazo[1,2b]嗒4-3-yl&gt; close bit 2.38 (s, 3H), 2.47 (s, 3H), 7.12 (s, 2H), 7.78 (d, 2H), 7.97 (d, 1H), 8.0 (d, 2H), 8.5 (s, 1H), 8.6 (s, 1H), 8.65 (d, 1H), 10.02 (s, 1H) 396 [MH]+ on the amine-based Isolute column Chromatography with methanol/dichloromethane (1:1)

Binding

Purified. 2 Purified by two-gas methane/methanol dispersion. 3 by ruthenium chromatography, the polarity of di-methane/methanol (99:1) was increased to (80:20) and purified by dissolving. 4 Purified by dissolving in dichloromethane/methanol (1:1) by 10 g of amine-based Isolute column chromatography. -53- This paper scale applies to Chinese National Standard (CMS) A4 specification (210X 297 mm) 1327146 A7 B7 V. Inventive Note (51) Examples 27-39 The following compounds were prepared in a manner similar to that described in Example 20. Example compound NMR M/z 27 2-{4-[N-(2-methoxyethyl)amine sulfonyl]anilino}-4-(2-methylimidazo[l,2b] morphine- 3-yl)pyrimidine (DMS0d6/CD3C02D): 2.8 (s, 3H), 2.87 (t, 2H), 3.15 (s, 3H), 3.3 (t, 2H), 7.36 (dd, 1H), 7.7 (d, 2H), 7.92 d, 1H), 7.98 (d, 2H), 8.15 (d, 1H), 8.64 (m, 2H), 9.97 (s, 1H) 438 [MH]- 28 2-{4-[N- (3-dimethylaminopropyl)aminesulfonyl]anilino}-4-(2-methylimidazo[l,2b]indole-3-yl)pyrazine 1.47 (m, 2H), 2.03 (s, 6H), 2.13 (t, 2H), 2.73 (t, 2H), 2.8 (s, 3H), 7.36 (m, 2H), 7.67 (d, 2H), 7.92 (d, 1H), 8.0 ( d, 2H), 8.17 (d, 1H), 8.67 (m, 2H), 10.0 (s, 1H) 465 [MH] 29 2_[4-(N-methylaminesulfonyl)anilino]-4- (2-Methylimidazo[1,2b] tau-3-yl)p is in violation of 2.4 (d, 3H), 2.8 (s, 3H), 7.17 (q, 1H), 7.37 (dd, 1H), 7.67 (d, 2H), 7.9 (d, 1H), 8.0 (d, 2H), 8.16 (d, 1H), 8.65 (m, 2H), 10.0 (s, 1H) 394 [MH]' 30 2-{ 4-[N-(2-methoxyethyl)amine cross-flavor]anilino}-4-(2-ethylimidazo[l,2b]indol-3-yl)pyrimidine 1.32 (t, 3H ), 2.87 (t, 2H), 3.15 (s, 3H), 3.27 (m, 4H), 7.38 (dd, 1H), 7.45 (s, 1H), 7.7 (d, 2H), 7.88 (d, 1H), 7.98 (d, 2H), 8.2 d, 1H), 8.65 (d, 2H), 10.0 (s , 1H) 453 [MH]+ 31 2-[4-(N-Methylaminesulfonyl)anilino]-4-(2-ethylimidazo[l,2b], column 11 well-3-yl) Density 1.33 (t, 3H), 2.38 (d, 3H), 3.25 (q, 2H), 7.2 (q, 1H), 7.38 (dd, 1H), 7.68 (d, 2H), 7.9 (d, 1H) , 7.98 (d, 2H), 8.2 (d, 1H), 8.63 (m, 2H), 9.97 (s, 1H) 410 [MH]+ 321 2-{4-[N-(2-methoxyethyl Aminesulfonyl]anilino}-4-(2-dimethylaminoimidazo[l,2b]indole-3-yl) B-density 2.85 (t, 2H), 2.97 (s, 6H), 3.17 (m, 5H), 7.3 (dd, 1H), 7.45 (t, 1H), 7.68 (m, 3H), 7.97 (dd, 1H), 8.1 (d, 2H), 8.49 (dd, 1H), 8.58 (d, 1H), 10.08 (s, 1H) 469 [MH]+ -54- Binding

k This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of invention (52) 332 2-{4-[N-(2-Dimethylaminoethyl)amine Sulfhydryl]anilino}-4-(5-methoxyimidazo[l,2b]-tower-3-yl) B-dense 2.23 (s, 6H), 2.82 (t, 2H), 3.0 (m , 2H), 4.08 (s, 3H), 7.08 (d, 1H), 7.58 (brs, 1H), 7.98 (d, 2H), 8.06 (d, 2H), 8.1 (d, 1H), 8.44 (s, 1H), 8.68 (d, 1H), 10.12 (s, 1H) 469 [MH]+ 34 2-[4-(N-Methylaminesulfonyl)anilino]-4-(5-methoxyimidazole And [1,2b] ☆ well-3-base) shouting 2.41 (d, 3H), 4.08 (s, 3H), 7.08 (d, 1H), 7.2 (m, 1H), 7.73 (d, 2H), 8.04 (d, 2H), 8.08 (d, 1H), 8.19 (d, 1H), 8.45 (s, 1H), 8.64 (d, 1H), 10.07 (brs, 1H) 412 [MH]+ 353 2-{ 4-[N-(2-methoxyethyl)aminesulfonyl]anilino}-4-(5-methoxyimidazo[1,2b]indole-3-yl) 2.9 (t, 2H ), 3.18 (s, 3H), 3.28 (m, 2H), 4.1 (s, 3H), 7.12(d, 1H), 7.43 (t, 1H), 7.76 (d, 2H), 8.04 (d, 2H) , 8.1 (d, 1H), 8.2 (d, 1H), 8.43 (s, 1H), 8.68 (d, 1H), 10.07 (s, 1H) 456 [MHf 36 2-{4-[N-(3- Methoxypropyl)amine sulfonate Anilino}-4-(5-methoxyimidazo[l,2b]indole-3-yl) D-bite 1.6 (quin, 2H), 2.78 (q, 2H), 3.17 (s, 3H) , 3.25 (t, 2H), 4.08 (s, 3H), 7.08 (d, 1H), 7.32 (t, 1H), 7.75 (d, 2H), 8.02 (d, 2H), 8.08 (d, 1H), 8.19 (d, 1H), 8.46 (s, 1H), 8.66 (d, 1H), 10.07 (s, 1H) 470 [MHf 374 2-{4-[N-(2-methoxyethyl)amine sulfonate Anthranyl]anilinyl}-4-(6,7-dimethylimidazo[1,2b]indole-3-yl) p-bite 2.37 (s, 3H), 2.56 (s, 3H), 2.9 ( t, 2H), 3.16(s, 3H), 3.31 (t, 2H), 7.35 (t, 1H), 7.75 (d, 2H), 8.01 (d, 1H), 8.05 (d, 2H), 8.52 (s , 1H), 8.48 (s, 1H), 8.64 (d, 1H), 9.9 (s, 1H) 454 [MH]+ 385 2-{4-[N-(2-methoxyethyl)amine sulfonate Anthranyl}-4-(6.methylimidazo[l,2b]indol-3-yl)pyrimidine 2.49 (s, 3H), 2.92 (q, 2H), 3.19 (s, 3H), 3.34 (q, 2H), 7.47 (t, 1H), 7.78 (d, 2H), 8.04 (d, 1H), 8.09 (d, 2H), 8.14 (s, 1H), 8.6 (s, 1H), 8.69 ( d, 1H), 8.74 (d, 1H), 10.1 (s, 1H) 440 [MHf 396 2-{4-[N-(2-ethoxyethyl)aminesulfonyl]anilinyl}-4- (Imidazo[l,2b]indole-3-yl)pyrimidine 1.04 (t, 3H), 2.90 (q, 2H), 3.35 (m, 4H), 7.44 (m, 2H), 7.76 (d, 2H), 8.08 (m, 3H), 8.36 (d, 1H), 8.66 (s, 1H), 8.70 (d, 1H), 8.80 ( d, 1H), 10.11 (s, 1H) 440 [MH]+ -55-

Binding

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

Reversed phase chromatography on a Hypersi 丨BDS C18 21χι〇〇mm column with acetonitrile/water/trifluoroacetic acid (10:90: (M) polarity reduced to (9〇: 1〇: 〇 纯化 purification. ) 2 Purified by methanol/diethyl ether/dichloromethane. 3 Purified by dilute methane/methanol (95:5) followed by dichloromethane / 2M methanolic ammonia (95:5). Purified by dipethane chromatography with di-methane/methanol (97:3). 6 Purified by further methanol dispersion. Example 40 ldidN-U-methylcycloprop-1-yl)aminesulfonyl 1 Aniline 丨_4 oxazolium oxime and U, 2 b] tower whistle ^ · 3 - yl) shouted chlorhexidine acid (0.22 ml, 3_3 mmol) was added to cool to 5. A solution of 2-phenylamino-4-(imidazo[i,2b]indol-3-yl)pyrimidine (Example 1 〇; 300 mg, 1.04 mmol) of sulphuric acid chloride (6 mL). The mixture was stirred for 3 minutes and then stirred at ambient temperature for 1.5 hours and then refluxed for 1.5 hours. Isopropanol (1 ml) and dimethylformamide (3 ml) of 1-amino-1-methylcyclopropane (Method 48; 2 ml) were added and mixture was stirred at ambient temperature for 8 hours. Evaporation of the solvent and the residue was purified by chromatography eluting eluting eluting eluting eluting eluting eluting 21%). NMR: 0.16-0.19 (m, 2H), 0.40-0.44 (m, 2H), 0.92 (s, 3H), 7.25 (dd, 1H), 7.55-7.60 (m, 3H), 7.86-7.90 (m, 3H), 8.15 (d, 1H), 8.48 (s, 1H), 8.53 (d, 1H), 8.62 (d, 1H), 9.95 (s, 1H) ; m/z -56- paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 male dragon) 1327146 A7 B7 V. Inventive Note (54): 422 [MH]+. Example 4 1 - 5 7 The following compound was prepared by the method described in Example 40. Example compound NMR M/z 41 2-{4-[N-(3-methoxypropyl)aminesulfonyl]anilinyl}-4-(imidazo[i,2b]»A17 well-3- Base &gt; 密密 1.58 (quin, 2H), 2.78 (q, 2H), 3.14 (s, 3H), 3.22-3.25 (m, 2H), 7.32 (t, 1H), 7.44 (dd, 1H), 7.75 (d, 2H), 8.05 (s, 1H), 8.16 (d, 2H), 8.34 (s, 1H), 8.63 (s, 1H), 8.68 (d, lH), 8.8(d, 1H), 10.12 ( s, 1H) 440 [MH]+ 42 2-[4-(N-propylaminesulfonyl)anilino]-4-(imidazo[l 2b]嗒啩-3-yl)&quot;·Speaking 0.79 (t, 3H), 1.38 (q, 2H), 2.69 (q, 2H), 7.32 (t, 2H), 7.45 (dd, 1H), 7.75 (d, 2H), 8.04 (s, 1H), 8.09 (d, 2H), 8.34 (d, 1H), 8.63 (s, 2H), 8.68 (d, 1H), 8.80 (d, 1H), 10.11 ( s, 1H) 410 [MH]+ 43 2-[4-(N-ethylaminesulfonyl)anilino]-4-(imidazo[1,2b]indole-3-yl) shouting 0.96 ( t, 3H), 2.78 (q, 2H), 7.30 (t, 1H), 7.43 (dd, 1H), 7.75 (d, 2H), 8.05 (s, 1H), 8.08 (d, 2H), 8.35 (d , 1H), 8.64 (s, 1H), 8.69 (d, 1H), 8.80 (d, 1H), 10.11 (s, 1H) 396 [MH]+ 44 2- [4-(N-allylamine sulfonate) Anthracenyl)aniline]-4-(imidazo[1,21)]indole-3-yl)pyrimidine 3.40 (t, 2H), 5.01 (d, 1H), 5.15 (d, 1H), 5.61-5.70 (m, 1H), .7.45 (dd, 1H), 7.56 (t, 1H), 7.78 (d, 2H), 8.04 (s, 1H), 8.07 (d, 2H), 8.35 (d, 1H), 8.64 (s, 1H), 8.70 (d, 2H), 8.80 (d, 1H), 10.12 (s, 1H) 408 [MHf -57- This paper wave scale applies Chinese National Standard (CMS) A4 specification (21〇x 297 1327146 A7 B7 V. INSTRUCTIONS (55) 45 2- [4-(N-propynylaminesulfonyl)anilino]-4-(imidazo[1,2b]indole-3-yl ) mouth bite 3 .64 (s, 2H), 7.44 (dd, 1H), 7.78 (d, 2H), 8.08 (m, 3H), 8.34 (d, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 10.13 (s, 1H) 406 [MH]+ 46 2-{4-[Ν-(2-(1-pyrazolyl)ethyl)aminesulfonyl]anilinyl}-4-(imidazo[1, 2b]嗒耕-3-yl)pyrimidine 3.11 (q,2H), 4.15 (t,2H), 6.20 (s, 1H), 7.39 (s, 1H), 7.44 (dd, 1H), 7.59 (t, 1H ), 7.65 (s, 1H), 7.74 (s, 2H), 8.08 (s, 1H), 8.09 (d, 2H), 8.32 (d, 1H), 8.64 (s, 1H), 8.69 (d, 1H) , 8.80 (d, 1H), 10.13 (s, 1H) 462 [MH]+ 47 2-{4-[Ν-(1,3-dihydroxypropan-2-yl)aminesulfonyl]anilinyl}- 4-(Imidazo[l,2b]indol-3-yl)pyrimidine 3.01-3.06 (m, 1H), 3.25-3.35 (m, 4H), 4.55 (t, 2H), 7.18 (d, 1H), 7.49 (dd, 1H), 7.80 (dd, 2H), 8.04 (s, 1H), 8.09 (dd, 2H), 8.35 (d, 1H), 8.68 (s, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 10.15 (s, 1H) 442 [MH]+ 48 2-{4-[Ν-(1-·^ylpropan-2-yl)aminesulfonyl]anilinyl}-4-( Imidazo[1,2b]tau-3-yl)metimidine 0.88 (d, 3H), 3.05-3.12 (m, 2H), 3.20-3.38 (m, 1H), 4.60 (s, 1H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.77 (d, 2H), 8.04-8.08 (m, 3H), 8.35 (d, 1H), 8.6 4 (s, 1H), 8.68 (d, 1H), 8.80 (d, 1H), 10.11 (s, 1H) 49 2-{4-[Ν-(1-methoxypropan-2-yl)amine continued Alkyl}-4-amino}-4-(3-di-[1,2b]3-amino) is called pyridine 0.90 (d, 3H), 3.05-3.15 (m, 1H), 3.15 (s, 3H), 3.23 -3.25 (m, 2H), 7.40 (d, 1H), 7.45 (dd, 1H), 7.78 (d, 2H), 8.04-8.09 (m, 3H), 8.35 (d, 1H), 8.64 (s, 1H) ), 8.70 (d, 1H), 8.80 (d, 1H), 10.15 (s, 1H) -58- Paper Wave Standard General Chinese National Standard (CMS) A4 Specification (210 X 297 mm) 1327146 A7 B7 V. Invention Description (56) 50 2-{4-[N-(2-Methylpropan-2-yl)aminesulfonyl]anilinyl}-4-(imidazo[1,2b]indol-3-yl) Pyrimidine 1.09 (s, 9H), 7.22 (s, 1H), 7.44 (dd, 1H), 7.78 (d, 2H), 8.03 (s, 1H), 8.08 (d, 2H), 8:34 (d, 1H) ), 8.64 (s, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 10.09 (s, 1H) 422 [MH]+ 51 2-{4-[N-(2-dimethylamino) Ethyl) sulfonyl]anilino}-4-(imidazo[1,2 荅 荅-3-yl) 啶 2.0 2.08 (s, 6H), 2.28 (t, 2H), 2.82 (t, 2H ), 7.24 (s, 1H), 7.42 (dd, 1H), 7.79 (d, 2H), 8.06 (s, 1H), 8.10 (d, 2H), 8.35 (d, 1H), 8.64 (s, 1H) , 8.70 (d, 1H), 8.80 (d, 1H), 10. 11 (s, 1H) 439 [MH]+ 52 2- [4-(N-Cyclobutylamine sulfonyl)anilino]-4-(imidazo[1,2b]indole-3-yl) Bite 1.42-1.50 (m, 2H), 1.75 (q, 2H), 1.88-1.95 (m, 2H), 3.65-3.64 (m, 1H), 7.45 (dd, 1H), 7.66-7.78 (m, 3H) ), 8.02-8.08 (m, 3H), 8.35 (d, 1H), 8.64 (s, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 10.11 (s, 1H) 422 [MH]+ 53 2-{4-[N-(l,3-dihydroxy-2-methylpropan-2-yl)aminesulfonyl]anilino}-4-(imidazo[l,2b]嗒耕-3 -base) 0.98 (s, 3H), 3.25-3.31 (m, 4H), 4.52 (t, 2H), 6.72 (s, 1H), 7.45 (dd, 1H), 7.80 (d, 2H), .8.02- 8.10 (m, 3H), 8.35 (d, 1H), 8.64 (s, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 10.10 (s, 1H) 456 [MH]+ 54 2-[ 4-(N-cyclopropylmethylamine sulfonyl)anilino]-4-(imidazo[1,2b] column 11 well-3-yl) π-dense 0.01-0.08 (m, 2H), 0.26 -0.30 (m, 2H), 0.70-0.79 (m, 1H), 2.59 (t, 2H), 7.40 (dd, 1H), 7.72 (d, 2H), 8.0 (s, 1H), 8.02 (d, 2H ), 8.30 (d, 1H), 8.60 (s, 2H), 8.64 (d, 1H), 8.78 (d, 1H), 10.05 (s, 1H) 422 [MH]+

Binding

-59-This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of invention (57) 55 2- [4-(N-Cyclopropylamine sulfonyl) aniline ]]-4-(imidazo[1»荅牛3-yl) shouting 0.01-0.08 (m, 2H), 0.10-0.15 (m, 2H), 1.72-1.78 (m, 1H), 7.10 (dd, 1H), 7.30 (s, 1H), 7.40 (d, 1H), 7.70-7.78 (m, 3H), 8.0 (d, 1H), 8.33 (s, 1H), 8.35 (d, 1H), 8.46 (d , 1H), 9.8 (s, 1H) 408 [MH]+ 56 2-{4-[N-(2-methoxyethyl)-N- 2.71 (s, 3H), 3.10 (t, 2H), 3.22 440 Methylamine sulfonyl]anilinyl}-4-(s, 3H), 3.42 (t, 2H), 7.42 (dd, [MH]+ (imidazo[1,2b] talyn-3-yl Pyrimidine 2H), 7.75 (d, 2H), 8.08 (d, 1H), 8.12 (d, 2), 8.32 (d, 1H), 8.68 (s, 1H), 8.70 (d, 1H), 8.80 ( d, 1H), 10.18 (s, 1H) 57 2-{4-[Ν-(1-hydroxy-2-methylpropane-1.2 (s, 6H), 3.20 (d, 2H), 4.75 (t, 440 2-yl)aminesulfonyl]anilino}-4- 1H), 7.09 (s, 1H), 7.49 (dd, 1H), [MH]+ (imidazo[1,2b]嗒-3-yl ), 7.82 (d, 2H), 8.09 (d, 1H) 1H), 10.15 (s, 1H) Example 5 8 -Methoxy-2-methylpropan-2-yl)amine sulfonyl 1 phenylamino hydrazine _4·[Imidazolium ,1, 2 bl嗒-3 -based pyrimidine

Binding

Sodium methoxide (96 g, 1.8 mmol) was added to 2-{4-[N-(2,2-dimercapto-p-propionyl)amine aryl] anilino}-4- (microbite) And [l, 2b] ta jing-3-yl) 〇 ( (method 46; 150 mg '0.36 mmol) in methanol (5 ml) and the mixture was heated at 50 ° C for 1.5 hours. The solvent was removed by evaporation, and the residue was dissolved in ethyl acetate/methanol, washed with water, dehydrated (MgS?4) and evaporated to remove solvent. The crude product was purified by EtOAc EtOAc EtOAc EtOAc (td. - This paper scale is suitable for gg materials (CNS) A4 specification (210X297 public: ¢) '~~~ --- 1327146 A7 B7 V. Invention description (58) 7-77 (dd, 2H), 8.0-8.05 ( m, 3H), 8.27 (d, 1H), 6.25 (s, 1H), 8.64 (d, 1H), 8.74 (d, 1H) ; m/z : 454 [MH]+. Example 5 9 〒oxy-2-methylpropanol·1·ylamine) Amines 1 base and 4, and fl, 2 bl cultivating -3-, θ θ The title compound (10 mg '7〇/〇)~1^:1.09 (5,611), 2.65 ((1,2^1), 3.05〇, 31·!), 7.25 (t,1H), 7.46 (dd, 1H), 7.78 (d, 2H), 8.05-8.10 (m, 3H), 8·30 (d, 1H), 8.64 (s, 1H), 8.68 (d, 1H), 8.80 (d, 1H) ), 10.1 (s, 1H) ; m/z : 454 [mh]+. Example 60

MilQiiLk (峨洛 bit-1-yl V2-T-propan-2-yl)amine sulfonyl] guanamine] spit and 丨l, 2bl 嗒 -3-, 忒咗2-{4-[1 ^-(2,2-Dimethylaziridine)aminesulfonyl]anilino}_4-azamidazo[1,2b]嗒'• well-3-yl)pyrimidine (Method 46; 150 mg, 0.35 The pyrrolidine (4 ml) was stirred with heating at 50 t for 2 hours and then at ambient temperature for 65 hours. The volatiles were removed by evaporation and the residue dissolved in ethyl acetate / methanol, washed with water and dehydrated (NaJO4). The solvent was removed by evaporation and EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (m5 4H), 6.96 (s, 1H), 7.44 (dd, 1H), 7.79 (d, 2H), 8.05 (d, 2H), 8.07 (d, 1H), 8 36 (d, 1H), 8.64 ( s, 1H), 8.69 (d, 1H), 8.80 (d, 1H), 10.08 (s, 1H) ; m/z : 493 [MH]+. 1327146 A7 B7 V. INSTRUCTIONS (59) EXAMPLE 6 1 2-{4-"N-(l-Methylthio-2-methylpropan-2-yl)aminesulfonyl-1anilinyl}-4-( Imidazolium, 2, brom-3-yl)pyrimidine 2-{4-[N-(2,2-dimethylaziridine)aminesulfonyl]anilinyl}·4-(imidazo[ l, 2b] indole-3-yl)pyrimidine (method 46; 150 mg, 0.36 mmol) and methanethiolate (125 mg, 1.8 mmol) in DMF (4 mL) The mixture was heated at 80 °C for 18 hours. The solvent was removed by evaporation, and the residue was dissolved in ethyl acetate/methanol, washed with water, and evaporated. The residue was crystallized eluted EtOAcqqqqq NMR: 1.15 (s, 6H), 2_10 (s, 3H), 2.65 (s, 2H), 7.40 (s, 1H), 7.50 (dd, 1H), 7.82 (d, 2H), 8.08-8.1 (m, 3H), 8.39 (d, 1H), 8.69 (s, 1H), 8.73 (d, 1H), 8.80 (d, 1H), 10.15 (s, 1H) ; m/z : 470 [MH]+. Example 62 U4-[N-(1-morpholinyl-2-methylpropan-2-yl)amine sulfonyl 1 amide 丨4_(Imidazo[1,21)1嗒_-3-yl Pyrimidine 2-{4-[N-(2,2-dimethylaziridine)aminesulfonyl]anilinobu 4 (imidazo[l,2b]indol-3-yl)pyrimidine (120 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The title compound (50 mg, 35%) was obtained from EtOAc: EtOAc: EtOAc: EtOAc: s, 1H), 7.43 (dd, 1H), 7.78 (d, 2H), 8.02-8.08 (m, 3H), 8 35 (d 1H), 8.64 (s, 1H), 8.71 (d, 1H), 8.80 (d, 1H), 10.08 (s[Η). -62- This paper wave scale applies to the tag family standard (CNS) A4 specification (2l〇x 297 male dragon) ------------- -

Binding

1327146

Example 63: Pyrimidine &quot;~~ Gassulfonic acid (0.23 mL, 3.3 mmol) was added to cool to 5. A solution of 2 phenylamino- 4-(imidazo[12b]indole _3_yl)pyrimidine (example n 3 (eight) mg, m.) of sulfinium chloride (6 ml). The mixture is at 5. (: stirring 30 minutes and then stirring at ambient temperature for 1 hour followed by reflux heating for 5 hours. The mixture was cooled to ambient temperature and 1,3-dimethoxy-2-aminopropane was added to the residue (Method 57; 14 Ethyl alcohol (20 ml) and dimethylformamide (1 ml), and the mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was separated by water and filtered to collect solids. &lt;t&quot;t is more dry&apos; obtained the title compound (322 mg, 66%). NMR: 3.10 (s, 6H), 3.21 (d, 4H), 7.42-7.58 (m, 2H), 7.78 (d, 2H), 8.02-8.08 (m, 3H), 8.35 (d, 1H), 8.65-8.70 (m, 2H), 8.80 (d, 1H), 10.09 (s, 1H) ; m/z : 470 [MH]+. 64-66

Binding

The following compounds were prepared in a similar manner to that described in Example 63. Example compound NMR M/z 64' 2-{4-[Ν-(1-ethoxypropan-2-yl)aminesulfonyl]anilinyl}-4-(imidazo[l,2b] 3-yl)pyrimidine 0.90 (d, 3H), 1.05 (t,3H), 3.08-3.12 (m, 1H), 3.22-3.30 (m, 4H), 7.39 (d, 2H), 7.45 (dd, 1H) , 7.79 (d, 2H), 8.03-8.09 (m, 3H), 3.35 (d, 1H), 8.64 (s, 1H), 8.70 (d, 1H), 8.80 (d, 1H) 454 [MH]+ k -63- This paper scale General Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1327146 A7 B7 V. Description of invention (61) 652 2-{4-[Ν-(1-propoxypropane-2 -amino)sulfonyl]anilino}-4-(imidazo[1,2b] talyn-3-yl)pyrimidine 0.79 (t, 3H), 0.94 (d, 3H), 1.40 (q, 2H) , 3.08-3.12 (m, 1H), 3.18-3.20 (m, 2H), 7.38 (d, 1H), 7.43 (dd, 1H), 7.78 (d, 2H), 8.03-8.09 (m, 3H), 8.36 (d, 1H), 8.62 (s, 1H), 8.68 (d, 1H), 8.81 (d, 1H), 10.1 l(s, 1H) 468 [MH]+ 663 2-{4-[Ν-(1 ,3-diethoxypropan-2-yl)amine sulfonyl]anilino}-4-(imidazo[l,2b]indole-3·yl)pyrimidine 0.99 (t, 6H), 3.23-3.31 (m, 9H), 7.42-7.51 (m, 2H), 7.78 (d, 2H), 8.02-8.09 (m, 3H), 8.34 (d, 1H), 8.62 (s, 1H), 8.70 (d, 1H) ), 8.80 (d , 1H), 10.08 (s, 1H) 498 [MH] + 1-ethoxy-2-aminopropane (Method 54) is the starting material, by chromatography with dioxane/isohexane (1: 1) The polarity was increased to dichloromethane/methanol (97:3) for purification by elution. 1-propoxy-2-aminopropane (Method 55) was used as a starting material by chromatography to afford (95:5) elution purification with the methylene chloride/methanol (1 〇〇: 〇) polarity. 31,3-Diethoxy-2-aminopropane (Method 56) is the starting material, and the polarity is increased by dichloromethane/isohexane (1:1) to dihalomethane/methanol by chromatography (985: 15) Lysis purification. Preparation of starting materials The starting materials of the above examples are commercially available or can be prepared from known materials by standard methods. For example, the following reactions illustrate, but are not limited to, the preparation of some of the starting materials used in the above reactions. ° -64 -

1327146 A7 B7 V. Description of the invention (62 Method 1 3-(1-hydroxyethyl)imidazo[1,2al pyridinium anhydrous neutral alumina (activity 1) (28.5 g) was added to the 2-amino group under nitrogen Pyrolysis (2.85 g, 30 mmol) of anhydrous di-methane (1 mL) in a stirred solution. Add 2,3-epoxybutyraldehyde (5.58 g, 30 mmol) of di-methane ( 1 〇 ml) and the reaction mixture was stirred for 18 hours. The reaction mixture was filtered, and the alumina cake was washed with dichloromethane (100 ml) and methanol/dichloromethane (1:1, 100 ml). The volatiles were removed (the bath temperature was maintained below 40 ° C). The title compound ( 586 mg, 12%) was obtained as a pale orange solid. 3H), 5.18 (quin, 1H), 5.5 (d, 1H), 7.7 (s, 1H), 7.88 (d, 1H), 8.5 (d, 1H), 9.0 (s, 1H). Method 2 3 - B基基米嗓 and "l, 2a ~ KI: _ 3- (1-hydroxyethyl) imidazo[l, 2a] pyridin (method 1; 3.87 grams, 23.7 pens) and short dioxide dioxide (21.1 grams) , 237 millimoles) soluble in acetone (3 〇 ml) Stir at ambient temperature for 72 hours. Filter the solution with celite, wash with acetone (4.times.50 mL) and then wash with methanol (3.times. The title compound (349 mg, 1%) was obtained as a pure crystalline white solid. NMR: 2.60 (s, 1H), 8.22 (d, 1H). ), 8.75 (s, 1H), 9·35 (m, 2H). Method 3 3-(3-Dimethylaminoprop-2-en-yl)dimidazolium i,2alpy-1-65-

This paper ruler (four) fiscal country standard (CNsTa4 specification (210 X 297/U 1327146 A7 B7

3-Ethyl imidazo[l,2a]pyridinium. A mixture of well (Method 2; 340 mg, 2 1 1 mmol) and DMFDMA (20 mL) was refluxed under nitrogen for 8 h. The mixture was cooled and evaporated to remove the solvent. The residue was chromatographed, EtOAc (EtOAc: EtOAc: EtOAc: 1H), 7.75 (d, 1H), 8.18 (d, 1H), 8.6 (s, 1H), 9.19 (s, 1H), 9.55 (dd, 1H); m/z: 218 [MH]+. Method 4 2- [4-Sulfosylaminoamino 1-4-($oxazo[1,231pyrazin-3-yl)pyrimidine-2-aminoamide- 4- (taste and [l, 2a ]p than 11 well-3 -base) π dense bite (Example 9; 350 mg '1.2 2 耄 Mo ear) was added successively to a sulfuric acid cooled in an ice bath and mixed to maintain a temperature &lt;25 ° C concentrated sulfuric acid (6 ml) )in. The reaction mixture was warmed to ambient temperature and mixed for 1 hour. The mixture was carefully poured into ice water (150 ml) and the ice was allowed to melt. The sodium hydroxide pellet was carefully added followed by a 1 Torr aqueous sodium hydroxide solution to adjust the solution from pH 0.5 to pH 12. The mixture was stirred at ambient temperature for 18 hours and the resulting precipitate was collected by filtration, washed with water (2×15 mL) and dried. The title compound (191 mg '52%) was obtained. NMR: 7·54 (d, 1H), 7.60 (d, 2H), 7.64 (d, 2H), 8.15 (d, 1H), 8.54 (d, 1H), 8.81 (s, 1H), 9.95 (br s , 1H) ; m/z : 367 [MH]- 〇 Method 5 3- (1-ylethyl) odor and H, 2al shouting 2-aminopyrimidine (2.85 g, 30 mmol) by method 1 The method described is -66- This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mil)

Binding

k 1327146 A7 B7 V. INSTRUCTIONS (64) The crude product was obtained by means of column chromatography on neutral alumina (activity 3) with two gas chambers/methanol (100:0 polarity increased to 95:5). Purification afforded the title compound (662 mg < 14%). NMR: 1.59 (d, 3H), 5.12 (quin, 1H), 5.39 (d, 1H), 7.15 (dd, 1H), 7.60 (s, 1H), 8.53 (dd, 1H), 8.96 (dd, 1H) ; m/z : 164 [MH] + 〇 Method 6 3 · Ethyl imidazolium n, 2 alpyridin-3-(1-ylethylethyl)imidazo[i,2a]pyrimidine (Method 5; 63 0 mg The title compound (3, 79 mg, 60%) was obtained eluted elute NMR: 2.56 (s, 3 Η), 7.29 (t, 1 Η), 8.76 (s, 1 Η), 8.80 (m, 1H), 9.78 (dd, 1H) 〇 Method 7 3-(3--Methylaminopropyl- 2-conjuxyl-bristyl)imipid and fi,2a]Calling 3-acetyl-imidazo[1,2 a]pyrimidine (Method 6; 370 mg, 2.2 9 mmol) as described in Method 3 The title compound (479 mg, 96%) was obtained. NMR: 2.94 (br s, 1H), 3.15 (br s, 3H), 5.83 (d, 1H), 7.22 (dd, 1H), 7.70 (s, 1H), 8.60 (s, 1H), 8.68 (dd, 1H), 8.96 (dd, 1H); m/z: 217 [MH]+. Method 8 ?-[4- 酿 苯 苯 ] , , , 4- 4- 4- 4- 4- 4- 4- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- Bite-3-yl) shouting (containing 70% isomeric mixture of 2-anilino-4-(imidazo[l,2a]pyrimidin-2-yl)pyrimidine) (Example 丨); 392 mg, 1.36 mmol Ear) Processed as in Method 4 and obtained with 2-[4-sulfonate-67- This paper method is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1327146 A7 B7

V. Title of the invention (65%) of the main component (70%) in a mixture of isomers of (65-anilino)-4-(imidazo[l,2a]pyrimidin-2-yl)pyrimidine (363 mg, 73%) Compound: Nmr: 7·47 (d, 1H), 7.45-7.7 (m, 5H), 8.57 (d, 1H), 8.93 (dd 1H), 9.02 (s, 1H), 9.82 (s, 1H), 10.4 (d, 1H). 'Method 9 5-Chloroimidazolium n, 2b~j 嗒 3- 3-amino-6-chlorine tart (5.0 g, 38.6 mmol) and chloroacetaldehyde (7.9 ml 7.9) A mixture of M solution, 46.3 mM) of 1-butanol (37 ml) was heated for 20 hours. The reaction was cooled to ambient temperature and filtered to give a crystalline solid which was washed with a small portion of 1-butanol and then with diethyl ether. (5 〇 ml) and the solution were adjusted to pH 1 小心 by careful addition of 40% aqueous sodium hydroxide solution. The obtained suspension was extracted with ethyl acetate. The organic extracts were combined, washed with saturated brine, dehydrated (NajSO4) and evaporated. Solvents. The residue was taken from EtOAc EtOAc (EtOAc:EtOAc. (d, 1H), 8.32 (s, 1H); m/z: 154 [MH]+. Method 10 Imidazolium H, 2 bl cultivating 5-air imidazo[1,2b] ploughing (Method 9; 5.82 g , 37.9 mmol, triethylamine (5.28 ml, 37.9 mmol) and 5 〇 / palladium / carbon (3 〇〇 mg) of ethyl acetate (233 ml) mixture stirred vigorously in hydrogen until hydrogen ceased The reaction mixture was filtered through celite. The filter pad was washed with ethyl acetate and evaporated to remove the volatiles from the filtrate. The residue was taken up in ice-cold pentane, and then collected, washed with pentane and dried to afford white solid. Title compound -68- This scale applies to China National Standard (CMS) A4 specification (210X 297 mm) 1327146 A7 B7 V. Description of invention (66 (3.6a, 81%) ° NMR (CDCl3): 7.03 (dd , lH), 7.78 (s, lH), 7.95 (m, 2H), 8.30 (d, 1H); m/z: 120 [MH] +. Method 11 3-bromoimidazo[1,2bl嗒N- Dichloromethane (2.7 g, 15.1 mmol) was added to the solution of hydrazine and [1,2b] hydrazine (method 10; 1.8 g '15.1 mmol) in chloroform (15 ml) and refluxed Heat and stir for 20 minutes. It was cooled to ambient temperature and saturated aqueous sodium carbonate solution (15 mL) and the mixture was stirred vigorously. Add more chloroform and water to dissolve the precipitated solids. The organic layer was separated, EtOAc (EtOAc m. CDCl3): 7_10 (dd, 1H), 7.80 (s, 1H), 7.95 (d, 1H), 8.47 (d, 1H); m/z: 198 _f. Method 12-13

The following compounds were prepared by the method described in the same manner as in Method 1 1 but reacted at a temperature of 4 weeks. Method Compound NMR M/z SM 12 3-bromo-5-methoxyimidazo[1,2b] 嗒 3.99 (s, 3H), 6.94 (d, 1H), 7.71 (s, 1H), 8.02 (d , 1H) 230 [MH]+ Method 41 13' 3-Han-5-(2,2,2-dioxaethoxy)imidazo[l,2b]嗒耕5.08 (q, 2H), 7.12 (d , 1H), 7.8 (s, 1H), 8.16 ((1, 1H) 298 [MH]+ Method 42 Recrystallized from ethyl acetate / isohexane.

k -69- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1327146 A7 B7

Method 14 3-Ethylimidazolium "1,2 bl isopropylmagnesium bromide (12.5 ml of 1 M in THF, 12.5 mmol) was added dropwise at -40 ° C and nitrogen over 5 minutes. To a solution of 3-bromoimidazolium n, 2b] hydrazine (Method 11; 1.98 g, 10 mmol) in anhydrous THF (1 mL). The reaction mixture was stirred at -4 ° C for 105 min then added N_Methoxy_N_methylacetamide (1.65 ml, 16 mmol of the mixture in _4 〇. 〇 and then mix for 30 minutes, then warm to ambient temperature and stir for another 9 。 minutes. Add acetic acid (126 ml The volatiles were removed by evaporation, and the residue was partitioned between dichloromethane (12 mL) and water (30 min). The separation layer and the aqueous layer were extracted with methane. The organic layer was combined and dehydrated (NadOd and evaporated) The title compound (1.25 g, 78%) was obtained as a brown solid. NMR (CDC13): 2.75 (s, 3H), 7.27 ( Dd, 1H), 8.08 (d, 1H), 8.45 (s, 1H), 8.62 (d, 1H); m/z: 162 [MH]+. Method 1 5 -16 The method described in Method 14 prepares the following Compound β Method Compound NMR M/z SM 15' 3-Ethyl-5-methoxyimi-[1,2b] tillage 2.64 (s, 3H), 4.0 (s, 3H), 7.15 (d , 1H), 8.17 (d, 1H), 8.3 (s, 1H) 192 [MH]+ Method 12 162 3-Ethyl-5-(2,2,2-trifluoroethoxy)imidazo[1 , 2b] 嗒耕 2.65 (s, 3H), 5.10 (q, 2H), 7.30 (d, 1H), 8.27 (d, 1H), 8.37 (s, 1H) Method 13 Recrystallization from ethyl acetate / isohexane • 70- This paper size is applicable to National Standard (CNS) Α4 (210X297 mm)

Binding

1327146 A7 B7 V. INSTRUCTION DESCRIPTION (68) 2 product with 5-(2,2,2-trifluoroethoxy)imidazo[l,2b]嗒&quot; Well 1: Mixture. Method 1 73-(3-Dimethylaminopropan-2-iso-1-indolyl)imidazolium "l,2 bl嗒3-ethoxylated imidazo[i,2b] 嗒 ( (Method 丨 4; I· 25 g, 7.76 mmol, suspended in DMFDMA (32 ml) and the mixture was heated in EtOAc and ioot: for 42 s. Evaporation to remove excess dimethyl acetal and the residue was partitioned with diethyl ether and isohexane. The title compound (1.58 g, 94%) NMR (CDC13): 3.00 (s, 3H), 3.17 (s, 3H), 6.20 (d, 1H), 7.13 (dd) , 1H), 7.92 (d, lH), 8.03 (d, 1H), 8.38 (s, 1H), 8.50 (d, 1H) ; m/z : 217 [MH]+ 0 Method 18-24 Similar Method 17 The following compounds were prepared by the method described. Method Compound NMR M/z SM 18 3-(3-Dimethylaminopropan-2-conn-1-yl)-2-methyl oxime [l, 2b] tar. (s, 3H), 2.87 (s, 3H), 2.9 (s, 3H), 6.27 (d, 1H), 7.27 (dd, 1H), 7.73 (d, 1H), 8.05 (d, 1H), 8.56 ( d, 1H) 231 [MH]+ Method 34 19 3-(3-Dimethylaminoprop-2-en-1-yl)-2-ethylbite [1,2 rushed tillage 1.23 (t , 3H), 2.87 (s, 3H), 3.0 (q, 2H), 3.13 (s, 3H), 6.23 (d, 1H ), 7.25 (dd, 1H), 7.70 (d, 1H), 8.07 (d, 1H), 8.56 (d, 1H) 245 [MHf Method 35 -71 - This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1327146 A7 B7 V. INSTRUCTIONS (69) 20 3-(3-Dimethylaminoprop-2-en-1-yl)-5-methoxyimidazo[1,2b]嗒耕2.9 (brs, 3H), 3.15 (brs, 3H), 4.02 (s, 3H), 6.43 (d, 1H), 7.0(d, 1H), 7.8 (d, 1H), 8.03 (s, 1H) , 8.05 (d, 1H) 247 [MH]+ Method 15 21 3-(3-Dimethylaminoprop-2-en-1-yl)-5-(2,2,2-trifluoroethoxy Imidazo[1,2b] tillage 2.94 (br s, 3H), 3.18 (brs, 3H), 5.16 (q, 2H), 6.3 (d, 1H), 7.18 (d, 1H), 7.8 (d, 1H), 8.14 (s, 1H), 8.2 (d, 1H) 315 [MH]+ Method 16 22 3-(3-dimethylaminopropan-2-indole-1-yl)-6,7-di Methylimidazo[1,2b] morphine 2.35 (s, 3H), 2.50 (s, 3H), 2.95 (br s, 3H), 3.15 (br s, 3H), 6.25 (d, 1H), 7.75 ( d, 1H), 8.20 (s, 1H), 8.50 (s, 1H) 245 [MH]+ Method 37 23 3-(3-Dimethylaminopropan-2-con-1-yl)-6- Imidazo[1,2b] tillage 2.4 (s, 3H), 2.90 (br s, 3H), 3.15 (br s, 3H), 6.2 (d, 1H), 7.74 (d, 1H), 7.97 (s , 1H), 8.19 (s, 1H), 8.56 (s, 1H) 231 [MH]+ Method 38 241 3-(3-Di-Aminopropyl-2-indol-1-yl)-2-dimethylamine Imidazo[1,2b] 嗒 2.96 (s, 12H), 5.9 (d, 1H), 7.13 (dd, 1H), 7.53 (d, 1H), 7.8 (d, 1H), 8.33 (d, 1H ) 260 [MH]+ Method 36

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A similar method was used, but heating was carried out at 100 ° C for 120 hours and the product was dissolved by chromatography using dioxane / methanol (95: 5). -72- This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1327146 A7 B7 V. Description of invention (7〇) Method 25 2-fluorophenyl hydrazine bicarbonate containing concentrated hydrochloric acid (6 ml Water (4.8 ml) was added to a mixture of 2-fluoroaniline (7.94 g, 71.2 mmol) and cyanamide (6.98 g, 166 mmol) and the mixture was heated at 11 5 °C for 2 _ 5 hours . The reaction mixture was cooled to ambient temperature; the trough was adjusted to pjj 13 by careful addition of 40% aqueous sodium hydride. The aqueous solution was extracted with ethyl acetate and the combined organic extracts were dried (Na.sub.2) and evaporated. The crude product was dissolved in water (4 mL) and carbon dioxide gas was passed through the solution until the pH of the suspension was maintained (about pH 9). The title compound (11.95 g '78%) was obtained as a white solid. NMR: 6.83 (m, 2H), 7.0 (m, 2H); m/z: 154 [MH]+. Method 26 N,N-Dimethyl-N'-e·gastrin-3-yl)acetamidine 3-amino-6-indole (1.29 g, 10 mmol) suspended in anhydrous toluene (2 〇 ml) and dimethyl acetamide dimethyl acetal (146 ml, 1 〇 millimolar) were added. The mixture was stirred and heated under reflux for 3 hours and then allowed to stand at ambient temperature for 18 hours. The insoluble matter and the filter paper were removed from the reaction mixture by washing with ethyl acetate. The filtrate was evaporated and the residue was crystallised eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut 6H), 6.92 (d, 1H), 7.25 (d, 1H); m/z: 199 [MH] + 〇 Method 27-2 8 The same compound was prepared by the method described in the same procedure. -73-

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k 1327146 A7 B7 V. DESCRIPTION OF THE INVENTION (71) Method Compound NMR M/z SM 271 N,N-Dimethyl-anthracene-(6-chloro-4,5-dimethylhydrazine) Well-3-yl) Acetamide 2.22 (s, 3Η), 2.24 (s, 3H), 3.02 (s, 3H), 3.1 (s, 3H), 8.38 (s, 1H) 213 [MH]+ 282 市, Ν-二Methyl-Ν'-(6-Ga-5-methyl °荅11 well-3-yl) Ethylamine 2.24 (s, 3H), 3.0 (s, 3H), 3.12 (s, 3H), 7.1 ( s, 1H), 8.45 (s, 1H) 199 [MH]+ Method 43 1 was heated at 120 ° C for 7 hours. 2 by column chromatography with isohexane / ethyl acetate (70: 30 polarity increased to 90: 10) Lysification purification: Method 29 k acetyl 5--5-methylimidazo[i, 2b 嗒Cultivated copper chloropropoxide (2.9 ml, 36.2 mmol) was added to a suspension of powdered sodium bromide (3.73 g '36.2 mmol) in ethanol (75 ml) and the mixture was stirred at ambient temperature for 2 hours. N,N-Dimethyl-N,-(6-chloroindol-3-yl)acetamidine (Method 26; 6.0 g &apos; 30.2 mmol) was added and the mixture was stirred and stirred under reflux for 5.5 hours. The reaction mixture was cooled to ambient temperature and evaporated to remove volatiles. Water (60 ml) was added to the residue. NMR: 2.6 (s, 3H), 2.7 (s, 3H), 7.57 (d, 1H), 8.23 (d, 1H); m/z: 209 [ΜΗ], Method 30-3 3 Method similar to Method 29. Preparation of the following compounds β

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-74-

1327146 A7 B7 Method Compound NMR M/z SM 30 3 -ethylidene·5-chloro-2-ethylimidazo[1,2b] tillage 1.23 (t, 3H), 2.7 (s, 3H), 3.02 ( q, 2H), 7.58 (d, 1H), 8.25 (d, 1H) 224 [MH]+ Method 39 311 3-Ethyl-5-Ga-2-dimethylaminoimidazo[l,2b]嗒Ploughing (CDC13): 2.78 (s, 3H), 3.13 (s, 6H), 7.13 (d, 1H), 7.63 (d, 1H) 239 [MH]+ Method 40 322 3·Binger-5-- 6,7-Dimethylimidazo[1,2b] tillage 2.4 (s, 3H), 2.62 (s, 3H), 2.65 (s, 3H), 8.50 (s, 1H) 224 [MH]+ Method 27 333 3-ethylindolyl-5-chloro-6-methylimidazo[l,2b] tillage 2.45 (s, 3H), 2.6 (s, 3H), 8.32 (s, 1H), 8.52 (s, 1H 210 [MH]+ Method 28 1 Acetonitrile was used as a reaction solvent and added at 65 ° C for 24 hours. V. INSTRUCTIONS (72) 2 Using DMF as a reaction solvent and heating at 70 ° C for 12 hours, then eluting the purified product with 2N methanol ammonia / di-methane (50: 50) by means of an SCX ion exchange column and from ethyl acetate /Methanol recrystallizes. 3 DMF was used as a reaction solvent, and sodium bromide was replaced with sodium iodide and heated at 70 ° C for 12 hours. Method 34 3-Ethyl-2-T-imidazolium "l, 2 bl cultivating 3-ethyl fluorenyl-5- oxa-2-methylimidazo[l, 2b] ploughing (Method 29; 4.8 g, A mixture of 22.9 mmol, triethylamine (3.21 mL, 22.9 mmol) and 5% palladium/carbon (1.6 g) in ethyl acetate (180 mL) was stirred vigorously in hydrogen until hydrogen ceased. Filtered through diatomaceous earth. The filter paper pad was washed with ethyl acetate and evaporated from the filtrate. The residue was iso-hexane-75- This paper scale was applied to Chinese national standard (CNS>A4 specification (210X297 mm) 1327146 A7 _______ B7 V. INSTRUCTIONS (73) Politics's over-consultation, the title compound (3.7 g, 92%) was obtained as a white solid. NMR: 2.6 (s, 3H), 2.73 (s, 3H) ), 7.43 (dd, 1H), 8.15 (d, 1H), 8.67 (d, 1H); m/z: 176 [MH] +. Methods 35-38 The following compounds were prepared in a similar manner as in Method 3 4 . NMR M/z SM 35 3-Ethyl-2-ethylimidazo[l,2b]Tal. 1.23 (t,3H), 2.73 (s,3H), 3.02 (q, 2H), 7.43 (dd , 1H), 8.18 (d, 1H), 8.68 (d, 1H) 190 [MH] + method 30 36 3-Ethyl-2-dimethylaminoimidazo[1,2b]嗒啩2.67 (s, 3H), 3.0 (s, 6H), 7.35 (dd, 1H), 7.93 (d, 1H), 8.5 (d, 1H) 205 [MH]+ Method 31 37 3-Ethyl-6,7-dimethylimidazo[l,2b] tillage 2.39 (s, 3H), 2.55 (s, 3H), 2.65 (s, 3H), 8.45 (s, 1H), 8.78 (s, 1H) 190 [MH]+ Method 32 381 3-Ethyl-6-methylimidazo[l,2b]«荅啩2.44 (s, 3H), 2.62 (s, 3H), 8.07 (q, 1H), 8.44 (s, 1H), 8.64 (d, 1H)+ 176 [MH]+ Method 3 3 1 using ethanol as the reaction solvent Method 39 N,N-Dimethyl-&gt;Γ-(6-gas tower 4-3-yl)propionamine oxygen tri-phosphorus phosphorus (9.32 ml '1 〇〇 millimolar) anhydrous toluene (3 〇ml) The solution was added dropwise to a stirred solution of dimethylpropanamide (10 mL, 1 mL) in anhydrous toluene (180 mL) over 15 min and the mixture was stirred at ambient temperature for 24 hours. Add 3-amino-6-gas cultivating (12.9 g, 100 mmol) -76- _ This paper scale is suitable for S g (CNS) Α 4 specifications (21G X 297 mil): 1327146

The solid and mixture were stirred and heated at 851 for 18 hours. The reaction mixture was cooled and settled and the toluene layer was removed by decantation. The residue was washed and decanted with more anhydrous water. The residue is dissolved in water and extracted with di-methane and the water layer is adjusted by carefully adding 40% aqueous sodium hydroxide solution. 11 12 ◊ Add methylene chloride and mix to remove insoluble impurities. The organic layer and the aqueous layer were separated and extracted with dioxane. The organic extracts were combined, dried (Na.sub.2) and evaporated to remove solvent. The title compound (4.4 g, 2 1%) was obtained. NMR (CDC1)3: 1.18 (t, 3H), 2.53 (q, 2H), 3.1 (s, 6H), 6.93 (d, 1H), 7.27 (d, 1H); m/z: 213 [MH]+ . Method 40 The following compound was prepared in a similar manner to that described in Method 39. Method Compound NMR M/z 40 Ν,Ν,Ν^Ν'·Tetramethyl-Νπ-(6·Chloro®%^井-3·基) Pulse (CDCI3) 3.0 (s, 12H), 7.5 (d, 1H), 7.67 (d, 1H) 228 [MHf method 4 1 5 dimethoxy imidazolium hydrazine, 2 bl decyl sodium solution (25% wt methanol solution, 56.5 g, 261.4 mmol) at ambient temperature Add to a solution of 5-chloroimidazo[1,2b] hydrazine (Method 9; 1 〇·〇g, 65.6 mmol) in anhydrous methanol (100 mL). The volatiles were removed by evaporation and the yellow oil residue was dissolved in di-methane (1 mL). The solution was washed with water (5 X 100 ml) until the water wash became neutral. The title compound (8.87 g, 91%) was obtained. NMR: 3.92 (s, 3H), 6.82 (d, 1H), -77- This paper wave scales Common Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1327146 A7 B7 V. INSTRUCTIONS (75) 7.59 (s, 1H), 7.99 (d, 1H), 8.03 (s, 1H) ; m/z : 150 [MH]+ 〇 Method 42 5-(2,2, 2-Trifluoroethoxy tomb V-mazole and [l, 2b phenolic hydrogenation #3 (432 mg ' ι〇·8 mmol) were added successively to 2,2,2-trifluoroethanol (10.8 mmol) And a solution of 5-azamidazo[1,2b] hydrazine (1.5 g, 9.8 mmol) in anhydrous DMF (15 ml), and the mixture was stirred for 18 hr. The title compound (2.05 g, 920 / EtOAc) EtOAc: EtOAc (EtOAc: EtOAc 2H), 7_0 (d, 1H), 7.64 (s, 1H), 8.1 (m, 2H); m/z: 219 [MH]+. Method 43 3-amino-6-chloro-5-methylpyridin Plough

A mixture of 3,6-monochloro-5-methylρ than 1^ (5 g, 30.7 mmol) in ethanolic ammonia (5 mL) was heated in a 135 ° C high pressure flask for 8 hours. The solvent was removed by evaporation and the residue was crystallised eluted eluted The organic solution was washed with water (2 χ 25 ml), dried (MgSO4 and evaporated to remove the volatile material. The crude solid was purified by hexanes/methanol (95:5). The title compound (1 3 g, 31% h NMR: 2.06 (s, 3H), 2.18 (s, 3H), 6.2 (br s, 4H), 6.74 (s, 1H), 7.26 (s, 1H) ; m/z : 143 [MH]+. Method 44 1-(2-Amine-ethyl)pyrazolone emulsified fishing (22.96 g '0.57 mol) added to p 唆 (1 μg, 〇Μ Mohr) in anhydrous acetonitrile (80 ml) solution and mixture at ambient temperature -78- This paper wave scale universal Chinese 家@家标准(CNS) A4 specification (2l〇x 297 public)------- ---- 1327146 A7 B7 V. Inventive Note (76) Mix for 30 minutes. Add tetrabutylammonium hydrogen sulfate (2.18 g, 6 4 mmol) and 2-chloroethylamine hydrochloride (19.78 g, 0.172). The mixture was heated under reflux for 24 hours. The mixture was cooled and filtered to remove insolubles. Evaporation was taken; solvent was removed and 49% hydrogen bromide (30 ml) was added to the residue followed by ethanol (100 ml) ).mixture The stream was heated and then cooled in ice. The resulting precipitate was collected and purified to give the title compound. mp. </ </ RTI> 3.20-3.24 (m, 2 Η), 4.38 (t, 2 Η), 6.30 (s, 1H), 7 5 〇(s 1Η) 7.79 (s,1Η), 7.98 (s,1Η). ' 'Method 45 toluene 礴ϋ. Shame amino}-4-(imidazolium, 2bl嗒-3-yl)pyrimidine 4-toluenesulfonium chloride (4_44 g '0.23 mol) was added to ~yl-2-methylpropan-2-yl)amine sulfonyl]anilino}-4-(imixo[丨^yl)pyrimidine ( Example 57; 3.41 g, 0.008 mol of pyridine (5 Torr) and &amp; compound was removed at ambient temperature for 24 hours. The mixture was then diluted with water and sonicated. The aqueous phase was decanted and the residue dissolved. The title compound (1.92 g, 42%) was obtained from ethyl acetate/methanol. ,6Η),2 38 〇3 3.79 (s,2Η), 7.40-7.45 (m,3Η), 7.59 (s,1Η),7 65·7^3Η)' 4H), 8.05 (d, 2H), 8.09 (d, 1H), 8.35 (d, lH)s 8 66 (si ' 8.70 (d, 1H), 8.80 (d, 1H), 10.13 (s, 1H). '(8)' Method 4 6 ?"4-丨1^-(2,2-dimethylaziridine)amine sulfonate ^^^^_4 (唛岫"1.2bl嗒g and-3-yl) shout Bite-79- This paper scale is suitable for SS material (CNS) A4 specification (21GX297 public seven acid removal (57 mg, 〇, 4 mmol) and then _ (5 ml) added to 2_ {4_[Ν_ (1·(4_Toluenesulfonyloxy)_2-methylpropan-2-yl)aminesulfonyl]anilino-4-(imidazole [丨,21]]嗒-3-yl)pyrimidine Method 45; 220 mg, 〇.38 考莫), and the mixture was stirred and heated under reflux for 2 hours. The mixture was cooled and filtered to remove the residue. The filtrate was washed with acetone and evaporated to remove the solvent to give an orange solid. 123 mg, 77%). NMR: 1.42 (s, 6H), 2-43 (s, 2H), 7.43 (dd, 1H), 7.84 (d, 2H), 8.08-8.12 (m, 3H), 8- 35 (d, 1Η), 8.68 (d, 1H), 8.70 (d, 1H), 8.8 (d, 1H), 10 2 (s5 1H). 'Method 47 Jiahua_cyclopropane) (8.24 ml, 0.095 mol) followed by DMF (several drops) added to 2-(1-methylcyclopropane)decanoic acid (9 42 g, 〇〇94 mol) cooled to 5 C in methane (150 ml) ) in solution The mixture was stirred for 5 minutes at 5 hrs and then stirred at ambient temperature for 3 hours. The solvent and excess chlorophyll chloride were removed by evaporation. The residue was dissolved in dichloromethane and added to a cooled ammonia (excess) methanol solution. The title compound was obtained by EtOAc: EtOAc: EtOAc: EtOAc (EtOAc: EtOAc: 1-Amino-1-methylcyclopropane bromide (2.87 ml '0.056 mol) was added to a solution of 〇5. (: sodium hydroxide (13.5 g, 0.338 mol) in water (100 ml). 1-(丨_Methylcyclopropane) Resveramine (5.70 g, 0.056 mol) water (50 ml) slurry and reaction mixture-80- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

The mixture was stirred at 5 ° C for 2 hours and then allowed to stand at ambient temperature for 24 hours. The mixture was then heated at 80 ° C for 2.5 hours, allowed to cool and the mixture was evaporated to give the title compound ( bp 75-80. (:). NMR: 〇.2 (q, 2H), 0.14 (q, 2H) 0.96 (s, 3H), 1.42 (s, 2H). Method 49 j_,3-Dimethoxy 2,2-carbomethoxypropanediethylamine (5 ml, 〇.〇3 6 mol) was added to cooling to 5 X: 1,3-dimethoxy-2-hydroxypropane (3.84 g, 0.032 mol) in dichloromethane (7 mL) in solution, followed by the slow addition of methanesulfonyl chloride (2 72 mL, 〇 〇35摩尔) The 'i compound was allowed to pass for 24 hours at the temperature of the week. The mixture was then adsorbed onto a hard gel and purified by chromatography on dichloromethane/isohexane (1:1) to give the title compound (3.74 g. , 59%). NMR: 3.15 (s, 3H), 3.28 (s, 6H), 3.52 (d, 4H), 4.78 (q, 1H). Method 50-52. Compound NMR 50 1-ethoxy-2-methanesulfonyloxypropene 1.10 (t, 3H), 1.28 (d, 3H), 3.14 (s, 3H), 3.42-3.48 (m, 2H), 3.62- 3.68 (m, 2H), 4-78 (q, 1H) 51 1-propoxy-2-methanesulfonyloxypropane 0.8 6 (t, 3H), 1.28 (d, 3H), 1.51 (q, 2H), 3.33-3.40 (m, 2H), 3.44 (d, 2H), 3.69 (d, 3H), 4.78 (q, 1H) 52 1,3-Diethoxy-2-methyl calcined oxypropene 1.12 (t, 6H), 3.16 (s, 3H), 3.41-3.45 (m, 4H), 3.55 (d, 4H), 4.75 (q, 1H) -81 - This paper wave scale applies China National Standard Rate (CNS) A4 specification (210 X 297 public poverty) V. Invention description (79) Method 53 1,3 - —Methyl-based 2-fold Aromatic propylene 1,3-dimethoxy-2-methanesulfonyloxypropane (method 49 · 3 knives 4 g, 19 mM) and # nitride steel (2 · 〇 3 g ' 31 mmol The DMa (55 ml) of the ear) was heated at 100 ° C for 8 hours and then allowed to stand at ambient temperature for 24 hours. The mixture was diluted with water 'extracted with ethyl acetate, and the extract was extracted from the mixture. The title compound (2 gram, 74%) was obtained from the title compound (m.). Method Compound SM 54 1-Ethoxy-2-azidopropene Method 50 55 Bupropoxy-2-azidopropionate Method 51 56 1,3-Diethoxy-2-azidopropane Method 52 Method 57 1,3-Dimethyl-2-aminopropane 10% Palladium/Carbon (500 mg) was added to 1,3-dimethoxy-2·azidopropane (Method 53 ' 2 g , 0.014 moles of ethanol (403⁄4 liters) in a solution and the mixture was expanded in the atmosphere at ambient temperature: mixing for 6 hours. The following compounds were prepared by filtration of the catalyst and removing the catalyst and paper, and washing with ethanol to obtain a solution of the title compound in ethanol (2 mL). -82- This paper size applies to the 8 national standard (CNS) Α 4 specification (210 X 297 mm > 1327146 A7 B7 V. Inventive Note (8〇) Method Compound SM 58 1-Ethoxy-2-aminopropyl Method 54 59 1-propoxy-2-aminopropane Method 55 60 1,3-Diethoxy-2-aminopropane Method 56 Example 67 The following description contains a compound of formula (I) or its pharmaceutically acceptable A representative pharmaceutical dosage form of a salt or an in vivo hydrolysable ester (hereinafter referred to as Compound X) for human therapeutic or prophylactic use: (a): lozenge I mg/ingot compound X 100 lactose Ph. Eur. 182.75 crosslinked carboxymethyl Cellulose sodium 12.0 Corn starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b): Tablets II mg/ingot compound X 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Corn Starch 15.0 Polyvinylpyrrolidone 2.25 Magnesium stearate 3.0 -83- This paper scale applies to China's 8 standards (CNS) A4 size (210X297 mm) 1327146 A7 B7 V. Description of invention (81) (c): Lozenge III Mg/ingot compound X 1.0 lactose Ph. Eur 93.25 croscarmellose sodium 4.0 corn starch paste (5% w/v paste 0.75 magnesium stearate 1.0 (d): capsule mg/capsule compound X 10 lactose Ph. Eur 488.5 magnesium stearate 1.5 (e): injection I (50 mg/ml) Compound X 5.0% w/v 1M. Sodium hydroxide solution 15.0% w/v 0.1M hydrochloric acid (adjusted pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (1): Injection II 1 mg/ml Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1 Μ hydroxide surface solution 15.0% v/v water for injection to 100% -84- This paper size is generally used in China National Standard (CNS) A4 specification (21〇x 297 mm) 1327146 A7 B7 V. INSTRUCTIONS (82) (g): Injection III (1 mg/ml, buffered to pH 6) Compound X 0.1% w/v Sodium phosphate BP 2, 26% w/v Citric acid 0.3 8% w/ v Polyethylene glycol 400 3.5% w/v Water for injection to 100% Note The above formulations can be prepared by well-known procedures known in the medical field. Tablets (a)-(c) may be coated by conventional means, for example to provide a coating layer of cellulose acetate phthalate. -85- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

Claims (1)

1327146 No. 091102^§ 育案--S Chinese, please Douli and other encirclement _ _ ^ conversion 1 6, apply for a patent garden 1. A compound of formula (1), Where: Ring A is the basis of formula (IA): One or more of X1, X2, X3 and X4 are nitrogen and the rest are CR5, wherein R5 may be the same or different; R1 is halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl , amine fluorenyl, thiol, sulfonyl, Cw alkyl, C2.6 alkenyl, C2.6 alkynyl, Cw alkoxy 'Cu alkyl fluorenyl, N-CCw alkyl) amine , Ν,Ν-βυalkyl)2amino, Cw alkanoylamino, N-(Cn6 alkyl)aminoindenyl, anthracene, fluorenyl-nonylalkyl) 2 amino fluorenyl, Cw alkane The base S(0)a wherein a is 0 to 2, Ν-βΜalkyl)aminesulfonyl or ?&lt;,1\[-((:|.6 alkyl)2aminesulfonyl; wherein 111 is visible In the case of a carbon atom substituted by one or more R 6 ; R 2 and R 5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amine, carboxyl, amine Brewing base, hydrogen 76484-990324.doc - 1 · This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 public) 1327146 A8 B8 C8 __ D8 VI. Apply for patent Fanyuan thiol, amine confirmation Base, Ci-6 alkyl, C2-6 dilute, C2-6 fast radical, C!.6 alkoxy, C,-6 alkyl alkane, Cw alkane Alkoxy, NJCw alkyl)amino, anthracene, Ν-βυalkyl) 2 amine, Cw alkanoylamino, N-CCw alkyl) Aminomethyl hydrazino, anthracene, Ν-β decyl 2Amino fluorenyl, Cw alkyl S(0)a wherein a is hydrazine to 2, Cw alkoxycarbonyl, NJCw alkyl) aminoxasulfonyl, alkyl) 2 amine sulfonyl, phenyl, hetero a cyclyl, phenylthio or (heterocyclyl)thio group; wherein any R 2 or R 5 may be optionally substituted on the carbon atom with one or more R 7 ; and if the heterocyclic group contains a - fluorenyl group, Nitrogen may be selected from the group of R8; η is 0 to 2, wherein R1 may be the same or different; R3 is halogen, nitro, hydroxy, amine 'carboxy, amine thiol, thiol, amine a C2-6 or a C2-6 group; ρ is 0-4; wherein R3 may be the same or different; R4 is a fluorene-fluorene group; wherein the lanthanide is selected from the group consisting of Cw alkyl, phenyl, heterocyclic, C3.8 cycloalkyl, phenyl C -6 alkyl, (heterocyclyl) Cw alkyl or C3-8 cycloalkyl Cw alkyl; wherein A may be optionally substituted on the carbon atom with one or more R 9; And if the heterocyclic group contains a -NH- group, the nitrogen may optionally be substituted from the group of r1g &gt; E is a chemical bond or -〇-, -C(O)-, -〇C(0)-, -C(0)0-, -N(Ra)C(0)-, -C(0)N (Ra)·, -N(Ra)-, -S(〇)a-, -S〇2N(Ra)- or -N(Ra)S〇2_ ; where Ra is hydrogen or optionally one or more r&quot;Substituted Cu base and a is 0-2; R9 is independently selected from oxo, halogen, nitro, cyano, hydroxy, tri-2- 76484-990324.doc This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1327146 ABCD 々, application for patent ceramyl fluoride, trifluoromethoxy, amine, carboxyl, amino sulfhydryl, thiol, sulfonamide, CN6 Alkyl, c2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C 6 alkyl alkanoyl, cN 6 alkyl fluorenyloxy, alkyl) amine, N,N-(Cb0 alkyl) 2Amino, Cl_6 alkylalkylamino, NJCu alkyl) amine broth, n, n-(cN6 alkyl) 2 aminomethyl decyl, Cl. 6 alkyl s(0)a wherein a is 0 to 2, Cw alkoxycarbonyl, alkoxycarbonylamino, benzyloxycarbonylamino, alkyl)aminesulfonyl and alkyl)2 aminesulfonic acid; wherein R9 may optionally be on carbon Or multiple Ri2 substitutions; q is 0-2, where R4 can be the same Different; and wherein p+q&lt;5; R6, R7, R丨丨 and R12 are independently selected from halogen 'nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amine, carboxyl, amine Mercapto, thiol, sulfonyl, methyl, ethyl, methoxy, ethoxy, ethane, decyl, ethylamine, diammonium, diethylamine, N - mercapto-N-ethylamino, acetamido, N-methylaminocarbamyl, N-ethylamino fluorenyl, N,N-didecylamino fluorenyl, N, N-diethylaminoindenyl, N-fluorenyl-N-ethylaminomethylindenyl, sulfonylthio, ethylthio, methyl sulfhydryl, ethyl sulfonyl, fluorenyl Alkyl, ethyl fluorenyl, decyloxycarbonyl, ethoxycarbonyl, N-decylamine sulfonyl, N-ethylamine sulfonyl, N,N-didecylamine sulfonyl, N,N-diethylamine sulfonyl or N-methyl-N-ethylamine; and R and R 〇 are independently selected from the group consisting of Ci.4, 〇ι·4, and Ci_4 Sulfosyl, C!-4 alkoxycarbonyl, aminomethyl hydrazino, alkyl) amino fluorenyl 'alkyl) amino fluorenyl, fluorenyl, decyloxycarbonyl, phenylhydrazine And phenylsulfonyl; 76484-990324.doc - 3 · This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) D8 Patent application scope X, medium heterocyclic group &quot; for containing 4-12 a saturated or partially saturated or unsaturated mono- or diterpene atom having at least one atom selected from nitrogen, sulfur or oxygen, M having an indication that otherwise it may be bonded via carbon or nitrogen, wherein -CH2- group visible ft Condition-C (〇)· base substitution; or a pharmaceutically acceptable salt thereof. 2'A compound of the formula (I) according to the first paragraph of the Shenqing patent scope, wherein X1, X2, X3, χ&gt; 4, one of nitrogen and the other is CR5, wherein r5 may be the same or different, or its pharmaceutically acceptable property salt. 3. A compound of formula (I) according to claim 1 wherein n is hydrazine or a pharmaceutically acceptable salt thereof. A compound of the formula (1) according to any one of claims 1 to 3, wherein R2 is selected from the group consisting of hydrogen, hydrazine-6 alkyl or n,N-(C,.6 alkyl)2 amine, or a pharmaceutical thereof Receptive salt. The compound of formula (1) according to any one of claims 1 to 3, wherein R5 is selected from the group consisting of hydrogen, C. -6 alkyl or C -6 oxalate; wherein R5 may be on carbon, i or more R7 is substituted; wherein R7 is selected from halogen, or a pharmaceutically acceptable salt thereof. 6. The compound of the formula (1) according to any one of claims 3 to 3, wherein R3 is an amine sulfonate or a halogen, or a pharmaceutically acceptable salt thereof. 7. A compound of the formula (Ι) of any one of claims 3 to 3 wherein p is hydrazine or 1 ' or a pharmaceutically acceptable salt thereof. 8. If you apply for a patent scope! The compound of the formula (1) of any one of 3, wherein: is an AE- group; wherein the A group is selected from the group consisting of Cl.6 alkyl, C3.8 cycloalkyl, (heterocyclyl)c "alkyl or -4-76484- 990324.doc This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 _____ 1327146 A8 B8 C8 ___·_D8 VI. Application for patent garden cycloalkyl Cw alkyl; where A can be seen on carbon One or more R9 substitutions; E is -N(Ra)S02-; wherein Ra is hydrogen or Cl 6 alkyl; R9 is independently selected from hydroxy, Cw alkyl, c2 6 alkenyl, c2-6 alkynyl, Cw alkoxy , Ν, Ν-βκ院) 2 amino group or c1-6 alkyl s(〇) a wherein a is 0; or a pharmaceutically acceptable salt thereof. 9. Any one of claims 1 to 3 of the patent application scope A compound of the formula (I), wherein q is hydrazine or 1, or a pharmaceutically acceptable salt thereof. 10. The compound of the formula (j) according to any one of claims 1 to 3, wherein P + q is 0, Or a salt of the formula (1), wherein X1, X2, X3 and X4 are One is nitrogen and the other is CR5, of which R5 can Same or different; η is 0; R2 is selected from hydrogen, sulfhydryl, ethyl or hydrazine, hydrazine-dimethylamino; R5 is selected from hydrogen, decyl, decyloxy or 2,2,2-tri Fluoroethoxy; R3 is sulfonyl or halogen; ρ is 0 or 1; R4 is fluorenyl-fluorenyl sulfonyl, fluorenyl-cyclopropylmethylamine sulfonyl, hydrazine-ethylamine sulfonate Base, Ν-propylamine sulfonyl, Ν-allylamine sulfonyl, Ν-2-propynylamine sulfonyl, fluorenyl-cyclobutylamine sulfonyl, hydrazine-tert-butylamine Sulfonic acid, hydrazine-cyclopropylamine sulfonyl, fluorenyl-(2-diaminoethyl)amine sulfonyl, fluorenyl-(2-decyloxyethyl)amine sulfonyl, fluorene- 2-pyrazol-1-ylethyl) 76484-990324.doc - 5 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1327146 ABCD VI. Patent application scope Amine sulfonyl, N-methyl·Ν_(2_methoxyethyl)amine sulfonyl, N_(1_%propylethyl)amine sulfonyl, N_(3-dimethylaminopropyl)amine sulfonyl' N-(3-methoxypropyl)amine sulfonyl, Ν·(3-hydroxy-2-hydroxymethylpropyl)amine sulfonyl, N-(l,3-dihydroxyprop-2-yl) Aminesulfonyl, Ν-(3-morpholinyl-2·A Alkyl-2-yl)aminesulfonyl, N-(l,3-dimethoxypropan-2-yl)aminesulfonyl, N-(l,3-diethoxyprop-2-) Aminesulfonyl, N-(l-methoxypropan-2-yl)aminesulfonyl, ν·. ·Ethoxypropyl-2-yl)amine sulfonyl, N-(l-pyridyl-2-yl)amine, ν_(3_methylthio-2-methylpropan-2-yl Aminesulfonyl, fluorenyl-(3-pyrrolidin-1-yl-2-methylpropan-2-yl)amine sulfonyl, fluorenyl-(3-decyloxy-2-methylpropano-2-) Aminesulfonyl, Ν-(2-methoxy-2-mercaptopropyl)amine sulfonyl, Ν-(1•propoxyprop-2-yl)amine sulfonyl or Ν-(3- Hydroxy-2·methylpropan-2-yl)amine sulfonyl; q is 0 or 1; p + q is 0, 1 or 2; wherein R3 may be the same or different and R4 may be the same or different; Acceptable salt. 12. A compound of the formula (1) according to the first aspect of the patent application, which is selected from the group consisting of: 2-{4-[N-(2-decyloxyethyl)aminesulfonyl]anilino}_4_(imipid[l , 2b]嗒井-3-yl)pyrimidine; 2-{4-[N-(3-methoxypropyl)aminesulfonic acid]anilinyl}_4_(imidazo[l,2b]嗒耕-3 -yl)pyrimidine; 2-[4-(N-propylamine sulfonyl)phenylamino]_4_(imidinary D[123]]嗒, well-3-3-pyrimidine; 2-{4-[ N-(2-methoxyethyl)amine sulfonyl]anilinyl fluorenyl 76484-990324.doc . g . This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1327146 A8 B8 C8 ___;_____D8 VI. Patent application scope: [1,2b]indole-3-yl)pyrimidine; 2-[4-(N-nonylaminosulfonyl)anilino]_4_(2_methyl „Mizozolo[丨,^ 嗒 -3--3-yl)pyrimidine; 2-{4-[&gt;1-(2-(1-pyrazolyl)ethyl)amine sulfonyl]anilino}_4_( Imidazo[l,2b]indole-3-yl)pyrimidine; 2-{4-[1^-(1,3-ethoxypropyl-2-yl)amine aryl]anilino}_4_( Sodium and [l,2b]indol-3-yl)pyrimidine; 2-{4-[Ν-(1,3-dioxyloxypropan-2-yl)aminesulfonyl]anilinyl }_4•(Mimi-[1,2b]嗒-3-yl)pyrimidine; 2-{4-[Ν-(1-ethoxypropan-2-yl)amine benzyl]anilinyl}_4_ (Imidazo[1,2b] column 11 well-3·yl) biting; 2-{4-[N-(2-ethoxyethyl)amine sulfonyl] phenylamino 4_(imidazo[ 1,213] Talq-3-yl) a bite; or a pharmaceutically acceptable salt thereof. 13. A method of preparing a compound of formula (1) or a pharmaceutically acceptable salt of claim i, The method includes (wherein each substituent is as defined in the formula (I) of claim 1 unless otherwise stated). The following step a) gives the pyrimidine of the following formula (II): (II) wherein L is a replaceable group; reacts with an amine of the formula (ΠΙ): 76484-990324.doc 1327146 8 8 8 8 ABCD Patent Application b) making the pyrimidine of formula (IV): (IV) reacting with a compound of formula (V) ό (V) or wherein one of Μ and Q is a replaceable group X and the other is a metal reagent Υ c) a compound of formula (VI): Reaction with compound of formula (VII): -8- 76484-990324.doc This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1327146 A8 B8 C8 D8 々, patent application scope Wherein ... is alkyl and R6 is hydrogen or R1; d) is an amine compound of formula (VIII): N, /NH. Reaction with a compound of formula (IX): Wherein E is a substitutable group; and if desired: i) converting a compound of formula (1) to another compound of formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)