TW200836725A - New compounds - Google Patents

Abstract

The invention relates to new bicyclic heterocyclic derivative compounds, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Description

200836725 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel bicyclic heterocyclic derivative compound, to a pharmaceutically acceptable composition comprising the above compound, and to the use of the above compound for treating a disease ( Use as 'cancer'. [Prior Art] U.S. Patent No. 7, 〇74, 801 (Eisai), U.S. Patent No. 2002/0041880 (Merck), WO Patent No. 98/54093 (Merck), 10 WO Patent No. 2006/091671 (Eli) Lilly), WO Patent No. 2003/048132 (Merck), WO Patent No. 2004/052286 (Merck), WO Patent No. 00/53605 (Merck), WO Patent No. 03/101993 (Neogenesis), WO Patent No. 2006/135667 ( BMS), WO Patent No. 2002/46168 (Astra Zeneca), WO Patent No. 2005/080330 15 (Chugai), WO Patent No. 2006/094235 (Sirtris Pharmaceuticals), WO Patent No. 2006/034402 (Synta Pharmaceuticals), WO Patent No. 01/18000 (Merck), U.S. Patent No. 5,990,146 (Warner Lambert) and WO Patent No. 00/12089 (Merck) disclose a series of heterocyclic derivatives. SUMMARY OF THE INVENTION A first aspect of the present invention provides a compound represented by the chemical formula (1): 6 200836725

Χι X2 and X3 are each independently selected from carbon or nitrogen, and at least one of & to & Γ 5 is nitrogen; Χ4 is CR3 or nitrogen; χ5 is CR6, nitrogen or c=〇; χι to No more than three nitrogen is provided in X5; it is a single bond or a double bond, and at least one of the five-membered rings is bonded to a 10-double bond; R3 is hydrogen, halogen, Cw alkyl, c2- 6 alkenyl, c2_6 alkynyl, Cl-6 alkoxy, Cw cycloalkyl, Cw cycloalkenyl, cyano, -6 alkyl, halogen (Ci-6 alkoxy or = oxime; A is an aromatic or a non-aromatic carbocyclic or heterocyclic group which is optionally substituted by one or more (e.g., 1, 2 or 3) Ra groups; R1 is -NHCONR4R5, -NHCOOR4 , -NH-CO-(CH2)n-NR4R5, -NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, 20-NHSO2R4 , 7 200836725 NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -N HCSSR4, -NHC(=NR4)NR5, NHC(=NR4)R5, -NH-C(=NH2)-NH-CO-R4, -NHCSOR4 Or -NHCOSR4; R4 and R5 are each independently hydrogen, Cl_6 alkyl, c2_6 alkenyl, C2_6 5 alkynyl, C3·8 cycloalkyl, C3-8 cycloalkenyl, Cw alkanol, Halogen Cw alkyl, -(CH2)n-NRxRy, -(CH2)s-C00Rz, -(CH2)n-0-(CH2)m-0H, (CH2)n, _(CH2)n-〇 An aryl group, a _(cH2)n-heterocyclic group or a (CH2)n-0-heterocyclic group, wherein the Ci 6 alkyl group, the c2 6 alkenyl group, the C2-6 alkynyl group,

The Cw cycloalkyl group, the C3_8 cycloalkenyl group, the aryl group and the heterocyclic group may be optionally substituted by one or more (e.g., 1, 2 or 3) Ra groups; the R, Ry and Rz systems are each independently hydrogen, Ci 6 alkyl, c 2_6 alkenyl, c 2_6 alkynyl, C w alkanol, _C00Ci 6 alkyl, hydroxyoxy, Ci 6 alkoxy, halo Ck alkyl, -CCKCHA-Cu alkoxy, Cu alkylamino, C3 - 8 cycloalkyl or C3_8 cycloalkenyl; 15 r2 and r6 are each independently halogen, hydrogen, Cw alkyl, Cw alkoxy, c2_6 alkenyl, c2_6 alkynyl, _CsN, c3 8 cycloalkyl, C3- 8-cycloalkenyl, -nhso2rw, -ch=n-orw, aryl or heterocyclic group, wherein the Cl-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, aryl group and heterocyclic group are optional Substituted by one or more Rb groups, and R2 and R6 are not hydrogen at the same time; 20 Rw is hydrogen or Ci-6 alkyl; R is i, cle6 alkyl, c2 6 alkenyl, c2 6 alkynyl , c3-8 cycloalkyl, C3-8 cycloalkenyl, -ORX, _(ch.〇_Ci 6 alkyl, -0_(CH2)n-0Rx, halo Cw alkyl, haloCi 6 alkoxy, Cl-6 alkanol, =0, =S, nitro, Si(Rx)4, -(CH2)S-CN, -S-Rx, -SO-Rx, -S02-Rx, 8 200836725 -CORx, - (CRxRy)s-COORz, -(CH2)s-CONRxRy, - (CH2)s-NRxRy, -(CH2)s-NRxCORy, -(CH2)s-NRxS02-Ry, -(CH2)s-NH-S02-NRxRy, -OCONRxRy, -(CH2)s-NRxC02Ry, -0 -(CH2)s-CRxRy-(CH2)t-0Rz or -(CH2)s-S02NRxRy; 5 Rb is a Ra or a -Y-carbocyclyl or a -Z-heterocyclyl group, wherein the carbocyclic group And the heterocyclic group may be optionally substituted by one or more (eg, 1, 2 or 3) Ra groups; the Y and Z systems are each independently a bond, -CO-(CH2)s-, -COO-, -(CH2)n-, -NRx_(CH2)n_, -(CH2)n-NRx_, -CONRx-, -NRxCO-, 10 -S02NRx-, -NRxS02-, -NRxCONRy-, -NRxCSNRy--0-( CH2)s-, -(CH2)s-0-, S-, -SO- or -(CH2)s-S02-; m and n are each independently an integer from 1 to 4; s and t are each independent An integer of 0 to 4; or a pharmaceutically acceptable salt, solvate or derivative thereof, 15 but the compound of the formula (I) is not: 3-(3-ethylamidophenyl)-6 -(4-methylphenyl)pyrazole (1,5a)pyrimidine (3-(3-acetamidophenyl)-6-(4-methylphenyl)pyrazolo(l,5a)py rimidine); 3-(3-acetamidine) Aminophenyl)-6-(4-decyloxyphenyl)n-pyridyl (l,5a)pyrimidine 20 (3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo(1, 5 a) pyrimidine); N-(4-{6-[3-(4-fluorophenyl)-1Η-4-. Bizozolyl]imidazo[l,2-a]_吼β-3-yl}phenyl)methylamine (N-(4 - {6-[3-(4-fluorophenyl)-lH- 4-pyrazolyl]imidazo[l 32-a] 25 -pyridin-3-yl}phenyl)methane sulfonamide ); 9 200836725 N-(4-{6-[3-(4-fluorophenyl)-1-triphenyl Methyl-1H-4-.Bizozolyl]-imidazo[1,2-a]-° ratio sigma-3-yl}phenyl)methyl schistosamine (N-(4- {6- [3-(4-fluorophenyl)-l-trityl-lH-4-pyrazolyl]-imida zo[l,2-a]pyridin-3-yl}phenyl)methane sulfon amide ); 5 N-cyclohexyl-N' -{2-Fluoro-4-[6-(l-triphenylindolyl-1H-4-exobazolyl)imidazo[l,2-a] pyridine-3-yl]phenyl}urea (N -cyclohexyl-N5- {2-fluoro-4-[6-(l-trityl- lH-4-pyrazolyl)i midazofl,2-a]pyridin-3-yl] phenyl} urea); N-{2-fluoro -4-[6-(l-triphenylmethyl-1H-4-pyrazolyl)imidazo[l,2-a] 10 acridine-3-yl]phenylpyrazine--isopropylurea Ν- {2-fluoro-4-[6-(l-trityl-lH-4-pyrazolyl)imidazo[l 52-a]py ridine-3-yl] phenyl}-N5-isopropyl urea); N-cyclohexyl -N'-{2-fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l,2-a] n ratio -3 -yl]phenyl} 15 (N-cyc lohexyl-N5- {2-fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l 52-a]pyridin-3-yl] phenyl} urea); N_12-fluoro·4-[6-(1Η_4 -.Bazozolyl imidazo[l,2_a]acridin-3-yl]phenyl}-N'-isopropyl propyl (N-12-fluoro-4-[6-(lH-4-pyrazolyl) Imidazo[l 52-a]pyridin-3-20 yl] phenyl)-N5-isopropylurea); or

Nl-{2-Fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l,2-a]pyridin-3-yl]phenyl}-4-fluorobenzamide (Nl - {2-fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l 52-a]pyridin-3 -yl]phenyl}-4-fluorobenzamide) 〇10 25 200836725 Detailed hair growth of the present invention :

The first-sorship system provides a chemical expression as shown in chemical formula (1).

1 & and each of the respective X3 is at least one of nitrogen; χ4 is CR3 or nitrogen; 10 is selected from carbon or nitrogen, and Xi X5 is CR6, nitrogen or c==〇;

No more than three of the nitrogen in Xl to X5;

Is a double bond; a single bond or a double bond, at least one of the five-membered ring is 15 ^ is hydrogen, i, Cl, C2 6 alkenyl, C2 6 based burnt clay, C3 .6 a cycloalkyl group, a c3_6 ring-dense group, a cyano group, a _ Ci 6 alkyl group 6 Ci-6 alkoxy group or a fluorene group; the genus is an aromatic or non-aromatic carbocyclic or heterocyclic group, Carbocycles and heterocyclic groups are optionally substituted by - or more (eg, 1, 2 or 3) = 20;

Rl is -NHCONR4R5, «NHCOOR4 11 200836725 -NH-CO-(CH2)n-NR4R5, _NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4 -NH-CO-(CH2) n-CSOR4, -NHS02R4, 5

10 15

L NHS02NR4R5, an NHCSNR4R5, -NHCOR4, -NHCSR4, -N HCSSR4, _NHC(=NR4)NR5, NHC(=NR4)R5, -NH-C(=NH2)-NH-CO-R4, -NHCSOR4 or -NHCOSR4 R4 and R5 are each independently hydrogen, Ci 6 alkyl, C2 6 alkenyl, c; 2-6 alkynyl, C3_8 cycloalkyl, C3-8 cycloalkenyl, CV6 alkanol, halo Cw alkyl, -(CH2)n -NRxRy, -(CH2)s-CO〇Rz, -(CH2)n-〇-(CH2)m-OH, -(CH2)n-aryl, _(CH2)n-〇_ aryl, _( CH2)n-heterocyclyl or -(CHA-O.heterocyclyl, wherein the Cw alkyl, C26 alkenyl, C26 alkynyl, C3-8 alkyl, C3-8 cycloalkenyl, aryl and heterocyclic Optionally substituted by one or more (eg, 1, 2 or 3) Ra groups; Rx, Ry and V are each independently hydrogen, Ci6 alkyl, alkenyl, c2-6 alkynyl, Cl-6 alkane Alcohol, _C00Ci 6 alkyl, hydroxyoxy, 6 alkoxy, dentate, -CO_(CH2)n_Ci 6 alkoxy, & calcined, C%8 cycloalkyl or c3-8 ring 20 R and R are each independently _, hydrogen, CM alkyl, Ci6 alkoxy, c2-6 alkenyl, c2_6 alkynyl, copper, C3 8 cycloalkyl, C3-8 cycloalkenyl, - NHS〇2R' -CH=N_ORW, aryl or heterocyclic group wherein the "alkyl, C2-6 Group, C2 a fast, Cheng Yun mounted η μ square shape and heterocyclyl group optionally substituted with one or more Rb groups, and "Different Rw and R6 is hydrogen or alkyl Cle6; ^ '

Ra is halogen, Cw alkyl, C2-6, C2-6, C3-8 12 200836725, C3-8 ring, -RX, -(CH2)n-〇-Ci- 6 alkyl, -0-(CH2)n-〇Rx, halogen Cu alkyl, halogen Cu alkoxy, Cu alkaloid, =0, =S, nitro, Si(Rx)4, -(CH2)s -CN, -S-Rx, -SO-Rx, -S02-Rx, -CORx, -(CRxRy)s-COORz, -(CH2)s-CONRxRy, 5 -(CH2)s-NRxRy, -(CH2) s-NRxCORy, -(CH2)s-NRxS02-Ry, -(CH2)s-NH-S02-NRxRy, -OCONRxRy, -(CH2)s-NRxC02Ry, -0-(CH2)s-CRxRy-(CH2) r0Rz or -(CH2)s-S02NRxRy; R is '-R or'----carbocyclyl or -Z-heterocyclyl, wherein the carbocyclic and heterocyclic groups are optionally one or more (eg, 1, 2 or 3) Ra 10 radical substitution; γ and z are each independently a bond, _C0_(Ch2)s_, -C〇〇_, -(CH2)n-, _NRXfine (CH2) N-, -(CH2)n-NRx-, _C〇NRX-, _NRxCO-, -S02NRx_, _NRxS02-, -NRxCONRy-, -NRxCSNRy_ -〇-(CH2)s-, -(CH2)s-〇-, S-, -SO- or -(0112)402-: m and n are each independently an integer from 1 to 4; s and t are each independently an integer from ^0 to 4; or a pharmaceutically acceptable Salts, solvates a derivative thereof, but the compound of the formula (I) is not: 3-(3-acetamidophenyl)_6_('methylphenyl)pyrazole (1,5 phantom pyrimidine; 2〇3-(3- Acetyl phenyl)_6_(4-methoxyphenyl)pyrazole (ija) and pyrimidine; N (4 {6-[3-(4-oxyphenyl)-indolyl) oxime and [i, 2_a]_吼吼-3-yl}phenyl)methylsulfonamide; N (4 {6 [3-(4-说笨基)_ι·trityl-1仏4_11 ϋ 基]]-咪tr sitting and [l,2_a]_pyridin-3-yl} stupyl) methyl·glycoside; 13 200836725 Ν·cyclohexyl Ν,·{2_Fluor_4_[6_(1_triphenyl) Methyl-m such as fluorenyl) oxazolo[1,2_a]acridin-3-yl]phenyl}urea; Ν-{2-^-4-[6-(1-diphenylmethyl- Heart^bisazolyl)isoazoloindole_3_yl]phenyl}-N,_isopropylurea; 'N-cyclohexyl-N,-{2-fluoro-4-[6-(1Η- 4-oxazolyl)-azolozolidine n,2_a]pyridin-3-yl]phenyl}urea; N-12 prepared 4·[6_(1Η_4_pyrazolyl) σ-mazole and succinylpyridinyl] Phenyl}-oxime,-isopropylurea; or + Ν1]2-fluoro |[6.(m such as 嗤 )) 嗤 嗤 [] l, 2 ♦ than precipitation | base] phenyl b 4-fluoro Benzoylamine. L·15 wherein, in the examples, a compound of the formula (1) is provided

(I) R2 to X2: 2 and Χ3 are each independently selected from carbon or nitrogen, and at least one of them to X3 is nitrogen; Χ4 is CR3 or nitrogen; X5 is CR6, nitrogen or c=〇 ; 20

No more than three nitrogens in Xl to I; 200836725 = is a single bond or a double bond, so that when \ is ^=〇, χ4 and x5 are bonded via a single bond to make it five yuan At least one bond in the ring is a double bond; R3 is hydrogen, a hydroxyl group, a Cl-6 alkyl group, a C2_6 thin group, a group, an L alkoxy group, a Cw cycloalkyl group, a C3-6 cycloalkenyl group, a cyanogen group , halo 6 alkyl, halogen Ci-6 alkoxy or = hydrazine; V 10 15

20 A is an aromatic or non-aromatic carbocyclic or heterocyclic group which is optionally substituted by one or more (eg, i, 2 or 3) Ra groups; The system is -NHC〇NR4R5, -NHCOOR4, -NH.C〇.(CH2)n.NR4R5, - bribe - Yangshao - (3) dish γ, NH-CO-(CH2)n-COOR4, -NH.C〇. (CH2)n.CSOR4, -nhso2r4, NHS02NR4R5, -NHCSNRV, -nhc〇r4, -nhcsr4, -N HCSSR4, _NHC(=NR4)NR5, nhc(=nr4)r5, -NH-C(=NH2)- NH-CO-R4, -NHCSOR4 or -nhc〇sr4; R4 and R5 are each independently hydrogen, Cl-6 alkyl, Cw alkenyl, C26 alkynyl, C3_8 cycloalkyl, (33-8 cycloalkenyl, Ci 6 Alkanol, halo 6 alkyl, -(CH2)n-NRxRy, -(CH2)s-CO〇Rz, -(CH2)n 〇_(CH2)m_〇iI, -(CH2)n-aryl, _(CH2)n-〇-aryl, (CH2)n_heterocyclyl or -(CH2)n-0-heterocyclyl, wherein the Ck alkyl, c2 6 alkenyl, C2 6 alkynyl, Cw naphthenic a group, a Cw cycloalkenyl group, an aryl group, and a heterocyclic group may be optionally substituted by one or more (eg, 1, 2 or 3) Ra groups;

Rx, Ry and rz are each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, 15 200836725 C2-6 alkynyl, Cl-6 ani alcohol, _C〇〇Ci nucleus, chlorooxy, "alkoxy, halogen" An alkyl group, a π〇_ΚΗ2)η々6 alkoxy group, a Ci 6 alkyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group; the broad R and 11 groups are each independently a halogen, a hydrogen, a CV6 alkyl group, Cu alkoxy 5 oxy, C 2 _6 dilute, C 2 ·6 fast radical, -C^N, cyclyl, C 3-8 cycloalkenyl, ·NHS 〇 2 Rw, _CH=N 〇 RW, aryl or heterocyclic group, Wherein the ~alkyl^2.6 alkenyl, C2.6 alkynyl, aryl and heterocyclic groups are optionally substituted by one or more Rb groups, and 2 and R6 are not simultaneously hydrogen;

Rw is hydrogen or Cl_6 alkyl; 10 R is halogen, Ci-6 alkyl, C2_6 alkenyl, c2_6 alkynyl, C3-8 lomo, C3_8 cycloalkenyl, _0Rx, _(CH2)n_〇 _Ci 6 alkyl, -0-(CH2)n-〇RX, halogen (^6 alkyl, halogen ci 6 alkoxy, c1-6 alkanol, =〇, =s, bowl base, Si(RKCH2VCNm〇) RX, _s〇2_rX, _corx, _(CRXRy)s_C00RZ, _(CH2)sC〇NRXRy, 15 _(CH2)s-NRXRy, -(CH2)s-NRxCORy, _(CH2)s-NRxS02-Ry, - (CH2)s-NH_S02-NRxRy, -〇CONRxRy, -(CH2)s-NRxC02Ry, _〇-(CH2)s-CRxRy-(CH2)r〇Rz or -(CH2)s-S02NRxRy;

Rb is an Ra or a -Y-carbocyclyl or a -z-heterocyclyl group, wherein the carbocyclic group and the heterocyclic group are optionally one or more (eg, 1, 2 or 3) Ra 20 Substituent substitution; Y and Z systems are each independently a bond, _c〇-(CH2)s_, -COO-, •(CH2)n-, -NRx-(CH2)n-, -(CH2)n-NRx- , -CONRX-, -NRxCO-, _S02NRx-, -NRxS02-, -NRxCONRy-, -NRxCSNRy--〇-(CH2)s-, -(CH2)s-0_, S_, _SO_ or -(CH2)s- S02-; 200836725 The claws and the 11 series are each independently an integer of from 1 to 4; the s and t systems are each independently an integer from one to *; the square group is a carbocyclic ring; and the heterocyclic group is a heterocyclic ring; 5 or - a salt, solvate or derivative thereof, which is acceptable for learning, but must have one condition: the compound of formula (I) is not: 3-(3-acetamidobenzylbenzene) (Saliva (1, called and feeding; 3-(3-acetamidobenzene)_6_(4-methoxyphenyl) hydrazine (1, (4) pyrimidine; Ν·(4-{6·[3_ (4-fluorophenyl)·1Η such as bazolyl] Xiaoxazole and Ha]·吼10 pyridine-3-yl}phenyl)methylsulfonamide; N-(4-{6-[3-(4 -|tphenyl)tritylmethylhydrazine. Sodium carbazole [l,2-a] _Pyridin-3-yl}phenyl)methylsulfonamide; N-% hexyl_N-{2-fluoro-4_[6·(1_tritylmethyl-1H_4_pyrazolyl)imidate[ l,2-a]pyridin-3-yl]phenyl}urea; 15 sense {2-Dongdong [6-(1-diphenylmethyl-111-4-portate oxime) oxazolo[1 ,2-&]° ratio biting_3_yl]phenyl}-N'_isopropylurea; N-cyclohexyl-N'-{2_fluoro_4-[6-(1Η-4-pyridyl) Azolyl imidazo[l,2-a] π-pyridin-3-yl]phenyl}urea; Ν_12-fluoro-4-[6-(1Η-4-pyrazolyl)imidazo[ijd]pyridine- 3_yl] 20 phenylindole'-isopropylurea; or

Nl-{2-Fluoro-4_[6-(1Η-4-pyrazolyl)imidazopyridinyl]phenyl}-4-fluorobenzamide. In one embodiment, a compound of formula (1) is provided: 17 200836725

among them,

Xi, X2 and X3 are each independently selected from carbon or nitrogen, and at least one of Χι quot" 5 to Χ3 is nitrogen; Χ4 is CR3 or nitrogen; Χ5 is CR6, nitrogen or C=0; ! No more than three nitrogen to X5; = a single bond or a double bond; 10 R3 is chlorine, _, Ci_6 alkyl, C2-6, C2-6 fast, Ci_6 alkoxy a c3_6 cycloalkyl group, a C3_6 cycloalkenyl group, a cyano group, a halogen Cw alkyl group, a halogen Ck alkoxy group or a hydrazine; ^ A is an aromatic or non-aromatic carbocyclic or heterocyclic group, the carbon The ring and heterocyclic group are optionally substituted by one or more (eg, 1, 2 or 3) Ra groups for 15 generations; R1 is -NHCONR4R5, -NHCOOR4, -NH-CO-(CH2)n-NR4R5 -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -NHS02R4, NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -N 20 HCSSR4, -NHC(=NR4) NR5, NHC(=NR4)R5, 18 200836725 -nh-c(=nh2)-nh-co-r4, NHCSOR4 or a NHCOSR4; R4 and R5 are each independently hydrogen, Cl-6 alkyl, c2-6 olefin Base, c2-6 alkynyl, 匕_8 cycloalkyl, ον8 cycloalkenyl, 6 alkanol, halo ci 6 alkyl, -(CH2)n-NRxRy ^ -(CH2)s-CO〇Rz . CH2)n-〇-(CH2)m-OH^-(CH2)n_aryl...(CH2)n_〇-aryl, _(CH2)n.heterocyclyl or -(CH2)n-〇· a heterocyclic group wherein the Ci_6 alkyl group, Gw alkenyl group, & alkynyl group, C3-8 alkyl group, C3_ The 8-cycloalkenyl, aryl and heterocyclic groups may be optionally substituted by one or more (e.g., 1, 2 or 3) Ra groups;

10 15

Rx, Ry and Rz are each independently hydrogen, Cl-6 alkyl, c2_6 alkenyl, C2_6 alkynyl, Cw alkanol, -COOCw alkyl, hydroxyl, cN6 alkoxy, Cw alkyl, -CO_ (CH2)n_Ci-6 alkoxy, Ci 6 alkylamino, C3.8 cycloalkyl or C3-8 cycloalkenyl; R2 and R6 are each independently hydrogen, C1-6 alkyl, c2-6 alkenyl, C2_6 alkynyl, C3·8 cycloalkyl, c: 3-8 cycloalkenyl, aryl or heterocyclic group, wherein the aryl and heterocyclic groups are optionally substituted by one or more Rb groups, and R6 is a hetero a cyclic group and the heterocyclic group is not pyrazolyl;

Ra is halogen, Cu alkyl, c2_6 alkenyl, C2-6 alkynyl, 03-8 cycloalkyl, c3-8 cycloalkenyl, -ORX, _〇_(CH2)n_〇Rx, halogen Ci6 alkyl, halogen Cu alkoxy, c1-6 alkanol, =0, = s, nitro, -(CH2)S-CN, -S_RX, _SO-Rx, _S〇2-Rx, _CORx, -(CRxRy)s_COORz, _ (CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, "(CH2)s-NRxS02-Ry " -OCONRxRy, -(CH2)s-NRxC02Ry, -〇-( CH2)s-CRxRy-(CH2)rORz or -(CH2)s-S02NRxRy;

Rb is an Ra or a mono-Y-aryl or a -z-heterocyclic group, wherein the aryl 20 200836725 group and a heterocyclic group are optionally substituted by one generation; or a plurality (eg, 1, 2 or 3) Ra 5 10 15 15 When the R 2 is a non-gas functional group, X5S CH or 00, and when R is hydrogen, R 6 is a non-hydrogen functional group, and the Y and Z systems are each independently a bond. Junction, · c〇_(cH2)s_, _c〇〇_, (CH2)n, -NR -(CH2)n·, -(CH2)n_NRX...c〇NRX_, nrXc〇, S02NR - . -NRxS02- ^ -NRxCONRy- ^ -NRxCSNRy-〇(ch2)s_, _(ch2)s-〇-, s_ _s〇 or _(CH2)s_s〇2_; m and n are each independently an integer from one to four; s And t are each independently an integer from one to four; the square group is a carbocyclic ring; and the heterocyclic group is a heterocyclic ring; or a pharmaceutically acceptable salt, solvate or derivative thereof, but β The compound of formula (I) is not 3_(3_acetamidophenyl)_6_(4-mercaptophenyl)pyrazole (1,5A) and pyrimidine or 3-(3-acetamidophenyl)_6_(4 _ 曱 oxybenzene) carbazole (1,5A) and pyrimidine. In one embodiment, a compound of the formula (1) is provided, wherein:

Xi, X2 and & are each independently selected from carbon or nitrogen, and at least one of X1 to χ3 is nitrogen; Χ4 is CR3 or nitrogen; Χ5 is CH, nitrogen or c=〇; Χι to X5 No more than three in the middle; 20 200836725 is a car bond or a double bond; R3 is hydrogen or = 〇; j is an aromatic or non-aromatic carbocyclic or heterocyclic ring, the carbocyclic ring And the heterocyclic group may be optionally substituted by one or more (e.g., 丨, 2 or 3) groups; 5 Rl is -NHC〇NR4R5, -NHCOOR4, -NH-C〇.(CH2)n-NR4R5 > -NH-CO-(CH2)n-COOR4 _NHS02R4, or a CSNR4R5; R4 and R5 are each independently hydrogen, Cl.6 alkyl, Ci6 alkanol, -(CH2)n-NRxRy, _(CH2 N4 or haloCl_6 alkyl; 10 R, Ry and RZ are each independently hydrogen, Ci-6 alkyl, Ci-6 alkanol, hydroxyloxy, Cw alkoxy, dentate Cl·6 alkyl or _C〇 _(CH2)n_Ci6 alkoxy; R is an aryl or heterocyclic group, which may be optionally substituted by one or more Rb groups; 15 R is halogen, Ci-6 alkane , C2-6 alkenyl, C2_6 alkynyl, C3_8 ring, C3_8 cycloalkenyl, -〇Rx, _〇_(CH2)n_〇Rx, halogen Cl_6 alkyl, halogen Cu Oxylate, c "6 ani alcohol, = 〇, = s, schlossyl, -(CH2)S-CN, -S-Rx, -SO-Rx, _S02-Rx, -C〇Rx, _(CRxRy)s_c〇 〇Rz, (CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, 20 -(CH2)s-NRxS02-Ry > -OCONRxRy, _(CH2)s-NRxC02Ry, - 0-(CH2)s_CRxRy-(CH2)r〇Rz or -(CH2)s-S02NRxRy; R is a 1-Y-aryl or -Z-heterocyclic group, wherein the aryl and heterocyclic groups are selective The ground is replaced by one or more (eg, 1, 2 or 3) Ra groups; but when the R 2 is a non-hydrogen functional group, χ5 is CH or C=0; 21 200836725 -(CH2)n- , Each of them is a single bond, co-NRx-(CH2)n_, _〇_$-〇(CH士; m and η are each independently an integer from 4 to 4; s and t are each independently a 0 to An integer of 4; a ring is a carbocyclic ring; and the heterocyclic group is a heterocyclic ring. ▲ "This is a - functional group or a part of a functional group of "CK base" Ο A saturated linear or branched hydrocarbon group of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl, isopentyl, neodecyl or And similar thereof. Examples of the correlation of -O-Cu alkyl group, wherein Ci_6 J, include: pentyloxy or hexyloxy group and the term "Ck alkoxy group" herein means that the alkyl group is as defined above. "C1-6 alkoxy 15 methoxy, ethoxy, propoxy, butoxy similar. Here, the term "Cw alkanol" refers to a Cw alkyl group via one or more hydroxyl groups. Substituted, related examples include: hydroxymethyl, hydroxyethyl, hydroxypropyl and the like. Herein, the term "C3·8 cycloalkyl" means a saturated monocyclic compound having 3 to 8 carbon atoms. Related examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like. The term "C3·6 cycloalkyl" as used herein means a saturated monocyclic compound having 3 to 6 carbon atoms. Related examples include cyclopropyl, cyclobutyl, cyclo25-pentyl, cyclohexyl, and the like. 22 200836725 Herein, the term "halogen" means a fluorine, gas, bromine or iodine atom. Herein, the term "halogen Cw alkyl" means, as described above, wherein at least - a hydrogen atom is substituted by a self. Related examples include: fluoroacetamidine, difluoromethyl or di-ethyl and their analogs. The term "®Ci.6 alkoxy" as used herein refers to a Ci6 alkoxy group as described above wherein at least a hydrogen atom is replaced by a peptidation. Related examples include difluoromethoxy or trifluoromethoxy and the like. Unless otherwise specified, the above-mentioned r carbocyclic and "heterocyclic" groups contain both aromatic and non-aromatic ring systems. Thus, for example, "carbocyclic and 10 heterocyclic groups" are aromatic, non-aromatic, unsaturated, partially saturated, and saturated, and heterocyclic ring systems. In general, such groups may be monocyclic or bicyclic or contain, for example, a 3 to 12 ring group, more often a 5 to 10 ring group. Examples of monocyclic groups include: groups containing 3, 4, 5, 6, 7, and 8 rings, typically a group containing 3 to 7 rings, and preferably 15 is a group containing 5 or 6 rings. . Examples of bicyclic groups include: groups containing 8, 9, 10, 11 and 12 rings, typically groups containing 9 to 1 ring. In addition to I, unless specifically stated, the carbocyclic ring and the heterocyclic group referred to herein may have a carbocyclic ring and a heterocyclic ring which may be unsubstituted or substituted by one or more, such as molecular fragments, molecular skeletons (m). 〇iecuiar scaff〇ld), or the above-mentioned functional 2-mercapto group, is substituted. Preferably, the "carbocyclic" and "heterocyclic" groups include carbocycles which are optionally substituted by one or more (eg, 1, 2 or 3) groups of 1^ or 1^ and Heterocyclic group. The carbocyclic ring and the heterocyclic group may be an aryl or heteroaryl group having 5 to 12 rings, preferably an aryl group or a heteroaryl group having 5 to 10 rings. Here, the term "芳 23 200836725基" refers to a carbocyclic ring having aromatic properties. The term "heteroaryl" includes a polycyclic ring (eg, a two-ring: a non-aromatic ring, and at least one ring is a aryl two: in the % system, the group is attached to a fragrance) Ring or - non-aromatic ring. Here, "non-aromatic. Lithium, earthy J-s system contains 1 aromatic (four), partially saturated and saturated carbocyclic ring and heterocyclic ring m, "unsaturated J" And the term "partially saturated" means that the sub-shares more than one covalent bond with other atoms, that is, a ring that contains a bond (eg, a c=c, Csc, or N=c bond). There are no multiple bonds between atoms in a structure. A saturated carbocyclic group includes a burnt group, which is defined as follows. A partially saturated carbocyclic group includes a ring-like group such as a cyclopentyl group, a cyclohexyl group, or a ring. Heptyl, and cyclooctyl, as defined below. Saturated heterocyclic groups include: piperidine, m 15 r 〇 〇 、 、 硫 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Partially saturated heterocyclic groups include: pyrazoline, for example: 2_pyrazoline and 3_pyryloline. Examples of heteroaryl groups include: having five to ten The ring, more preferably a five- to ten-membered ring, a monocyclic or bicyclic group. For example, the heteroaryl group may be a five- or six-membered single ring, or each of the five- and six-membered rings may be thick. And a double 20 ring, a double ring fused to two six-membered rings, or a double ring fused to two five-membered rings, and each ring may include four or less hetero atoms selected from the group consisting of Nitrogen 'sulfur, and oxygen. Typically, the heteroaryl ring includes up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, for example, a single heteroatom. In the example, the heteroaryl ring includes a ring having a nitrogen atom to 24 200836725. The nitrogen atom in the heteroaryl ring may be basic, such as imidazole or pyridine, or may be Substantially non-basic, such as nitrogen in the indole or pyrrole. In general, in the heteroaryl group (including any amine group substituted on the ring), the nitrogen source The number of 5 sub-groups is not more than five. Examples of five-membered ring heteroaryl groups include, but are not limited to: pyrrole, °fu (fu Ran), thiophene, imidazole, furazan, oxaz〇le, oxadiazole, oxatriazole, isoxazole, σ thiazole, isoxiazole, isopyrazole, pyrazole, triazole, and tetrazole groups. In addition, examples of five-membered heteroaryl groups include clogging Examples of thiadiazole 〇 six-membered ring heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine. Pyrimidine and triazine. For example, a bicyclic heteroaryl group can be a group selected from the group consisting of: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; 2〇b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms a fused pyrimidine ring; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; 25 200836725 e) with one containing i or 2 rings a pyrazole ring in which a 5- or 6-membered ring of a hetero atom is fused to each other; f) an imidazole ring fused to a 5- or 6-membered ring containing fluorene or two ring hetero atoms; g) a heterogeneous ring containing 5 or 6^ rings of a ring-shaped hetero atom; h) a heterocyclic ring which is fused to a 5 or a ring containing i or 2 ring hetero atoms; Ο 15 20 i) with an anthracene ring containing 1 or 2 cyclic heterocycles; ^5 or 6-membered rings of heteroatoms are slightly coincident with each other j) and one containing 1 or 2 rings. Hetero (tetra) ring; the atomic ring of the cut atom is fused to each other k) and a porphin ring containing i, 2 or 3 钿 and fused on top; The 5- or 6-membered ring of a hetero atom is mutually D- and contains [, 2 or 3 ring-shaped fused ring; the original 5_ or 6-兀% is called one or two. The oxazole ring; the 5- or 6-membered ring of eight heteroatoms are mutually thick n) and - contain! Or 2 ring chewing rings; 5 or 6-membered rings fused to each other) and a cyclohexyl ring containing 1, 2, 2, or 3 fluorene; The 5- or 6-membered ring is conjugated to each other and a cycloheptyl ring fused to 4 μ of the 1, 2 or 3 ring. 5 or 6-membered rings of eight heteroatoms 26 25 200836725 5 Ο 10 15 Ο 20 Specific examples of bicyclic heteroaryl groups having two five-membered rings fused to each other include, but are not limited to, imidazole thiazole ( For example, imidazole [2, oxime] thiazole and sputum sputum (eg, scent ^ [l, 2-a] miso). Specific examples of bicyclic heteroaryl groups containing a six-membered ring and a five-membered ring fused to each other include, but are not limited to, benzofuran, benzthiophene, benzimidazole , benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, Ind (indole), isoindole, indolizine, indoline, isoindoline, 嘌呤 (eg, adenine, bird mouth ticket), σ bow Indazole, ° ratio ♦ and mouth tightly determined (pyrazolopyrimidine (eg, π than sitting on [i,5-a]. 唆), three 17 sitting and cancer bite (triazolopyrimidine (eg, [1, 2 , 4] three saliva [l,5-a] shouting °), benzodioxole (benzodioxole) and mouth than σ sitting and nfc^ (pyrazolopyridine (eg, squat [1,54]) group. Another example of a bicyclic heteroaryl group containing a six-membered ring and a five-membered ring fused to each other includes a mouth-square σ sitting ratio. (imidazopyridine) Specific examples of bicyclic heteroaryl groups having two six-membered fluorene groups include, but are not limited to, 12 quinoline, isoquinoline, chroma, Thiochroman, chromene, isochromene, chroma, isochroman, benzodioxan, quinolizine, benzoxine Benzoxazine, benzodiazine, mouth ratio, pyridopyridine, 喧喔琳27 200836725 (quinoxaline), quinazoline, cinnoline, 酞嗓(phthalazine), naphthalene, naphthyridine, and pteridine groups. Examples of polycyclic aryl groups having an aromatic ring and a non-aromatic ring and heteroaryl 5 groups include: tetrahydronaphthalene) Tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran, 2,3-dihydrobenzene [1,4] Dioxin (2,3-dihydro-be Nzo[l,4]dioxine), benzene [1,3] dioxin 10 (benzo[l,3]dioxole), 4,5,6,7_ tetrahydrobenzopyrene (4,5,6 , 7-tetrahydrobenzofuran), σ 丨ΰ 丨ΰ 丨ΰ (indoline) and indane (indane) groups. In addition, examples of polycyclic heteroaryl groups having an aromatic ring and a non-aromatic ring include: tetrahydrotriazolopyrazine (eg, 5,6,7,8-tetrahydro-[1,2 , 4] three sitting 15 [4,3-&] mouth 嗓). A nitrogen-containing heteroaryl ring must have at least one cyclic nitrogen atom. In addition, each ring may contain up to four heteroatoms, and its heteroatoms Is selected from the group consisting of: nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring system contains up to 3 heteroatoms, such as 1, 2 or 3 heteroatoms, more typically up to 2 nitrogen atoms, for example 20 single nitrogen atoms. The nitrogen atom in the heteroaryl ring may be basic, such as: imidazole or pyridine, or may be substantially non-invariant, such as: ° indole (indole) Or a nitrogen atom in the β ratio of 11 (pyrrole). In general, the number of nitrogen atoms in the heteroaryl group (including any amine group substituted on the ring) is not more than five. 28 200836725 Examples of nitrogen heteroaryl groups include, but are not limited to, π pyridyl, pyrr〇iyi 'imidazolyl, σ Oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxaz〇lyl, thiazolyl, isoindole Isothiazolyl, furazanyl, pypypyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl ), triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, (tetrazolyl), quinolinyl, isophthalene Isoquinolinyl, 10 benzimidazolyl, benzoxazolyl, benzoxazole, benzzisoxazole, benzthiazolyl, and benzoidin Junji (^6112丨8〇1:11丨&2〇16),°弓布基基(丨11(1〇1;71), 311-°引σ奇基基(3H-indolyl), 异叫Isoindolyl, σ-indolizinyl, iso-indolizyl, purinyl (eg, adenine [6-aminopurine]), (Bird 嘌呤 [2- Purin-6-hydroxy])), saliva indazol-yl (indazolyl), Lin Ji noise (quinolizinyl), call-benzoxazin-yl (benzoxazinyl), call benzodiazepin-yl (benzodiazinyl), and instigate roar. Pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl . Examples of a polycyclic heteroaryl group having a nitrogen atom and having an aromatic ring and a non-aromatic ring include: tetrahydroisoquinolinyl, tetrahydroquinolinyl 29 200836725 (tetrahydroquinolinyl), and a bow Indolinyl. Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups. An example of a non-aromatic heterocyclic group is a group having a 3 to 12 membered ring, more usually a 5 to 5 membered ring. For example, the group may be monocyclic or bicyclic, and typically has from 1 to 5 ring atoms, more often 1, 2, 3, or 4 ring atoms, and the atom is selected from nitrogen, oxygen, And sulfur. For example, the heterocyclic group may include: a cyclic ether (eg, in tetrahydrofuran and a dioxane), a cyclic oxime (eg, tetrahydrothiophene and 10 Among the dithianes, cyclic amines (eg, in pyrrolidine), cyclic amides (eg, in 0 pyloric), cyclic thiazide (cyclic thioamides), cyclic thioesters, cyclic ureas (eg, in imidazolin-2-one), cyclic esters (eg, in butyrolactone), cyclic sulfones ( For example, in cyclobutyrene and cyclobutene, cyclic sulphoxide, cyclic sulphonamide, and combinations thereof (eg, thiomorpholine) . Specific examples include morpholine, piperidine (eg, 1-piperidine, 2-piperidine, 3-Butidine, and 4-trailer), piperidone, and 11 pyrrolidine. ) (such as 1-吼洛烧, 2-°比洛烧, and 3-σ ratio 11), mouth ratio 20 _ (pyrrolidone), azetidine, apyran (pyran, Such as 2Η-^σ南 or 411-吼 )), dihydrothiophene 'dihydropyran, dihydropyran, dihydrofuran, dihydrothiazole, dihydrothiazole), four Tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyranium 30 200836725 5 Γιο 15 ί) 20 (tetrahydropyran, such as 4-tetrahydropyridylpyranyl), Imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine (piperazone), piperazine, and N-alkyl-based oxazine (such as N-methylpyrazine). In general, preferred are non-aromatic heterocyclic groups including: saturated groups such as piperidine, pyrrolidine, azetidine, morpholine ), travel. (piperazine) and N-burning tour. In a nitrogen-containing non-aromatic heterocyclic ring, the ring must contain at least one cyclic nitrogen atom. For example, the heterocyclic group may comprise: a cyclic amine (eg, in pyrrolidine), a cyclic amide (eg, pi-portion, piperidone) Or caprolactam, cyclic aglycone (eg, isothiazolidine l, l-dioxide, [1,2] thiazinane 1,1·2 Oxygen ([l,2]thiazinane l,l-dioxide) or [l,2]thiazepane 1,1-dioxy ([l,2]thiazepane 1,1-dioxide) and combinations thereof. Examples of specific nitrogen-containing non-aromatic heterocyclic groups include: aziridine, morpholine, thiomorpholine, brigade (eg, 1_pai, 2- Tourism, 3-tourism and 4-bred bite), °biluo (eg, 1-° piroxime, 2-indole, and 3-° ratio), 0 pirone (pyrrolidone), dihydrothiazole, imidazoline, imidazolidinone, σzo 11 oxazoline, 0 thiazoline, 6Η-1, 2,5- π 嗓 嗓 嗓 (6H-l, 2,5-thiadiazine), 2- σ than py 琳 (2-pyrazoline), 3- ° ratio ° 琳 琳 (3-pyrazoline), ° than sizzling 31 200836725 (pyrazolidine), pieperazine, and N-burning tourism (eg, Ν_methyl tour). The heterocyclic group may be a polycyclic fused ring system or a bridged ring system, such as bicyclic, tricyclic, and oxa and aza. Compounds (eg, adamantane and xa-adamantane). For more details on condensing and bridge ring systems, see Jerry March (10)Organic, 4th edition, Wiley

Interscience, Inc., pp. 131-133, 1992. 10 non-aromatic carbocyclic groups include: a cycloalkyl group (such as a cyclohexyl group and a cyclopentyl group), a cyclic fluorenyl group (such as a cyclopentenyl group, a cyclohexenyl group, a cycloheptyl group, and a cyclooctenyl group). And a cyclohexadienyl group, a cyclooctyltetraenyl group, a tetrahydronaphthenyl group, and a decaminyl group, each of which may be unsubstituted or substituted by one or more Take 15 generations. For example, a heterocyclic group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents. Wherein the "hybrid" group is an early or double ring, generally having no substituent or having 1, 2, or 3 substituents. ί , .... In the above, a 11 represents a single bond or a double bond. Those skilled in the art will recognize that when X5 is C=0 or when R3 is =0, x4&x5 is linked via a 20 single bond. A Specialized Embodiment of the Invention The chemical formula (i) a_(i)t of the ring system defined by Χ1-Χ5 is as follows: 32 200836725

C

33 200836725

The chemical formula (I)u-(I)v 34 200836725 of other ring systems defined by Xi-X5 is as follows:

In the embodiment, the two bonds in the 5-membered ring are double-bonded. In one embodiment, Χι represents C. In the examples, X1, X3 and X5 represent c, ax2 and X4 represent nitrogen (i.e., a cyclic system as defined by the formula (1)a). In another embodiment, X1, X3, X4, and Χ5 represent c, a niche (i.e., as in the formula (I) e riding ring system). In another embodiment, X1, X3 and X4 represent c, and & and χ5 represents nitrogen (i.e., a ring system as shown in formula (1)f). In another embodiment, 'X1 and X2 represent x4 for CR3 (eg, CH), and the representative nitrogen-5 represents CR (eg, C-Me) (ie, as shown in the formula + (I)h) Ring system). 15 20 Medium 'Χι, Χ2, Χ4, and Χ5 represent c, the gas (ie, = chemical ring-type ring system). In another embodiment, υ Χ 5 represents biliary, such as crystallization = 2v and Χ 4 represents C, and & and in the examples, χ2, χ3, χ not in the ring system) ° another - as in the chemical formula (1) Request form. And χ_即' 35 200836725 In another embodiment, 'x2, x3 and X5 represent c, & ι and x4 represent nitrogen (i.e., a ring system as shown in formula (I)r). In one embodiment, X1-X5 represents a ring system as shown in formula (1) a, (1) e, (1) f, (I) J, (I) k, (1) q or (1) 。. In still another embodiment, 'χ^χ5 represents a ring system as shown in the chemical formula (I) a or (1). In the further embodiment, Xl_X5 represents a ring system as shown in the chemical formula (1). In the implementation of money, when Xl, X3 and & represents c, and the heart and X4 represent nitrogen, R1 represents a group of non-NHc〇R4. (15) In the examples, when X1, X2, and X4 represent c, and Χ3 represents nitrogen, and R1 represents a group other than _NHc〇(cH2)nNR4R5 or -NHCONR4R5. Representative of HA stands for phenyl and R1 represents a group of non-NHCOR4. In the examples, when X1, X3 and X5 represent C, and the core and 乂4 represent nitrogen, Ra represents a non-〇 group. In one embodiment, when x2, X3, X4 and x5 represent C, and X! represents nitrogen, R1 represents a group other than _NHc〇r4 or _deleted into 4. 20 azolyl) 'When χ5 represents cr6, and r6 represents a heterocyclic group, the heterocyclic group is a non-D-salt group (eg, selectively substituted. In an embodiment, 'χ2, Χ3, and X5 represents C, Xl and Χ4 represent an atmosphere, and R1 represents ·_NHc〇nr4r5, a represents a non-phenyl group. 4 Chemical formula of the ring system defined by A (I) A-(I) lanthanide As shown below: 36 200836725

Its group (I) L can be any isomer of imidazole (e.g., (I) L2). In one embodiment, A represents a group selected from the group consisting of Formulas (I) A to (I) J and (I) L to (1) 0. 37 200836725 In the examples, A is a non-fluorenyl group. In the -: example, 'A is selected from: (10), (1) N, and (1) 〇. In the case of Bayes, A is a (1) a group, and the (1) a group may be substituted with one or more (e.g., 2 or 3) Ra groups. Preferably, in the embodiment, wherein & represents nitrogen, ring A is added to the above oxime group by a stone anti-atom. In the yoke example, A represents a monocyclic aromatic carbocyclic ring or a heterocyclic ring system having a ring of 5, 6 or 7 members. In another embodiment, a represents a 6/〇 carbon % ring: in still another embodiment, A represents a phenyl group (ie, a ring system as shown in formula (I) A). Substituted by one or more (eg, f 3 squadrons. In one embodiment, A represents unsubstituted native 〆 via a _(CH2)s C 〇 NRXRy (eg, _c〇n (eg, a phenyl group substituted by a group of CN), Cl.6 alkyl (e.g., methyl) or ca (e.g., methoxy). In the case of 1 fortune, A represents a monocyclic carbon ring or has 5, 6 or 7 riding a heterocyclic ring m in another - implementation of wealth, A represents a 6-membered carbon ring ring. In the re- _ real _ towel, A represents - phenyl (ie, a formula (1) A ' ring a system) or a (four) group (ie, as in the formula or (1C), ring system) 'and optionally substituted by - or multiple (eg, (a) or 3) Ra groups. Wherein A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring-type system (e.g., phenyl or (tetra)yl), and is in the 3-position or heterodisubstituted; when A represents a phenyl group, In the example, = is relative to the position of the seat that X! joined. Standing on the base 38 20083 6725 In one embodiment, A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (eg, phenyl or fluorenyl), and is substituted at the 5-position by R1, and is more selective Substituted at the 3-position by a single Ra group. In one embodiment, A represents an unsubstituted phenyl group or a 5-(CH2)s-CONRxRy (eg, a CONH2), -(CH2) S-CN (eg, a CN), halogen (eg, fluorine), (^-6 alkyl (eg, methyl), (^-6 alkanolyl (eg, -ch2oh) or -ORx (eg, 曱A phenyl group substituted with an oxy or -〇CH(Me)2) group. In yet another embodiment, A represents an unsubstituted phenyl group. In one embodiment, R1 represents -NHCONR4R5, 10-NH-CO_ (CH2)n-NR4R5, -NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -NHS02R4, NHS02NR4R5, -NHCSNR4R5, - NHCOR4, -NHCSR4, -NHCSSR4, -NHC(=NR4)NR5, NHC(=NR4)R5, 15-NH-C(=NH2)-NH-CO_R4, -NHCSOR4 or -NHCOSR4; In one embodiment, R1 Represents a NHCONR4R5, -NHC00R4, -NH-CO-(CH2)n-NR4R5, -NH-CO-(CH2)n-COOR4, -NHS02R4, or -NHCSNR4R5. In one embodiment, R1 represents A NHCONR4R5, _NHC00R4, 20 NHS02NR4R5, -NH_(CH2)n-CONR4R5, -NH, CH2-aryl, -NH-CO-(CH2)n-NR4R5, -NH-CO-(CH2)n-COOR4, - NHS02R4, or -NHCSNR4R5 In one embodiment, R1 represents -NHCONR4R5. In still another embodiment, R 4 represents halogen or Cu alkyl (eg, fluorenyl), and R 5 represents hydrogen, Cu 39 200836725 alkyl (eg, 'fluorenyl, ethyl or butyl), _(CH 2 ) n —NR x Ry ( For example, mono(CH2)2NH2 or mono(CH2)3NH2), -(CH2)n-aryl (e.g., a phenyl group optionally substituted by a halogen atom such as a fluorine atom), or a halogen Cl-6 Alkyl (eg, -CH2-CF3). In one embodiment, R1 represents -NHCONR4R5. In still another embodiment 5, r4 represents hydrogen or a Ci-6 alkyl group (e.g., fluorenyl), and R5 represents an anthracene, Cu alkyl group (e.g., fluorenyl, ethyl, butyl, _CH(Me)2. -CH2CH(Me)2 or -C(Me)3), by one or more Ra groups (eg, a CH2-C(Me)2-CH2-NH2, -CH2-CH(Me)-OMe or- CH6_C(F)2_CH2NH2) substituted Ci-6 alkyl, Ci-6 alkenyl 10 (eg, -CH2-CH(OH)-CH2OH), -(CH2)n-NRxRy (eg, -(CH2) 2NHCOOt-Bu, —(CH2)2NH2 or mono(CH2)3NH2), _(CH2)n-aryl (eg, phenyl substituted by a halogen atom such as a fluorine atom), _(CH2 An n-heterocyclic group (e.g., -CH2_dioxaolanyl (optionally substituted with one or more Cw alkyl groups (e.g., fluorenyl), -CH2-tetrahydrofuran or -CH2-15 piperidinyl)), or a halogen Ci_6 An alkyl group (e.g., -(CH2)2-F, -CH2_CH-F2-CH(Me)-CF3 or -CH2-CF3). In one embodiment, when A represents a phenyl group and R1 represents a NHCONR4R5, R4 and R5 represent a non-phenyl group. In one embodiment, R1 represents -NHCOOR4. In yet another embodiment, 20 R4 represents Ci_6 alkyl (eg, fluorenyl) or halo CU6 alkyl. In still another embodiment, R4 represents a Cu alkyl group (e.g., fluorenyl) or a halogenated Cu alkyl group (e.g., -CH2-CF3). In still another embodiment, R4 represents a Cu alkyl group (e.g., fluorenyl). In one embodiment, R1 represents _NH_CO-(CH2)n-NR4R5. In an embodiment of 200836725, η represents 1, and "and R5 both represent hydrogen. In one embodiment, R1 represents _NH-C〇_(CH2)n_c〇〇R4. In yet another embodiment η represents 2, and R4 represents hydrogen. In one embodiment, R1 represents _NHS〇2R4. In yet another embodiment, 5 r4 represents C, -6 alkyl (eg, methyl) or - (CH2) n-NRxRy (eg, Nh2 or NMe2). In one embodiment, R1 represents -NHCSNR4R5. In yet another embodiment, one of R4 and R5 represents hydrogen and the other represents ci6 ray (eg, And ethyl). In one embodiment, R1 represents -NHCORR. In yet another embodiment, R4 represents Ck alkyl (eg, methyl, ethyl or propyl) or Cl-6 alkanol (eg, -CH20H). In yet another embodiment, R1 represents -NHCONR4R5 (eg, -NHCONHEt or -NHCONHCH2CF3), 15 or an NHCSNR4R5 (eg, an NHCSNHEt). In still another embodiment, R1 represents -NHCONR4R5 (eg, - NHCONHEt) Or a NHCONHCH2CF3). In still another embodiment, R1 represents -NHCONHCH2CF3. In one embodiment, R1 represents NHS02NR4R5. In yet another embodiment 20, R4 generation Wherein R5 represents a halogen Ci-6 alkyl group (eg, -CH2-CF3). In one embodiment, R1 represents -NH_(CH2)n_CONR4R5. In yet another embodiment, η represents 1, and R4 represents hydrogen, and R5 represents hydrogen or Cw alkyl (e.g., fluorenyl). When R2 or R6 represents a heterocyclic group, in one embodiment, the heterocyclic ring 200836725 is a non-carbazolyl group (e.g., selectively a group substituted by a carbazolyl group. In one embodiment, when R2 represents hydrogen, Χ5 represents CR6, wherein R6 represents a non-hydrogen group. 5 In one embodiment, when Χ5 represents CH or nitrogen R2 represents a non-hydrogen group. In one embodiment, when R2 represents a non-hydrogen group, Χ5 represents CH, nitrogen or c=o. In one embodiment, when x5 represents CR6, and wherein When R6 represents a group other than hydrogen 10, R2 represents hydrogen. In one embodiment, R2 represents an aryl or heteroaryl group optionally substituted with one or more Ra groups. In one embodiment, R2 Represents an aryl or heteroaryl group which is optionally substituted by one or more Rb groups. In one embodiment, R2 represents a phenyl group which is optionally substituted by an Rb group. In the embodiment, R2 represents an aryl group (e.g., phenyl) which is optionally substituted by one or more (e.g., 1, 2 or 3) 0 groups, the # group of which is selected from the group consisting of halogens (e.g., Fluorine), halo Cw alkoxy (eg, -OCF3), -ORx (eg, 20 methoxy or -OCH2OHCH2OH), Cu alkanol (eg, a CH2OH), -(CRxRy)s-COORz (eg, -COOH, -COOMe, -C(Me)2-COOH, -CH2-C00H or -C(Me)2-C00Me), one (CH2)S-CN (eg, -CH2CN), -(CH2)S- NRxRy (eg, -NMe2, -(CH2)2-NH2, -(CH2)2-NMe2 42 200836725 5 Ο 10 15 ί; 20 or -NH-CO-CH2-methoxy), or -0-(CH2 a group consisting of n-〇Rx (eg, 〇(CH2)2·ethoxy). In one embodiment 'R2 represents an aryl group (eg, phenyl) optionally substituted with one or more (eg, 1, 2, or 3) 0 groups, the Rb group of which is selected from: halogen (eg, , fluorine or chlorine), hydrazine (eg, D5), halogenated Cu alkyl (eg, -CF3), halogenated alkoxy (eg, 〇CF3), -〇Rx (eg, methoxy or one OCH2OHCH2OH) , Cu calcination (eg, i-Pr), Cu allyol (eg, -CH2OH), -(CRxRy)s-COORz (eg, -COOH, one COOMe, -C(Me)2-C00H, -CH2- C00H or -C(Me)2-COOMe), -(CH2)S-CN (eg, -CN or -CH2CN), one (CH2)s-NRxRy (eg, -NMe2, -(CH2)2-NH2 -(CH2)2-NMe2 or -NH-CO-CH-methoxy-), -0-(CH2)n-ORx (eg, -0-(CH2)2-ethoxy), -(CH2) s-C0NRxRy (eg, a C0NH2, a CONHMe, -CONHEt, a CONH-iPr, -CH2-C0NHMe, -CONH_(CH2)2-OMe or -CONH-(CH2)2-NH2), -S02-Rx ( For example, -S02Me), -(CH2)s-S02NRxRy (eg, -S02NH2), -(CH2)s-NRx-S02-Ry (eg, -NHS02Me or one CH2-NHS02Me), • (CH2)s-NH -S02-NRxRy (eg, one NH-S02-NMe2). In still another embodiment, R.sup.2 represents a halo (eg, fluoro), -Z-heterocyclic group (eg, -CH2_morpholinyl, _CH2 piperazinyl, -CH2-piperidine). An aryl group (eg, phenyl) substituted with -CH-R2-azetidyl), -(CRxRy)s-C00Rz (eg, -C00H or -C(Me)2-C00H), wherein The heterocyclic group may be optionally substituted with a Cu 43 200836725 alkyl (e.g., fluorenyl) group or a -(CRxRy)s-COORz (e.g., a COOH) group. In one embodiment, R2 represents an aryl group optionally substituted with a -Y-aryl (e.g., -Y-phenyl) group. 5 In one embodiment, Y represents -0-(CH2)s- (eg, -o-ch2.). In one embodiment, R 2 represents a mono-Z-heterocyclic group (eg, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z). An aryl group substituted with a triazolyl group, a -Z-piperidinyl group or a -Z-piperazinyl group, wherein the above heterocyclic group may be optionally one or more (eg, 1, 2 or 3) The Ra group is substituted by 10, wherein the Ra group is selected from: Cw alkyl (e.g., fluorenyl) or -(CRxRy)s-COORz (e.g., -C00H, -COOMe or -COOtBu). In one embodiment, R 2 represents a mono-Z-heterocyclic group (eg, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z). · Oral than sulphate, -Z-tetradecyl, -Z-branches, -Z-pyryl, -Z-diaza 15 heterocycloheptyl (-Z-diazepanyl) or -Z_tetrahydro The aryl group substituted by σ, wherein the above heterocyclic group is optionally substituted by one or more (e.g., 1, 2 or 3) Ra groups, wherein the Ra group is selected from the group consisting of: a group (eg, methyl or ethyl), =0, -C0Rx (eg, -COMe) or -(CRxRy)s-COORz (eg, -C00H, -COOMe or -COOtBu) groups. In yet another embodiment, R2 represents a selectively halogenated (e.g., fluoro), -Z-heterocyclic group (e.g., -CH2-morpholinyl, -CH2-piperazinyl, -CH2- An aryl group substituted with piperidinyl, -CH2-azetidinyl, -(CRxRy)s-C00Rz (eg, -C00H or -C(Me)2_C00H), the above heterocyclic group may be selected It is optionally substituted by a Cw alkyl group (e.g., 曱44 200836725 base), or -(CRxRy)s-COORz (e.g., -COOH). In still another embodiment, R2 represents a group optionally substituted by a halogen (e.g., fluoro) or an a-Z-heterocyclic group (e.g., a 0112-morpholinyl or -CH2-piperazinyl). The aryl group (e.g., phenyl) wherein the above heterocyclic group is optionally substituted with a 5 Ci-6 group (e.g., fluorenyl). In still another embodiment, R2 represents an aryl group (e.g., phenyl) that is optionally substituted with a halogen (e.g., fluorine) atom. In still another embodiment, R2 represents 4-gas-phenyl. In one embodiment, R2 represents a 5-membered heterocyclic group optionally substituted with one or more Ra groups. In one embodiment, R2 represents a 5-membered heteroaryl group optionally substituted with one or more Ra groups. In one embodiment, R2 represents a heterocyclic group optionally substituted with an Rb group. In one embodiment, R2 represents a heterocyclic group optionally substituted with a -Z-heterocyclyl or -(CH2)s-NRxRy group. In one embodiment, R.sup.2 represents a heterocyclyl hydrazide (eg, morpholinyl, piperazinyl, pyridinyl, optionally substituted with one or more (eg, 2 or 3) Rb groups. σ thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl, the Rb basis is selected from: =〇 (eg, 11 pyridinone), Ci_6 leukoxyl (eg, methyl), one (CH2)s-NRxRy (eg, -NH2), -0RX (eg, decyloxy), -C0Rx ( For example, -COMe) or a C"alkanol (e.g., -CH20H) group. In one embodiment, R.sup.2 represents a heterocyclic group (eg, morpholinyl, piperazinyl, pyridyl) optionally substituted with one or more (eg, br. 45 200836725 2 or 3) Rb groups. , thienyl, pyrazinyl, phenylthienyl, furan, imidazolyl, pyraz〇iyi, benzodioxolyl, pyrrolidinyl , azetidinyl, 5-pyrrolidine, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, triazolyl, Tetrazolyl, oxadiazolyl, isosazolyl, benzodioxolyl, tetrahydrotriazopyrazine or pyrimidinyl, Its Rb basis is selected from: :=〇 (eg, pyridone or 1〇5.oxo-4,5-dihydro-[1,3,4]oxadiazolyl), =S (eg, thio _4,5-Dihydro-[1,3,4]oxadiazole), halogen (such as fluorine), alkyl (eg, methyl, ethyl, propyl, i-Pr or t-Bu) , halogenated base (eg, a CH2-F, -CF3 or -ch2cf3), C3-8 ring burn (eg, cyclopropyl), —(CH2)s-NRxRy (eg, —NH 2 ), —ORx (eg, hydroxy, oxime 15 or-0-iP〇, —(CHOn-O-Cw alkyl ( For example, -CH2_0-Me), -CORx (eg, -COMe), Jane (CRxRy)s-COORz (eg, -COOH, a COOEt or -COOt-Bu), -S-Rx (eg, a S-Me ), -S02-Rx (eg, a S02-Et), -(CH2)s-NRxRy (eg, -NH2), 20 _(CH2)s-S02NRxRy (eg, -S02-NMe2) or Ck alkanol ( For example, a -C(OH)(Me)2 or a CH2〇H) group. In one embodiment, R2 represents a group optionally substituted by one or more (eg, 1, 2 or 3) Rb groups. Substituted heterocyclic group (eg, morpholinyl, piperazinyl, 1 σ sigma, σ syl, pyridazinyl, benzo sigma, sulphur, 46 200836725 imidazolyl, °pyrazolyl, benzodioxolyl, β-pyrrolidone, azetidinyl, saponin, oxazolyl, sputum Thiazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, ooxa Diazolyl), isoxazolyl, benzodioxolyl, tetrahydrotriazopyrazine or pyrimidinyl, the Rb group of which is selected from ·· =0 (eg , pyridone or 5-oxo-4,5-dihydro-[1,3,4]oxadiazolyl), =S ζ) (eg, thio-4,5-dihydro- [1,3,4]oxadiazole), halogen (such as fluorine), Cw 10 alkyl (eg, decyl, ethyl, propyl, i-Pr or t-Bu), halogen Ci_6 alkyl ( For example, -CH2-F or -CF3), C3-8 cycloalkyl (eg, cyclopropyl), -(CH2)s-NRxRy (eg, -NH2), -ORx (eg, hydroxy, methoxy or -Oi-Pr), -CORx (eg '-COMe), -(CRxRy)s-COORz (eg, -COOH, -COOEt or -COOt_Bu), 15 -S-Rx (eg 'one S-Me), ( Such as '-S〇2-Et), -(CH2)s-NRxRy (eg, -NH2), -(CH2)s-S02NRxRy (eg, a S02-NMe2) or Cu alkanol J (eg, -C( OH) (Me) 2 or -CH20H) group. In yet another embodiment, R2 represents an oxazole, a stilbene, a triazole, a tetrazole, and a tetrazole, which are optionally substituted with one or more Ra20 groups. More than pyrazole, thiadiazole, thiazole, imidazole or oxathiadiazole. In still another embodiment, R 2 represents an oxazole, an oxadiazole, a triazole, a tetra-47 200836725 azole (tetrazole), a ruthenium, which is optionally substituted with one or more Ra groups. Thiadiazole or oxathiadiazole In another embodiment, R2 represents a thiadiazole, thiazole, which is optionally substituted with one or more Ra groups. Or imidazole. In yet another embodiment, R2 represents a group optionally substituted by a Ck alkyl group (e.g., methyl or ethyl) or -S-Rx (e.g., -S-Me). Substituted 5-membered heterocyclic group (eg, oxazole, σ dioxin, triazole (eg, 1, 2, 3-triazole or 1, 2, 4) - triazole, tetrazole, thiadiazole or oxathiadiazole. In yet another embodiment, R2 represents a Ck alkyl group. (eg, methyl or ethyl) or -S-Rx (eg, -S-Me) substituted oxadiazole (eg, 1,3,4_σ dioxin), tetrazole (tetrazole) or quinone (thiadiazole, such as 1,3,4-嗟二峻 (l , 3,4-thiadiazole)). In yet another embodiment, R2 represents a group optionally substituted with one or more Ra groups (eg, one or two substituted Cw alkyl groups (eg, CH3, CH20H, (CH2)2OH or (CH2) 2NH2)) Pyrazole substituted. In yet another embodiment, R2 represents a pyrazole that is selectively substituted with one or more Ra groups (eg, one or two C i -4 alkyl groups (eg, fluorenyl groups). In yet another embodiment, R2 represents an oxazole, sulphur 2, substituted by one or two optionally substituted Cw alkyl groups (eg, 'CH3, CH20H) or =0 groups. Triazole, tetrazole, imidazole, thiadiazole or σσ 嗤 嗤 48 200836725 (oxathiadiazole) 又一 In another embodiment, R2 represents An oxazole, σ dioxin, triazole, tetrazole, substituted by one or two selectively substituted Cw alkyl groups (eg, CH3, CH2〇H), Further, in another embodiment, R2 represents an aryl group (e.g., benzene) which is optionally substituted by a halogen (e.g., fluorine). And R2 represents a 5-membered heterocyclic group optionally substituted by a Cu alkyl group (e.g., decyl or ethyl) or -S-Rx (e.g., -S-Me) (e.g., σ evil σ sits, tetrazole or thiadiazoie) In yet another embodiment, R2 represents a selectively-mono-Z-heterocyclic group (eg, -Z-aza) a heterocyclic group substituted with a cyclobutane group, a -Z-piperazinyl group, a -Z-morpholinyl group or a -Z-piperidinyl group (e.g., a ratio of 11 to a base or a feeding group). Wherein R2 represents a heterocyclic group which is optionally substituted by a mono-Z-heterocyclic group 15 (e.g., -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl) (e.g., In another embodiment, R 2 represents a selectively-mono-Z-heterocyclic group (eg, '-Z-l-decyl, -Z _ morphinyl, Z _ four-mouse) a heterocyclic group substituted with a ntbyl group or a -Z-succinyl group (e.g., a σ ratio of a decyl group). In still another embodiment, R2 represents a group optionally substituted by -(CH2)s-NRxRy ( For example, a -heterocyclic group (e.g., pyridyl) substituted with a group - in one embodiment, R2 represents a halogen (e.g., fluorine or chlorine). In one embodiment, R2 represents a selectively One or more Rb groups 49 200836725 (eg, -CH2〇H, -C(OH)(Me)2 or -CF3) substituted by a Ci-6 alkyl group (eg, A Or an ethyl group. In one embodiment, R 2 represents a C 3-8 cycloalkyl group (eg, cyclopropyl). In one embodiment, R 2 represents -CH=N-ORw (eg, a CH=N-OH 5 Or a CH=N-OMe). In one embodiment, R2 represents -NHS02Rw〇, -NHS02Me). In one embodiment, R2 represents a Cu alkoxy group (e.g., methoxy or ethoxy group). In one embodiment, 'R2' represents a C2-6 alkynyl group (e.g., acetylene or propyne) optionally substituted with an Rb group (e.g., 10Si(Me)4). In yet another embodiment, R2 represents a Cw alkynyl group (e.g., acetylene) optionally substituted with an Rb group (e.g., -OC-Si(Me)4). In yet another embodiment, R2 represents a C2-6 alkynyl group (e.g., B-fast) which is optionally substituted with an Rb group (e.g., cyclopropyl). In one embodiment, R2 represents -CsN. In one embodiment, R2 represents a C2-6 alkenyl group (e.g., -CH=CH-C00Et or a CH=CHCONHMe) optionally substituted with an Rb group. In one embodiment, R6 represents halogen, hydrogen, Cl-6 alkyl, Cw alkoxy, C2-6 alkenyl, c2-6 alkynyl, -hN, C3-8 cycloalkyl, C3.8 ring 20, - NHS〇2RW, _CH=N-ORw, or a 3-6 membered monocyclic heterocyclic group, wherein the Ci-6 group, Cw alkenyl group, C2_6 alkynyl group and heterocyclic group are optionally substituted by one or more Ra Replaced by the group. In one embodiment, R2 and R6 are optionally substituted with an Rb group. In a further embodiment, Rb comprises a Ra group or a _γ-aryl group or a _z_ 50 200836725 heterocyclic group. In one embodiment, the Y and Z systems each independently represent -CO-, -0-(CH2)s- or ·NH-(CH2)n-. In one embodiment, the Y and z series each independently represent a bond, 5 C0, -CH -, -(CH2)2, -(CH2)3 or -〇-. In one embodiment, Z represents a bond, CO, (e.g., '-CH'-, -(CH2)2, or -(CH2)3) or -〇_. In yet another embodiment, z represents -(CH2)n- (eg, -CH2-). Ο 10 15

In one embodiment, Z represents a bond, CO, -(CH2)n- (eg, '-CH2-, -(CH2)2 or -(CH2)3), -NH-(CH2)n- (eg , -NH-) or a 0_. In yet another embodiment, Z represents a (CH2)n- (eg, a CH2-). In one embodiment, Z represents a bond, CO, -(CH2)n- (eg, -CH2-, one (ch2)2 or -(CH2)3) or -0-. In one embodiment, Z represents a bond or -CH2-. In one embodiment, Rb represents a Ra group or a -γ-aryl or -Ζ-heterocyclic group, wherein the aryl group and the heterocyclic group are optionally one or more (eg, 1 , 2 or 3) substituted by the Ra group. In one embodiment, the compound of formula (I) is as shown in formula (la) or (lb):

51 20 200836725 (la) (lb) wherein 5 A represents an aromatic carbocyclic or heterocyclic hydrazone which may be optionally substituted by one or more (eg 1, 2 or 3) Ra groups; r1 Representative -NHCONR4R5, -NHC00R4, -NH-CO-(CH2)n-NR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -NHS02R4, -NHS02NR4R5,- NHCOR4; Ο 10 R4 and R5 each independently represent hydrogen, Ci6 alkyl, C26 alkenyl, C2-6 alkynyl, c3-8 cycloalkyl, c3-8 cycloalkenyl, Ci-6 alkanol, _Cm alkyl, -( CH2)n_NRxRy, -(CH2)s-C00Rz, 15

-(CH2)n-0-(CH2)m-0H, -(CH2)n-aryl, _(CH2)n_〇_aryl, -(CHI heterocyclic or -(CH2)n_〇_ a heterocyclic group wherein the cardinyl group, the alkenyl group, the CM alkynyl group, the CM cycloalkyl group, the CM cycloalkenyl group, the aryl group and the heterocyclic group 6 are optionally one or more (eg, 丨, 2) Or 3) substituted by Ra group; rx, y and rz each independently represent hydrogen, Ci 6 alkyl, c "dilute, c2-6, Cl.6, alcoholic, secret, Ci 6 Oxygen, tooth CN6 alkyl, -CO-(CH2)n-Cl-6 alkoxy, C3 8 ring or &cycloalkenyl; 20 R2 each independently represents hydrogen, -aryl or heterocycle a group, the aryl group and the heterocyclic group in 1 may be optionally pure or substituted with a plurality of groups; Ra represents halogen, Cl.6 alkyl, cycloalkyl, ~cycloalkenyl, ·0RX, gamma A•6 炫, -o-(ch2v〇rh6, _ Ci oxy, c" ethoxyl group, 52 25 200836725 =0, =S, nitro, -(CH2)s-CN, _S-RX , -SO_Rx, -S02_Rx, -CORx, -(CRxRy)s-COORz, -(CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, -(CH2)s-NRxS02- Ry, -OCONRxRy, -(CH2)s-NRxC02Ry, 5 -0-(CH2)s-CRxRy-(CH2)r0Rz Or -(CH2)s-S02NRxRy group;

Rb represents a Ra group or an a-Y-aryl or -Z-heterocyclyl group, wherein the aryl group and the heterocyclyl group are optionally one or more (eg, 1, 2 or 3) The Ra group is substituted; the Y and Z series each independently represent a bond, -C0_(CH2)s_, 10 -COO-, -(CH2)n- > _NRx-(CH2)n-, -( CH2)n-NRx-, -C0NRx-, -NRxCO-, -S02NRx-, -NRxS02-, -NRxC0NRy-, -NRxCSNRy- -0-(CH2)s·, _(CH2)s-0-, S- , -SO- or -(CH2)s-S02-; m and n are each independently representing an integer from 1 to 4; 15 s and t are each independently representing an integer from one to four; and aryl represents one A carbocyclic ring; a heterocyclic group represents a heterocyclic ring; or a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof. Preferably, examples of the A, R1 and 20 R2 groups in the above chemical formulas (la) and (lb) are those indicated in the above chemical formula (1). In one embodiment, the compound of the formula (I) is a compound as defined in the above formula (la). In one embodiment, the compound represented by the formula (1) is a sub-formula of the formula (la) and is a compound defined by the formula (Ic) 53 200836725 substance: R4

10 (Ic) wherein Ra, R2, R4 and V are as defined above, and the integers of Tables 0 to 3. W is defined. In the examples, the compound represented by the chemical formula (1) is a sub-form: (--f_handy and is defined by the chemical formula (10):

A series of special preferred examples of the variables Ra, R2 and R5 are given here. 54 200836725 In particular, one of J or L is carbon and the other is nitrogen. In one embodiment, both J and L are carbon. In particular, R5 is an alkyl group which is optionally substituted by a Ra group. In particular, R5 - an ethyl group which is optionally substituted. Preferably, R5 is a tri-I-ethyl group. Specifically, R2 is a selectively substituted phenyl group or a 5-6 membered monocyclic heterocyclic ring. A special preferred example of R2 is given here. C. In one embodiment, the compound represented by the formula (1) is a sub-formula of the formula (la) and is a compound defined by the formula (Ie):

In one embodiment, R2 is a phenyl-15 group optionally substituted with Rb. In another embodiment, R2 is a phenyl group which is optionally substituted by Ra. In one embodiment, the Ra or Rb group is located at the 3- or 4-position of the phenyl ring. In one embodiment, when the benzene ring is substituted by Ra, the Ra group is at the 4-position in the benzene ring. In one embodiment, when the phenyl ring is substituted by Rbm and the Rb group is a -Y-carbocyclic (eg, Y-aryl) group or a -Z-heterocyclyl 55 200836725 group, the Rb group The group is located in the third position in the benzene ring.

In one embodiment, the Rb group is selected from the group consisting of halogen (eg, fluorine or gas), hydrazine (eg, D5), halogen Cw alkyl (eg, -CF3), halogen CV6 alkoxy (eg, one) OCF3), -ORx (eg, decyloxy or mono-OCH2OHCH2OH), C1.6 5 alkyl (eg, i_Pr), Cu alkanol (eg, CH2OH), -(CRxRy)s-COORz (eg, -COOH , -COOMe, -C(Me)2-COOH, -CH2-COOH or -C(Me)2-COOMe), one (CH2)S-CN (eg, a CN or -CH2CN), -(CH2)s -NRxRy (eg, one NMe2, one (CH2)2-NH2, -(CH2)2-NMe2 or one NH-C0-CH2-decyloxy), 10-0-(CH2)n-0Rx (eg, - 0_(CH2)2-ethoxy), -(CH2)s-CONRxRy (eg, -CONH2, a CONHMe, -CONHEt, a CONH_iPr, -CH2-CONHMe, -CONH-(CH2)2-OMe or a CONH -(CH2)2-NH2), -S02-Rx (eg, -S02Me), 15

(CH2)s-S02NRxRy (eg, -S02NH2), -(CH2)s-NRx-S02-Ry (eg, -NHS02Me or one CH2-NHS02Me), -(CH2)s-NH-S02-NRxRy (eg, One NH-S02-NMe2). In one embodiment, the Rb group is selected from the group consisting of: halogen (eg, fluorine), halogen

Ci_6 alkoxy (e.g., -0CF3), -0RX (e.g., methoxy or mono-OCH2OHCH2OH), Cu ani alcohol (e.g., a CH20H), 20-(CH2)2-NH2, -(CRxRy)s-C00Rz (eg, -C(Me)2-C00H -C(Me)2-C00Me) (eg -CH2CN) (eg, a NMe, -C00H, a COOMe, -CH2-C00H or -(CH2)s-CN - (CH2)s-NRxRy-(CH2)2-NMe2 56 200836725 or an NH-CO-CH2-methoxy) or -0-(CH2)n-0Rx (eg, a 0-(CH2)2-B Oxy). In one embodiment, the Rb group is selected from the group consisting of: halogen (eg, fluoro), -Y-aryl (such as a '-Y-phenyl) group or a heterocyclic group (eg, -Z) - morphinyl, 5-Z-azetidinyl, - verbose- fluorenyl, _Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl, wherein The heterocyclyl group may be optionally substituted by one or more (e.g., 1, 2 or 3) Ra groups, and the Ra group thereof is selected from: a Cu alkyl group (e.g., a fluorenyl group) or - (CRxRy)s-C00Rz (eg, -C00H, -COOMe or -COOtBu) groups, and wherein Z is 10 C0, CH2 or a bond. In one embodiment, the Rb group is selected from: -Z a heterocyclic group (e.g., -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-0, -Z-pyrazolyl, -Z- a tetrazole (tetrazolyl), a -Z-pyrozine group, a hydrazine-piperazinyl group, a hydrazine-diazacycloheptyl group, or a hydrazine-tetrahydropyranyl group, wherein the heterocyclic ring is 15 The group may be optionally substituted by one or more (eg, 1, 2 or 3) Ra groups, and the Ra group thereof is selected from: an alkyl group (eg, methyl or ethyl), = , -C0Rx (eg, -COMe) or -(CRxRy)s-C0 a group of 0Rz (e.g., -C00H, -COOMe or -COOtBu), and wherein Z is CH2 or a bond. In still another embodiment, R2 represents a group optionally substituted by a halogen (e.g., fluorine). a substituted aryl (e.g., phenyl) group. In still another embodiment, R2 represents a 4-fluoro-phenyl group. In one embodiment, the compound of formula (1) is a child of formula (la) Formula (sub_formula), and is a compound defined by the chemical formula (If) 57 200836725

J and L· are each independently selected from: carbon or nitrogen; 5 Ω is carbon or nitrogen; P, R, S, T may be carbon, nitrogen, oxygen or sulfur, but the ring contains no more than one hetero atom 4; R12 is selected from hydrogen, halogen, amine, hydroxyl, d_4 alkyl (such as: methyl, ethyl, n-propyl, isopropyl and t-butyl), via a hydroxyl group, C13 10 a Cu-based group substituted by a group or a group (eg, a fluorenyl group, a tri-methyl group, a monofluoroethyl group, a trifluoroethyl group, a decyloxy group), a Cu alkylsulfonyl group (eg, a methyl group) Sulfhydryl), C2_4 cycloalkyl (eg, cyclopropyl) and Cl_3 alkoxy (eg, methoxy); and r is 0, 1, 2 or 3. 15 In particular, one of J or L is carbon and the other is nitrogen. In one embodiment, J and L are carbon. In particular, R5 is an alkyl group which is optionally substituted with an Ra group. In particular, R5 is an ethyl group which is optionally substituted. Preferably, R5 is a trifluoroethyl group. In one embodiment, Q is nitrogen and P, R, S, and T are all carbon. 58 200836725 s and bismuth form an aromatic ring. The carbon V:: ^ρ. It is:: replaced by any substance other than hydrogen 5 Preferably, helium, oxygen or sulfur. Both S and T are nitrogen and the rest are carbon, preferably r is 0 or 1. Ο 10 In one embodiment m is selected from the group consisting of hydrogen, amine, s〇2NMe2, c-dialkyl (eg, decyl, ethyl, n-propyl, isopropyl), hydroxy, decyloxy a Cm alkyl group substituted with a phenyl group (eg, hydroxymethyl, trifluoromethyl, monofluoroethyl, trifluoroethyl, decyloxymethyl), and cle3 alkoxy (eg, methoxy) ). Preferably, R12 is selected from the group consisting of: hydrogen, or a Cl3 alkyl group (e.g., f group, ethyl group, n-propyl group, or isopropyl group). Preferably, R12 is a methyl group. In one embodiment, the compound represented by the chemical formula (1) is a sub-formula (sllb-formula) of the formula (la) and is a compound defined by the chemical formula (ig): Η

R 12s 59 200836725 wherein Ra, q, R5, P, Q, R, S and T are as defined above, and R12r, R12p, R12s and R12t may be R12 as recited above. In one embodiment, Q is nitrogen. In another embodiment, Q is nitrogen 5 and one or both of P, R, S, T are also nitrogen. In one embodiment, R121* and R12p are each independently selected from the group consisting of: a gas, an amine group, a methyl group, a trifluoromethyl group, and a methoxy group. In one embodiment, when R12r or R12pi is a non-hydrogen group, the other is hydrogen. In one embodiment, P-R12p is C-H. In one embodiment, the compound of formula (I) is selected from the group consisting of: Examples 2-17, 19, 24, 26-62, 64-67, 75, 77-97, 100.109, 111-115, Compounds shown in 117, 119-13, 133-156, 158-166, 168-234, and 236-418. In one embodiment, the compound of formula (1) is selected from the group consisting of: Examples 2-17, 19, 24, 26-62, 64-67, 75, 77-97, 100-109, 111-115, 117 , 119-13, 133_156, 158_166, 168-234, and 236-400. In one embodiment, the compound of formula (I) is selected from the group consisting of: 20 Examples 2-17, 19, 24, 26-62, 64-67, 75, 77-97, 100-109, 111-115 Compounds shown in 117, 119-131, 133-156, 158-166, 168-234, and 236-381. In one embodiment, the compound of formula (I) is selected from the group consisting of: Examples 2-17, 19, 24, 26-62, 64-67, 75, 77-97, 60 200836725 100-109, 111- Compounds shown in 115, 117 and 119-126. In one embodiment, the compound of formula (I) is a non-fluorene-{4-[7-(4.fluoro-phenyl)-imidazo[l,2-a]acridin-3-yl. ]-phenyl}acetamidamine (N-{4-[7-(4-fluoro-phenyl)-imidazo[l ,2-a]pyridin-3-yl]-5 phenyl }- acetamide, E75) and { 2-[7-(4-Fluoro-phenyl)-miso-[1,2-a]acridin-3-yl]-phenyl}carbamic acid 2,2,2-trifluoro-ethyl ester ({3-[7-(4-fluoro- phenyl)-imidazo[l,2-a]pyridin-3-yl]·phenyl }-carbamic acid 2,2,2-trifluoro-ethyl ester, E192) . In one embodiment, the compound of formula (I) is any one or more of the compounds shown in non-examples 401-418. In still another embodiment, the compound of formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[l,2-a]npyridin-3-yl]- Phenyl}-3-(2,2,2_trifluoro-ethyl)-urea 15 (1- {3-[7-(4-fluoro-phenyl)-imidazo[l 52-a]pyridin-3-yl ]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, Example 59) or a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof (eg, 1-{ 3-[7-(4-fluoro-phenyl)-imidazo[l,2-a]acridin-3-yl]-phenyl-p-3-(2,2,2-trifluoro-ethyl)- Urea Hydrochloride. 20 In a second aspect of the invention, a compound of the formula (II) is used to produce a medicament for treating a fibroblast growth factor receptor (FGFR) enzyme-related disease: 200836725

(Π) wherein Xi-X5 and hydrazine are as defined in the compound represented by the chemical formula (1): 5 u represents an integer of 0 to 2;

Rla represents -NHCONR4R5, -NHCOOR4, -NH-CO-(CH2)n-NR4R5, -NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2) n-CSOR4, -NHS02R4, -NHS02SR4, 10 -NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -NHCSSR4, -NR4R5, -C(=NR4)NR5, halogen, Ci, 6 alkyl, aryl, -CO- Aryl, heterocyclyl, -CO-heterocyclyl, -CONR4R5, -(CH2)n-NR4COR5^-(CH2)S-CN, -OR4 or a COOR4 wherein the aryl group and the heterocyclyl group are optional Substituted by one or more than 15 (eg, 1, 2 or 3) Ra groups, and the 1 group is as defined in the compound of formula (I); R4 and R5 are as in the formula ( I) is defined in the compound shown, and must have a condition that when one of R4 and R5 represents hydrogen, the other represents a non-aryl or -heterocyclic group; 20 R2 is It is as defined in the compound represented by the formula (I). 62 200836725 In one embodiment, a compound of the formula (II) is provided and used in the manufacture of a medicament for treating a fibroblast growth factor receptor (FGFR) enzyme-related disease:

(II) wherein the definitions of Xi-Xs and A are as expressed in the compound represented by the chemical formula (1): u represents an integer of 0 to 2; 10 Rla represents - NHCONR4R5, -NHCOOR4, -NH-CO-(CH2) n-NR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -NHS02R4, -NHSC^SR4, -NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -NHCSSR4 , _NR4R5, _C(=NR4)NR5, (: 6 alkyl, aryl15, -CO-airyl, heterocyclic, -CO-heterocyclyl, -CONR4R5, -(CH2)n-NR4COR5, one ( CH2)S-CN, -OR4 or a COOR4, wherein the aryl group and the heterocyclyl group are optionally substituted by one or more (eg, 1, 2 or 3) Ra groups, and the Ra The group is as defined in the compound of the formula (1); 2〇R4 and R5 are as defined in the compound of the formula (I); 63 200836725 R2 is as defined in the compound of the formula (I), but Without being limited by the privoso. In one embodiment, Rla represents a heterocyclic group, and the heterocyclic group is optionally selected from one or more Ra groups: =S; -COOR4; -C0- 5 heterocyclic - (CH2)S-CN; -(CH2)n-NR4COR5, -CONR4R5 or -NR4R5 substituted. In one embodiment, Rla represents a heterocyclic group (eg, pyridyl, pyrazolyl) , indazolyl, indolyl or triazolyl, and the heterocyclic group may be optionally substituted by one or more Ra 10 groups, and The Ra group is selected from the group consisting of: halogen (e.g., chlorine) or =S (e.g., triazole thione). In the consistent application, 'Rla represents a heterocyclic group (e.g., ο than σ sitting group ( Pyrazolyl) or triazolyl, and the heterocyclic group may be optionally substituted by one or more Ra groups selected from: =S (eg, 15 dihydrogen three-degree sitting In one embodiment, Rla represents -C00R4 (eg, -COOMe). In one embodiment, Rla represents a -CO-heterocyclyl (eg, -CO-morpholine is based on an embodiment) Rla represents -(CH2)s-CN 20 (e.g., -CH2-CN). In one embodiment, Rla represents -(CH2)n-NR4COR5 (e.g., -CH2-NHC0Me). In one embodiment, Rla represents -NR4R5. In yet another embodiment, R4 and R5 each represent hydrogen, or one of R4 and R5 represents hydrogen and 64. The other represents Ck alkyl (e.g., ethyl). A conr4r5 In one embodiment, Rla, represents (e.g., -CONHMe). In one embodiment, U represents 〇 or J. In one embodiment, A represents an aromatic carbocyclic group, and the aromatic carbocyclic group is optionally substituted by _ or more, and the Ra group is selected from a C 6 alkyl group ( For example, methyl is widely used in an embodiment, and A represents a sulfonyl heterocyclic group (eg, (for example, a benzene Ra group, a σ ratio of a 10 15 group, a pyrazolyl group, a fluorenyl group) Ind〇lyl) or indazolyl, and the aromatic heterocyclic group thereof may be optionally substituted by one or more Ra groups, and the Ra group thereof is selected from halogen (eg, chlorine) In one embodiment, when A represents an unsubstituted phenyl group, an unsubstituted thienyl group or a phenyl group substituted with a -OH, -〇Me or -NH2 group, 'R2 represents a selectivity. a substituted aryl or heterocyclyl group. In one embodiment, when A represents unsubstituted phenyl, unsubstituted thiazolyl, phenyl substituted via a CN group, When unsubstituted pyridinyl or unsubstituted porphinyl, R2 represents a non-4-methoxyphenyl group or a (CH2)s-NRxRy, -Y-aryl or -Z- Substituted ring Or a heterocyclic group. Preferably, the specific example shown by the above formula (II) is the one referred to in the above formula (I). In one embodiment, as in the formula (II) The compound shown is a compound selected from the group consisting of: Examples 1, 18, 20-23, 25, 63, 68-74, 76, 98-99, 110, 116, 118, 132, 157, 167 and 235. 65 200836725 In one embodiment, the compound of formula (II) is a compound selected from the group consisting of: Examples 1, 18, 20-23, 25, 63, 68-74, 76, 98-99, 110, 116, and 118. In one embodiment, the fibroblast growth factor receptor (FGFR) enzyme 5 associated disease is a non-tumor related disease (eg, any disease other than cancer discussed herein). In one embodiment The fibroblast growth factor receptor (FGFR) enzyme-related disease herein refers to a state of a disease. In one embodiment, the fibroblast growth factor receptor (FGFR) enzyme-related disease is in this system. Refers to a state of bone health. Special features of human bone growth include Cranial suture abnormal osteogenesis (craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer's syndrome, achondroplasia, and thanatophoric dwarfism (also known as the tomatophytic dysplasia) 〇 In particular, except for special instructions, the relevant examples of formula (I) include Sub-formula, such as (la), (lb), (Ic), (Id), (Ie), (If), (Ig), and chemical formula (II), and chemical formula (I), (la Subgroups, examples or examples of (lb), (Ic), 20 (Id), (Ie), (If), and (Ig). Thus, for example, examples of therapeutic use, pharmaceutical formulations associated with formula (I), and compound preparation steps, also represent chemical formulas (I), (la), (lb), (Ic), (Id) , (le), (If), (ig), (π), and chemical formula 66 200836725 (I), (la), (lb), (Ic), (Id), (Ie), (If), Subgroups, examples or examples of Ig), and (II). Similarly, preferred embodiments, examples or examples of the compounds of the formula (I) can be applied to the chemical formulas (I), 5 (la), (lb), (Ic), unless otherwise specified. (Id), (Ie), (If), (Ig), (II), and Chemical Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (II) of the sub-base, examples or examples. Preparation of a compound as shown in the formula (1) In this unit, as in other units, unless otherwise indicated, each reference in the formula (I) has the same meaning as in the formula (II), and other subgroups And the representative meaning of the examples is as follows. The compound of the formula (I) can be prepared by a conventional technique known to those skilled in the art. In particular, the compound of formula (I) may be 15 via an aromatic chloride, bromide, iodide or pseudo-halogen, such as trifluoromethanesulphonate » triflate or Tosylate, which is prepared by coupling with an aromatic acid or a stannane derivative under the catalysis of Yuji. In particular, the Suzuki coupling reaction 20 series is widely used to synthesize such compounds. The Suzuki coupling reaction can be carried out under normal conditions in a palladium catalyst (such as bis(tri-b-butylphosphine)palladium) or tetrakis(triphenyl-). Phosphine)-palladiimi)) or a test! Palladacycle catalyst (eg, in Bedford, RB and Cazin, C. S. 25 J. (2001) C/zem. Commwn, 1540-1541, as described in the article! Ba Catalyst 67 200836725), and It is prepared in the presence of a base (e.g., a carbonate similar to potassium carbonate), and the details will be described below. The reaction can be carried out in a polar solvent such as an aqueous solution (including: ethanol water), or an ether (eg, ethylene glycol dimethyl ether or dioxane), and the reaction mixture is generally heated, such as Add 5 heat to a temperature of 80 ° C or higher (eg, more than 10 〇. As shown in Reaction Scheme 1, the sputum is called imidazo[l,2-a]pyridinecore) Commercially available starting materials are synthesized using Formula A (to give 3,7 disubstituted rings) or Formula C (to give 3,6 disubstituted rings). 10 4-Chloro _. Ratio π -2- 4-chloro-pyridin-2-ylamine or 4-bromo-pyridin-2-ylamine is dissolved in a suitable solvent with chloroacetaldehyde. The imidazole acridine ring is obtained by refluxing with the same. The 7-chloro-imidazo[l,2-a]pyridine which is dissolved in a suitable solvent can be subsequently iodine. For example, N-iodosuccinimide is used for moth formation at room temperature. For example, 'using a metal-catalyzed reaction allows appropriate functional groups to be added to the halogen. In particular, a suitably functionalized 20 boric acid or a boronic ester thereof can be reacted with an iaryl group. Such a conversion reaction is generally referred to as a "Suzuki reaction" and can be referred to as Rossi ei α/ (2004) Introduction of Synthesis, 15, 2419. 68 200836725 The Suzuki reaction is usually carried out in a mixed solution of water and an organic solvent. Suitable suitable organic solvents include: toluene, tetrahydrofuran, 1,4 - 1,4-dioxane, 1,2-dimethoxy ethane, acetonitrile, N-fluorenyl 5-pyrrolidone, ethanol, decyl alcohol and dimethyl decylamine. The reaction mixture is then heated. To, for example, a temperature exceeding 100 ° C. The reaction is carried out under an alkaline environment. Suitable bases include: sodium carbonate, potassium carbonate, carbonic acid planing, and potassium phosphate. Examples of suitable catalysts include ··two (three-t -butylphosphine)palladium(0), tris(dibenzylideneacetone) 10 dipalladium(0) 'bistriphenylphosphine di-palladium palladium, palladium(II) acetate, tetrakis(triphenylphosphine)palladium ( 0), bis(tricyclohexylphosphine)palladium(0), 1,1'-bis(diphenylphosphine) II Ferrocene palladium(II) chloride, dichlorobis(trimethoxyphosphorus) palladium(II), 2'-(dimethylamine)-2-biphenylphosphonium palladium(II) bis-bicycloheptene A phosphine complex and a 2-(didecylamine)ferrocene-1-yl-chloro-15-palladium(II) bis-bicycloheptene phosphine complex. In some cases, some additional ligands may be added to make the reaction easier. Examples of suitable ligands include: tri-tert-butyl, 2,2-bis(diphenylphosphino)-1,1-binaphthalene, triphenylphosphine, 1,2-bis(diphenylphosphine) Ethane, 1, bismuth(bisphenylphosphino)ferrocene, tricyclohexylphosphine, 20 9,9-dimercapto-4,5-bis(diphenylphosphino)oxaxene, 1,3 - bis(diphenylphosphino)propane, 2-(di-t-butylphosphine)diphenyl, 2-dicyclohexylphosphino-2'-(η,n-dimethylamine)diphenyl, three O-tolylphosphine, 2·(dicyclohexylphosphine)biphenyl, 2-dicyclohexylphosphine-2',4',6^triisopropylbiphenyl, tris(2-furyl)phosphine, 2-di Cyclohexylphosphine-2',6'-dioxime 69 200836725 Oxybiphenyl and 2 -di-tert-butylphosphine-2 ',4,6 '-triisopropylbiphenyl.

General Route A

General Route C

Other examples of functionalization of i-proteins by metal catalysis include: reaction with an organotin reagent (Stille reaction), reaction with a Grignard reagent, and reaction with a nitrogen affinity agent. An overview of these conversion reactions and further development information is documented in 'Palladium Reagents and Catalysts' 10 [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 15 Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0]. In particular, one can be used to convert the arylamine via palladium catalysis. The reaction should be a Buchwald-Hartwig reaction (see Hartwig, J. F. (1998) jngew. CAem. 37, 2046-2067). Starting with an aryl halide or a pseudohalide (eg, triflate), the reaction is based on a strong test, such as sodium kri-butoxide and catalyst 5 (eg · Tris-(dibenzylideneacetone)-di-palladium, Pd2(dba)3) or 2,2'-bisdiphenylphosphine-1,1'-binaphthyl (2, The reaction is carried out in the presence of 2'-bis(diphenylphosphino)-l'l-binaphthyl, BINAP. 10 In particular, as the compound of formula (II), the aryl halide can be used by using a metal catalyst (eg, double Triphenylphosphine palladium dichloride), reacted with 3-aminobenzeneboronic acid to form a urea, amide, and secondary amine prior to bond formation. The amino precursor 〇15 The reaction sequence in the reaction formula A can be substituted in the order of the reaction formula B. As shown in the reaction scheme 2, it is located at the ratio of the saliva [l, 2-a] ° (imidazo[ The halogen group at the 7th position of l,2_a]pyridine) may be replaced with a rotten acid group or an ester group for other purposes. Used in any metal catalyzed reaction. For example, when iS is to be converted to a monocarboxylic acid 20 group, its halogen is coordinated with a palladium catalyst and a phosphine based on a suitable alkali-containing (eg, KOAc) solvent (eg, 2°). In the dioxane, the reaction is suitably replaced by a side compound. 71 200836725 General Formula E Ar

Ar Ar

Once the synthesis reaction is carried out, a series of functional group conversion methods can be applied to the imidazopyridine compound substituted with a bisaryl group to further obtain a compound represented by the formula (I) and, in particular, as shown in the chemical formula (II) Compound. The conversion method of the functional group is, for example, hydrogenation (e.g., using Raney nickel catalyst), hydrolysis, deprotection, and oxidation. 10

In particular, as shown in Reaction Scheme 3, the introduction of its amine functional group can be used for sulfonyl urea, sulphonamide, urea, amide, secondary amine. Amine), and the synthesis of carbamate.

Scheme 3 15 amide linkage can be prepared by the use of formic acid or its reactive derivative 72 200836725 with an amine under standard amide formation conditions. The coupling reaction between the carboxylic acid and the amine can be carried out in an environment having a reagent for generally forming a peptide linkage. Examples of such reagents include: dicyclohexylcarbodiimide (DCC, reference to Sheehan (2/(1955)丄4^^,.〇/^5^(:.77,1067) ), 1-ethyl-3-(3'-diaminopropyl) carbodiimide (1 _ethyl_3_(3 '_dimethylaminopropyl)_carbodiimide, EDC, 10 can be referred to Sheehan as β/ (1961) /· Org· C /zem·, 26, 2525), an uronium-based coupling agent such as 7- 0-(7-azobenzotriazol-1-yl)·tetramethylurea hexafluorophosphate ( (9-(7-azabenzotriazol-l-yU-WiV^iV'-tetramethyluronium hexafluorophosphate, HATU, see Carpino, LA (1993) 丄 15 Amer·C/zem· Soc·, 115, 4397), and scalar coupling a phosphonium-based coupling agent, such as 1-benzo-triazolyloxytris (pyrrolidino) phosphonium hexafluorophosphate, PyBOP, see Castro et al (1990) 20 Tfeira Aedron 31, 205). Carbodiimide-based coupling agent can be more compatible with 1-nitrogen Benzotriazole spit (1-1^(11>01;^2&seven 6112〇1:1^2〇16,110 people 1:) or 1-mer base stupid and trinitrogen (1-]^( 11:0\}^^112(^1^2〇16,11061:)—same (combined) use (refer to Konig ei a/, C/zem. 5er·, 103, 708, 2024-2034). A preferred coupler reagent comprises EDC and DCC in combination with HOAt or HOBt. 73 200836725 In general, the coupling reaction is carried out in a non-aqueous, aprotic solvent (eg acetonitrile, dioxane, Dimethyl sulfonium (dimethylsulphoxide), dichloromethane, dimethyl decylamine, or N-methyl 比 (N-methylpyrrolidone), 5 or a selectively It is carried out in an aqueous solvent with the addition of one or more miscible cosolvents. The reaction can be carried out at room temperature or when the reactivity of the reactants is poor (e.g., an aniline having an electron withdrawing group similar to the electron deficiency of sulphon amide). The reaction can also be carried out in a non-interfering manner (% in a base, for example, in a tertiary amine such as triethylamine or W-diisopropylethylamine). Further, a reaction of a monocarboxylic acid can be used. a derivative (eg, an anhydride or an acid chloride). The reaction with a reactive derivative (eg, an anhydride) is generally carried out by passing an amine and an anhydride at room temperature at a base (eg, Stirring is carried out in the environment of pyridine. 15 Amine can be obtained by reducing a nitrogen compound under standard conditions. For example, the reaction is carried out at room temperature in a polar solvent (eg, ethanol or hydrazine). In the presence of a base amine and a catalyst (eg, palladium on carbon), it may be affected by catalytic hydrolysis. Urea is also prepared using standard methods. For example, these compounds can be passed through 2〇. The reaction is carried out by reacting an amine compound with an appropriately substituted isocyanate in a polar solvent such as DMF. The reaction is carried out at room temperature. Further, urea as shown in the chemical formula (1) Via carbonyl diimidazole (carb In onyl diimidazole (CDI), an amine is prepared by reacting an appropriately substituted amine. The reaction is generally carried out in a polar solution 200836725 (eg, THF) and heated (eg, using a microwave). Heater) to about 15 ° C. In a solvent (eg, dichloromethane), at room temperature or lower, the coupling reaction of two amines forming urea, non-interference In the presence of a test (such as triethylamine), the use of triphosgene (bis(trichloromethyl) carbonate) can be more effective than CDI. The substance of CDI is phosgene, not triphosgene. The compound containing carbamate as shown in formula (I) can be obtained by a person with ordinary knowledge by using standard synthetic amine formate. The method, for example, is: reacting a monoamine compound with a chloroformate derivative of the formula R^OC^CO-Cl, and reacting it in a conventional state. As shown in the chemical formula (I) Compounds containing sulfonamide can be used A method of quasi-synthesizing a sulphonamide. For example, an amine-based compound may be the same as a sulphonyl chloride group or a chemical formula (R^SO^O in the chemical formula RhC^Cl). The reaction is generally carried out in a non-interfering test (eg, a tertiary amine (eg 'triethylamine, or diisopropylamine, or acridine)) in an aprotic solvent (eg Further, q is carried out in acetonitrile or a monochlorinated hydrocarbon (e.g., dioxane). Further, when the base (e.g., pyridine) is a liquid, the base itself can be used as a solvent for the reaction. In a suitable aprotic solvent (eg, THF), the sulfonium urea can be prepared by reacting an amine compound with a base such as triethylamine and an appropriately substituted sulfamoyl chloride. Got it. When Rla is a primary amine, the compound of formula (I) can be prepared from a series of methods using an amine compound in accordance with the method of 2008. Reductive amination reaction with an appropriately substituted aldehyde or ketone in an environment with various reducing agents (refer to Ced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons) , 5 1992, pp898-900). For example, in an aprotic solvent (e.g., dichlorohydrazine) at ambient temperature, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride. It can also be obtained by performing a nucleophilic displacement reaction with an amine-based compound and a reactant having a leaving group (e.g., a halogen). In addition, amide or urea compounds can be prepared from Suzuki by an appropriately substituted boric acid (eg, 1-methyl-3-[ 3-(4,4,5,5-tetramethyl) -[1,3,2]disoxaboropen-2-yl)-phenyl]urea (1 -Methyl-3-[3-(4,4,5,5-tetramethyl-[l,3 52]dioxaborolan-2-15 yl)-phenyl]-urea) or 3-Methoxy-5-nitro-phenyl boronic acid pinacol ester 〇 Such synthetic methods are described herein. Alternatively, the secondary amine can form a ring with a suitable reactive group via a cyclization reaction, as shown in Reaction Scheme 4. 76 200836725

Scheme 4 This reaction is carried out in an anhydrous solvent (eg, toluene) with the amine compound and 1, Γ-thiocarbonyldi-2(1H)-pyridone 5 (l,l'-thiocarbonyldi-2 ( lH)-pyridone) reacts. Typical reaction conditions are heating to an excited state for 1 hour followed by treatment with hydrazine hydrate to form thiosemicarbazide. Next, cyclization is carried out in such a manner that diethyl chlorophosphate is added dropwise as it is. This method may result in another cyclized product, so a separate separation step may be required. When R1 is another example (e.g., thiourea, thioamide, thiocarbamate (e.g., O-substituted thiocarbamates or S-substituted thiocarbamates), dithiocarbamate, amidine, and guanidine) Compounds such as the formula (I) 15 can be obtained via an amine intermediate using a series of conventional interconversion methods (refer to Advanced Organic Chemistry by Jerry March, 4th Edition, John). Wiley & Sons, 1992) ° Suitable starting materials and reactants for use in these reactions are commercially available from the company 77 200836725, or may be synthesized by well-known standard synthetic procedures (as found in (d) ad by Jerry March, 4th

Edition, John Wiley & Sons, 1992 > ΐλ Sl Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman 5 (ISBN: 0-471-31192-8), 1995, or refer to the following implementation The method described in the example). For example, a range of useful functionalized aniline and aminopyridine starting materials, as well as metal catalysts, are commercially available. Many boric acid groups suitable for use in the preparation of the compounds of the present invention, such as boric acid, or boric acid esters, or trifluoroboric acid, are commercially available, for example, by Boron Molecular Limited of Noble Park, Australia, or Combi. -Blocks Inc. of San Diego, USA. However, suitably substituted boric acid groups are not commercially available, and can be synthesized via well-known standard synthetic procedures, for example, by 1^^^^^^^^^^^(1811211]<:丨, Into (1995) CAem· and ~, 95, 2457 are prepared by the method shown. Thus, 15 the corresponding boron compound is reacted with monoalkyllithium (eg, butyllithium), followed by boron. The acid ester (for example, (iprOhB) is reacted to obtain a boronic acid group. The reaction is carried out in a dry polar solvent such as tetrahydrofuran, and in a low temperature environment (e.g., -78 ° C). Pinacolatoboronate can also be composed of a boron compound and a diborate (eg, (Ms (pinacolato) diboron), phosphine (eg, tricyclic) Tricyclohexyl-phosphine, and the reaction of a (0) reagent (eg, tris(dibenzylideneacetone)-dipalladium(O)). The reaction of borate formation is generally carried out in a dry polar aprotic solvent (eg, dioxane or DMSO). It is carried out in an environment of up to about 100 ° C or, for example, 80 ° C. According to the requirements, the boronic acid ester derivative obtained by the method of 78 200836725 can be hydrolyzed to obtain the corresponding boric acid or converted into a trifluoroborate. All of the above reactions can be used to functionalize various heterocyclic forms of Formula I, and the synthesis methods are as follows. 5 ° than mouth Π , 5-al olo 口 ( (PyrazoloH, 5-alpvrimidine) σ is more than [l,5-a], and Pyrazolo[l,5-a]pyrimidine can be suitably substituted with aminopyrazole (VI) and fragment (Vn) (fragment). (VII)) Synthesized, as shown in Reaction Scheme 5A, 10 and wherein Ra can be hydrogen or Ri. This reaction can be accomplished in a single step or in two steps, wherein Xi and X2 are electrophilic carbons (ie, carbonyl groups) , masked carbonyl (ie, acetal), dilute amine, co-sulphur or alkyne) (Perkin I, J. C. S. (1979), 3085-3094). X3 Is a suitable substituent which is R2 or a group such as a halogen or a pseudohalogen which can be introduced into R2 to the reaction 15. Pyrazole (VI) can be A substituted pyrazole [l,5-a] is prepared via cyclization of an appropriately substituted free or masked 1,3-dicarbonyl derivative. Pyrazolo [ 1,5-a] pyrimidine). Generally, the cyclization reaction takes place in an alcohol solvent or in mono-toluene or mono-acetic acid, and may be added with additives (for example, piperidine, sodium ethoxide, HCl, AcOH, 20). pTsOH, or ZnCl2) is present therein (J. Med. Chem. (2001), 44 (3), 350-361; Bull. Korean Chem. Soc. (2002), 23 (4), 610-612; Australian Journal of Chemistry (1985), 38(1), 221-30). 79 200836725

Ra

(VI) (VII)

Scheme 5A A special synthetic reaction scheme for the preparation of 3,7-disubstituted pyrazole [l,5-a]pyrimidine (Pyrazolo [l,5-a] pyrimidine) is shown in Figure 5B of Reaction Scheme 5B. The 吼σ 坐 sits and the pyrazolopyrimidine ring system is obtained by reacting a substituted malonaldehyde as a fragment VII with an aminopyrazole. The substituted malonaldehyde may be substituted by a cyclic functional group (e.g., 2-(4-fluoro-phenyl)-propane) or by a latent functionality (e.g., as desired). Substituted by ilin in 2-bromo-propanedialdehyde, and further derivatized at the position of substitution, as shown in the reaction scheme below. In a cyclization reaction, a malonaldehyde dissolved in a solvent is added to the 3-amino ratio, followed by the addition of an acid (e.g., glacial acetic acid). The reactants are then subjected to a cyclization reaction by heating under reflux. Thereby, a compound represented by the formula (I) can be synthesized via a halogenation reaction and a metal catalytic reaction described herein. 200836725

Scheme 5B The compounds of the formulae (VI) and (VII) are conventionally known compounds which can be synthesized by well-known techniques. Many of the pyrazoles of formula (VI) are commercially available. Alternatively, it can be synthesized starting from the _ class by conventional techniques (e.g., as described in EP 308020 (Merck), or by Schmidt in Helv. Chim. Acta. (1956), 39, 986- 991 and the method described in Helv. Chim. Acta. (1958), 41, 1052-1060, or 10 pyrazole in the formula (VI) or as shown in the formula (I) by a conventional standard method The compound is prepared by conversion to an R1 functional group, wherein the Ra is hydrogen, halogen, nitrogen, an ester, or an amide. For example, when R1 is a halogen, a coupling reaction with tin or cation can be performed. 15 mouth than saliva FI,5-a"lp ratio (Pvrazolo "l,5-a~1Pvrazine) 81 200836725

Reaction of a mixture of 2-bromo-5-A-mouth compared to oral (2-乜1:〇1]1〇-5 - iodo-pyrazine) and copper (I), under inert conditions , a suitable solvent and base (eg, DMF/Et3N), with ethynyl-trimethyl-silane, using a catalyst (eg, 5 Pd (PPh3) 4), at room temperature The next reaction gives 2-bromo-5-trimethyldecyl ethynyl l^l#(2-Bromo-5-trimethylsilanylethynyl-pyrazine)°ilt#^4 without further purification, and can then be used 〇_(three O-(mesitylenesulfonyl)hydroxyl amine reacts to form an N-amino group adduct (ie, 6-bromo-2-tridecylfluorenyl-pyrazole [l,5-a Pyrazine 10 (6-bromo-2-trimethylsilanyl-pyrazolo [l,5-a]pyrazine)) oxime and cyclization with a base (eg, K2C03) to form a pyrazolopyrazine core, such as a reaction Flowchart 6 shows.

Substituents at positions 3 and 7 can be attached via halogenation and reaction with a latent functional group at positions 3 and 7 by catalysis of a metal catalyst. 82 200836725 mouth ratio f 1,5-a"! mouth ratio 0 (Pyrazolofl, 5-alpvridine) 3-bromopyridine and an appropriately substituted boric acid in a solvent (eg, under alkaline conditions (Na2C03) In the presence of DME), and in the presence of a palladium catalyst, 5 reacts to form a 3-substituted pyridine (as in Reaction Scheme 7). Next, under inert conditions, O-(Mesitylenesulfonyl)hydroxylamine is reacted with 3-substituted to form N-aminopyridine, which is N_ The amine bite can be used directly without further purification. The N-adduct is carried out using an alkali (K2C03) with 10 and 2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester under an inert atmosphere. Cyclization gives 3-carboxylate pyrazole [l,5-a] pyridyl. The formic acid S can be removed by, for example, using an acidification reaction of sodium hydroxide to form an acid followed by decarboxylation in tetraphosphoric acid.

The introduction of the substituent at the third position can be carried out by catalyzing a metal catalyst by reacting a halogen aryl group with N-iodosuccinimide (N-iodosuccinimide). Mouth meter ° "4,5-bl0 than the mouth (lmidazo "4,5-blpyridine" imidazole [4,5-b] pyridine ring system from monoaniline (aniline) and 2-chloro-3-5 amine 吼σ (2_chloro-3 -amino pyridine) was obtained by a reaction as described in J. Heterocyclic Chemistry (1983), 20(5), 1339 (as shown in Reaction Scheme 8).

Ph

Scheme 8 10 Alternatively, another method having an intermediate product with more functional groups is disclosed in US 06723735 (as shown in Reaction Scheme 9).

NaNO, N NH0

cHCI

ArNH〇

Et3N, NMP 100 °C

Hco2h 90 °C

NHPh e 9 Αγ·Β(ΟΗ)2 -

Ar' Pd(PPh3)4 1,3-propanediol Na2C03 (aq) DME

Scheme 9 84 200836725 The above-mentioned similar aryl group can be subjected to a series of metal catalyzed reactions to form the desired compound of formula (I). The pyridine dmidazo "4iclpvridine" 3-aryl_3Η·imidazole [4,5-c] pyridine ring system can be determined by a 3H-imidazole [4'5 0] ratio σ and an aryl group, using, for example, Biorg The method described in Med. Chem. Lett. U. 4), 14, 5263 is obtained by reaction (as shown in Reaction Scheme 10).

Cul, K2C03 1,10-phenanthroline ----^

DMF 110〇C Reaction Scheme 10 As is known, positional isomer products can be separated by chromatography. The method of making this material further changed to obtain the desired substitution pattern is as follows (as shown in Reaction Scheme 11). 85 200836725

R'= aryl, NR1R2 X=Halogen, OR Reaction Scheme 11 reacting with an oxidizing agent (eg, 3-chloroperbenzoic 5 acid) to produce N-oxide, which is N-< The compound can be rearranged with each of the reactants (e.g., P0C13, S0C12) to form a disubstituted 3H-imidazo[4,5-c]pyridine. This positional isomer product can then be separated via chromatography. Under the catalysis of a metal catalyst (e.g., palladium), X can be replaced by reaction with a suitable nucleophile to provide an aryl and amino substituted product. (10) Another example is shown in Reaction Scheme 12. 6-chloro-3H-imidazo[4,5-c]pyridine The synthesis method is described in J. Heterocyclic Chem (1965), 2(2), 196-201. In the presence of a metal catalyst (e.g., I bar), the chlorine group can be replaced by a nucleophilic group. The aryl and amine substituted product is obtained. In this process 15, a protecting group (e.g., a carbamate or a phenyl group) can be used. The process is further processed to give an N-aryl compound. 86 200836725

Arv

R= aryl, NRjR2, Reaction Scheme 12 5 1,5·Diaryl-1H-Molyzed Miso (1,5-Diarvl-lH-benzoimidazole)

The synthesis of Ar, 1,5-bisaryl-1H-benzimidazole is described in detail in Biorg·Med. Chem. Lett (2003), 13, 2485-2488 (as shown in Reaction Scheme 13 10).

2. Zn/AcOH, 60 °C 3. HC(OEt)3, 100 °C

1. ArNH2 ΝΜΡ 110 °C

Ar.B(OH)2

Pd(PPh3)4 Na2C03 Dioxane/H2〇 80 °C

Schemel3 15 Displaces fluorine from 4-bromo-1-fluoro-2-nitro-benzene to aniline, which is then reduced and cyclized with triethyl orthoformate to give a desired substitution. Bromo-benzoimidazole 〇87 200836725 The product can be further reacted with bromine under metal catalysis to form 1,5-disubstituted benzo. Oral sulphate, 2-c1, iridazomcipvrimidine, disubstituted saponin [1,2-c] cancer bite (imidazo[l,2_c]pyrimidine) can be prepared by the preparation procedure as in Reaction Scheme 14 .

CI

Scheme 14 10 This reaction is initiated by 7-chloro-weijun [1,2-(:] mouth 唆 as a starting material, and its synthesis is described in Yanai et al, Heterocyclic compounds. XVIII Synthesis of imidazo[l, 2 -c]- and 15 pyrimido[l,2-c]pyrimidine derivatives, Yakugaku Zasshi (1974), 94(12), 1503-14. This material can be further processed using any of the above reactions. When the 7th position is a nitrogen-saturated saturated heterocyclic group, and Example 20 is as follows: morpholine, a SNAr reaction can be carried out (for example, in 88 200836725 "Advanced Organic Chemistry by Jerry March, 4th edition, pages 641- The SNAr reaction described in 644) is, for example, the embodiment described in US Pat. No. 4,503,050, as shown in Reaction Scheme 15.

Scheme 15 When the 7th position is an aryl or heteroaryl group, the SNAr group 10 can be replaced by a similar compound using a standard cross cation coupling reaction (eg, Reaction Scheme 16). Show).

Scheme 16 15 mouth rice mouth sitting f 1,2-c"|口密口定定-5-ketone (Imidazo "l J-clpyrimidin-S-one" 89 200836725 3,7 disubstituted imidazole [l,2-c] Pyrimidine-5-one may be 7-chloro-6H-imidazo[1,2-c]pyrimidin-5-one (7-Chloro-6H-imidazo[l,2-c]pyrimidin-5-one,CAS number 5 56817 -09-5) Prepared for the starting materials, such as Maggiali βία/ (1982) Acta Naturalia de TAteneo Parmense, 18(3), 93-101 and Bartholomew ei W (1975) Journal of Organic Chemistry, 40 (25), as described in 3708-13. 7-Ga-6H- u rice bran [l,2-c] 13-densidine-5-keto 10 (7-Chloro-6H-imidazo[l,2-c ]pyrimidin-5-one) can be induced by a nucleophilic substitution reaction (eg, SNAr reaction) or added using a Suzuki reaction based on the 7th position (eg, reaction scheme π). This compound can be used in the reaction of eucalyptus Before further functionalization, the above method is iodinated.

Scheme 17 Alternatively, 7-chloro-6H-imidazo[l,2-c]pyrimidin-5-one (7-Chloro-6H-imidazo[l,2-c]pyrimidin-5-one) can be directly moth 90 200836725 The following intermediates are used in the reactions described herein (eg, Reaction Scheme 18)

5 Scheme 18 Further, other oxygen-containing heterocycles can be synthesized by appropriate hydrolysis of the chlorine derivative. The protecting compound is subjected to alkaline hydrolysis to afford the pyridone. And the reaction can be used in 10 H20/Me0H or H20/dioxane solution of NaOH (or NaOH/H2〇2), using literature (eg, Australian J. Chem. (1984), 37(12), 2469 The chlorine 0 described in -2477) is carried out by a chloropyridine hydrolysis method. 15 mouth rice mouth sitting "1,2-bl violation Qin (Imidazo "l,2-b"|pyridazine) 91 200836725

Br

Scheme 19 The synthesis of the 5-nuclear [l,2_b]pyridazine (imidazo[l,2-b]pyridazine) 5 nucleus can be carried out using pyridazin-3-yl amine derivatives. It is synthesized by the method described in Reaction Scheme 19, and can be referred to J. Heterocyclic Chem. (2002), 39 (4), ρ737·742. The substitution method at the third position can be referred to the example in J. Med. Chem (2006), 49 (4), ρ1235-1238 to obtain a compound substituted at the 3,7 position. 10 Other heterocyclic ring synthesis can be carried out using conventional techniques, such as

Comprehensive Heterocyclic Chemistry I (Edited by AR Katritzky, C_W. Rees, Elsevier, 1982) and Comprehensive Heterocyclic Chemistry II (Edited by AR Katritzky, CW Rees, EFV Scriven, Elsevier, 1996, ISBN 0-08-042072-9) The method described. In many of the above reactions, it may be necessary to protect one or more of the substituted position groups to prevent substitution of the substituents to undesired positions as the reaction proceeds. Examples of protecting groups, as well as methods for protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T:· Giceen 92 200836725 and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). For example, once The group may be protected in the form of an ether (-OR) or a monoester (_〇C(=〇)R), for example: t-butyl ether; phenyl, diphenyl oxime ( Benzhydryl, diphenylmethyl), or trityl, 5 triphenylmethyl ether; trimethylsilyl or tert-butyldimethylsilyl ether; or acetate (- 0C(=0)CH3, -OAc)) For example, an acid or hydrazine may each be in the form of an acid (aceta, R-CH(OR)2) or a ketal (ketal, R2C(OR)2). While protected by hydrazine, the carbonyl group (>c=o) in the acetal and ketal is converted to a di-ether by, for example, a method in which 10 is reacted with a primary alcohol. The aldehyde or ketone system can be regenerated by hydrolysis using a large excess of water in which the acid is contained. The monoamine group can be protected by the form of amide (-NRC0-R) or urethane (-NRCO-OR), for example: monomethyl decylamine (-NHC0-CH3); benzene Benzyloxy amide (ΝΗ_0(Ι:Η2(^6Η5, _NH-Cbz); 15 —t-butoxy amide (-NHCO-OC(CH3)3,-NH -Boc); - 2 · diphenyl-2-propoxy amide, -NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), a 9-mercaptopurine 9-fluorenylmethoxy amide (-NH-Fmoc), 6-nitroveratryloxy amide (-NH_Nvoc), 2-trimethylsulfanylethyl oxime 2-trimethylsilylethyloxy amide (-NH-Teoc), a 2,2,2-trichloroethyloxy amide (-NH-Troc), an allyloxy guanamine (allyloxy) Amide, _NH_Alloc), or a 2(-phenylsulfonyl)ethyloxy 93 200836725 _ s ( ( 2 2 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Protective amine package for cyclic amine and heterocyclic NH group : toluenesulphonyl (tosyl) and a methanesulphonyl (mesyl) group and a phenyl group 5 (eg, a para-methoxybenzyl (PMB) group. It may be protected in the form of a monoester, for example, a Cu alkyl ester (e.g., monodecyl ester; a tert-butyl); - Ci_7 haloalkyl group (e.g., 'Ci_7 tricarbyl base); one ^ three Ci-7 calcined a base chopping base-Ci_7 alkyl vinegar; or a C5-2O aryl-C1-7 alkyl group ('1 (eg, monophenyl ester; monoazobenzene); or, an amide Protected by the form of a methyl amide. For example, a thiol group is protected by a thiol ether (_SR), for example, benzyl thioether; Acetamidomethyl ether (-S-CH2NHC(=0)CH3). The key intermediate in the preparation of the compound of the formula (I) is a compound of the formula (XX). A novel chemical intermediate as shown in the chemical formula (XX) is another aspect of the invention. Another aspect of the invention is prepared as described herein, as in formula (I)

A compound represented by G, which comprises: (1) a compound represented by the formula (XX) or (XXI) or a protected form thereof, and an appropriately substituted isocyanate or an appropriately substituted amine, which are placed in a few bases (carb) Reaction in the presence of 〇nyl diimidazole 'CDI); or 94 200836725

(ii) reacting a compound represented by the formula (XX) or (XXI) or a protected form thereof with an appropriately substituted aldehyde or ketone; or 5

(iii) a compound of the formula (XX) or (XXI) wherein Xi-5, A, and R2 are as defined herein, or a protected form thereof, and an appropriately substituted carboxylic acid or active derivative Carry out the reaction

H〇N--A

(XX) (xxi) Next and remove any of the protecting groups present; 95 200836725 and then selectively convert one of the compounds as shown in formula (i) to another compound of formula (I). In one embodiment, the step of preparing the compound of formula (I) further comprises: (iv) reacting a compound as shown in formulas (V) and (VI),

10

Wherein R1 and R2 are the same as R1 and R2 as defined in the compound represented by the formula (I). In one embodiment, R1 represents -ΝΗΟΟΝ(Η)((^_6 alkyl) or -NHCON(H)(CH2CF3), and R2 represents 4-fluorophenyl. As another aspect of the invention, A novel intermediate product is provided. In one embodiment, the novel ten product is selected from the group consisting of: 1-(3-di-phenyl)-3-(2,2,2-di-ethyl)-pulse 20 (1-(3-Bromo-phenyl)-3-(25252-trifluoro-ethyl)-urea); 7-(4-fluoro-phenyl)-imidazole [l,2-a] acridine 96 200836725 (7- (4 «Fluoro-phenyl)-imidazo[l 2 2-a]pyridine); and 7_(4-fluoro-phenyl)_3·Moth-1:7 m spit [l,2-a] ° than 唆 (7 -(4-Fluoro-phenyl)-3-iodo-imidazo[l,2-a]pyridine). 5 pharmaceutically acceptable salts, solvates or derivatives thereof, unless otherwise specified, in this unit , as described in the units of other applications, the reference meaning of the functional group referred to in the formula (I) is the same as the reference meaning of the functional groups in all other subgroups, and preferred examples and examples thereof are This article is described in this article. 10 Unless otherwise specified, the reference meaning of a specific compound in the text may also represent its ion. State, its salt, its solvate (solvate), its isomer, its tautomer, its N_oxide, its ester compound, its prodrug (pr〇drug), its isotope, and its protective form, for example, as described below; 15 is preferably its ionic form, or a salt thereof or a tautomer thereof or an isomer thereof Or an N-oxide or a solvate thereof; and more preferably, an ionic form thereof, or a salt thereof or a tautomer thereof or a solvate thereof or a protected form thereof, many of which are represented by the formula (I) The compound may be present in the form of a salt thereof, for example, an acid addition salt or, under special conditions, organic and inorganic base salts (e.g., carboxylic acid, 20 sulfonic acid, and phosphate). All of the above salts are included. Within the scope of the present invention, and the reference meaning of the compound as shown in the formula (I) includes the salt type of the compound. The salt of the present invention may be a parent compound containing a test or acid moiety, via士口 j Pharmaceutical Salts: Properties, Selection, 25 and Use, P. Hei Synthesized by the method described in nrich Stahl (Editor), Camille G. Wermuth 97 200836725 (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, the salt can be formed by reacting a free acid formed from such a compound or an appropriate test or acid in water or an organic solvent, or a mixed solution thereof; The phase (e.g., diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) is used as the above solvent. An acid addition salt can be formed from a series of acids (including both inorganic and organic acids). Related acid addition salts include a salt formed from an acid selected from the group consisting of: acetic acid, 2,2-diacetoacetic acid, adipic acid, alginic acid, ascorbic acid (ascorbic, such as , L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+ ) camphoric acid ((+) camphoric), camphor-sulphonic, (+)-(15)_ camphor 15 -10-heme ((+)-(15)-〇&11^ 11〇1*-10-8111卩11〇111〇), capric, caproic, caprylic, cinnamic, citric, cyclohexylamino Cyclic, dodecyl sulphuric, ethane-l, 2-disulphonic, ethanesulphonic, ethyl 20 stone 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D_ Portuguese D-gluconic, glucuronic (eg, D-glucosin), glutamic (eg, L-glutamic acid), α-S-glutaric acid ( --oxoglutaric), glycolic acid, 25 hippuric, hydrobromic, hydrochloric acid 98 200836725 (hydrochloric), hydrogen hydriodic, isethionic , lactic acid (such as (+)-L_lactic acid, (soil)-DL-lactic acid), lactobionic acid, maleic acid, malic, (a)-L-malic acid ( (-)-L-malic), malonic acid, (earth)-DL·malonic acid 5 ((士)-DL-mandelic), methanesulphonic, naphthalenesulphonic , such as: naphthalene-2-sulphonic), naphthalene-1,5-diacetic acid (naphthalene-155-disulphonic), 1-yl-2-naphthoic acid (l_hydroxy-2- Naphthoic), nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphonic ), propionic acid (pro Pionic), L-.pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, Succinic, sulphuric, tannic, (+)_L·15 tartaric acid ((+)-L-tartaric), thiocyanic, toluene (toluenesulphonic (eg, p-toluenesulphonic), undecylenic, and valeric acid, such as acylated amino acid And a special group of cation exchange resin, which comprises: acetic acid, hydrochloric acid, hydriodic, phosphonic acid Nitric), lactic acid, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic , toluenesulphonic A 99 200836725 methicillin (methanesulphonic; mesylate) ), ethanesulphonic, naphthalenesulphonic, valeric acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid, and nialic acid a salt formed by (lactobionic). 5 The group of another acid addition salt comprises one selected from the group consisting of: acetic acid, adipic, ascorbic, aspartic, citric, DL-lactic acid (DL-lactic) ), fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic acid 10 (DL) -malic), a salt formed from methanesulphonic, sebacic, stearic, succinic, and tartaric. The compound of the benzene invention may exist in a single or double-salt form depending on the pKa value of the acid of the salt formed. 15 If a compound is assumed to be an anionic or anionic functional group (e.g., -COOH may be -COCT), it may form a suitable salt with a cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na+ and K+), alkaline earth metal ions (e.g., Ca2+ and Mg2+), and other cations (e.g., Al3+). Exemplary examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR4+). An example of a suitable ammonium ion is via: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine 100 200836725 (ethanolamine) , diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, And ammonium ions derived from amino acids (eg, lysine and arginine). One example of quaternary ammonium is n(ch3)4+. The compound containing a monoamine functional group represented by the formula (I) may be obtained by a reaction of a quaternary ammonium salt, for example, a person having ordinary knowledge and an alkylating agent by a conventional technique. ) Anti-10 should be obtained. Such quaternary ammonium is also included in the range of the chemical formula (1). The salts of the compounds of the present invention are conventional pharmaceutically acceptable salts, and related examples of pharmaceutically acceptable salts are at Berge as a/. (1977), fPharmaceutically Acceptable Salts/' J. Pharm. Sci .f Vol· 66, pp. 1-19 — Discussed in the article. However, the non-pharmaceutically acceptable salt of 15 may also be an intermediate product which can be converted into a pharmaceutically acceptable salt. Such non-pharmaceutically acceptable salts are also part of the invention, for example, when used to purify or isolate a compound of the invention, it is a useful salt. The compound having an amine functional group as shown in the formula (I) may also be formed into an N-oxide. Examples of the compound having an amine functional group represented by the formula (I) also include an N.oxide. A compound having a plurality of amine functional groups, one or more of which may be oxidized to form an N-oxide. A specific example of an N-oxide is a N-oxide of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. 25 N-oxides can be obtained by reacting the corresponding amine with an oxidizing agent (e.g., peroxygen 101 200836725 hydrogen or peracid (e.g., peroxygen), see (10) ced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, examples in pages. Further, the N-oxide can be prepared by the procedure described in 1^.^¥· Deady 〇S>/2. Comm. (1977), 7, 509-514), wherein the amine compound is m-chloroperoxybenzene. Formic acid (wP-chloroperoxybenzoic acid, MCPBA), for example, is carried out in an inert solvent (for example, dioxane). Specific examples of N-oxides include: morpholine N-oxides and alpha ratios to N-oxides. The compound represented by the formula (I) may have various stereoisomers and tautomerics, and the compound of the formula (I) contains all of its forms. For the avoidance of doubt, a compound may exist in the form of a plurality of stereoisomers or tautomers. Although only one of them is described, other aspects are included in the formula (I). 15 For example, examples of other tautomeric forms include ketones, alcohols, and enolates, and other di-transmutants such as the following: ketones/alcohols (described below), imines (imine) / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione (thi〇ket〇ne) / thiophene (enothiol), and nitro (nitro) / isonitro (aci_nitr〇). V \ 〇H H+ —C —C ^ — c=c 7 1 , / \ keto enol \ ,〇/ \ enolate 102 200836725 Unless otherwise specified in the context, a compound as shown in formula (1) contains one or more palms a chiral centre, and may be present in two or more optical isomers, such as the compound of formula (I), including all of its optical isomers (eg, mirrored isomers) ), epimers and diastereoisomers, and individual optical isomers, or mixtures (eg, racemic mixtures) or more than two optical isoforms Structure. 〇10 This optical isomer can be distinguished by its optical activity (ie, + and - isomers, or d and / isomers), or by the "R and S" names proposed by Cahn, Ingold, and Prelog. For definitions, please refer to Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and 15 Cahn5 Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415 content. Optical isomers can be separated by a range of techniques, including chiral chromatography (chromatography on a chiral support) or other such techniques. Another method for separating optical isomers other than palm chromatography can be by palmitic acid (eg, (+)-tartaric acid, (-)-pyroglutamic acid ((-)-pyroglutamic acid), (a) -(-)-di-toluoyl-L-tartaric acid, (+)-malonic acid ((+)-mandelic 25 acid), (a)-malic acid ((-)- Malic acid), and (·)-camphorin 103 200836725 ((a)-camphorsulphonic) forms a salt of a diastereoisomer, which is separated by preferential crystallization, and then the salt is separated Separation to obtain a single species of mirror image isomer in a free base. Ο 10 15 ϋ 20 The compound of formula (I) has two or more optically isomeric forms, a pair of mirror image isomers ( One of the enantiomers may have better properties than the other, for example, biological activity. In some cases, only one of the mirror image isomers may be used for medical purposes or one of a plurality of non-reciprocal isomers. Therefore, the chemical formula (I) is provided in the present invention. The compound shown has more than one chiral centre, wherein at least 55% of the compound of formula (1) (eg, at least 60%, 65%, 70%, 75%, 80%, 85%) , 90%, or 95%) is in the form of a single optical isomer (eg, an enantiomer or a diastereoisomer). In a typical embodiment, such as a chemical formula The amount of 99% or more (i.e., almost all) of the compound shown in (I) may exist in the form of a single optical isomer (i.e., a mirror image isomer or a non-isomer). Containing a compound having one or more isotopic substitutions, the reference meaning of a particular element also includes all isotopes of the element. For example, the reference meaning of hydrogen includes 1Η, 2H (D), and 3H (T Similarly, carbon and oxygen The reference meanings each include 12C, 13C, and 14C and 16〇, and 18〇. These isotopes may or may not have radioactive materials. In one embodiment of the invention, the compound does not have a radioisotope. Such compounds are more suitable for medical use. However, in another embodiment, 104 200836725 the compound may comprise one or more radioisotopes. These radioisotope compounds can be used for medical diagnostic purposes. Esters (e.g., a carboxylic acid ester having a monocarboxylic acid group or a monohydroxy group as shown in the formula (I) and an acyloxy ester compound) are also included in the range of the chemical formula (I) 5. In one embodiment of the present invention, the formula (I) also includes a compound having a carboxylic acid group or a hydroxyl group as shown in the formula (I). In another embodiment of the present invention, the range represented by the formula (I) does not include an ester having a carboxylic acid group or a thiol group as shown in the formula (I). An example of the related ester is A compound containing a -C(=0)0R group, wherein R is a monoester substituent, such as a Cu alkyl group, a C3-20 heterocyclic group, or a C5-2G aryl group, preferably a Cu alkyl group. Examples of special ester groups include, but are not limited to: -c(=o)och3, -C(=0)0CH2CH3, -c(=o)oc(ch3)3, and -C(=〇) 〇Ph. A special example of an acyloxy group includes, but is not limited to, -0C(=0)CH3 (acetoxy), _0C(=0)CH2CH3, -0C(= 0) C(CH3)3, _〇C(=0)

Ph, and -0C (=0) CH2P1i.

Further, the inclusion in the chemical formula (i) also includes a plurality of forms of any compound, a solvent compound (solvate, such as a hydrate), a complex compound (e.g., with a compound such as cyclodextrin). Forming an inclusion complex or a clathrate, or a complex with a metal, and a prodrug. By "prodrug" is meant, for example, any compound which is biologically active as shown in formula (I) in vivo. 105 200836725 For example, certain prodrugs are esters of the active compounds (eg, a physiologically acceptable metabolically stable ester). During metabolism, the linkages in its ester group (_C(=0)0R) are cleaved to form an active drug. Such an esterified product can be formed by esterification, for example, esterification of a carboxylic acid group 5 (_C(=0)0H) in any parent compound with other reactive groups in any parent compound under protection. It is then deprotected to form an esterified product. Examples of metabolically stable esters include those compounds of the formula -C(=0)0R wherein R is:

a Cu group (eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, 10 -iBu, -tBu);

Cu amide (Ci-7 aminoalkyl) (eg, amine ethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl (2-(4- Morpholin)ethyl)); and acyloxy-Cwalkyl (eg, methoxyl-15; methoxyethyl; pivaloyloxymethyl; ethoxylated oxime) Acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-indenyl)ethyl-carbon charcoal oxy)ethyl (1 - (1 -methoxy-1) -methyl)ethyl-carbonyloxyethyl); 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropyl 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl Cyclohexyloxy-carbon anthraceneoxymethyl 106 200836725 (cyclohexyloxy-carbonyloxymethyl); 1-cyclohexyloxy-carbonyloxyethyl; 4-(tetrahydrogen oxy-oxygen) Base) charcoal methoxymethyl ((4-tetrahydr) Opyranyloxy) 5 carbonyloxymethyl) ; 1 _(4_tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrazopyridylpyranyl) (4-tetrahydropyranyl carbonyloxymethyl); and 1-(4-tetrahydropyranyl sulphate) 10 (l-(4-tetrahydropyranyl)carbonyloxyetliyl)) In addition, some prodrugs are enzymes. An active compound obtained by activation, or an active compound obtained by a chemical reaction (for example, antigen-directed enzyme pro-drug therapy (ADEPT), gene-targeted enzyme prodrug therapy (gene- Directed enzyme 15 pro-drug therapy, GDEPT), and ligand-directed enzyme pro-drug therapy (LIDEPT), etc.). For example, the prodrug may be a monosaccharide derivative or other glycoside co-product, or may be an amino acid ester derivative. The reference to the "derivative" includes: its ionic 20 type, salts, solvent compounds, isomers, tautomers, N-oxides, esters, prodrugs, isotopes, And protection type. According to one aspect of the invention, there is provided a compound as defined herein, or a salt, tautomer, N-oxide, or solvent compound thereof. According to another aspect of the invention, there is provided a compound, a salt or a solvent compound, as defined herein. Compounds of formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), and (II), (la), (lb) , (Ic), (Id), (Ie), (If), (Ig), and (II) and the reference meanings of the subgroups thereof as defined herein are 5 salts or solvate compounds thereof Or tautomers, or N-oxides. Protein tyrosine kinases (PTK) The compounds described herein inhibit or coordinate the activity of certain tyrosine 10 kinases, and thus the compounds can be used for diseases or infections caused by tyrosine kinases. Treatment or prevention, especially FGFR.

FGFR tyrosine kinases (PTK) receptor 15 fibroblast growth factor (FGF) family regulates a range of physiological functions, including: mitosis Mitogenesis, wound healing (wound healing), cell differentiation, and angiogenesis, and development. Normal and abnormal 20 (e.g., proliferation) cell growth phenomena are affected by FGFs, as well as local concentrations of extracellular signalling molecules that are autocrine and paracrine factors. Autocrine FGF signaling may be a state in which the steroid hormone dependent cancer deteriorates into a hormone-independent state (Powers, α/· (2000) 25 Endocr. Relat· cancer, 7, 165-197) 〇108 200836725 FGFs Receptors and their receptors are expressed in an increased degree in various tissues and cell lines, and their over-expression is thought to be caused by malignant phenotype. In addition, a number of oncogenes have homologous genes encoding growth factor 5 receptors, and there is a potential for abnormal activation of FGF-dependent signaling in human pancreatic cancer (see Ozawa). , with α/· (2〇〇1), Teratog. Carcinog. Mutagen., 21, 27-44) The prototypic member is an acid fiber matrix ◎ cell growth factor (acidic fibroblast growth) Factor (fibroblast growth 10 factor, FGF), aFGF or FGF1) and basic fibroblast growth factor (FGF), bFGF or FGF2, and to date, at least twenty Different members of the FGF family have been identified. The response of cells to FGFs is via four high affinity transmembrane 15 protein tyrosine-kinase fibroblast growth factor receptors (FGF) receptors. FGFR) is delivered as Nos. 1 to 4 (FGFR1 to FGFR4). By the addition of a ligand, the receptor becomes a dimer and the specific cytoplasmic tyrosine residue itself is acidified or auto- or trans-phosphorylate. Intracellular signals act as regulatory nuclear transcription factors. If the path of action of FGFR1 is interrupted, it may cause the proliferation of tumor cells, which is caused by the activation of endothelial cells in the form of a tumor. The overexpression and overactivity of FGFR1 in tumor-associated vascular tubes 109 200836725 (tumor-associated vasculature) can be used as a study of the rules of tumor angiogenesis. Fibroblast growth factor receptor 2 (fibroblast growth factor (FGF) receptor 2) is very acidic and/or alkaline strongly affected by fibroblast growth factor 5 and keratinocyte growth factor ligands. Impact. Fibroblast growth factor receptor 2 also has an effect on the osteogenic effects of FGFs during osteoblast growth and differentiation. Mutations of fibroblasts () Growth factor receptor 2, which regulate the development of complex functionalities, cause an abnormality in cranial sutures, ossification, craniosynostosis, The effect of FGFR signaling rules on intramembranous osteogenesis. For example, in the head of the head and refers to the deformity (AP, which is a cranial suture ossification immature phenomenon), most of the examples are related to the growth of fibroblast growth factor receptor 2 (gain_of- Point mutations in function) 15 (Reference from Lemonnier, α/. (2001), J. Bone Miner·Res·, 16, 832-845). In addition, from the screening of patients with primary synaptic craniosynostoses and mutations, the repeated occurrence of FGFR2 mutations is related to the severity of Pfeiffer's disease (cf. Lajeunie et al5 European Journal of Human Genetics). (2006) 14, 20 289-298). Specific mutations of FGFR2 include: W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2. Many serious abnormalities in the development of human bones, including the tower head and the deformity (Apert), Crouzon's disease, Jackson-Weiss's disease, Beare-Stevenson cutis gyrata's disease, and Pfeiffer's disease, line 25 and fibroblast growth The mutation of the factor receptor 2 gene is involved. Most, 110 200836725 Not all, Pfeiffer Syndrome (PS) is caused by a remutation of the fibroblast growth factor receptor 2 gene (cf. (1996) Am. J. Hum. Genet., 58, 491-498; Plomp, et al. (1998) Am. J. Med. Genet, 75, 245-251), and recent findings 5 indicate that mutations in fibroblast growth factor receptor 2 disrupt the dominance. One of the main rules of the specificity of the ligand. That is, the interface type of the mutation of the two fibroblast growth factor receptors, FGFR2c and FGFR2b, has developed the ability to bind to and activate the atypical FGF ligand. Loss of ligand specificity can cause abnormal signaling, and as far as known, the various phenotypes of these symptoms are due to ectopic ligand association of fibroblast growth factor receptor 2 (ectopic Activation by ligand-dependent (Reference to Yu, α/· (2000), Proc. Natl. Acad. Sci. USA, 97, 14536-14541) o FGFR3 receptor tyrosine kinase (FGFR3 receptor tyrosine 15 Genetic abnormalities (eg, chromosomal shifts or point mutations) can cause ectopic or de- deregulated activation of the FGFR3 receptor. These abnormalities are connected to the bladder, hepatocellular, oral squamous cell carcinoma, cervical carcinoma, multiple myeloma 20 sons. Set (reference from 0\¥618, (1: 丄 (2000), to (2/., five 11 (1〇0:. 尺61· Cancer, 7, 165; Qiu, W. et. al. ( 2005), World Journal Gastroenterol, 11 (34). Therefore, FGFR3 inhibitors are useful for the treatment of multiple myeloma, bladder, and cervical cancer. FGFR3 is also overexpressed in bladder cancer, especially It is invasive 111 200836725 in bladder cancer. FGFR3 is often activated by mutations in urothelial carcinoma (UC) (cf. Journal of Pathology (2007), 213(1), 91-98). Increased performance is usually associated with mutations (85% of mutant tumors are highly expressed), but 42% of tumors with 5 overexpression do not detect mutations, including many myometrial invasion tumors (muscle- Invasive tumors) 〇 So, can inhibit FGF The compound of R will enable a method for preventing tumor growth or inducing apoptosis of tumor cells, particularly by inhibiting angiogenesis. Therefore, it is expected that this compound can be effectively used for the treatment or prevention of diseases such as cancer. An abnormal phenomenon of hyperplasia. In particular, a tumor having an activating mutation of a receptor tyrosine kinase or an upregulation of a receptor tyrosine kinase, which may be particularly sensitive to such inhibitors. Patients with activating mutations in isoforms of RTKs may also find it very economical to use RTK inhibitors. 15 The overexpression of FGFR4 is also associated with prostate and squamous cell carcinoma (see Ezzat, S·, W α) Plant (2002) The Journal of Clinical Investigation, 109, 1 ; Wang by a / (2004) Clinical Cancer Research, 10). In addition, germline polymorphism (Gly388Arg) also with the lungs, breasts, colon, It is associated with an increase in the degree of prostate cancer 20 (see from Wang α/. (2004) Clinical Cancer Research, 10). Furthermore, the truncated type of FGFR4 (region with kinase) was also found in 40% of pituitary tumors, but not in normal tissues. Recent studies indicate that in typical lobarular carcinoma (Classic Lobular 112 200836725 carcinoma, CLC), the expression of FGFR1 is associated with tumor growth. Lobular carcinoma (CLC) accounts for 10-15% of all breast cancers. In general, when p53 and Her2 are deficient, the expression of estrogen receptors is fixed. In case 5 of about 50% of lobular carcinoma (CLC), amplification of the 8pl2 to ρΐΐ·2 gene was used as an explanation for the etiology, and it was shown to be associated with an increase in the expression of FGFR1. A preliminary study of FGFR1 using siRNA guidance, or the use of receptor small molecule inhibitors, indicates that cell lines are particularly sensitive to inhibition of the information transfer process by this amplified fixed reaction line (see Reis-Filhoeia/. (2006) Clin Cancer Res. 10 12(22): 6652-6662). Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, is caused by abnormal proliferation and differentiation in skeletal myogenesis. FGFR1 has 15 overexpression in early stage rhabdomyosarcoma tumor formation, and hypomethylation with 51-terminal CpG island and AKT1, NOG, and BMP4 genes are abnormal. Performance related (Reference from Genes, Chromosomes & Cancer (2007), 46(11), 1028-1038). Fibrosis caused by abnormal or over-deposited fibrous tissue is a major medical problem. This phenomenon occurs in many diseases, including liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis. And natural wound healing. The evolutionary mechanism of this pathological fibrosis has not been studied, 113 200836725 but is attributed to various ectopic associations with increased fibroblasts and extracellular matrix proteins including collagen and fibronectin. Cytokine, including: tumor necrosis factor (TNF), fibroblast growth factor (FGFF*s), platelet derived growth factor (PDGF), and transforming growth Factor/3 (transforming growth factor beta, TGF-cold) activity. This causes a change in organizational structure and function, and ultimately leads to the development of lesions. A number of clinical studies may explain the up-regulation of fibroblast growth factor (FGF) in 10 clinical pulmonary fibrosis samples (see Inoue, ei (1997 &2002); Barrios, Take a/. (1997)). It has been reported that TGFpl and PDGF are associated with the fibrosis process (see Atamas & White, 2003) and there is more public information indicating that an increase in FGF and an increase in fiber growth may be a response to the increase in 15 TGFpl (Reference) From Khalil, to α/·, 2005). The potential therapeutic relationship with this fibrotic state process has been reported as a clinical effect of Pirfenidone in Idiopathic Pulmonary Fibrosis (IPF) (Arata, W α/·, 2005). Idiopathic Pulmonary Fibrosis (20 IPF) (also referred to as cryptogenic fibrosing alveolitis) is a progressive pulmonary scab. Gradually, the airbag of the lungs is replaced by fibrous tissue, which increases in thickness, resulting in the loss of an irreversible tissue capacity (delivering oxygen into the blood). Symptoms of this condition include short-lived, chronic dry cough (chronic dry 114 200836725 coughing), fatigue (fatigue), chest pain, and loss of appetite, resulting in rapid weight loss. This condition is very serious, and after nearly 5 years, there will be a nearly 50% mortality rate. 5 Intravascular ancient vascular endothelial growth factor (VEGFR) chronic hyperplasia is usually accompanied by deep angiogenesis, which can cause or maintain an inflammatory and / or proliferative state, or Causes tissue to be destroyed by invasive hyperplasia of blood vessels (cf. 10 Folkman (1997), 79, 1-81; Folkman (1995), Nature

Medicine, 1, 27-31; Folkman and Shing (1992) J. Biol. Chem., 267, 10931) The angiogenesis system is often used to describe neovascular or replacement blood vessels, or neovascularisation. . In embryos, the establishment of vasculature is necessary and physiologically normal. However, in most mature tissues, angiogenesis usually does not occur except for ovulation, menstruation, or wound healing. However, in many diseases, stable or messy angiogenesis has emerged. For example, in arthritic diseases, new microvasculature invades the joint and destroys 20 cartilage (see from (1:〇1¥1116^&311&11(18.〇1:1:(1992),^[ /2 dozen. and /21/所·D^·, 51,919). In the disease of diabetes (and many different eye diseases), new blood vessels invade into the macula or other eye structures. It may cause blindness (cf. from Brooks, to α/· (1994) 0//, 79, 1157). The process of atherosclerosis is also related to angiogenesis (cf. from 25 Kahlon, with α/· ( 1992) Can·乂CarAo/·, 8, 60). Tumor growth at 115 200836725 and metastasis was also confirmed to be angiogenesis dependent (cf. Folkman (1992), Cancer Biol, 3, 65; Denekamp, (1993) Br. J. Rad., 66, 181; Fidler and Ellis (1994), vol.//, 79, 185). About how angiogenesis is involved in various diseases, through the identification of angiogenesis by 5 Inhibition studies have been investigated. These inhibitors are generally distinguished as: secreted for reactions in the angiogenesis cascade reaction (eg, endothelial cells are activated by angiogenic signals); synthesis and release of degradative enzymes; endothelial cell migration; endothelial cell proliferation; and 10 microvascular formation. In many stages, many people have tried various methods to discover and develop compounds that are used to stop angiogenesis at various stages. There are some reports that indicate angiogenesis inhibitors, through the action of separate mechanisms, for some diseases. Help, such as cancer and metastasis (Ref. 15 from O'Reilly, α/· (1994) Ce", 79, 315; Ingber, ei α/· (1990) 348, 555), eye related diseases (reference From Friedlander, to α/· (1995) iSWewce, 270, 1500), arthritis (cf. Peacock, W al. (1992), J. Exp. Med., 175, 1135; Peacock et al. (1995), CW/·Jmmwn·, 160, 178), and hemangioma (cf. from 20 Taraboletti, a/. (1995) J. Pain/n*s7·, 87, 293). Receptor tyrosine kinases (RTKs) play an important role in the biochemical signaling between the plasma membranes of cells. These transmembrane molecules have a special extracellular ligand binding domain, and these extracellular ligand binding regions are permeable to a 25-mer cytoplasmic membrane fragment and intracellular tyrosine kinase. Region 116 200836725 (tyrosine kinase domain) connection. The binding of the ligand to the receptor causes activation of the receptor-associated tyrosine kinase, which causes the receptor for the tyrosine fragment and other intracellular proteins to be phosphorylated at the same time, further causing a cascade of cellular responses. To date, at least nineteen distinguishable RTK subfamilies have been identified by the degree of similarity of amino acid sequences. Vascular endothelial growth factor (VEGF), a polypeptide, has been shown to promote endothelial cell division in vitro, and stimulates angiogenesis in vivo. VEGF 0 is also thought to be associated with abnormal angiogenesis (cf. Pinedo, 10 H.M., et al. (2000), The Oncologist, 5 (90001), 1-2). VEGFR is a pr〇tein tyrosine kinases (PTKs). In cell function, PTK catalyzes the phosphorylation of specific tyrosine fragments in proteins, thereby regulating cell growth, survival, and differentiation (see Wilks, AF (1990), corp. h GrowiA Factor 15 Research, 2 , 97-111; Courtneidge, SA (1993) Dev. Supp.l, 57-64; Cooper, JA (1994), Semin. Cell Biol·, 5(6), 377-387; Paulson, RF (1995), Semin. Immunol. ^ 7(4), 267-277; Chan, (/ AC (1996), Cwrr. Oph./mmwwo/., 8(3), 394-401) o Three PTK receptors for VEGF have been Identified: VEGFR-1 20 (Flt-1); VEGFR-2 (Flk-1 or KDR) and VBGFR-3 (Flt>4). These receptors are involved in angiogenesis and are involved in signal transduction. (Reference from Mustonen, T. (1995), W α/·, /· heart / / 5zW ·, 129, 895-898). The most interesting of these is VEGFR-2, which is one of the initial 25 in endothelial cells. The transmembrane receptor PTK is expressed. The VEGFR-2 activity by VEGF is a key step in the initial signaling process of tumor angiogenesis. The expression of VEGF may be a positive effect on tumor cells, and In response to such stimulation, there is a response to the promotion. One of the above-mentioned stimuli is hypoxia, which can enhance the expression of VEGF in tumors and 5 related host tissues. VEGF ligand VEGFR-2 is activated by binding to the extracellular VEGF binding site, which results in receptor double polymerization of VEGFR and autophosphorylation of the intracellular kinase region of VEGFR-2 of the tyrosine fragment. The kinase region transfers the monophosphate from ATP to the tyrosine fragment, thereby providing a white to downstream binding site for the signalling of VEGFR-2, and finally angiogenesis (cf. from McMahon, G. (2000) Jhe Oncologist, 5(90001), 3-10) Inhibition of the kinase binding site of VEGFR-2 will stop the phosphorylation of the tyrosine fragment and interrupt the angiogenesis. The nascent line is a physiologically stimulating step of angiogenesis, 15 which is regulated by various cytokines (eg, neovascular factors). Although in the solid tumors, the potential pathophysiologic rules have been studied for more than 30 years, angiogenesis is triggered by Chronic Lymphocytic Leukemia (CLL) and other malignant hematological disorders. The mechanism has been studied in nearly 20 years. Information about angiogenesis has been gradually increased by various experimental methods, as well as in the bone and lymph of patients with CLL. Although the rules of vascular neovascularization in pathophysiologic are still to be comprehensively studied, experimental data show that many angiogenic factors play an important role in the development of the disease. Vascular new 118 200836725 The biologic marker can also be used as a distinguishing symptom of CLL disease. This means that VEGFR inhibitors may also be used to aid in the treatment of leukemias (eg, CLL). In order for a tumor to reach a larger volume, it must develop a relevant vasculature. It has been suggested that targeted treatment of tumor vasculature can achieve the effect of limiting tumor enlargement and is useful for the treatment of cancer. For tumor growth observations, small tumors can survive in tissues that do not have any tumor-specific vascular tubes. Tumors capture other non-tumor specific vascular tubes due to hypoxia in the center of the tumor. Recently, a series of proangiogenic factors and anti-angiogenic factors have been identified and guided the concept of an "angiogenic switch", which is the process of angiogenesis in tumors. Stimulating factors and the normal proportion of inhibitors can cause their own vascularization. Its angiogenic hub is guided by the same gene transfer that drives malignant transformation: activation of oncogenes 15 and loss of tumor suppressor genes. Many growth factors are used as positive regulators of angiogenesis. The most common ones are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin. Proteins (e.g., thrombospondin (Tsp-Ι), angiostatin, and endostatin) can be used as a negative regulation of angiogenesis. In experimental mice, inhibition of VEGFR2 (but not VEGFR1) was markedly affected. 119 200836725 Angiogenesis hub, neovascularization, and early tumor growth. In late tumors, the blockade properties of phenotypic resistance to VEGFR2 gradually emerged, although the initial inhibition of tumor growth, but the tumor re-growth during treatment. The resistance of this tumor to VEGF resistance is related to the regeneration of tumor angiogenesis and is not affected by VEGF and hypoxia-associated proangiogenic factors, including the FGF family. These different pre-angiogenic signals are implicit in the retreat of blood vessels and tumors, and the blockade of FGF is gradually slowed down by VEGF. In experimental mice, inhibition of VEGFR2 (but not VEGFR1) significantly affected angiogenesis hubs, neovascularization, and initial tumor growth. In the later tumors, the blocking property of the phenotypic resistance of VEGFR2 gradually emerged. Although the tumor growth was inhibited at the initial stage, the tumor grew again during the treatment. The resistance of this tumor to drug resistance of VEGF is related to the regeneration of tumor neovascularization and is not affected by VEGF 15 and hypoxia-related proangiogenic factors, including the FGF family. These different pre-angiogenic signals are implicit in the retreat of blood vessels and tumors, and the blockade of FGF is gradually slowed down by VEGF. It has been reported that an FGF-trap adenovirus 20 line can bind to and block various ligands of the FGF family (FGF1, FGF3, FGF7, and FGF10), and can effectively inhibit in vitro Regeneration of blood vessels within the collective. In fact, the treatment of FGF traps is effective in reducing tumor growth when applied to the regenerative phase of experimental mice relative to the anti-VEGFR2 agent (anti-VEGFR2) alone. This reduction in tumor growth is accompanied by a decrease in angiogenesis (which is observed from the phenomenon of decreased blood vessel density within the tumor).

Batchelor et al. confirmed the use of a pan-VEGF receptor, a protein-dependent protein kinase inhibitor 5 (AZD2171), in the second phase of patients, and normalized the blood vessels of the glioblastoma. (normalization) phenomenon (refer to from Batchelor as α/·, 2007, cancer Ce//, 11(1), 83-95). In the case of living breast cancer, the reason for its use of AZD2171 is the effect of reducing the density of blood vessel distribution (refer to Miller ei d., 2006, C7z_n·; #症和12, 10 281 -288). Furthermore, it has been observed, via the example of an orthotopic glioma, that the time efficiency of transporting an anti-VEGFR2 antibody can be enhanced (optimized) using a radiation method. During normalization, the oxidative condition increases, the pericyte coverage increases, and the angiopoietin-1 increases, resulting in an increase in interstitial pressure and tumor permeability. Increased (reference from Winkler W α/·, 2004, Cancer Ce// 6, 553-563). Its normalization can be quantified by using gradient echo, spin echo, and contrast enhancement of magnetic resonance imaging (MRI), and blood volume and relative vessel size can be measured. , 20 and vascular permeability. The authors noted that the increase in circulating progenitor cells (CPCs) and plasma FGF2 (plasma FGF2) levels after drug blockade confirmed the use of the AZD2171 treatment line in association with increased CECs, SDF1, and FGF2. From the MRI measurement results, an increase in the plasma level of 121 200836725 SDF1 and FGF2 was observed, indicating a relative increase in blood vessel density and size. Thus, the number of normalized blood vessels measured by MRI using circulating biomarkers provides an effective measure of response to antiangiogenic agents.

PDGFR A malignant tumor is a product of uncontrolled cell proliferation. Cell growth is regulated by a slight balance between growth-promoting 10 factor and inhibition of the growth factor (growthinhibiting factor). In normal tissues, these factors control and regulate cell differentiation and growth to maintain the organ in its normal state and function. Malignant cells can escape this control; their natural equilibrium is destroyed (by some mechanisms) and cannot be regulated, causing abnormal cell growth. 15 In the process of tumor growth, an important growth factor is platelet-derived growth factor (PDGF), which contains a family of peptide growth factors, which are via the peptide growth factor. The cell surface tyrosine kinase receptor (PDGFR) transmits information and stimulates various cellular functions 20 (including growth, proliferation, and differentiation). The performance of PDGF has been shown to occur in a number of different solid tumors (including: glioblastomas and prostate cancer). The tyrosine kinase inhibitor Imatinib mesylate, chemical name 4-[(4-methyl-1-piperazinyl)indolyl]-Ν·[4-methyl-3- [[4-(3-Acridine25-yl)-2.yl)pyridyl]amino]-phenyl]benzoguanamine methanesulfonate 122 200836725 (4-[(4-methyl-1 -piperazinyl) Methyl]-N-[4-methyl-3-[ [4-(3-p yridinyl)- 2-ylpyridinyl] amino]-phenyljbenzamide methanesulfonate), which blocks Bcr-Abl oncoproteins and cell surface tyrosine kinase receptors The activity of c-Kit has thus been demonstrated to be useful in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumour. Imatinib mesylate is also a potent PDGFR kinase inhibitor and has recently been used to treat chronic myelomonocytic 10 leukemia based on the activation of PDGFR mutations in these diseases. ) and glioblastoma multiforme. In addition, an oral anticancer drug, Sorafenib (BAY 43-9006), has the chemical name 4-(4-(3-(4-Gas-3(trifluoromethyl)phenyl)ureido)phenoxy) -N2-(2-(4-(4-chloro-3 15 (trifluoromethyl)phenyl)ureido)phenoxy)-N2-methylpyridine - 2-carboxamide), It is lighter than the Raf signaling pathway and the VEGFR/PDGFR signaling cascade, which inhibits cell proliferation and tumor angiogenesis. Sorafenib is currently being developed for the treatment of a range of cancers including hepatitis and kidney cancer. 20 These symptoms are all diseases associated with PDGFR activation (eg, hypereosinophilic syndrome). The activation of PDGFR is also associated with other malignancy, including: chronic myelomonocytic leukemia (CMML). In another malignant disease, dermatofibrosarcoma 25 protuberan, a permeable skin tumor, causes chimerism when the gene encodes a reciprocal translocation of the PDGF-B coordination 123 200836725 base. (chimeric) constitutive secretion of the ligand and activation of the receptor. Imatinib, a PDGFR inhibitor, has activity against these three diseases. Advantages of Selective Inhibitors The development of differentiated, selective FGFR kinase inhibitors provides a new opportunity to use these standard light agents in sub-group patients (with diseases caused by FGFR regulatory disorders) ) treatment. Compounds with lower inhibitory activity against the activity of additional 10 kinases (particularly VEGFR2 and PDGFR-beta) provide an opportunity to have differentiated side-effect or toxicity profile to The indications for these treatments are more effective. Inhibitors of VEGFR2 and PDGFR-beta are associated with toxicity (eg, associated with hypertension or edema, respectively). When a 15 VEGFR2 inhibitor is used, the condition of hypertension limits the amount of drug used and may therefore limit the use of certain patients and require clinical management. Biological Activity and Use of Treatment 20 The compounds of the present invention, and subsets thereof, inhibit or modulate the activity of fibroblast growth factor receptor (FGFR) and/or inhibit or regulate vascular endothelial growth Activity of vascular endothelial growth factor receptor (VEGF), and/or inhibition or regulation of platelet derived growth factor receptor 25, and which can be used as a prophylaxis or treatment at 124 200836725 Said related diseases. Furthermore, the compounds of the invention, and subsets thereof, can be used as a prophylactic or therapeutic kinase related disease or infection. The prevention or treatment of a disease state or the meaning of an infection (e.g., cancer) as described herein includes alleviating or reducing the symptoms of cancer. 5 Here, the term "modulation" means that it is applied to the activity of stimulating _, which is expected to change the biological activity of the kinase protein. Thus, modulation encompasses physiological changes that can significantly increase or decrease kinase activity. In the following examples, the adjustment may be interpreted as r inhibition." The tune () section can be performed directly or indirectly, and may be regulated by any mechanism and any physiological level 10, including at the level of gene expression (including, for example, transcription, translation, and / or post-translational modification, the level at which a gene encodes a regulatory element that directly or indirectly affects kinase activity. Thus, modulation may imply an increase/inhibition of the performance, or over-expression, or low performance of the kinase, including 15 gene amplification (ie, ploidy replication of the gene) and/or increased or decreased performance via transcriptional effects, As with hyper- (or hypo-) activity and by (de-)activation of the kinase protein (de-) activation. Here, "modulated", "modulating", and "modulate" all have the same meaning. 20 Here, the term "mediated", as described in conjunction with a kinase in a text (applies to various physiological processes, diseases, states, conditions, treatments) Therapies), treatments, and interventions are applied to these various steps, diseases, conditions, conditions, treatments, and in a limited state, so that the kinase can act as a living organism. Sexual roles are among them. When the term refers to a disease, state, or condition, its biological role through a kinase may be direct or indirect, and may be necessary and/or sufficient to diagnose the condition, or state of the disease (or Further, the reason). Thus, the activity of 5 kinases (and especially abnormal kinase activity, such as overexpression of kinases) need not be the biggest cause of disease, condition, or condition; conversely, after careful consideration, kinase-related diseases and conditions Among the states, or states (including multifactorial aetiologies and complex pathways), their kinases are only partially involved. When the term refers to treatments, prophylaxis, or interventions, the biological role played by a kinase may be direct or indirect and may be necessary and/or sufficient. To diagnose, prevent, or cure: its intervention. Thus, the disease state or condition is associated with a kinase and includes resistance to any drug or course of treatment for cancer. 15 Thus, for example, in the present invention The compound is assumed to be useful for alleviating or alleviating the effects of cancer. In particular, a compound represented by the formula (I) and a sub-group thereof are inhibitors of FGFR. For example, the compound of the present invention has a FGFR1 And FGFR2, FGFR3, and/or FGFR4, and more particularly, are selected from the group consisting of FGFR1, FGFR2, and FGFR3. Preferred compounds are one or more selected from the group consisting of FGFR1. Compounds of FGFR2, and FGFR3, and FGFR among FGFR4. Preferred compounds of the invention are those having an IC5G value of less than 0.1 μΜ. 126 200836725 The compounds of the invention also have Properties against VEGFR. The compounds of the invention also have properties against PDGFR kinase. In particular, the compounds are inhibitors of PDGFR, for example, inhibiting PDGFR A and/or PDGFR B. 5 Furthermore, many of the compounds of the invention have The selectivity of FGFR 1, 2, and/or 3 kinases, and/or FGFR4 relative to VEGFR (particularly VEGFR2) and/or PDGFR, and such compounds are a preferred embodiment of the invention. In particular, the compound has selectivity for VEGFR2. For example, many of the compounds of the invention have an IC5 value against FGFR1, 2, and / 10 or 3, and/or FGFR4 against VEGFR (in particular, VEGFR2) and / Or the IC5 enthalpy of PDGFRB is ten to one hundred times. In particular, the preferred compound of the present invention has a characteristic of 10 times or more against or inhibiting FGFR (particularly, FGFR1, FGFR2, FGFR3, and/or FGFR4), More preferably, the compound of the present invention has 100 times or more the property of inhibiting or inhibiting FGFR (particularly 'FGFIU, FGFR2, FGFR3, and/or FGFR4), relative to or against VEGFR2. and It can be achieved by the methods described herein. For the regulation or inhibition of the activity of FGFR, VEGFR and/or PDGFR, 20 such compounds are resistant to soil growth or tumor-inducing cells. ,is useful. Thus, it is expected that this compound can be used to treat or prevent non-hyperplasia, such as cancer. Further, the compound of the present invention can be used for the treatment of a disease in which the disease is abnormal hyperplasia, cell dying, or differentiation. 127 200836725 In particular, a tumor having a VEGFR activating mutation, or a tumor having a VEGFR elevation, and a patient having a high level of serum lactate dehydrogenase may be particularly sensitive to the compounds of the present invention. A patient having any of the isoform 5 activating mutations of any of the specific RTKs described herein may be treated with a compound of the invention. For example, VEGFR may be overexpressed in acute leukemia cells, in which progenitor cells can be expressed in VEGFR in acute leukemia cells. In addition, a particular tumor (having an activated mutation, or an elevation of any FGFR isoform, or overexpression (eg, 10 FGFR1, FGFR2, or FGFR3, or FGFR4)) may be particularly susceptible to the compounds of the invention, and thus Patients with this particular tumor can be treated with the compounds of the invention. Preferably, the treatment is directed to or directed against a mutant form of the receptor tyrosine kinases described herein. The method of detecting a tumor having this mutation can be carried out by a conventional method (e.g., RTPCR and FISH). Cancers that can be treated include, but are not limited to, cancer, such as bladder cancer, breast cancer, colon cancer (eg, colorectal cancer, colon adenocarcinoma, colon adenoma), kidney Cancer, epidermis cancer, liver cancer, lung cancer (eg 'lung adenocarcinoma, small cell lung cancer, and non-small cell lung carcinoma, esophageal cancer, gallbladder (gal Bladder, ovarian cancer, pancreatic cancer (eg, exocrine pancreatic carcinoma), gastric cancer, cervix cancer, endometrium cancer, thyroid cancer, prostate (prostate) cancer, or skin cancer (eg, 128 200836725 squamous cell carcinoma); hematopoietic tumour of lymphoid lineage (eg, leukemia, acute lymphocytic) Leukemia), chronic lymphocytic 5 leukemia, B-cell lymphoma, Τ·cell lymphoma (Tc Ell lymphoma), Hodgkin's Lymphoma, non-Hodgkin's Lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoiesis Hematopoietic tumour of 10 myeloid lineage (eg, leukemia, acute and chronic myelogenous leukemias, bone marrow: myeloproliferative syndrome, myelodysplastic syndrome) ), or promyelocytic leukemia; multiple myeloma: thyroid follicular cancer; Tumors of Mesenchymal origin (eg, fibrosarcoma)

20 (fibrosarcoma), or rhabdomyosarcoma); central or peripheral nervous system tumors (eg, astrocytoma, neuroblastoma, glioma, or schwannomas) Schwannoma); melanoma; seminaloma; terato carcinoma; osteosarcoma (Osteosarcoma); xeroderma pigmentosum; keratoctanthoma; thyroid follicular Carcinoma; or Kaposi's sarcoma. 129 200836725 Certain cancers are resistant to specific drugs. They may be caused by the type of tumor itself or the compound used for treatment. Therefore, 'multiple osteosynthesis The reference meaning of (multiple myeloma) includes: proteosome inhibitor (bortezomib) sensitive multiple myeloma, or refractory multiple osteomyelitis. Similarly, chronic myelogenous leukemias (chronic myelogenous leukemias) Reference significance includes: chronic osteogenic leukemia sensitive to imitanib and refractory (refrac Tory) Chronic myelogenous leukemia (chronic myelogenous leukemias) also known as chronic myeloid leukemia, chronic granulocytic leukem, or CML. Acute myelogenous leukemia, also known as acute myeloblastic leukemia, acute granulocytic leukemia, acute non-mphocytic leukaemia, or AML transcript The compounds of the invention may also be used in the treatment of hematopoetic diseases of abnormal cell proliferation, whether pro-malignant or stable (e.g., myeloproliferative diseases). Myeloproliferative diseases 20 (myeloproliferative diseases, MPD) is a disease group in which bones multiply with excess cells. It is associated with myelodysplastic syndrome and may gradually evolve into myeloproliferative syndrome. Myeloproliferative diseases include: Poiycythemia vera (PV), essential thrombocytopenia (essential 130 200836725 thrombocythemia), and primary myelofibrosis (also: T-cell) T-celllymphoproliferative disease contains such diseases that have evolved from natural killer cells. Herein, the term "B-cell lymphoma" includes a diffuse large B-cell lymphoma. In addition, the compound of the present invention can be used for the gastrointestinal tract. Cancer (also known as gastric cancer) (eg, gastrointestinal stromal tumour). Gastrointestinal cancer means the gastrointestinal tract in a malignant state, including: esophagus, stomach, liver, biliary system, pancreas, bowels, and anus (anus). The 15 cases of the tumour of mesenchymal origin are Ewings Sarcoma. Thus, among the pharmaceutical compositions, a disease or infection having abnormal cell growth is treated by the method of the present invention, and an example of the disease or infection in which the abnormal cells grow is cancer. Special subsets of cancer include: multiple myeloma, bladder cancer, cervical cancer, prostate, and thyroid cancer, lung cancer, breast cancer, and intestine cancer. Another subset of cancers include multiPle myeloma, bladder cancer, and cervical cancer. Furthermore, the compounds of the present invention may have an effect of inhibiting the activity of FGFR (e.g., FGFR1) 131 200836725 5 Ο 10 15 ϋ 20, and may be particularly useful for treating or preventing breast cancer, particularly typical Lobular carcinoma. . The compounds of the present invention have FGFR4 activity and are therefore useful for treating prostate or pituitary cancers. In particular, the compounds of the present invention are useful as FGFR inhibitors and are therefore useful in the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder (bladder) cancer, lung cancer, ovarian cancer (Ovarian Cancer), breast cancer, stomach cancer, colorectal cancer, and oral squamous cell carcinoma 〇, subset of cancer Also included is multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal Cancer, and thyroid cancer. In particular, the compounds of the invention may treat multiple myeloma (in particular, multiple myeloma with t(4; 14) transfer or FGFR3 overexpression), prostate (prostate) Cancer (hormone refractory prostrate carcinoma), endometrial cancer (in particular, endometrial tumor with activating mutation in FGFR2), and breast cancer (in particular, lobular Breast cancer). In particular, the compounds can treat lobular carcinoma in situ (eg, typical lobular in situ 132 200836725 carcinoma (CLC) o compounds that have a function of resisting FGFR 3 activity can be used as a treatment for multiple myeloma and multiple myeloma Bladder tumor. In particular, its compound can be used to treat t(4; 14) translocation positive multiple myeloma. Compounds with resistance to FGFR 2 activity can be used. For the treatment of endometrial cancer, ovarian cancer, gastric cancer and colorectal cancer. FGFR2 also has a phenomenon in epithelial ovarian cancer 10, so the present invention The compounds may be particularly useful for the treatment of ovarian cancers (e.g., epithelial ovarian cancers). The compounds of the invention may also be useful in the treatment of tumors with VEGFR2 inhibitors or VEGFR2 antibodies (e.g., Avastin). )) - used as pre-treatment with 15 . In particular, the compounds of the invention may also be used for treatment Anti-VEGFR2 tumor (VEGFR2_resistant tumour) 〇 VEGFR2 inhibitor or antibody can be used to treat thyroid cancer and renal cell carcinoma, so the compound of the present invention can be used for the treatment of 20 anti-VEGFR2 symptoms Adenocarcinoma and renal cell carcinoma. Such cancers may be inhibitory against any one or more FGFRs selected from: FGFR1, FGFR2, FGFR3, FGFR4 (eg, one or more FGFRs selected from: FGFR1, FGFR2, or FGFR3) Cancer with sensitivity. 133 200836725 Whether a specific or non-specific cancer is sensitive to the will of FGFR, VEGFR or PDGFR signaling, Cell growth can be used (Cel1 growth as Say): Examples 79 and 80 are blocked. In the above, or identified by the method described in the section "Methods of Diagnosis". Further, the 'compound of the present invention' has an activity of inhibiting FGFR, VEGFR, or PDGFR. A compound which is particularly effective for use in the treatment or prevention of cancers based on the number of & upgrades of FGFR, VEGFR, or PDGFR, for example, Section herein describes the beginning of the cancer in the content of 10. According to the researchers, certain FGFR inhibitors can be used with other anticancer agents. For example, it binds to an inhibitor having an effect of inducing apoptosis and another agent which uses a different mechanism to regulate cell growth, and thus can simultaneously have two pharmacological properties for treating cancer development. An example of such a combination will be described below. Furthermore, the compounds of the invention may be used to treat other symptoms caused by hyperplasia, such as type 2 diabetes or non-insulin deficiency diabetes, autoimmune disease, head trauma, stroke (stroke) ), epilepsy, neurodegenerative disease (eg, Alzheimer's disease), motor neurone disease, progressive nucleus pruritus Progressive supranuclear palsy, corticobasal degeneration, and Pick's disease (eg, autoimmune disease and neurodegenerative disease). 134 200836725 For its sub-group of diseases, the compounds of the invention are useful in the treatment of: inflammatory diseases, neovascular diseases, and wound healing 〇FGFR, VEGFR and PDGFR, as known, in cells 〉Autumn 5 (apoptosis), angiogenesis, cell proliferation, cell differentiation, and cell metastasis play an important role, and thus the compounds of the present invention can also be used to treat diseases other than cancer: chronic inflammatory diseases , such as systemic Lupus Erythematosus, autoimmune mediated 10 glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease ), autoimmune diabetes, Eczema hypersensitivity reaction, asthma (asthma), COPD, rhinitis, and upper respiratory tract 15 disease; cardiovascular disease, such as cardiac hypertrophy (cardiac hypertrophy) Restenosis, atherosclerosis; neurodegenerative disease, such as Alzheimer's disease, AIDS-related dementia, Parkinson's disease, Parkinson, Disease ), amyootropic lateral sclerosis, retinitis pigmentosa, spinal muscular atophy, and cerebellar degeneration; glomerulonephritis (glomerulonephritis); myelodysplastic syndrome, ischemic injury-related myocardial infarction 135 200836725 (myocardial infarction), stroke (stroke) and reperfusion injury, arrhythmia ), atherosclerosis, toxin-induced or alcoholic liver disease, haematological disease, such as: chronic anemia (chronic 5 anemia) and aplastic anemia (Aplastic Anemia); musculoskeletal system Degenerative diseases such as: osteoporosis (Osteoporosis) and arthritis (Arthritis), aspirin-induced asthma (aspirin-sensitive rhinosinusitis), cystic fibrosis (cystic fibrosis), multiple sclerosis (multiple sclerosis), kidney diseases, and cancer pain. In addition, the mutation of FGFR2 is associated with many serious abnormalities in human bone development, so the compounds of the present invention can be used to treat abnormalities in human bone development, including: ossification of cranial sutures Craniosynostosis, apex refers to apert syndrome (AP), Crouzon's disease, Jackson-Weiss's disease, 15 Beare-Stevenson's cutis gyrate syndrome, and Pfeiffer's disease. Further, the compound of the present invention has an ability to inhibit the activity of FGFR (e.g., FGFR2 or FGFR3), and thus can be particularly useful for treating or preventing skeletal diseases. The specific skeletal muscle-related disease is soft 20 bone atrophy (achondroplasia) or thanatophoric dwarfism (also known as thanatophoric dysplasia). The compound of the present invention has the activity of inhibiting FGFR (eg, FGFR1, FGFR2 or FGFR3). The ability to specifically treat diseases that are used to treat or prevent fibrotic symptoms. Diseases of the present invention for treating fibrotic symptoms 136 200836725 Includes diseases in which abnormal or excessive fibrotic deposition is present in tissues, such as: liver cirrhosis, glomerulonephritis, pulmonary fibrosis (pulmonary) Fibrosis), systemic fibrosis, rheumatoid arthritis, and the natural process of wound healing. In particular, the compounds of the invention have the effect of treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis. In the tumor-associated vasculature, the overexpression and activation of FGFR and VEGFR provide the research of the compound of the present invention as a preventive and disruptive effect on tumor angiogenesis. In particular, the compounds of the invention may be useful in the treatment of cancer, cancer metastasis (Metastasis), leukemia (eg, CLL), ocular diseases (eg, age-related macular degeneration, especially wetness). (wet form) age-related macular degeneration eye), lack of 15 bloody proliferative retinopathy (ischemic proliferative retinopathies) (eg, retinopathy of Prematurity (ROP) and diabetic retinopathy (Diabetic Retinopathy), rheumatoid joints Rheumatoid arthritis, and hemangioma. Since the compounds of the present invention inhibit PDGFR, they can also be used to treat some tumors as well as leukemias, including: glioblastomas (eg, glioblastoma multiforme, prostate) Cancer, gastrointestinal stromal tumour, liver cancer, kidney cancer, chronic myeloid leukemia, chronic mononuclear leukemia 137 200836725 (chronic myelomonocytic leukemia, CMML), and excessive eosinophilia Hypereosinophilic syndrome, rare proliferative blood disease, and dermatofibrosarcoma protuberan, infiltrative skin tumour 〇5 The compounds of the present invention inhibit FGFR1-4, VEGFR and/or PDGFRA/ The efficacy of B can be measured using the experimental method described below, and the measured inhibition of the compound can be expressed as an IC5G value. Preferably, the compound of the present invention has an IC5G value of less than ΙμΜ, more preferably less than 0.1 μΜ. The compound provided has inhibition or regulation 10 functions of FGFR activity, and envisioned for preventing or treating diseases or symptoms associated with FGFR kinase. In one embodiment, the invention provides a compound for use in therapy. In yet another embodiment, the invention Provided is a disease or a symptom for preventing or treating FGFR kinase. 15 Thus, for example, the compound of the present invention can be used for soothing or alleviating the symptoms of cancer. Therefore, in one aspect, the present invention provides a compound. For the preparation of a medicament for the prevention or treatment of a disease or condition associated with FGFR kinase, the compound of which is as defined in formula (1). 20 In one embodiment, the invention provides a compound for use in the preparation of a An agent for preventing or treating a disease or a symptom as described herein is produced. In still another embodiment, the present invention provides a compound for use in the preparation of an agent for the prevention or treatment of cancer. Providing other: 138 200836725 A method of preventing or treating a disease or symptom associated with FGFR kinase, the method comprising administering a patient A compound of the formula (I). In one embodiment, a method for preventing or treating a disease or a symptom as described herein is provided, which comprises administering a compound of the formula 5 as shown in the formula (1). In still another embodiment, a method of preventing or treating cancer is provided, the method comprising administering to a patient a compound of the formula (1). A method of soothing or ameliorating a disease or symptom associated with FGFR kinase, the method comprising administering a compound of the formula (1) to a patient. A method for inhibiting FGFR kinase, the method comprising contacting the kinase with a compound of the formula (I) having an inhibitory kinase property. A method of using a compound of the formula (I) to inhibit FGFR kinase activity to modulate cellular processes such as cell division. A compound represented by the formula (I) is used as a regulation of a cellular process (e.g., cell division) by inhibiting FGFR 15 kinase activity by using a compound represented by the formula (I). A compound represented by the formula (I) is used as a modulator (e.g., an inhibitor) of FGFR. A compound such as the formula (1) is used to produce an agent which modulates (e.g., inhibits) FGFR activity. A compound of the formula (I) is used to produce an agent which modulates cellular processes (e.g., cell division) by inhibiting the activity of FGFR. The use of a compound of formula (I) to produce an up-regulation of GF 200836725 5 c, 10 15 u 20 for the prevention or treatment of FGFR kinase (eg, FGFR1, FGFR2, FGFR3, or FGFR4) An agent for a disease or condition. A compound represented by the formula (I) is used to produce an agent for preventing or treating cancer caused by an increase in FGFR kinase (e.g., FGFR1, FGFR2, FGFR3, or FGFR4). The compound of the formula (I) is used to produce an agent for preventing or treating a cancer patient, and the cancer is selected from the group consisting of a genetic aberration having a FGFR3 kinase. A compound as shown in the chemical formula (1) is used to produce an agent for preventing or treating a cancer patient, and the patient is diagnosed as a subgroup having a partial genetic aberration of FGFR3 kinase. A disease caused by the promotion of an increase in FGFR kinase (e.g., FGFR1, FGFR2, FGFR3, or FGFR4), which comprises administering a compound of the formula (1). A method of soothing or alleviating a disease or condition caused by an increase in FGFR kinase (e.g., FGFia, FGFR2, FGFR3, or FGFR4), the method comprising administering a compound of the formula (I). A method of preventing or treating (or soothing to reduce) a & cancer pain or presumed to have a cancer patient, the method comprising: (1) causing a patient to undergo a medical test to determine whether it has a FGFR3 gene mutation (§enetic) And (ii) the patient having the FGFR3 gene mutation is administered to a compound represented by the formula (1) (having an ability to inhibit FGFR3 kinase activity). A method for preventing or treating (or soothing or alleviating) a disease caused by an increase in FGFR kinase (eg, FGFR1, FGFR2, FGFR3, or FGFR4) 140 200836725 or a symptom; the method comprising: (1) making a patient undergo a diagnosis test to determine Whether or not the FGFR kinase (eg, FGFR1 'FGFR2, FGFR3, or FGFR4) is elevated, and (ii) subsequently administering the compound having the FGFR kinase elevation to a compound of the formula (I) (having FGFR kinase activity inhibits 5). Mutant kinases Drug-resistant kinase mutations increase the number of patients treated with kinase inhibitors. At the time of treatment, this condition occurs, in part, in areas of the protein that bind to or react with a particular 10 inhibitor. Such mutations reduce or increase the binding of the inhibitor to the kinase and the occurrence of inhibition. It can occur on any amino acid fragment that reacts with the inhibitor or that has a support for the target binding to the inhibitor. An inhibitor that does not require binding to a mutated amino acid fragment, which may be less susceptible to mutations and maintain effective inhibition of the enzyme during binding to the labeled stem kinase 15. Characteristics (Reference to Carter da/ (20〇5), PNAS, 102(31), 11011-110116). These mutations have been found in PDGFR in patients receiving imatinib, especially the T674I mutation. The clinical importance of these mutations 20 is growing and is believed to be the underlying mechanism of impedance src/Abl inhibitors in patients. In addition, the phenomenon of chromosomal translocation or point mutation is also found in FGFR, so that gain-of-function, over-expressed, or an increase in activated biological state can be achieved. 25 Therefore, the compounds of the present invention are particularly useful for the expression of a mutant molecule 141 200836725 (e.g., FGFR or PDGFR (a T674I mutant comprising PDGFR-beta and PDGFR_alpha, particularly PDGFR)). Methods for diagnosing such tumors can be judged using techniques well known in the art (e.g., RTPCR and FISH). 5 It is known that mutations in the retained threonine residue of the ATP binding site in FGFR can cause resistance to the inhibitor. In FGFR1, the amino acid proline 561 (valine561) is mutated to Methionine, which is associated with the mutations found in the aforementioned Abl (T315) and EGFR (T766), and the Abl 10 (T3 15) And the EGFR (T766) line is associated with resistance to selective inhibitors. The experimentally confirmed data indicates that the mutant of FGFR1 V561M has resistance to tyrosine kinase inhibitors relative to the wild type. 15 Pharmacy Formulations Since the active compound can be administered directly, it is preferably presented as a pharmaceutical composition (eg, a formulation) containing at least one active compound of the invention, and one or A plurality of pharmaceutically acceptable carriers, adjuvants, excipients, diluents 20, fillers, buffers, stabilizers, preservatives Preservatives, lubricants, or other conventional materials, and optionally other therapeutic or prophylactic agents. Accordingly, the present invention further provides a pharmaceutical composition as described above, and provides a preparation comprising a mixture of at least one of the above-described active compounds and one or more drugs 142 200836725, a commercially acceptable carrier, excipients Pharmaceutical compositions of buffers, adjuvants, stabilizers, or other conventional materials. As such, the term "pharmaceutically acceptable" relates to a compound, material, composition, and/or agent (inclusion) which, under sufficient medical judgment, may be The tissue of a body (eg, human) is used in contact without excessive toxicity, moodiness, depression, or other problems or complexity, and the ratio of benefits/harm is within a reasonable range. Each carrier, adjuvant, etc. must also be "pharmaceutically acceptable" to be compatible with other materials 10. A pharmaceutical composition comprising a compound of the formula (I) can be exemplified by a conventional technique such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. Further, in another aspect, the present invention provides a compound as shown in Chemical Formula (I) 15 and a sub-group thereof, and is presented in the form of a pharmaceutical composition. Its pharmaceutical composition can be administered orally, parenterally, intranasally

V (intranasal), ophthalmic, otic, rectal, intra_vaginal, or transdermal administration. These 20 are originally composed of parenteral drugs, which can be administered intravenously, intramuscularly, intraperitoneally, subcutaneous directly or by injection, infusion or other methods. Dosing. The drug delivery method can be delivered by rapid injection (Bolus 143 200836725 injection), short term infusion, or interm term infusion via the use of a suitable infusion pump. Pharmaceutically acceptable formulations for parenteral administration include water-soluble and water-insoluble sterile injection solutions, which may contain 5 anti-oxidants, buffers, and bacteriostats. Co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposomes Composition 10 components (to form a liposome), gelable polymers (to form a polymeric gel), lyophilisation protectants, and combinations of these agents, especially The active composition is stabilized in a soluble form, and the formulation is adjusted to a state of osmotic pressure with the blood of the recipient. The pharmaceutically acceptable formulation for parenteral administration may be a water-soluble and water-insoluble sterile suspension, and may contain a suspension reagent and a thickening agent (referred to from R. G. Strickly (2004), Solubilizing excipients u. in oral and injectable formulations, Pharmaceutical Research, Vol 21(2), p 201-230). 2〇Liposomes are closed globular vesicles containing an outer lipid bilayer membrane and an internal water-soluble core layer with a total diameter of approximately <100 μιη. Depending on its hydrophobicity, a drug with moderate hydrophobicity can be coated or embedded in the liposome and dissolved in the liposome. If the drug becomes part of a lipid bilayer membrane, the hydrophobic drug can also be dissolved in the liposome, and in this case, the hydrophobic drug 25 is dissolved in the lipid site of the lipid bilayer membrane. 144 200836725 5 c 10 15 Ο 20 This formula can be packaged in single or multiple doses, such as sealed ampoules and vials, and can also be stored in a refrigerated (lyophilized) state. In addition, a sterile liquid carrier (e.g., water) may be added for use as an injection prior to use. A pharmaceutically acceptable formulation can be obtained via lyophilising, a compound of formula (1), or a subset thereof. The lyophilising process requires a composition to be freeze dried. The terms freeze-drying and lyophilization are synonymous here. Immediate injections and suspensions can be prepared via sterile powders, granules, and pills. The pharmaceutical composition for parenteral injection of the present invention may also comprise a pharmaceutically acceptable sterile water-soluble and water-insoluble solution, dispersing agent, suspending agent, or emulsifier, so that the sterile powder can be sterile before use. The solution is dissolved or dispersed to be suitable for use. Suitable water-soluble and water-insoluble carriers, diluents, solvents, or vehicles, including water, ethanol, and polyalcohols (eg, glycerol, propylene glycol) Propylene glycol), polyethylene glycol, and the like, carboxymethylcellulose and mixtures thereof, vegetable oils (eg, olive oil), and injectable organic esters (eg, Ethyl oleate). Proper fluidity can be adjusted, for example, by using a coating material (e.g., lecithin), dispersing the appropriate particle size, and using an surfactant. The compositions of the present invention may also comprise adjuvants (e.g., preservatives, wetting agents, emulsifying 145 200836725 agents, and dispersing agents). In order to prevent the growth of microorganisms, a series of antibacterial agents and antifungal agents such as paraben, chlorobutanol, phenol sorbic acid, and It is similar to 5 things. It may also contain an isotonic agent (e.g., sugar, sodium chloride, and the like) as needed. In order to prolong the absorption time of the injectable drug, a preferred embodiment of the present invention may be obtained by an agent which prolongs absorption (for example, aluminum monostearate and gelatin). The system is administered in a form suitable for administration, such as injection or infusion. In the case of intravenous injection, the solution can be prepared or injected into an infusion bag containing a pharmaceutically acceptable adjuvant (eg, 0.9% salt or 5%) prior to administration. glucose). In another preferred embodiment, the pharmaceutical composition is administered sub-cutaneously (s.c.) in an appropriate form of 15. Pharmaceutically acceptable agents for oral administration include tablets, capsules, caplets, pills (卩1118), (1〇261^68), (8>^:1^8), solutions (solutions), powders, granules, (elixirs) and suspensions, sublingual tablets, wafers or patches, and buccal patches ). Thus, the composition of the tablet may comprise a single formulation of the active compound together with an internal diluent or carrier (eg, a sugar or sugar alcohol (eg, lactose, sucrose, sorbitol, or mannitol). And/or non-saccharide-derived diluents (eg, sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof 146 200836725 (eg, mercapto cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl) Phenolic hydroxypropyl methyl cellulose, and starch (eg, corn starch). The tablet may also contain standard components such as binding and granulating agents (eg, polyvinylpyrrolidone) , disintegrants 5 (eg, swelling: cross-linked polymers (eg, cross-linked carboxymethylcellulose), lubricants (eg, stearates), preservatives ( Preservatives) (eg, paraben), antioxidants (eg, BHT), buffers (eg, acidate or f4 citrate buffer), and blowing agents (eg, citric acid) Salt/bicarbonate mixed compound Such adjuvants are well known and therefore need not be discussed further herein. Capsules can be administered in the form of gelatin or soft gels and include solid, semi-solid, or liquid forms. The active compound is formed therein. The gel capsule can be formed from an animal gel, or a synthetic, or plant-derived equivalent. 15 The solid pharmaceutical form (eg, tablets, capsules, etc.) can be coated or uncoated, and Typically, there is a coating such as a protective coating (e.g., wax or lacquer) or a release controlling coating. The coating I;: a coating (e.g., a propionate resin (Eudragit) The polymer) can be designed to have the property of releasing the active composition between the gastrointestinal tract. Therefore, the coating system 20 is designed to be lysed under the pH condition of a certain gastrointestinal tract, and optionally The compound is released in the stomach, or in the ileum, or in the duodenum. In addition to the coating, the agent may be presented in a solid matrix comprising a release agent (eg, 'release delay') The compound can be released in different acidic or alkaline environments in the gastrointestinal tract by 147 200836725. In addition, the matrix material or release-delay coating can be erodible polymers (eg, anhydrous horses) Maleic anhydride polymer, which sustainably corrodes when the agent passes through the gastrointestinal tract. Alternatively, the active compound can be shipped in a system for controlling the permeability of the compound. The above-described formulation for permeability control release, and other delayed release, or sustained release can be prepared according to the methods of the prior art. The pharmaceutical composition comprises from about 1% to about 95%, preferably from about 20% to about 90%, of the active ingredient. For example, the pharmaceutical composition of the present invention may be a single 10 agent (e.g., Ampoules, vials, suppositories, drags, tablets, or capsules). It is obtained by combining the active composition with a solid carrier, and if necessary, granulating the obtained mixture, after adding appropriate excipients to the drug bond, the dragee core, or the gel 15 capsule. The mixture may be reprocessed as needed. It may also be incorporated into a plastics carrier to allow the active composition to be dispersed, dispersed or released at a measured level. L/ The compounds of the invention may also be formulated Solid dispersion. Solid dispersion is a homogeneous fine dispersion phase with two or more solids in it. Solid solution (20 sub-dispersion system), a kind of solid dispersion, which is widely used in medicine (see ( Chiou and Riegelman (1971), J. Pharm. Sci., 60, 1281_1300), which are effective for increasing the rate of dissolution and increasing the biological efficacy of drugs which are not readily soluble in water. A solid dosage form of the above solid solution 148 200836725 (solid dosage). The solid dosage form comprises tablets, capsules, and chewable tablets. Conventional adjuvants can be used with The solid solution is mixed to provide the desired dosage form. For example, a capsule may comprise a solid solution and a disintegrant and a lubricant ' or (b) a disintegrant, a lubricant, and a surfactant. A tablet may contain the solid solution and at least a disintegrant, a lubricant, a surfactant. And a glidant. Chewable tablets may comprise a solid solution with a bulking agent, a lubricant, and a sweetener (such as artificial a sweetener), and a suitable fragrance. The pharmaceutically acceptable formulation can be a "patient packs" containing all of the requirements for a single treatment, usually Blister pack. The advantage of the patient pack over traditional prescriptions is that 15 patients are allowed to access the patient's contents because the patient's pack is the item required by the patient from a large medical source. It is usually not possible for patients to find the necessary use of large medical sources by themselves. The contents of the patient's pack can help the patient follow the medical instructions. Compositions for topical use include ointments, salves, sprays, patches, 20 gels, droplets, and implants (eg, ophthalmic implants). Such compositions can be prepared by conventional techniques. The rectal and intravaginal administration comprises pesosades and suppositories, for example, which can be prepared via preforming or waxy materials comprising one of the active compounds. ° 149 200836725 Inhalation administration can be achieved by inhalation of powder composition or liquid or powder spray, or by standard type of inhalation device or sprayer (aeros〇l dispensing devices). Inhalation administration, the powder generally comprises both the active compound and an inert solid powder diluent (e.g., lactose). 5 A compound of formula (I) may be presented as a single pharmaceutical form and will generally contain sufficient compound to achieve the desired biological activity. For example, the formulation may comprise from 1 nanogram to 2 grams of active composition (e.g., 1 ng to 2 mg of active composition). In this range, a particular secondary range is from 0.1 mg to 2 g of active composition (generally more than 1 mg to 1 g 10 (eg, 50 mg to 500 mg)), or 1 microgram to 20 mg (eg, ,; [Symotic to 10 mg (eg '0.1 1 gram to 2 mg)) active composition. For oral administration, a single agent may contain from 1 mg to 2 g, more typically from 10 mg to 1 g, such as from 50 mg to 1 g, (e.g., from 1 mg to 1 g) of the active composition. The active compound can be administered in a sufficient amount (e.g., in a human or animal condition) to achieve the desired medical effect. Examples of Pharmacy Compositions (1) Drugs 钹 20 A tablet containing a compound of the formula (I) can be obtained by mixing 50 mg of the compound with 197 mg of lactose (Bp) as a diluent. And 3 mg of magnesium stearate as a lubricant, which is obtained by compression into a tablet by a conventional technique. 25 (ii) Capsules 150 200836725 Capsules are prepared by mixing 100 mg of a compound of formula (I) with 100 mg of lactose and filling the mixture into a standard opaque hard sac (standard opaque hard) Gelatin capsules)

5 (iii) Injectable Form I parenteral injection is carried out by dissolving a compound of formula (I) (eg, a salt form) in water containing 10% propylene glycol. A solution of 1.5 weight percent of active compound is obtained. The solution was filtered, filled into an ampoules (Ampoules), and sealed 10 .

Πν) Injectable Form II The parenteral injection method is a compound (for example, a salt form) (2 mg/ml) and a mannitol (50 15 mg/ml) as shown in the formula (I). Dissolve in water, sterilely filter the solution and fill in a sealable 1 ml vial or ampoule.

(v) Injectable Form III The formulation of the iv delivery via injection or infusion may be dissolved in 20 mg/ml of water by a compound (e.g., a salt form) as shown in formula (I). be made of. The vial was sealed and sterilized by high pressure.

(vi) Injectable Form IV Formulation 25 for intravenous administration via injection or infusion may be prepared by dissolving a compound (e.g., a salt form) as shown in formula (I) in 151 200836725 with a buffering agent. (eg, 0. 2 Μ acetic acid pH 4.6) in 20 mg/ml water. The vial was sealed and sterilized by high pressure. (vii) Subcutaneous injection form 5 The method of subcutaneous administration can be carried out by mixing a compound of the formula (I) with a pharmaceutically acceptable grade of corn oil to obtain a solution having a concentration of 5 mg/ml. The composition is then sterilized and placed in a suitable container. Viii); Lvophilised type 10 A test solution of a compound of the formula (I) is placed in a 50 ml vial and lyophilized. During the drying process, the composition was frozen using a one-step freezing method (at -45 °C). Raise the temperature to -10 ° C, then to -45 ° C, then the first drying at +25 ° C for 3400 minutes, then increase the temperature to 50 ° C at a progressive speed for secondary drying . The pressure between 15 dry and secondary drying is set to 80 millitor. 〇 Treatment The above-mentioned compounds of the formula (I) and subsets thereof can be used for the prevention or treatment of FGFR-related diseases or infections. Examples of diseases and infections have been described in the previous section. This compound is generally administered to a receptor which is required to be accepted, for example, a human or animal patient, preferably a human. The amount administered to the compound is an effective amount for the treatment or prevention of the disease, and is usually a non-toxic amount. 25 However, in certain conditions (eg, life-threatening diseases), 152 200836725 The amount of the compound shown in formula (i) may be out of range and has toxic effects or side effects, so it must be considered when administering the drug. To the required amount and the corresponding toxic level. 5 〇 10 15 ί 20 This compound can be administered over a long period of time in treatment or only for a short period of time. Furthermore, it can be administered discontinuously or continuously. Suitable compounds of formula (I) are administered at a rate of from 100 picograms per kilogram of body weight to 100 milligrams, more preferably from 5 nanograms per kilogram of body weight to 25 milligrams, and more preferably Preferably, it is 10 ng to 15 mg per kilogram of body weight (e.g., 1 gram to 1 gram per kilogram of body weight, more preferably 1 gram to 20 mg, for example, from 1 to 10 mg), depending on the need. increase or decrease. The compound of the formula (1) may be administered per ounce, or, for example, administered at intervals of 2, 3, or 4, or 5, or 6, 7, or 10, or 14, or 21, or 28 days. Compounds that are not poorly audible can be administered orally in a range of doses, for example, i to test, 2 to 800, or 5 to 5 bark (eg, 2 to 2 or 10 to 1000 mg), special Dosage examples include 1 (), H, and 80 mg. This compound can be taken once or more times a day. This compound can be taken continuously (ie, uninterrupted daily during treatment). In addition, this compound can be taken intermittently, that is, during the entire chemotherapy period, for a period of time, one (for example, one week), then for a period of time (for example, one week), and then another - Start taking it for a period of time (for example, - week). = ring-failed administration, for example - a ring of sputum:: weekly taking ^ one or two weeks of taking 'a week to stop, · or three weeks to take, one week to stop, or one week, two weeks stop knowing , or taken four weeks, discontinued for two weeks; or 153 200836725 for one week, three weeks for discontinuation, one or more cycles (eg, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or More cycles). In a more specific mode of administration, the patient may be immersed in a compound as shown in formula (I) for one hour and lasts up to ten miles, especially 5 days, up to five days a week, and Treatment is repeated within a range (eg, two to four weeks, in particular, every three weeks). In addition, a patient may be infused every other hour for five consecutive days as shown in formula (1) and repeated every three weeks. (In another method of administration, the patient will be given 10 30 minutes to 1 hour of infusion according to different conditions 'for example, 1 to 5 hours (eg, 3 hours). In another special mode of administration The patient will be given a 12 to 5 day infusion, in particular, 24 to 72 hours. However, the amount of the final compound must be in accordance with the amount required for the disease or physiological condition and must be carefully considered by the physician. The compound may be administered alone or in combination with one or more other compounds to treat a particular disease, such as Neoplastic I Disease (eg, cancer). Others may be associated with, for example, a chemical formula (ϊ The drugs shown together (at the same time or at different times) include, but are not limited to: Topoisomerase I inhibitors 20 Antimetabolites Tubulin dry drug (Tubulin) Targeting agents) DNA binders and Topoisomerase II inhibitors Alkylating agents 25 monoclonal antibodies Monoclonal Antibodies) 154 200836725 Anti-Hormones Signal Transduction Inhibitors Proteasome Inhibitors DNA methyl transferases 5 Cytokine and Vitamin A Retinoids Chromatin targeted therapies Radiotherapy, as well as other therapeutic or prophylactic agents; for example, agents that alleviate or soothe side effects caused by chemotherapy. Specific examples of the agent include: anti-vomiting agent 10, and prevention or alleviation of neutropenia associated with chemotherapy, and prevention of red gold balls or white blood cells (for example, erythropoietin (EPO), granules) A complex disease caused by a decrease in granulocyte macrophage-colony stimulating factor (GM-CSF) and granulocyte 15 colony-stimulating factor (G-CSF). In addition, agents that inhibit bone resorption, such as bisphosphonate agents (eg, zoledronate, pamidronate, and ibandronate) are also included (eg, bisphosphonate agents). Ibandronate)), anti-inflammatory reagents (eg, dexamethazone, prednisone, and prednisolone), and blood cells used to reduce growth hormone in patients with terminal hypertrophy Level and IGF-I reagents (eg, brain hormone somatostatin) is a long-acting octapeptide-type acetic acid ol 2008 367 200836725 koji peptide that mimics natural hormone somatostatin ( Octreotide Acetate)). It also contains reagents such as antidote to reduce folic acid or folinic acid (eg, leucovorin), and can be used to treat water and blood vessel embolism (thromoembolic). Agents such as side events (e.g., megestrol acetate) Each of the compounds of the present invention can be administered individually according to a schedule and according to special rules. The compound of the formula (I) may be administered in combination with one, two, three, four or more pharmaceutical agents, preferably one or two, more preferably one, which may be simultaneously Do not administrate or administer the drug sequentially. When administered sequentially, it can be separated by a short period of time (eg, 5-10 minutes) or a relatively long interval (eg, 1, 2, 3, 4, or more hours, which is more desirable) Long), the exact amount of use must be based on the nature of the medical reagents. The compounds of the invention may also be administered in combination with non-chemotherapy (e.g., radiation therapy, photodynamic Therapy, gene therapy; surgery and diet control). For use in combination with other chemotherapeutic agents, for example, a compound of the formula (1) may be formed together with one, two, three, four, or more pharmaceutical agents (including two, three, four, or More medicine 20 with reagents). In addition, separate therapeutic agents can be separately formed separately, as desired, and presented together in a kit. A person of ordinary skill in the relevant art may use this compound in combination with other pharmaceutical agents in accordance with his or her general knowledge. 156 200836725 Methods of Diagnosis Before administration of a compound as shown in formula (I), the patient must be screened to determine if there is a degree of treatment with a compound that is required to be active against FGFR, VEGFR and/or PDGFR. 5 For example, a biological sample obtained from a patient can be used to analyze whether there is a symptom or disease, such as cancer, because the patient has or is affected by an abnormal or abnormal protein (which causes FGFR, VEGFR and/or PDGFR). Increased activity level, or particularly sensitive to normal FGFR, VEGFR and/or PDGFR activity, or increased growth factor ligand activity level 10, or increased biochemical activity downstream of FGFR, VEGFR and/or PDGFR activity) . Such abnormalities that are sensitive to FGFR, VEGFR and/or PDGFR activation include: cell>apoptotic pathways inhibition or loss, elevation of receptors or ligands, or various receptors or ligands The occurrence of sudden changes (such as PTK variants). Mutations or elevations of FGFR1, FGFR2 or FGFR3 or FGFR4, particularly those caused by FGFR1 overexpression, FGFR2 or FGFR3 gain-of-function mutations, are particularly sensitive to FGFR inhibitors. For example, the functional FGFR2 caused by point mutations can be judged by some symptoms 20 (cf. Lemonnier, W α/· (2001), J. Bone Miner. Res., 16, 832-845). In particular, activating mutations in FGFR2 have been diagnosed in 10% of endometrial tumors (cf. Pollock ei a/, Oncogene, 2007, 26, 7158-7162). In addition, genetic variants of the FGFR3 receptor tyrosine kinase (eg, staining 157 200836725 translocation or point mutation) cause abnormal or deregulated, and the sustained activation of the FGFR3 receptor is considered to be multiple Myeloma is associated with bladder and cervical cancer (see Powers, CJ, βία/ (2000), Endocr. Rel. Cancer, 5, 165). A specific mutation of T674I in the PDGF receptor was found in patients receiving imatinib. Furthermore, the gene amplification of 8pl2_pl 1 _2 was found in ~50% of typical cases of Classical Lobular carcinoma (CLC) (λ was found, and this was associated with an increase in FGFR1 expression). The first 10 steps for siRNA against 卩0卩111, or small molecule inhibitors of the receptor, suggest that the cell line masking this broadening action is particularly sensitive to the suppression of this signaling pathway ( Reference is made to Reis-Filho ei α/. (2006), Clin Cancer Res. 12(22), 6652-6662). Also, biological samples obtained from patients can be used to analyze whether to lose 15 FGFR, VEGFR. Or the negative regulation or repression of PDGFR. Here, the term "loss" includes: control of regulated or repressible genes r, deletion of sequences, truncation of genes (eg, by mutation), gene transcription The truncation of the product, or the deactivation of the gene transcript (eg, via a canonical mutation), or by another gene product. 2 〇 "up-regulation" is the improvement or overexpression of the expression. ,include: Due to amplification (ie, multi-gene replication) and increased expression via transcription, as well as high activation and activation (including activation via mutation). Therefore, patients may need to be diagnosed to measure FGFR, VEGFR And/or an improved feature of PDGFR. The term "diagnosis 158 200836725 (diagnosis)" includes screening. The marker used contains genetic markers (including, for example, DNA to confirm FGFR, VEGFR and / Or a mutation in PDGFR. Here, the term "marker" includes the property of confirming the enhancement of FGFR, VEGFR and/or PDGFR (including enzyme activity, enzyme level, enzyme status (eg, whether A marker for phosphorylation, and the mRNA level of the above proteins. Diagnostic tests and screening must generally be performed by tumor section samples, blood samples (isolated by tumor cells and contained in tumor cells), biopsy (stool) Biopsies), sputum, chromosomal analysis, pleural fluid, peritoneal fluid, buccal spe Ars), biopsy, or a sample of urine. Protein mutations and enhancement confirmation and analysis can be measured by those skilled in the art. Screening methods include, but are not limited to: Standard method (eg, reverse-transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization (eg, fluorescence in situ hybridization (FISH)) Patients with FGFR, VEGFR and/or PDGFR mutations are identified as being particularly suitable for treatment with FGFR, VEGFR and/or PDGFR inhibitors. Before treatment, tumors must be screened for presence of FGFR, VEGFR and/or PDGFR variants. Screening actions typically involve direct sequencing, oligonucleotide, microarray analysis, or mutation-specific antibodies. In addition, the diagnosis of tumors with associated mutations can be performed using conventional general techniques (e.g., 25 RT-PCR and FISH). 159 200836725 Further, for example, mutations in FGFR or VEGFR2 can be confirmed by a tumor slice test using PCR and a direct sequencing method of PCR sequencing. The skilled artisan will use conventional techniques to determine whether overexpression, activation, or mutation of the above protein occurs in the assayed sample. • Screening by RT-PCR, the amount of mRNA in the tumor is estimated by replicating cDNA from mRNA and then amplifying the cDNA by PCR. In the method of PCR amplification, the selection of promoters and conditions for amplification is within the scope of the prior art in the art. Nucleic acid modification and PCR are carried out using conventional methods. See Ausubel, F.M. βί eds. (2004)

Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, Μ·Α· ei a/” eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San 15 Diego. The reaction method and modification of the nucleic acid can also be carried out as described in Sambrook et al., (2001), 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. In addition, there is a commercially available RT- PCR kits (e.g., Roche Molecular Biochemical), or methods described in U.S. Patent Nos. 2, 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 can also be used to assess mRNA expression. An example of an in situ hybridization technique may be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649). 25 In general, in situ hybridization (in situ) Hybridization contains 160 200836725 for the following main steps: (1) immobilization of the tissue to be analyzed; (2) pre-hybridization of the sample (prehyb Ridification) to increase compatibility with a light nucleic acid; (3) hybridization of a nucleic acid to a nucleic acid in a biological structure or tissue; (4) washing after removal of a nucleic acid fragment that has not been hybridized; and (5) measurement Hybrid nuclear 5 acid fragment. In the conventional example, the probe used for detection is labeled with a radioactive element or a fluorescent sensor. For example, a preferred probe can measure about 50, 100, or 200 nucleotides. Up to about 1000 or more nucleotides to meet specific hybridization requirements for emergency and target nucleic acids. Standard methods for using FISH can be found in Ausubel, FM ei a/·, eds (2004) Current Protocols in 10 Molecular Biology , John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John MS Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077- 088; Series: Methods in Molecular Medicine o 15 The relevant methods of gene expression are described in (DePrimo a/. (2003),

Million MC 3:3). In short, the method is roughly as follows: double-stranded cDNA is subjected to preliminary single-stranded cDNA synthesis using total RNA using a (dT)24 oligomer (Oligomer), followed by random hexamer primers to synthesize a second strand cDNA. . Its double-stranded cDNA can be used as a model for cRNA tube transcription using biotinylated ribonucleotide. Chemical fragmentation of CRNA can be performed by reference to the method in Affymetrix (Santa Clara, CA, USA) followed by overnight hybridization on Human Genome Arrays. In addition, the protein expressed by the mRNAs can be examined by immunohistochemistry using a tumor group 25, using a microtitre plate 161 200836725 5 Γ: 10 15 u 20 via solid phase immunoassay (solid Phase immunoassay), Western blotting, 2-dimensional SDS_polyacryl amide gel electrophoresis, ELISA, flow cytometry, and other conventional assays to measure Its special protein. The use of site specific antibodies is included in the measurement method. Those of ordinary skill in the art will know how to measure the elevation of FGFR, VEGFR and/or PDGFR, or the mutation or mutation of FGFR, VEGFR and/or PDGFR in the usual manner. The degree of abnormality of a protein (e.g., FGFR or VEGFR) can be measured, as measured by standard enzyme assays as described herein. Activation or overexpression of tissue, such as tumor tissue, can also be measured. It is known by measuring the activity of a lysine kinase using a method (e.g., the method described in Chemicon International). The known conjugated kinase can be obtained by immunoprecipitation of a sample lysate and measuring its activity. Methods for measuring the overexpression or activation of FGFR or VEGFR (including its isoforms) include measuring its microvessel density. For examples of this method, see Orre and Rogers (Int J Cancer (1999), 84(2) 101. The method described in -8). Markers are also used in these methods, for example, in VEGFR examples containing CD31, CD34, and CD105 (refer to Mineo as α/· (2004) J Clin Pathol. 57(6), 591-7). Thus, such assay techniques can also be used to assay tumors that can be treated using the compounds of the invention. The compounds of the invention are particularly useful for treating patients with FGFR mutations. 162 200836725 The G697C mutation in FGFR3 was observed in 62% of oral squamous cell carcinoma, and it caused activation of kinase activity. The activating mutation of FGFR3 was also observed in the case of bladder cancer. These mutations contain six different and varying degrees of mutations: 5 R248C, S249C, G372C, S373C, Y375C, K652Q In addition, the polymorphism of Gly388Arg in FGFR4 was found with prostate (prostate) 'An increase in colon, lung, and breast cancer, and spread. Accordingly, another aspect of the present invention comprises the use of Compound 10 of the present invention to produce a medicament for treating or preventing a disease or condition having the disease or symptom The patient is screened and suffering from the disease, and the disease can be treated as a compound that is resistant to FGFR activity. Special mutations to be made in patients include G697C, R248C, S249C, G372C, S373C, Y375C in FGFR3, The K652Q mutation is polymorphic to Gly388Arg in 15 and FGFR4. Another aspect of the invention comprises a compound of the invention for use in prevention Or treating a cancer patient whose patient is selected from a subgroup 2 having an FGFR gene abnormality (eg, G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4). Measurement of vascular normalization using MRI (eg, using MRI) Gradient echoes, spin echoes, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) and with circulating biomarkers (circulating progenitors) Progenitor cells (CPCs), CECs, SDF and FGF2) together with 163 200836725, can identify anti-VEGFR2 tumors that can be treated with the compounds of the invention. Experimental method 5 LC-MS system Yao Yi folding and its method (Analytical LC_MS system and method description) In the examples, the prepared compounds were subjected to liquid chromatography and mass spectrometry, and a commercially available instrument (Waters Platform LC-MS (1 system, Waters Fractionlynx LC-MS system) was used. ), and using the standard 10 measurement method and the commercially priced column (Phenomenex, Waters etc), but in the field Those of conventional art and according to their requirements as determined changes. The different isotopes of their atoms can be distinguished to give a single mass, and the mass of the resulting compound is the mass of a single isotope (eg, 35C1; 79Br, etc.). 15

Mass Directed Purification LC-MS System LC-MS (or HPLC) is a standard and efficient method for purifying small organic molecules (e.g., compounds described herein). The methods of liquid chromatography (LC) and mass spectrometry (MS) can be adjusted to improve the separation of raw materials and increase the sensitivity of MS to sample testing. . The right to optimize the efficiency of the LC method can be achieved by using different columns, different eluents, and different modifiers, with different chromatographic gradients. Methods for optimizing LC-MS are well known in the art. Thus, such methods can be used to purify compounds. These methods have been described in 164 200836725 on Rosentreter U, Huber U·; Optimal fraction collecting in preparative LC/MS; J Comb Chem·; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C·, Development of a custom high-throughput preparative liquid 5 chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem·; 2003; 5(3); 322-9 0 The system for purifying the compound by LC-MS is Waters Fractionlynx system or Agilent 1100 LC-MS, and those having the prior art 10 can determine according to their needs and needs. Specifically, HPLC analysis can be carried out using a reverse phase method, but a normal phase method can also be used instead of reverse phase chromatography. Since this method is very effective for small molecule purification in the literature, and the eluent is positively correlated with positive ion electrospray mass spectrometry, reversed-phase chromatography is used in most LC-MS systems. LC and volatile acid modifiers. The best chromatographic method was selected based on many literature experiences. A typical method is to perform LC-MS analysis using one of the most suitable chromatographic methods (low or high pH) for the structure of the compound. If the result of the analysis is good, you can use this method as a more appropriate method to make 20 use. A series of chromatographic solutions (eg, forward or reverse phase chromatography LC; acid, base, polar, or lipophilic buffered mobile phase; basic modifiers) can be used to purify the compound. Thus, the skilled artisan can purify the compound via the LC-MS method described herein. 25 All compounds were dissolved in 100% MeOH or 100% DMSO. 165 200836725 General synthetic path

General formula A

Step A1 - Formation of the general imidazole pyridine ring:

NaHC〇3 (16.8 g, 200 mmol, 2.0 equiv) was added to 4-Chloro-pyridin-2-yl amine dissolved in C 1 〇 EtOH (170 ml). In a solution of 12.8 g, 100 mmol, 1.0 equiv), then chloroacetaldehyde (19. 0 ml, 150 mmol, 1.5 equiv) was added. The mixture was refluxed for 6 hours. The solvent was removed from the reduced house and the crude mixture was separated from EtOAc using water. The organic layer was washed with brine (brine), dried (MgSO4), filtered and evaporated. The product was purified by column chromatography (SiO 2 eluting with 50% EtOAC_ petroleum ether) to afford 13.2 g of product. 166 200836725 General iodine anti-Pang

Add N-disc diimide imine (Ni〇d〇succinimide) (43.6 g, 194 mmol, 1·5 equiv) to 7-gas-imidazole 5 [l,2_a] dissolved in dmF (280 ml) ° Ch (7-Chloro-imidazo[l,2-a]pyridine, 30.9 g, 186 mmol, 1·〇equiv), and the mixture was stirred overnight at room temperature. It was diluted with water (84 ml), saturated brine (bdne, 280 ml) and extracted with EtOAc (560 ml). The aqueous layer was then extracted with EtOAc (3 X 280 mL). The organic layer after the addition was washed with water (2×280 ml), 10 10% w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4), filtered and dried in vacuo to give The residue was triturated with diethyl ether (2 mL), filtered and washed with diethyl ether (2.times.50ml). In the third position, step ~A3a - age wood and deer

Add 3-aminobenzeneboronic acid (2.5 g, 10.57 mmol), 2M Na2CO3 (21.6 ml) [to remove bubbles via nitrogen gas] 20 to 7-chloro-3-iodo-imidazole dissolved in acetonitrile (100 ml) And [l,2-a]pyridine 167 200836725 5 Ο 10 (7-Chloro-3-iodo_imidazo[l,2-a]pyridine, 2.8g, lOmmol), followed by the addition of bis(triphenylphosphine)palladium(II) Gas (bis (tiiphenyl phosphine) palladium (II) chloride, 0.35 g, 0.49 mmol). The mixture was heated at 70 ° C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS 〇 4), filtered and concentrated under reduced pressure. Then purified by column chromatography using Biotage (Si〇2, with 80% EtOAC_ petroleum ether to 100%) EtOAC eluted) to give 1.9 g of product. MS: [M+H]+ 244 Step A3b - 钤太反鹿

Q 15 Add 3-aminobenzeneboronic acid (0.69g, 4.8mmol) and 2M Na2C03 (6.93ml) [to remove air bubbles via nitrogen gas] to 3·iodine-7- dissolved in DME (20ml) 3-(3-morpho-4-ylmethyl-phenyl)-imidazo[l,2 -a]pyridine, 1.55 g, 3.72 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.139 g, 0.12 mmol). The mixture was heated overnight at 75 ° C, then diluted with water and extracted with EtOAc. The organic layer was washed with brine (br.), dried (MgSO4), filtered, evaporated, evaporated, evaporated, evaporated, Product. MS: [M+H]+385 200836725 Step A4 General addition of the catalytic seventh position ring Step A4a - Eucalyptus reaction

5 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (4_(4,4,5,5-Tetramethyl_[l ,3,2]dioxaborolan_2-yl)_pyridine, 0.078g, 0.36mmol), K2CO3 (〇·25g, 1.8minol), MeOH (0.5ml), EtOH (0.5ml), and H20 (0.75ml) [via nitrogen Removal of bubbles] Add N-[3-(7-chloro-imidazo[l,2_a]pyridin-3-yl)-10 phenyl]acetamidamine (N-[3-) in benzene (0.5 ml) (7-Chloro_imidazo [l,2-a]pyridin-3_yl)-phenyl]-acetamide, 0.090 g, 0.3 mmol), followed by the addition of bis(tri-t> butylphosphine) 1 bar (0) (0.003 g, 0.0058 mmol). The mixture was heated in a CEM Discover microwave synthesizer (50 W) at 140 °C using microwave irradiation until the reaction was completed. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. MS: [M+H]+ 329 20 Step A4b - Suzuki reaction 169 200836725

N

Add 4-L-phenylphenyl acid (4-fluorophenylboronic acid, 0.059 g, 4-2 mmol) and 2M Na2C03 (1.2 ml) [to remove bubbles via nitrogen gas] to N-[3-( dissolved in DME (4 ml) 7-Chloro-imidazo[l,2_a]pyridin-3-yl)-ζ^ 5 phenyl]acetamidamine (>1_[3-(7-(1;111〇1>〇-:[11^ (1&2〇[1,2-&]卩>^(1111-3-yl)-phenyl]_acetamide, O.lg, 0-35mmol), followed by tetrakis(triphenylphosphine)palladium (0 (0.018 g, 0.015 mmol). The mixture was evaporated with EtOAc EtOAc EtOAc. And purified by HPLC 10 to give 0.045 g of product. MS: [M+H]+ 346 Step A4c - Buchwald reaction

Add morpholine (0.03ml, 0.35mmol), NaC^Bu 15 (0.096g, 0.96mmol) [to remove bubbles via nitrogen gas] to 1 in anhydrous hydrous dioxane (4ml) -[3-(7-gas-flavors sit and [l,2-a]^b.din-3-yl)-phenyl]-3-ethyl-urea (l-[3-(7-Chloro) -imidazo 170 200836725 [l52-a]pyridin-3-yl)-phenyl]-3-ethyl-urea5 0.1g5 0.32 mmol), followed by BINAP (0.021g, 0.033mmol) and Pd2(dba)3 (three ( Dibenzylideneacetone) (0); tris-(dibenzylideneacetone) dipalladium (O), 0.016 g, 0.017 mmol). The mixture was heated overnight at 80 ° C, then diluted with EtOAc EtOAc (EtOAc)EtOAc. To give 0.015 g of product. MS: [M+H]+ 366

1-[3-(7-Gas-imidazo[l,2-a]acridin-3-yl)-phenyl]-3-ethyl-gland (l-[3-(7-chloro-imidazo) [l,2-a]pyridin-3-yl)-phenyl]-3-(/ ethyl urea, 200 mg? 0.636 mmol 5 1 equivalent (equivalent), prepared by the method of Step 15 Fla), 1-mercaptopyrazole 4-methylpyrazole-4_boronic acidpinacol ester (commercially available, 265 mg, 1.272 mmol, 2 equivalents), potassium carbonate (527 mg, 3.816 mmol, 6 equivalents), and di(tri-tert-butyl) Dissolve (〇) (16 mg, 0_032 mmol, 0.05 equivalents) in a mixed solution of ethanol (10 ml), toluene (10 ml) 20 and water (10 ml), and heat at 70 ° C for 24 hours. The mixture was separated from water by ethyl acetate. The organic layer was washed with saturated brine 171 200836725 water (brine), dried (MgSO4), filtered and evaporated in vacuo. SP4, 25S, flow rate 25 ml/min, gradient 0% to 20% decyl alcohol in ethyl acetate) to give 1-ethyl-3-{3-[7-(l-methyl-1H-) as a white solid. Pyrazol-4-yl)-imidazole 5 and [1,2-a] 11 〇定-3-yl]-phenyl}-pulse (l-ethyl-3-{3-[7-(l-methyl-lH-pyrazol-4-yl) - imidazo[l,2-a] Pyridin-3-yl]-phenyl} -urea) MS: [M+H]+ 36 Step A4e - using microwave conditions

K3P〇4 (636 mg, 3 mmol) dissolved in water (1 ml) was added to l_[3-(7-gas-flavor σ sita[1,2-a]a 〇定-3-yl)-phenyl] -3-(2,2,2-Sandon-ethyl)-pulse

2-trifluoro-ethyl)-urea (370 mg, 1.0 mmol) and 140,1-dimethylamino scutellaria xanthine-1H-° ratio -4- benzyl acid (140,1 -Dimethylsulfamoyl-1H-pyrazole-4) -boronic acid (440 mg, 2.0 mmol). After adding S_Phos (41 mg, 0.1 mmol) and Pd2 (dba) 3 (45 mg, 0.05 mmol), the mixed solution was deoxygenated, followed by microwave irradiation at 130 °. C. The mixture was heated for 30 minutes. The mixture was separated from CH2C12 eluted with water, and then the obtained product was filtered and dried in vacuo to give a solid solid (350 mg). MS: 172 200836725 [M+H]+ 508

General formula B

Step B1 - General Palladium Catalysis, Substitution Reaction at the 7th Position of the Ring Step B1 a - Suzuki Reaction of the Aromatic Ring

10 Step Bib - Reaction of the saturated ring of Buchwald

Using the method as described in general procedure A, step 4c 15 Step Blc - heterocyclic coupling of eucalyptus reaction 173 200836725

7-mectame and [1,2-&]° bite (0.58, 2.54111111〇1,1 equivalent (equivalent), using the procedure of step Α1 to 4-diamine-2-amine (not 5 4-Qloro-pyridin-2-yl amine), 1-mercapto-5-(4,4,5,5-tetradecyl- [1,3,2]dioxaborolan-2-yl)-1Η- ° 嗤(1-methyl-5-(4,4,5,5-tetramethyl-[ 1,3,2] 〇 Dioxaborolan-2-yl)_lH_pyrazole, l.lg, 5.08 mmol, 2 eq.), bis(tri-tert-butylphosphine)palladium(0) (66 mg, 0.13 mmol, 0.050 eq.), and 10 potassium carbonate (2.1 g) 15.24 mmol, 6 equivalents) were dissolved in a mixed solution of ethanol (10 ml), toluene (10 ml) and water (10 ml), and heated at 75 ° C for 2 hours. The mixture was separated from water by ethyl acetate. The organic layer was then washed with a saturated aqueous solution of saline, dried (MgS04), filtered, and evaporated to remove solvent. The residue was purified by column chromatography (Biotage SP4, 15 25S, flow rate 25 ml/min, gradient 0% to 20% decyl alcohol in ethyl acetate) (5 to give 7-(2- -2-2H-pyrazole _3_yl)-imidazo[l,2-a] v/ 0 is more than 7-(2-metliyl_2H-pyrazol-3-yl)-imidazo[l,2,a] Pyridine, 350mg, 70%) MS: [M+H]+ 199 〇20 Step B1 d 7-『3-(4-Methyl-piperazin-1-ylindenyl V-methyl-l-imidazopyridinium Synthesis of (7-f3-(4-Methvl-piperazin-1 -vlmethvn-phenvll-imidazori, 2-alpvridine) 174 200836725

Cacl is prepared using the method described in General Procedure A, Step A4a, and 3-formylphenylboronic acid.

〇, 5 N-methylpiperazine (1·1 ml, 10.2 mmol, 1.2 equiv) was added to 3-imidazole dissolved in toluene (30 ml) and decyl alcohol (10 ml). 2-Amidazo[l52-a]pyridin-7-yl-benzaldehyde (1.889 g, 8.5 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 3 hr and then solvent was evaporated. The crude imine product 10 was then dissolved in a solution of ethanol and decyl alcohol (1:1, 30 ml), and sodium borohydride (483 mg, 12.75 mmol, 1.5 equiv) was added thereto in several portions. The reaction mixture was stirred overnight overnight and the solvent was removed in vacuo. The reaction was quenched by the slow addition of aqueous 2N NaOH (20 mL). Then ethyl acetate was added to separate the layers. The organic layer was washed with brine, dried (MgSO4), 15 and evaporated. The compound was purified by column chromatography (eluent eluting with 5% EtOAc: hexane) to give the desired compound. step. Step B2 ^(匕

CYC/Ar 20 as described in General Procedure A, Step A2 200836725 Step B3a - General Elm Reaction, in the third position

Ar

As described in general procedure A, step A3a or A3b, step B3b - general eucalyptus reaction, in the third position

Ar/CYC

Ar Ar/CYC Method as described in general formula B, step Blc 10

Synthesis of general formula C-3,6-disubstituted compounds

Step C1 - General Palladium Catalysis, Addition Reaction at the Sixth Position of the Ring

176 200836725 3-Dimethylanisole (0.2-bromoanisole, 0.24 g, 1.3 mmol), 2M Na2C03 (1.5 ml) [with air bubbles removed via nitrogen] was added to dissolve in EtOH (2.7 ml), toluene (2.7 ml) Imidazo[l,2_a]pyridin-6-ylboronic acid (imidazo[l,2-a]pyridin-6-ylboronic acid, 0.162 g, 1 mmol) in solution 5 followed by addition of tetrakis(triphenylphosphine) (0) (tetrakis (triphenylphosphine)) palladium (0), 0.059 g, 0.05 mmol). The mixture was heated overnight at 70 ° C, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and evaporated. The product was obtained after drying (0.3 g). MS: 10 [M+H]+ 225 Step Cl (b)--Palladium-catalyzed addition reaction of 箆6 position ring

15 2-[3-Phenoxyphenyl]-4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolan (2-[3_methoxyphenyl]-4,4 , 5,5,_tetramethyl-[l,3,2]_ dioxaborolane, 0.304g, 1.3mmol), 2MNa2C03 (1.5ml) [with bubbles removed via nitrogen] added to EtOH (2.7ml) and toluene (2.7 Methyl) in the form of 6-bromoimidazo[l,2a]pyridine, 0.197 g, 20 lmmol, followed by tetrakis(triphenylphosphine)palladium (〇) (〇.〇59g, 0.05mmol). The mixture was heated at 70 ° C for 2 hours. It was then diluted with water and extracted with EtOAc. The organic layer was washed with brine (brine), dried (MgSO4), filtered and concentrated under reduced pressure to give the product 177 200836725 (0.3 g) ° MS: [M+H]+ 225 Step C2 - Iodination

As described in General Procedure A, Step A2. Step C3 - General General Suzuki responds to position 3

General C4

CI

(3-acetylaminophenyl) boronic acid (0.11 g, 0.7 lmmol), 178 15 200836725 K2C03 (0.59 g, 3.55 mmol), MeOH (1 ml), EtOH (1 ml), H20 (1.5 ml) [to remove bubbles via nitrogen gas] was added to 6-chloro-3-iodo-imidazo[1,2-a]pyridine (0.2 g, 0.71 mmol) dissolved in toluene (1 mi), followed by two (Tri-t-butylphosphine) palladium (〇) (〇.〇〇6g, 0.0116mmol). The mixture was heated at 100 ° C for 2 hours, then an excess of boric acid (〇·〇6 g) and bis(tri-t-butylphosphine)palladium(0) (0.006 g) were added and the reaction was further heated for 2 hours. It was diluted with water and extracted with EtOAc. The organic layer was washed with brine (br.), dried (MgSO4), filtered and evaporated. f, MS: [M+H]+ 286 10 Add bis(tri-t-butylphosphine) Ι ε (0) (0.004 g, 0.0077 mmol) to l-[3-(6-chloro-m-m- s. [l, 2_a] ° ratio -3-yl)-phenyl]-ethanone (O.lg, 0.35 mmol), benzene succinic acid (〇.〇43 g, 0.35 mmol), K2C03 (0.29 g, 2. A solution of lmmol), MeOH (0.5 ml), EtOH (0.5 ml), H20 (0.8 ml) [with air bubbles removed via nitrogen]. The mixture was heated in a CEM developed microwave synthesizer (50 W) to 155 °C under microwave irradiation until the reaction was completed. The reaction was diluted with water and extracted with EtOAc. The organic layer is washed and dried with saturated brine (brine)

The mixture was dried (MgSO4), filtered and evaporated. MS: [M+H]+ 328 20 General Modification D, at position 7 The latent functionality of the imidazo[l,2_a]pyridine at position 7 can be utilized for further synthetic use. 179 200836725

Step D1 - Hydrogen 4匕 (Hydrogenation)

10 ml) of 1-{3-[7-(3-cyanononyl-phenyl)-imidazo[l,2-a]upyridin-3-yl]-phenyl}-3-ethyl-urea (1_{3-[7-(3-0>^11〇11161;11;/1-卩1^11;/1)-imidazo[l,2-a]pyridin-3-yl]-phenyl}- 3-ethyl-urea, 0.03 g, 0.76 mmol). The mixture was shaken in a hydrogen atmosphere for 48 10 hours at ambient temperature. The catalyst was filtered under reduced pressure with GF/A paper, followed by trituration with MeOH and drying of the solid to afford 12 mgs. MS: [M+H]+ 400 Step D2 - Hydrolysis 180 200836725

2M NaOH (0.48 ml) was added to 1-(4-{3-[3-(3-ethyl-ureido)-phenyl]-imidazo[l,2-a] dissolved in EtOH (0.4 ml) Acridine _7_yl}_ phenylmethyl)-3-methyl-tour 唆-3-carboxylic acid acetyl ester (1-(4_{3-[3-5 (3-Ethyl-ureido)-phenyl]- Imidazo[l,2_a]pyridin_7_yl}-benzy l)-3-methyl-piperidine-3-carboxylic acid ethyl ester, 0.020g5 0.037mmol). The reaction was heated to 50 ° C for 24 hours, then concentrated under reduced pressure and ethanolified by HPLC to give the product. MS: [M+H]+ 512 10 Step D3 - Boc Deprotection Step D3a - Boc Deprotection

4-(4-{3-[3-(3-ethyl-ureido)-phenyl]-imidazo[l,2-a]acridin-7-yl}-phenyl)-scarlet- 1-Retiny tert-butyl@旨(4-(4-{3_[3- 181 200836725 (3-Ethyl-ureido)-phenyl]-imidazo[l ,2-a]pyridin-7-yl}-pheny l) -piperazine-l-carboxylic acid tert-butyl ester, 0.015 g, EtOAc (EtOAc)EtOAc. MS: 5 [M+H]+ 441 D3b: 1 -(2-Amino-ethyl)-3-{3-"6-(4- gas-stupyl)-mouth is more than mouth and f 1,5_al口密定定_3_基笨基i_脉10 i 1-(2-Amino-ethvn-3-13-r6-(4-fluor〇"phenvl)-pyrazol〇r 1,5- alpvrimidin-3- Preparation of vll-phenvli-urea)

TFA (2 ml) was slowly added to [2-(3-{3-[6-(4-fluoro-phenyl)-carbazole[l,5-a] dissolved in CH2C1 (4 ml). Pyrimidin-3-yl]-15 phenyl}•ureido)-ethyl]-amine tert-butyl phthalate ([2-(3_{3-[6-(4-Fluoro-phenyl)-pyrazolo[l , 5-a] pyrimidin-3-yl]-phenyl }-u reido)-ethyl]-carbamic acid tert-butyl ester, 390 mg, 0.80 mmol). After 1 hour, the solvent was evaporated in vacuo. The residue was taken up in MeOH and taken to a EtOAc (20 g). Elution with 2M NH3_MeOH 20 eluted in vacuo to afford 182. Step D4 - Pyridone formation

Π 5 Step D4a Add hydrogenated n to bite (〇.59g, 5.1mmol) to 1-ethyl-3-{3-[7-(6•曱oxy-acridin-3-yl)-imidazole [l,2-a]Acridine-3-yl]-phenyl}urea (1-ethyl-3 -{3-[7-(6-methoxy-pyridin-3-yl)-imidazo [l,2- a] pyridin-3-yl]-phenyl}, urea, O.lg, 0.258 mmol). The mixture was heated to 150 ° C for 15 minutes, diluted with water, and the precipitated solid was filtered. The solution was concentrated under reduced pressure and purified by HPLC to yield (O.OOlg). MS: [M+H]+ 374 Step D4b

1-Ethyl-3·{3·[7-(2-methoxyl σ -4 -4 yl) _ mouth rice. Sit and [l,2-a] 〇定定-3 -yl]-phenyl}-urea (l-Ethyl-3-{3-[7-(2-metlioxy-pyridin- 183 200836725 4-yl) -imidazo[l52-a]pyridin-3-yl]-phenyl}-urea? 0.03 g, EtOAc (EtOAc) (EtOAc) The reaction was concentrated under reduced pressure and then EtOAcEtOAcEtOAc MS: [M+H]+ 374·

mCPBA (29 mg, 0·17 mmol, 1.2 equiv·) was added to 1·ethyl-3-[3-(7-σ 口 口定-3-基-口米°) dissolved in CH2CI2 (5 ml) Sit and [1,2-&] mouth is more than 10 ° -3-yl) _ phenyl]-urea (l-ethyl-3_[3_(7-pyridin_3-yl-imidazo [l,2-a]pyridin -3-yl)-phenyl]-urea, 50 mg, 0.14 mmol, 1 equiv·), and was stirred at room temperature for 12 hours. Then another portion of mCPBA (29 mg, 0.17 mmol, 1.2 equiv.) was added and stirred at room temperature for 2 hours. 2N NaOH was then added to the reaction mixture and separated from water by CH2C1215. The organic layer was dried (MgS04), filtered and the solvent removed in vacuo. The oil phase separated is purified by column chromatography (SiO 2 ), eluting with 10% MeOH:CH 2 Cl 2 to give N-oxide as a yellow solid (7 mg, 13%) 〇20 General modification D6 - go Debenzvlation 184 200836725

10 7-(3-Benzyloxypyrrolidin-l-yl)-imidazo[7-(3-Benzyloxypyrrolidin-l-yl)-imidazo[7-(3-Benzyloxypyrrolidin-l-yl)-imidazo[7-(3-Benzyloxypyrrolidin-l-yl)-imidazo[ l,2-a]pyridine, 68 mg, 0.23 mmol) was dissolved in CH2C12 and cooled to EtOAc. Trimethylsilyl iodide (41 pL, 1.3 equiv) was added and the mixture was stirred for an additional 30 minutes before the solution was warmed to room temperature. MeOH (4 mL, excess) was added and the mixture was evaporated. The product was purified by column chromatography (0 - 80% MeOH in Et20). MS: [M+H] + 204. Step D7

Add 1 M HCl (2 ml) to Ν_[(Ε)·3·{7-[4_(2,2-dimercapto-[1,3]dioxolan-4-yl) dissolved in MeOH (31111)曱oxy)-phenyl]-imidazo-15 [l,2-a]pyridin-3-yl}-1_(Ε)-ethylene-but-2-enyl]-acetamide (N-[ (E)_3-{7-[4_(2,2-Dimethyl-[l,3]dioxolan-4-ylmethoxy)_ phenyl]-imidazo[l ,2-a]pyridin-3-yl}- l-eth -(E)-ylidene-but-2 185 200836725 -enyl]-acetamide, 0.24 g, 0.52 mmol) was stirred at ambient temperature for 1 hour, then concentrated under reduced pressure and purified by LC to yield . MS: [M+H]+ 418 5 Step D8 — Demethylation (Demethvlation)

1M of BBr3 10 dissolved in CH2C12 (1.84 ml) was added to 1·{3-[7-(5·methoxymethyl-[1,3] dissolved in CHCl3 (1 ml) at a temperature of -78 °C. , 4]thiazol-2-yl)-imidazo[l,2-a]acridin-3-yl]•phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l -{3-[7-(5-methoxymethyl-[l,3,4]thiadiazol_2-yl)-imidazo[l 52-a]pyridin-3-yl]-phenyl} - 3-(2,2,2- Trifluoro-e thyl)-urea, 280 mg, 0.60 mmol). The reaction was stirred for 1 hour before the reaction temperature returned to room temperature, and then poured into a saturated bicarbonate solution to stop the reaction. The solid was filtered and washed with EtOAc (EtOAc)EtOAc MS: [M+H]+ 449. 186 200836725

General modification E, in the 7th position

Synthesis of El- 1-Bromo-3-(2-methodol-Vethoxy-benzene)

2-Diethylethylether (0.56 ml, 6 mmol) was added to bromobenzene (0.865 g, 5 mmol) dissolved in MeOH (1 - 5 ml), followed by K2C03 (0.68 g, 5 mmol). The mixture was heated to 100 °C using microwave irradiation in a CEM development microwave synthesizer (50 W) until the reaction was complete. The reaction was diluted with diethyl ether and the solid was filtered. Filtration and concentration under reduced pressure gave the product (yel. 8 g). 15 Step E2-Change i-Korean to boric acid 187 200836725

Tricyclohexyl phosphine (0.028 g, 0.098 mmol), KOAc (0.12 g, 1.23 mmol), bis (pinacolato), 0.23 g, 0.9 mmol) Nitrogen removal gas 5 bubbles] added to 1-[3·(7-gas-啸峻和[l,2_a]pyridin-3-yl)-phenyl]-3 dissolved in dioxime (5 ml) -ethyl-urea (l_[3-(7-Chloro-imidazo[l 52-a]pyridin-3-yl)-phenyl]-3-ethyl-urea, 0.258 g, 0-82 mmol), followed by Pd2 ( Dba) 3 (0.038g). The mixture was heated overnight at 80 ° C, then filtered over a GFA filter paper, washed with CH.sub.2 C. The reaction mixture was used directly. Step E3 - Conversion of borate groups to aryl groups using a eucalyptus reaction

Dicyclohexyl-(2',6'-dimethoxy-biphenyl-2-yl)-phosphane, 200836725 [ S-PHOS], 0.038 g, 0.0625 mmol), potassium citrate (0.31 g, 1.6 mmol) [Break the bubbles via nitrogen gas] to 1 dissolved in dioxane (5 ml) and water (2.5 ml) -ethyl-3-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2 -a] acridine-3-yl]-phenylurea 5 (1-Ethyl-3-{3-[7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2 -yl)-imidazo[l 52-a]pyridin-3-yl]-phenyl}-urea (0.333 g, 0.82 mmol), followed by the addition of Is II acetate (0.008 g, 0.04 mmol). C was continuously heated for 48 hours, then triturated in CH2C12 and washed again with CH2C12. After filtration, concentrated under reduced pressure and purified by HPLC to give an imp. product. MS: [M+H]+ 431 Step E3b - Suzuki Reaction 15 Use the conditions used in the general Suzuki reaction A4b. Step E3c - (3-Γ7-Π-Methyl-1H_imidazole-4-V哚Oxazino 1,2,2-pyridin-3-yl 1 - stupidin-3-(2,2,2-tris-ethyl)-urea ({3丄7-(1^1〇1:1^1-lH_imidazol-4-vlVimidazofl,2-alpvridin-3 -vll-pheiLY_l} - 3-(2 20 ,2,2-trifluoro-ethyl)-urea ) Step E3c uses the conditions used in the general Suzuki reaction A4e 200836725

4-Odo-l_methyl_lH-imidazole (83 mg, 0.39 mmol), SPHOS (6.5 mg, 0.016 mmol) and Pd2 (dba) 3 (7 mg, 0.0076 mmol) dissolved in dioxane (2 ml) in a MW tube. ) to 5 l-[3-(7-Boronic acid -imidazo[l,2-a]pyridn-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (0.15 G, 0.39 mmol) was stirred and then K3P04 (252 mg, 1.18 mmol) dissolved in water (1.2 ml). The mixture was heated to 120 ° C for a period of time in a CEM Discover microwave synthesizer (300 W). The mixture was cooled to dryness then EtOAc (EtOAc) elute elute The residue was purified using I) HPLC to give the product (8mg). MS: [M+H]+ = 415. Step E3d -1·{3-"7-(2-Methyl-thiazol-4-yl-oxazolidine "l,2-al acridine 15 -3- 1-molylindole-3-(2,2,2trifluoro-:lVMn-H_"7-(2_Methvl-thiazol-4-yl)-imidaz〇r 1 <t2-a1pyridin-3-vl1-phenvn- 3-(2,2,2-t rifluoro-ethvlVurea) 190 200836725

PdCl2dppf (19 mg, 0.3 mmol) was added to 1 _[3_(7_Side-salt-salt and [1,2-a]π ratio bite-dissolved in two mouth-burning (4ml) and water (lml) 3·yl)·phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (l_[3_(7-Boronic acid 5 _imidazo[l,2_a]pyridn-3-yl)_phenyl] -3_(2,2,2-trifluoro_ethyl

-urea, 200 mg, 0.26 mmol), 4-bromo-2-methyloxime (61 mg, 0.34 mmol), and K3PO4 (168 mg, 0.79 mmol) [with air bubbles removed via nitrogen] and stirred. The reaction was heated to 80 ° C for 4 hours. The mixture was cooled and separated with EtOAc / EtOAc (EtOAc)EtOAc. The residue was purified using HPLC i) to give product (26 mg). MS: [M+H]+= 432. Step E3e 191 200836725

The carbonic acid I color (228 mg, 0.7 mmol) was added to 1_{3·[7_(4,4,5, dissolved in toluene (2 ml), n-butyl f) alcohol (2 ml), and water (0.5 ml). 5-tetradecyl 5-[1,3,2]disoxazolidine-2-yl)-imidazo[l,2_a]pyridin-3-yl]-phenyl}-3-(2,2 ,2_trifluoro-ethyl)-urea (1-{3-[7-(4,4,5,5彳61:^11^1:11}4-[l,3,2]dioxaborolan-2- Yl)-imidazo[l,2-a]pyridin_3-yl]-pheny l}_3-(2,2,2-trifluoro-ethyl)-urea,107mg,0.23mmol) and 2_bromo-[1,3,4 Thiadiazole (96 mg, 0.55 mmol). The reaction mixture was deoxygenated and 10 tetrakis (triphenylphosphine) palladium (0), 81 mg, 0-07 mmol. The reaction mixture was again degassed and heated to 80 ° C overnight. The mixture was then cooled, separated with EtOAc and H.sub.2, and the organic layer was separated, dried (M.sup.4), filtered, and the solvent was removed in vacuo. This crude product was purified by HPLC to give 18 mg of 15 product. MS: [M+H]+ 419. General strip F, in position 3, the latent functionality of the 3rd position of imidazo[l,2-a]pyridine can be utilized for subsequent synthesis 192 200836725

Step Fla-urea formation

10 三 Triethylamine (3.3 ml, 23.4 mmol) and ethyl isocyanate (0.93 ml, 11.7 mmol) were added dropwise to 3-(7-gas-imidazole dissolved in THF (30 ml) [l,2-a] u-(7-Chloro_imidazo[l,2-a]pyridin-3-yl)-phenyl amine) [as described in step A3a] Method] (1.9g, 7·8 mmol). The mixture was stirred at 50 ° C for 2 hours and then dried under reduced pressure. The crude mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The product was purified with EtOAc (EtOAc (EtOAc) elute 15 Step Fib-2 Step Urea Synthesis 193 200836725

3-[7-(4-Fluoro-phenyl)-imidazo[l,2-a]«•bipyridin-3-yl]-5-isopropoxy-phenylamine (3-[7_( 4-Fluoro-phenyl)_imidazo[l,2-a]pyridin- 5 3-yl]-5-isopropoxy-phenyl amine) (90 mg, 0·25ηπηο1) and p-nitrophenyl chlorodecanoic acid (50 mg, 0.25) Methyl) was dissolved in DME (1.5 ml) and heated to 60 ° C for 2 hours. After cooling to room temperature, DIPEA (0.13 ml, 0.75 mmol) and 2,2,2-trifluoro-ethylamine (0.12 ml, 1.50 mmol) were added and the mixture was stirred for 3 days. The solvent was removed in vacuo and 10 crude residue was purified by reverse EtOAc. The material obtained was purified using SCX(R) to give the product as a brown solid. MS: [M+H]+ 487. Step F2 - Formation of sulfonyl urea

Triethylamine (0.14 ml, 1.0 mmol, 3.0 equiv) and diammonium 194 200836725 sulfonium chloride (0.069 ml, 0.5 mmol, 1.5 equiv) were added dropwise to the solution in Thf (3.3 ml) 3-[7-(4-D-Phenyl)-imiphtho[1,2_a]. η定-3-yl]-phenylamine (3-[7-(4-Fluoro_phenyl)-imidazo[l,2-a]pyri(iin-3-yl]· phenyl amine, 100 mg, 0·33 Ment, 1 · 0 equiv) The mixture was stirred overnight at 60 ° C and the mixture was evaporated under reduced pressure. The crude mixture was separated from EtOAc using water, and the organic layer was washed with brine and brine. Dry (MgS 4) and concentrate under reduced pressure. The product was purified using HPLC to give 40 mg of product. 10 Step F3a - amide formation

15 (N-(3-dimethylaminopropyl)-Nf-ethylcarbodiimide hydrochloride, 70 mg, 0.36 mmol, 1.1 equiv) and 1-carboxybenzenetriazole (49 mg, 0.36 mmol, 1.1 equiv) added to DMF (2) Methyl 3-[7-(4•fluoro-phenyl)-imidazo[l,2-a]acridin-3-yl]-phenylamine (3-[7_(4-Fluoro-phenyl)_imidazo [l,2-a]pyridin_3_yl]-phenyl amine, 100 mg, 0.33 mmol, 1.0 equiv) and glycolic acid (34 μΐ, 0.4 mmol, 1.2 equiv). The reaction mixture was stirred overnight at 60 °C. The solvent is removed and water is added to form a gum. Ethyl acetate was added to precipitate, and the obtained compound (20 mg) was obtained after filtration. 195 20 200836725 Step F3b - amide is opened

3-[7-(4-F-Phenyl-phenyl)-amido[l,2-a]^ is more than indole-3-yl]-phenylamine (3-[7-(4-Fluoro-phenyl)- Imidazo [l52-a]pyridin-3-yl]-phenyl amine, 0_lg, 0.33 mmol), followed by dropwise addition of pr〇pi〇nyl chloride (28 μl, 0.33 mmol). The reaction was disturbed overnight at room temperature before the solvent was removed by vacuum. The residue was triturated in EtOAc and the solid was filtered. The filtrate was evaporated and the residue was crystalljjjjjjjjjj MS: [M+H]+ = 36〇.

Triethylamine (0.1381111, 0.99111111〇1) was added to 196 200836725 3-[7-(4-fluoro-phenyl)-imidazo[l,2-a]acridine dissolved in butyl 1^(3.31111) 3-yl]-phenylamine (3-[7-(4_Fluoro-phenyl)_imidazo[l,2-a]pyridin_3-yi]_phenylamine, 0.1 g, 0.33 mol), followed by dropwise addition of thiol-formic acid Methyl chloroformate (38 μl, 0.50 mmol). The reaction mixture was stirred overnight at 560 ° C, cooled and the solvent was removed in vacuo. The residue was separated by hydrazine and HW, and the organic layer was separated, dried (MgSO.sub.4), filtered, and solvent was removed by vacuum. The crude material was purified using reverse phase HPLC to afford product (33mg). MS: [M+H]+ = 362· Ο

10 Add 1,1'-Sulphur Dreams 2-2(11ΐ)_ ϋ σ σ 嗣 (l, l'-thiocarbonyldi-2 (lh)-pyridone, 0.51g, 0.65mmol) to 15 dissolved in water toluene (20ml) of 3-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-&]0-biti-3-yl]-phenylamine (3- [7-(3-]^1〇印11〇1丨11-4-7111161:11;71-phenyl)-imidazo[l,2_a]pyridin-3-yl]-phenyl amine, 0.25g, 0·65 In mmol), stir and heat to 110 ° C for 1 hour. The reaction was cooled to ambient temperature, diluted with CH2C12, washed with water and brine (br.), dried (Na2S04), filtered and concentrated under vacuo to give a brown oil. The residue was taken up in EtOAc (4 mL) EtOAc (EtOAc) After the end of the addition reaction, the reaction was stirred at this temperature for 15 minutes and concentrated under reduced pressure. The materials used will be further purified below.

The temperature was maintained at <25 ° C, and diethyl chlorophosphate (0.23 ml, 1.58 mmol) was added dropwise to the thiosemicarbazide (0.305 g, dissolved in DMF (5 ml). 0.66 mmol). After 30 minutes, additional diethyl phosphate was added. The reaction mixture was taken into water and extracted with EtOAc. The aqueous phase was concentrated under reduced pressure and the residue was triturated in ethanol and filtered. The filtrate was concentrated under reduced pressure and purified by HPLC to give &lt MS: [M+H]+ 469 This reaction can also be applied to the synthesis of other cyclic products, such as the amine-thiadiazole. Step F6-reductive amination 200836725

Acetic acid (17 μM, 0.40 mmol, 1.2 equiv) was added to 3-[7-(4-indol-phenyl)-mouth sulphate dissolved in toluene (30 ml) and decyl alcohol (1 〇ml). l,2-a]^^_3-yl]-phenylamine (3-[7-(4-FluoΓO-phenyl)-imidazo[l,2-a]pyridin_3-5 yl]_phenyl amine,100 mg,0.33 M, 1.0 equiv). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The crude imine product was dissolved in a mixed solution of ethanol and methanol (1:1, 30 ml), and a portion of sodium hydride (20 mg, 0.5 mmol, 1.5 equiv) was added in portions. The reaction mixture was stirred overnight overnight and the solvent was removed in vacuo. The reaction was stopped by slowly adding 10 N NaH (20 ml). Then ethyl acetate was added to separate the layers. The organic layer was washed with brine and dried (MgSO.sub.4). The compound was purified using hplc to give the desired product. Step F7 - Grab. Servant, 15

199 200836725 (54 mg, 0.66 mmol) was added to 3-[7-(4-fluoro-phenyl)-imidazo[l,2-a]acridin-3-yl]-benzene dissolved in EtOH (0.5 mL) 3-[7-(4-fluoro-phenyl)-imidazo[l52-a]pyridin-3-yl]-phenyla mine, 100 mg, 0.33 mmol) [as shown in step A3a]. The counter 5 should be heated to 78 ° C for 18 hours. It was then triturated in MeOH and the obtained solid was filtered. The solid was then subjected to a reverse phase HPLC to give the product (7 mg). MS: [M+H]+ 361 GENERAL PROCEDURE Η - The third position of the imidazolium n,2-alpyridine is attached to the trisubstituted 10 stupid synthetic step H1: 3-indole-quinone-morpholin-4-yl --Momoimidazolyl H,2-alpyridine-3-yl 1 - 5 - Shisuke-stirty Lunaan 15 (3-r7_(3-Morpholin-4-vlmethvl-phenvn-imidazo"l, 2-alpvridi nB -yll-S-nitro-benzamide)

取代Using the method of the general formula A, step A3b, to replace 3-aminobenzeneboronic acid with (3-aminobenz-5-y-phenyl)boronic acid 〇MS: [M+H]+ 458. Step H2: 3-Amino-5-"7-indole-morpholin-4-ylmethyl-jamolimidazolyl-ri.2-alpyridine-3-200 200836725-Based 1-indoleamine (3-Amino- 5-r7-(3-morpholin-4-vlmethvl_phenvlVimidaz〇ri· 2-a1pvridin-3-vl1-benzamide>)

Pd(OH)2 (30mg), 3-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazole (and [l,2_a] ° ratio -3-yl]-5_ Benzyl-benzoguanamine (3-[7-(3_111〇1^11〇1111-4- ylmethyl-phenyl)-imidazo[l 32-a]pyridin-3-yl]-5-nitro-benz amide) (135mg 2N HC1 (0.15ml), and HC02NH4 (150mg, 2.4tnmol) were dissolved in Et0H/H20 (4:1, 5ml) and stirred at 90 ° C for 90 minutes with nitrogen ring. Cool to room temperature After the mixture was diluted with MeOH and EtOAc (EtOAc m.). Step H3: 3-AcetvlaminQ-5-r7-(3-morpholin-4-vlmethvl-phenyl>)-imida ζοΓΙ ,2-a1pyridin-3-yl1-^l Ij Mr (benzamide)

3-Amino-5-[7-(3-morpholin-4-ylindole 201 200836725 phenyl-phenyl)-imidazo[l,2-a] «bipyridyl- dissolved in dry DMF (2 ml) 3-Amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[l 5 2-a]pyridin-3_yl]- benzamide, 90 mg), AcOH ( 29pL, 0.5 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and 5 N-(3-dimethylaminopropyl)-IT-ethylcarbodiimide hydrochloride (3- dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The mixture was then separated from CH2C12/H20. After layering, the aqueous layer was placed in SCX ζ\匣It was washed with MeOH, followed by 2 EtOAc (MeOH) eluted eluted eluted eluted elut elut elut elut elut elut elut elut elut elut DMSO〇: 10.26 (1H, s), 8.68 (1H, d), 8.12 (1H, s), 8.07 (2H, brs), 7·99 (1H, s), 7·87 (1H, s) ,7·83 (1H,s), 7.81-7.72 (2H,m),7.54-7.43 (2H,m),7·43-7·34 (2H,m), 15 3.66-3.54 (6H,m) , 2.47-2.36 (4H m), 2·11 (3H, s) · Step H4: Ν-Π-cyanomorpholin-4-ylindenyl-stupyl V imidazolium I / [ 1,2-al ratio - 3-; ^ 1 _ 笨乙乙胺(N- n-Cvano-5-r7-(3-morpholin-4-vlmethvl-phenvl, -imidazo 20 rK2-a1pvridin-3-yll-phenylI - acetamide) is used as in general step H The preparation is carried out in the steps of HI and H3, and in step 1, 3-amino-5-nitrobenzonic acid is replaced by 3-amino-5-cyanobenzeneboronic acid. NMR (400 MHz, DMSO) -A): 10.45 (1H, s), 8.71 (1H, 25 d), 8·12 (1H, t), 8·08 (1H, t), 8·01 (1H, brs), 7.94 ( 1H, s), 7.88 (1H, t), 7.82-7.72 (2H, m), 7.49 (1H, t), 7·44·7·35 (2H, 202 200836725 m), 3.67-3.54 (6H, m ), 2.47-2.36 (4H, m), 2.13 (3H, s) · Step H5: N-{3-曱气基·5·Γ7-(3-morpholin-4-ylmethyl-mosyl V imidazole And "1,2_al mouth is more than -3- phenyl phenyl acetaminophen 5 (N- {3-Methoxy-5-r7-(3-morpholin-4-ylmethvl-phenYl>)-imida ζοΓΙ,2- Alpvridin-3-νΙΊ-phenyl}- acetamide)

Further, as in Example H, the steps m, H2 and H3 are used. In step 1, the 3-amino group is replaced by 3-methoxy-5-nitrophenyl boronic acid pinacol ester 10 (18). Carbonyl-5-nitrophenylboronic acid. 4 NMR (400 MHz, DMS0〇: 10.11 (1H, s), 8.64 (1H, d), 7.97 (1H, s), 7·82 (1Η, s), 7.78-7.73 (2Η, m ), 7.51-7.45 (2Η, m), 7.40-7.36 (2Η, m), 7·33 (1H, t), 6.93 (1H, dd) 5 3·83 (3H, s), 3.63-3.55 (6H, m), 2.41 (4H, s), 2.08 (3H, s). 15 Step I - Synthesis of boric acid and esters

Boric acid II 2-Methane-N-"4-(4,4,5,5-tetradecyl-"h3,21 dioxa borane-2-yl>l· 20 stupid 1-B Indoleamine (2-Methoxv-N-f4-(4,4,5,5-tetramethvl-"l,3,2~]dioxaborolan-2 -viyphenvll- acetamide) 203 200836725

5 Ο 10 Ο 15 Triethylamine (〇·95 ml, 6.84 mmol,) and methoxyethyl hydrazine chloride (0.417 ml, 4.56 mmol) were added dropwise to 4-(4) in THF (20 ml). ,4,5,5-tetramethyl-[1,3,2]dioxaboropentan-2-yl)-phenylamine (4-(4,4,5,5-Tetramethyl-[l, 3,2]dioxaborolan-2-yl)-phenylamine, 1 g, 4.56 mmol), the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS: M+H]+ 292 boric acid 12 2_methyl-2-"4-(4,4,5.5-tetramethyl-"1,3,21 dioxa haloborane-2-yl)- stupid Methyl 1-propionate (2-Methyl-2-"4-(4.4.5,5-tetramethvl-ri J.Zldioxaborolan-lv l>phenyl1-propi〇nic acid methyl ester)

204 200836725 5 Ο 10 15 (2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester , 0.5g, 1.94mmol), [1, Γ-bis(diphenylphosphino)ferrocene] Palladium(II) chloride ([151 f-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 80 mgs, 0.97 mmol), dppf (40 mgs, 0.07 mmol), and potassium acetate (0.596 g, 6.07 mmol) ) added to 4,4,5,5,4',4',5,5'-octadecyl-2,2'-di-1,3,2-di in dioxane (4ml) Pyrithione (4,4,5,5,4',4',5',5'-Octamethyl-2,2'-bi-l,3,2-dioxaborolane, 0.74g, 2.91 mmol) And heated to 80 ° C overnight. The reaction mixture was diluted with EtOAc EtOAc EtOAc (EtOAc m. 305 〇boronic acid 13 1-methyl-5-(4,4,5.5-tetramethyl彳1丄21 dioxa borane-2-yl)-111- 0 ratio g-butan-2-one (l- Methvl-5-(4,4,5,5-tetramethvl-"l,3,21dioxaborolan-2-vlV lH-pvridin-2-one)

K Add K2C03 (6.36, 45.7 mmol) and Mel (2.84 ml, 45.7 mmol) to 5-bromo-1H-° bis-2-one (5-Bromo-lH-pyridin-2) dissolved in DME (40 ml) -one, 4g, 22·9 mmol), and the mixture was heated to 80 ° C for 2 hours and cooled overnight. The reaction was filtered and 205 20 200836725. The solid was washed with DME. After filtration, it is concentrated in vacuo, EtOAc (EtOAc) elute. 5 5-bromo-1-indenyl-1H-pyridin-2-one (0.5g, 2.65 mmo1) [reaction by removing gas through the gas], [1, bismuth-bis(monophosphine) Ferroferrin I-bar (II) ([l5lf-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), 59mgs, 0.080 mmol), dppf (88mgs, Γ 0.16 mmol) and potassium acetate (0.77g, 7.84mmol) Add to 4,4,5,5,4,4,5,5,-octamethyl-2,2,-di-1,3,2-di in dioxane 10 (40ml) Heat to 80 ° C for one week in hetero-oxypentaborane (0.88 g, 3.46 mmol). The reaction mixture was diluted with EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Purification by column chromatography using EtOAc 15 as eluent afforded the product (j. MS: [M+H]+ 224 shed acid 16 l-[3-(4,4,5,5-tetramethyl-"1,3.21 dioxa borane-2-yl)-methyl 1 3-20 (2,2,2-digas-ethyl)-pulse n-r3-(4,4,5,5-Tetramethvl-f 1,3,21dioxaborolan-2-vlVphenvl lS-^^^-trifluoro -ethylVurea) Step 1: 1-(3 -> odor-stupidyl)-3-(2,2,2-disorganoethyl) vein (l-(3-Bromo-phenvlV3 -(2,2,2) -trifluoro-ethvlVurea) 206 200836725

3-Bromophenyl isocyanate (1.0 ml, 8.1 mmol) was slowly added to 2,2,2·trifluoroethylamine (3.2 ml) dissolved in THF (10 ml) under stirring at rt. , 40 mmol) in solution. After 1 hour, the reaction was heated to room temperature and maintained for 16 hours. The solvent was evaporated in vacuo to give the compound (2.5 g, solid). Towel NMR (400 MHz, DMSO-d6): 9·00 (1H, s), 7·86 (1Η, t), 7·33 (1Η, ddd), 7·26 (1Η, t) 5 7·18 (1Η, ddd), 6.89 (1H, t), 4.03-3.92 (2H, m). 10 Step 2: M3-(4,4,5,5-tetramethyl-"1,3,21 dioxa borane-2-yl stupid 1-3-(2,2,2-di -ethyl V vein (l-f3-(4,4,5.5-Tetramethvl-"l,3,21dioxaborolan-2-vlVphenvl 1-3-(2,2,2-trifluoro-ethylVurea)

ϋ 15 1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)·urea (1-(3-Bromo_phenyl)-3_) dissolved in dry DMSO (7 ml) 2,2,2-trifluoro-ethyl)-urea) (2.1 g, 7.1 mmol), bis(pinacolato diboron, 3.6 g, 14 mmol) and KOAc (2.1 g, 21 mmol) Evacuation deoxygenation / refilling with N2 (x3). 20 PdCl2ddpf (512 mg, 0.7 mmol) was added, and the mixture was again deoxygenated 207 200836725 (x2), followed by stirring and heating at l ° ° C, N 2 for 3 hours. The reaction was cooled to room temperature and allowed to stand at this temperature for 18 hours. The mixture was separated with Et0Ac/H20 and filtered using Celite®. After layering, the aqueous layer was extracted with EtOAc (EtOAc). The organic layer extract was washed with water (xl), brine (bine) (xl), then dried (MgSO4), filtered and evaporated. The residue was triturated in petroleum ether to give compound (2.6 g, solid). 4 NMR (400 MHz, CDC13): 7.65 (1H, s) 5 7·60 (1H, d), 7.49 (1H, d), 7.37 (1H, t), 6.64 (1H, brs), 5.20 (1H, Brs), 3.99-3.86 (2H3 m)? 1.35 (12H, s). 10 Boric acid 17 1-methyl 4.5,5-tetramethyl-"1,3,21 dioxa haloborane-2-ylbenzene Base"I-pulse 15 Π-Methvl-3-Γ3-(4,4,5,5-tetramethvl-ΓΙ ,3,21 dioxaborolan-2-v n-phenvll-urea")

For example, the preparation of 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3_(2,2, 2·Trifluoro-ethyl)-urea (l-[3_(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, Prepared in the same manner as 2-trifluoro-ethyl)-20 urea, 16), but in step 1, 2,2,2-trifluoroethylamine was replaced with decylamine dissolved in THF (2M). 4 NMR (400 MHz, CDC13): 7.59-7.53 (2H, m), 7.50 (1H, d), 7.34 (1H, t), 2·83 208 200836725 (3H, s), 1·33 (12H , s). Boric acid 18 3 -fluorenyl-5-fancy-stactyl acid pinacol 5 (3-Methoxv-5-nitro-phenvl boronic acid pinacol ester)

1-Bromo-3-methoxy-5-nitro-benzene (387 mg, 1.7 mmol), bis-pinacol borate (850 mg, 3.3 mmol) dissolved in dry DMSO (3.5 mL), and KOAc A mixture of (490 mg, 5.0 mmol) was deaerated / 10 refilled with N2 (x3). PdClddpf (61 mg, 0.08 mmol) was added to the mixture, and oxygen (x3) was again removed, followed by stirring and heating at 100 ° C under N 2 for 16 hours. After cooling to room temperature, the mixture was separated with EtOAc / H20 and then transferred with Celite. The layers were separated and the aqueous extracted with EtOAc (EtOAc). The organic layer was washed with brine (xl), followed by drying of t' 15 (Na2S 〇 4), sputum and evaporation. The residue was purified using EtOAc (EtOAc) (EtOAc (EtOAc) 4 NMR (400 MHz, CDC13): 8·23 (1H, d), 7.79 (1H, t), 7.62 (1H, d), 3·90 (3H, s), 1.36 (12H, s) · 20 boric acid 19 1-Ethyl-3-"3_(4,4^5,5-tetramethyl-port, 3,21 diheteroarborane-2-yl)-phenyl V urea 209 200836725 n-Ethvl- S-rS-M^.SS-tetramethvl-n, 3,21dioxaborolan-2-yl>) -phenyll-urea)

Add triethylamine (58 ml, 410 mmol, 3.0 equiv) and ethyl isocyanurate 5 (3 ml, 205 mmol, 1.5 equiv) to 3-(4,4) in THF (300 ml) ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)aniline, 30 g, 137 mmol, 1.0 equiv). The reaction was cooled to room temperature and diluted with diethyl ether (600 mL). The precipitate was filtered, and the solid was washed with &lt Boric acid 110-113 1-"4-(4,4.5.5-tetramethyl-1丄2-dioxa borane-2-yl)methylmethyl 1-amine (1 -r4-(4.4,5.5 -Tetramethvl-l,3,2-dioxaborolan-2-vl)benzvl1 15 -amine)

K2C03 (2 eq), amine (1.25 eq), and (4-bromomethylphenyl) boronic acid pinacol ester (leq) were dissolved in dry DMF (1 ml / The mixture was stirred for 20 hours at room temperature, and the mixture was separated by Et20/H20. The organic layer 210 200836725 was washed with water (xl), brine (xl), then dried (Na2S04), Filtration and evaporation to give the title compound as the title product. MS: [M+H] + 110 P 1-[4_(4,4,5,5_tetramethyl-[1,3,2 Dioxaborolan-2-yl)-benzoinyl]-azetidin (l-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxa borolan- 2-yl)-benzyl]-azetidine) 274 111 hnO l-[4-(4,4,5,5-tetramethyl·1;1,3,2]dioxaborolan-2-yl) -Benzyl]-pyrrolidine (l-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxa borolan-2-yl)-benzyl]-pyrrolidine) 288 112 rf hnJ 1-methyl_4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoinyl]-piperazine ( 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[ 1,3 ,2]dioxaborolan-2-yl)-benzyl]-piperazin e) 317 113 η 0 (±) (±)_1_[4-(4,4,5,5·tetradecyl·1,3,2-dioxa oxo-2-yl)benzyl]-3-fluorenyl-唆-3-竣酸酯((土)-l-[4-(4,4,5,5-Tetramethyl-l,3,2-dio xaborolan-2-yl)benzyl]-3-methyl -piperid ine-3-carboxylic acid ethyl ester) 388 211 200836725 Boric acid 114 4-(2,2-dimethyl-anthracene 1.31 di-pentovacyclo-4-ylmethyl-methyl-boronic acid (4-(2) ,2-Dimethvl-n .31dioxolan-4"ylmethoxv>)-phenvl-boroni 5 c acid)

H Add sodium hydride (200 mg, 5.0 mmol, 1.0 equiv) in portions to 4-bromophenol (865 mg, 5.0 mmol, 1.0 equiv) in DMF (10 ml). Then add 4-(chloroindolyl)-2,2-dimethyl-1,3-dioxo 10 pentane (4_(chloromethyl)-2,2_dimethyl-l,3-diox〇lane, 0.78 in several portions. Ml, 5.5 mmol, 1.1 Equiv). The reaction mixture was heated to 70 °C overnight. The reaction mixture was then cooled to room temperature, decyl alcohol (10 ml) was added and the solvent was removed under reduced pressure. The crude mixture was separated into water with ethyl acetate and layered. The organic layer was washed with water, dried (MgSO4), and evaporated. The crude mixture was purified by column chromatography eluting with EtOAc EtOAc EtOAc n-BxiLi (2.25 ml of a 1.6M solution in hexanes, 3·6 mmol, 1.0·0 equiv) was added dropwise to the THF (10 ml) in a nitrogen atmosphere at -78 °C. A bromine compound (ΐ·〇g, 3·6 mmol, ΐ·〇eqUiv) 20 _. After 15 minutes, add the solution of trimethylpyrrolidate (1.3 ml, 12.3 mmol, 3.5 equiv) slowly (the addition time must be more than 15 minutes. The reaction mixture is warmed to room temperature and placed overnight. The solvent is removed by vacuum method The mixture was separated by diethyl ether and Sorenson's buffer solution (pH 5·5-Na2HP〇4 in water and KH2P〇4). The aqueous layer was extracted with diethyl ether (3×), and the organic layer was taken with water. Saturated brine (brine), dried (MgSO4), filtered, and concentrated under reduced pressure to give a colorless solid product (852 mg, 94%). Botanic acid 115 Step 1: 4-(4-D. -1- 绕 酸 r r r r4-r4-Brom〇"phenoxvVpiperidine-1 -carboxylic acid tert-butvl ester)

Add Na2C03 (1.6 g, 18.9 mmol) and (B0C) 20 (1.3 g, 5 ·9ππηο1) to 4-(4-bromo-phenoxy)-piperidine (4, dissolved in dioxane (20 ml). (4_Bromo-phenoxy)-piperidine, lg, 3.9 mmol), followed by 15 water (20 ml). After stirring at ambient temperature for 48 hours, the solvent was evaporated and evaporated. The organic layer was washed with brine and dried (MgSO4) and concentrated under reduced pressure to give product (1.2 g) 〇20 Step 2················ _"1丄21二杂气戍 borane-2-yl V-gas-based 1-piperidin-1-carboxylic acid tert-butyl ester (4-"4,4,5,5-Tetramethvl-"U3 ,21dioxaborolan-2-vlVr)heno xvl-piperidine-l-carboxvlic acid tert-butvl ester) 213 200836725

Add bis(pinacolato diboron5 0.93g, 36.5 mmol), KOAc (0.83g, 84.5 mmol), PdCUddpf (0.061g, 5 0.84mmol), and dppf (0.092g, 0.16mmol) 4-(4-Bromo-phenoxy)-piperidine-1 -carboxylic acid tert dissolved in dioxane (25ml) -butyl ester, lg, 2.8 mmol) [The reaction was bubbled through a nitrogen atmosphere], then the mixture was stirred and heated to 80 ° C for 16 hours. After cooling to room temperature, the mixture was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS: [M+H]+ (no mass ion used crude) (15 boric acid 118 N-methyl-2-indole 3-(4,4,5.5-tetramethyl-"1,3,21 dioxane to boron Alkyl-2-yl)-methyl-acetamide (N-Methvl-2-"3-(4,4.5,5-tetramethvl-ri,3,21dioxaborolan-2-yl)-phenvl-acetamide") 214 200836725

1-Hydroxybenzotriazole (1 - hydroxybenzotriazole 0.37 g, 2.73 mmol) and TBTU 2-(1Η-benzotriazol-1-yl)-l,l,3,3- dissolved in DMF (15 ml) Tetramethyluronium tetrafluoroborate 5 (2-(1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 0.88 g, 2.73 mmol) solution was added to DMF (15 ml) [3-(4,4,5,5_tetradecyl-[1,3,2]disoxaborolan-2-yl)-phenyl]acetic acid ([3_(4,4,5, 5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]acetic acid, 0.60 g, 2.28 mmol). Then triethylamine 10 (0.95 ml) and mercaptoamine (1.2 ml) were added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified by reverse chromatography to give a boronic acid/acid mixture which was used directly. MS: [MH+] 276 (ester), [MH+] 193 (acid)· 15 boric acid 119 (3-methyl trace ϋ ϋ 酮) (T3_methvlpiperazinone) phenvl boronic acid) 215 200836725

(3-Bromomethylphenylboronic acid, neopentyl glycol ester (0.45 g, 1.6 tnmol), NaHC03 (0.34 g, 4 mmol) and Nal (O.Olg, 0.74 mmol) were dissolved in dry THF/DMSO. (10 ml: 2.5 ml) of piperazine-2-one (0.2 g, 520 mmol). The reaction mixture was heated under reflux for 12 hours, then cooled and passed through a C18 reverse layer suction column to give a colorless gum. Take it directly. MS: [MH+] 235 Borate 120 10 1-(3-Amino-2,2_dioxin-propyl)-3-"3-(4,4,5.5_四甲Base_"1,3,21 dioxaborolan-2-ylphenyl 1-urenn nn-Amino-2*2-difluoro-propvl)-3-r3-(4,4,5,5-tetramethvl - ri,3,2"ldioxaborolan-2-vlVphenvll-urea) 15 Step 1: ^0TSr0^ — H2NyVNH2 ο Ο Ο 7 7N ammonia dissolved in decyl alcohol (14.3 ml, 101.9 mmol, 4 equiv) under nitrogen atmosphere The aqueous solution was added to diethyl difluoromalonate (5 g, 25.5 mmol, 1 equiv) dissolved in decyl alcohol (15 ml). After the reaction was completed, the mixture was concentrated under reduced pressure. The crude mixture was triturated in petroleum ether to give 2,2-difluoro-propanediamine as a white solid. 216 200836725 (2,2-difl Uoro-malon amide) (98%) 〇Step 2: -h2n^>C^nh2 Η2Ν^ΧγΝΗ2 〇〇5 2,2-Difluoropropanediamine (2,2-) dissolved in THF (26ml) (^^11〇1*〇-malonamide, 1.34g, 9.7mmol) was added to BH3.THF [1 Μ dissolved in THF] (58ml, 58mmol). The reaction mixture was heated to 45 ° C and stirred overnight. It was cooled in an ice-bath and treated with 2M EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - Propane-1,3-diamine (0.92 g). MS: [M+H]+ 111. Step 3: ί

15 2,2-Difluoro-propane-1,3-diamine (0.4 g, 2.2 mmol) and triethylamine (1.5 ml, ll mmol) were added to 2-(3·isocyanide) dissolved in THF (15 ml) Acid phenyl)-4,4,5,5-tetradecyl-[1,3,2]-diadeoxyborane, pinacol ester (2_(3-isocyanatophenyl)_4,4,5,5_tetramethyl -[l,3,2]_dioxab 217 200836725 orolane, pinacol ester, 0.135g, 0.55mxn〇l) in ' stirring at ambient temperature until the reaction is complete. The solid was filtered, washed with THF <~> filtered, concentrated under reduced pressure and dried to give compound &lt MS: [M+H]+356 boric acid 121 2-(four-individual-pyran-4-yloxy)-4-0-butidine-based acid (2-(tetrahydro-pyran-4-yloxYV4-pYridinvlboronic acid) ) Ο

At a temperature of 0 C, 4-hydroxytetrahydropyran (1.02 ml, 10 mm 〇l) was added to NaH (0.4 g, 10 mmol) dissolved in THF (20 ml). The reaction mixture was warmed to room temperature 15 and stirred for 30 minutes before dropwise addition of 4-bromo-2-pyridine (0.89 ml, 8.0 mmol). The reaction mixture was spoiled for 18 hours before the reaction was stopped with Et0H (1 ml). The mixture was separated by CHzCl2 and fj2 and extracted with <RTI ID=0.0>> The organic layer was collected, dried (Mgjg 〇 4) and the solvent was removed by vacuum. Purification using column chromatography gave 4_-di-2-(tetrahydro-indolepyran-4-yloxy)_.唆 20 (4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine). MS: [MH]+ 258, 260 218 200836725

4,4,5,5,H,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolan (4) 4,55554,54f,5 ,, 5,-octamethyl-2,2,-bi-l 53,2-dioxaborolane, 5 〇.39g, 1.55mmol) and acetic acid (0.27g, 2.3lmmol) were added to DMSO (5ml) 4->Smell_2-(tetrachloro- σ-pyran-4-yloxy)-σ ratio (4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine, 0.2g, 0.77 Mm) (by N2 to degas). Then PdCl2ddpf (0.028 g, 0.04 mmol) was added, then the reaction mixture was again degassed and heated at 100 ° C for 10 5 hours. The compound is passed through a C18 reverse layer pipette column to give the desired compound and can be used directly. MS: [MH]+ 224· Boric acid 122 4-"4,4,5,5-tetramethyl-[1丄21 dioxa borane-2-yl)- stupid base 1-

Tert-butyl piperidine-1-carboxylate (4-r3"(4.4,5,5-Tetramethvl-n.3<t21dioxaborolan-2-yl)-pheno xvl-piperidine-1-carboxylic acid tert-butvl ester)

Cs2C〇3 (44.4 g), 136.3 mmol, 3.0 equiv) and 4-曱219 200836725 醯黄醯基oxy_派咬-1-酸酸"TS|(4-metlianesulfonyloxy-piperidine-l-carboxylic acid tert-butyl Ester , 19.0 g, 68.2 mmol, 1.5 equiv) added to 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-dissolved in NMP (100 ml) 2-yl)-phenol (3-(4,4,5,5-tetramethyl-5 [153,2]dioxaborolan-2-yl)-phenol, 10.0 g? 45.4 mmol, 1.0 equiv). Heating the reaction mixture The reaction mixture was cooled to room temperature, then diluted with water and extracted with EtOAc. The organic layer was washed with 2N KOH, water, brine, dried (MgS04), filtered The title compound was purified by column chromatography eluting with EtOAc (EtOAc) eluting 1H NMR (400 MHz, CDC13): 7·42 (1Η, d), 7.37 (1Η, d), 7.31 (1Η, t), 7.03 (1Η, dd), 4·61-4·49 (1H, m ),3·76·3_62 (2H,m), 3.47-3.32 (2H,m), 1.99-1.86 (2H,m),1.86-1.70 (2H,m), 1·49 (9H, s). Borate 124 l-"3_(4,4,5,5-tetramethyl-"1,3,21 dioxa borane-2-yl) stupid 1- 3-(2,2,-diox-ethyl oxime - "3-Γ4.4.5,5-Tetramethvl-"1,3,21 dioxaborolan-2-vl)_phenvl 20 1-3-r2.2,- Difluoro-ethvn-urea>) again

The preparation was carried out in the same manner as in the step 16 except that 2,2-difluoroethylamine was replaced by 2,2-difluoroethylamine 220 200836725. 1H NMR (400 MHz, CDC13): 7.64-7.53 (2H, m), 7·48 (1H, d), 7·35 (1H, t), 6.46 (1H, s), 5·88 (1H, tt ), 3.61 (2H, td), 1.34 (12H, s). 5 Borate 125 1-(2-fluoro-ethyl)-3-"3-(4,4,5,5-tetramethyl-" 1,3,21 dioxa borane-2-yl) stupid 1- Π -(2-Fluoro-ethvn· 3-"3-(4,4,5,5-tetramethvMl ,3,21 dioxabo Rolan-2-vlVphenvll-urea)

The preparation was carried out in the same manner as in Step 16 except that 2,2,2-trifluoroethylamine was replaced by 2-fluoroethylamine. 1H NMR (400 MHz, CDC13): 7.60 (1H, s), 7.55 (1H, d), 7.50 (1H, d), 7·34 (1H, t), 4·51 (2H, dt), 3.56 ( 2H,dt),1.33 (12H,s)· O 15 borate 126 (2-丨3-"3彳4.4.5,5-tetramethyl-"1,3,21 dioxane pentaborane-2 -基)-Ja- 1-月^基}"Ethyl)-Amino acid tert-butylate ((2 - (3-[3-(4,4<t5,5-Tetramethvl-rK3,21dioxaborolan-2- YlVph 20 enyll-ureidol-ethvD-carbamic acid tert-butvl ester) 221 200836725

Prepared in the same manner as in Step 16 except that 2,2,2-trifluoroethylamine was replaced with (2-amino-ethyl)-amine decanoic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6): 8·59 (1H, s), 7·77 (1H, s), 7·47 (1H, dt), 5 7·26-7·17 (2Η, m ), 6.84 (1Η, t), 6.16 (1Η, t), 3.18-3.07 (2Η, m), 3.07-2.95 (2H, m), 1.39 (9H, s), 1.29 (12H, s). Borate 127 (3_(3-"3_(4.4.5.5-tetramethyl-"1,3.21 dioxa borane-2-yl]-----------1 ureidopropylpropyl phthalate t-butyl ester ( Ύ3 - {3-"4(4.5,5-Τ6ΐτ&Γη^1:1ιν1-Γ1,3,21dioxaborolan-2-vl)-ph enyll-ureidol-propylVcarbamic acid tert-butvl ester)

(3-Amino-propyl)-carbamic acid tert-butyl ester, 0.79 ml, 4·5 mmol, at room temperature under nitrogen atmosphere (3-amino-propyl)-carbamic acid tert-butyl ester Slowly adding 2-(3-isocyanato-phenyl)-4,4,5,5-tetradecyl-[1,3,2]disazopentyl boron dissolved in dry THF (8 ml) with stirring. Alkyl (2-(3-isocyanato-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxabo rolane, lg, 4.1 mmol). After 16 hours, the solvent was evaporated in vacuo and residue 222 2008 367.25 was isolated from Et0Ac/H. The organic layer was washed with brine (xl), dried (Na2SO4), filtered, and evaporated to give a colorless solid compound (1.6 g). 1H NMR (400 MHz, DMSO-d6): 8·52 (1H, s), 7·77 (1H, s), 7·47 (1H, dt), 5 7.25-7.17 (2Η, m), 6· 80 (1Η,t),6·08 (1Η,t),3.13-3.02 (2Η, m),3·02·2·89 (2H,m),1·57-1·48 (2H,m) ,1·39 (9H, s), 1.29 (12H, s). Borate 128: M5-(4,4.5.5-tetramethyl-"1.3.21 dioxa borane-2-f } 10 base ratio. D--3-yl 1-(2,2,2-tris-ethyl)-pulse (128:1-Γ5-(4,4,5.5-Tetramethyl-TL 3.21 dioxaborolan-2 -vlVpv ridin-3-vl1-3-(2,2,2-trifluoro-ethvlVurea>)

15 Add bis (pinacolato diboron, 0.88 g, 3.45 mmol) to 1-(5-bromo-p--3-yl) dissolved in dehydrated DMSO (3 mL) -3-(2,2,2·三败ethyl)_urea (l-(5-bromo-pyridin-3-yl)-3-(2,2,2-trifluoro-ethyl)-urea, 0.51 g , ι·72 mmol). The bottle of the reaction was filled with N2 and PdCUdppf (4 〇 mg, 0.05 mmol). Then refill A and heat to 100 °C for 22 hours. After cooling to room temperature, H20 (30 mL) and EtOAc (30 mL) were added and the two phases separated 223 200836725. The organic layer was washed with H20 (2 x 35 mL). The organic layer was then dried over MgS04, filtered and concentrated under reduced pressure and the product was taken directly. Benzate 129- 5 (four mouse-mouth ratio kounan-4-yl)-"3-(4,4,5,5-tetradecyl-f 1,3,21 dioxane 戍 烧-2 -Base)-stupyl-1.amine ([Tetrahvdro-pvran-4-vlV"3-(4,4,5,5-tetramethvl-Fl,3,21dio xaborolan-2-vn-phenvll-amine) c Step 1 : (3->odoro-phenyl)-(tetrazo-pyran-4-yl)-amine

10 15 Ο 20 Sodium triacetoxyborohydride (1.48 g, 7 mmol) and acetic acid (0.3 g) were added to 3-bromo-phenylamine (0.54 ml, 5 mmol) dissolved in DCE (20 ml) and tetrahydro-4 Η -β 1,4-ketone-4-ketone (tetrahydro-4H_pyran-4-one, 0.5 g, 5 mmol). The mixture was stirred for 18 hours before stopping the reaction with IN NaOH (10 ml). The mixture was separated with Et20 and H20, the aqueous layer was extracted with Et20, organic layers were collected, dried (MgS04), filtered, and solvent was removed in vacuo to give a colorless liquid. Purification by column chromatography (0 - 80%EtOAcEtOAcEtOAc) MS: [M+H]+ = 256,258 Step 2: (tetrapyran-4-yl)-"3-(4,4,5.5-tetramethyl-"1,夂21二杂气224 200836725 shed -2_yl)-stupylamine ((Tetrahydro-pyran-4-vlVr3-(4.4.5,5-tetramethvl-rK3,21dio xaborolan-2-vn-phenvll-amine)

5 Add bis (pinacolato diboron, 0.4g, 1.55 mmol) and potassium acetate (0.23 g, 2.31 mmol) to DMSO (5 ml) (3- desert- Phenyl)-(tetrazo-pyran-4-yl-amine, 0.2 g, 10 0.77 mmol). The reaction was deoxygenated, and PdCl2ddpf (28 mg, 39 μηιοί) was added, and the mixture was again deoxygenated and stirred, and heated to 100 ° C for 18 hours under a nitrogen atmosphere. The crude reaction mixture was purified using reverse enthalpy chromatography (0 - 100% MeCN in H20) to afford a pale brown gum product (0-24 g). MS: [M+H]+ = 304 C; 15 banic acid 5 is intended for 130 _ N-ethyl-3-(4,4,5,5-tetramethyl-1,3,2_ two gas shed Alkan-2-yl)mosamine (N-ethvl-3-(4,4.5<t5-tetramethvl-K3,2-dioxaborolan-2-yl) benzamide) 225 20 200836725

EDAC (0.17 g, 〇.88 mmol), HOAt (0.12 g, 0.88 mol), and triethylamine ((Uml, 〇. 8 mmol) were added to 5 Ο 10 Ο 15 3-(4) dissolved in THF (6 ml) ,4,5,5-tetramethyl·1,3,2-dioxaborolan-2-yl)benzoic acid (3_(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan -2-yl)benzoic acid, 0.2 g, 〇8 mmol). After adding ethylamine (0.4 g, 0.8 mmol), the reaction mixture was stirred at room temperature for 2 hours, then CH2C12 and 5% citric acid Separate (citric acid), separate the organic layer, wash it with saturated dicarbonic acid, brine, dry (MgS〇4), transition, and remove the solvent by vacuum. The crude residue can be removed. Used directly in the next reaction. MS: [M+H]+ = 276 borate 131 N-azabutane-3-(4,4,5,5-tetramethyl-1,3,2 - dioxa borane-2-yl) meglumine-crackamine (N-azetidine"3-(4.4.5.5-tetramethvl-l<t3<t2-dioxaborolan-2-yl>) benzamide)

0y0 Ο ο 226 200836725 The same procedure as in step 130, but replacing the ethylamine with azetidine. MS: [M+H]+ = 288 orthoester 132 - {2-"4-(4,4,5,5-tetradecyl-[~1.3.21 dioxanoxaborane 5-2-yl) Lamethoamine 1-ethyl-amidamine tert-butyl phthalate ({2-"3-(4.4,5,5-Tetramethvl-"l ·3,2~Ι(Ηοχαΐ3〇Γ〇ΐΗη-2-ν1&gt) ;)·^6ηζο vlaminol-ethvU-carbamic acid tert-butvl ester)

The same procedure as in step 130 was followed except that the ethylamine was replaced with tert-butyl N-(2-aminoethyl)carbamate. MS: [M+H]+ = 391 15 oxalate 133 _ N_isopropyl-3-(4,4,5,5-tetramethyl-1,3.2-dioxaxanthene-2- Baseline) N-isopropvl-S-^^.SS-tetramethvl-K3,2-dioxaborolan-2-vl>) benzamide) 227 200836725

The same procedure as in step 130 was followed except that the ethylamine was replaced with isopropylamine. MS: [M+H]+ = 290 5 酸酸酉 134 - (4-ethyl>-p-qin-1-yl-tetradecyl^-"1,3,21-dioxa borane -2-yl)-molyl}-methanone "4-ethvl-piperazin-l-vlW3-(4,dtetramethvl-"l,3,21-dio xaborolan-2-vn-phenvll-methanone")

The same procedure as in step 130 was followed except that ethylamine was substituted with 1-ethyl-piperazine. MS: [M+H]+= 345 15 borate 135 - 4-"3-(4,4,5,5-tetramethyl-"l,3,21 dioxa borane-2-yl )-Methylmethyl l-oxime, 41 diazepeptane-l-carboxylic acid tert-butyl ester (^ni^dJJ-TetramethvWUJldioxaborolan-S-vn-benzov ll-"l,41diazepane-l-carboxvlic acid tert- Butvlester) 228 200836725

The same procedure as in step 130, but substituting ethylamine·MS with [1,4]diazepenane-l-carboxylic acid tert-butyl ester 5 [M+H]+ = 431 borate 136 - 2-Π-isopropyl group 5-nitro-molly)-4,4,5,5-tetradecyl-"1,3,21 Heterocarbon to borane (2-(3-Isopropoxv-5-nitro-phenvl>)-4.4, 5.5-tetramethyl-ri .3.21 10 dioxaborolane 0 Step 1

Isopropyl iodide (0.37 ml, 3.70 mmol) was added to 3-bromo-5-nitro-phenol (0.40 g, 1 ·83ηπηο1) and 15 K2C03 (0.51 g) dissolved in dry DMF (2 ml). , 3.67 mmol), and the mixture was stirred for 18 hours. The reaction mixture was separated by Et 〇Ac/H20. The organic layer was washed with water (xl), brine (xl), dried (Na.sub.2.sub.4), filtered, and the solvent was removed in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) 1H NMR (400 MHz, CDC13): 20 7·94 (1H, t), 7·67 (1H, t), 7·36 (1H, t), 4.71-4.57 (1H, m), 229 200836725 1· 40 (6H,d) 〇Step 2 5

The same procedure as in Step 18 was carried out without purification, and the crude product was used directly in the next step. Borate 137 - 3-nitro-5-(4,4,5,5-tetramethyl-, 3,21 diheteropentaborane-2-ylphenyl 1-indole 10 (3- Nitro-5-(4,4,5,5-tetramethvl-"1,3,2~|dioxaborolan-2-vl)-ph enyD-methanol) Step 1 NO. NO.

BH3.THF (1.0 M in THF, 100 ml) was added dropwise to a solution of 3-bromo-5-nitro-benzoic acid (15.0 g, 61 mmol) dissolved in dry THF (100 ml). Solution. The reaction mixture was stirred overnight at room temperature before being added to saturated NaHC03 (aq). Et20 was then added to the reaction mixture and stirred for 20 minutes and separated. The water layer is extracted with Et20 (x2), and the organic layer is partially collected and extracted with IN NaOH (xl), brine (xl), dried (Na2S〇4), filtered, and the solvent is vacuumed. Method 230 200836725 Removed. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) 1H NMR (400 MHz, CDC13): 8.31 (1H, s), 8.20 (1H, s) 5 7.89 (1H, s), 4.84 (2H, s). 5 Step 2 Γ:

The same procedure as in Step 18 was carried out without purification, and the crude product was used directly in the next step. 10 borate 138 - 1-"4-fluoro-3-(4,4,5,5-tetramethyl-, 3,21 dioxa pentyl bromide-2-yl)-stupyl 1-3 -(2,2,2-di-ethyl)-pulse - "4-Fluoro-3-(4,4,5,5-tetramethvl-"l,3,21 dioxaborolan-2-v D-phenyll -B-^^^-trifluoro-ethylVurea) 15 Step 1

2-Chloro-l-fluoro-4-isocyanato-benzene (5.0 g, 29 mmol) was slowly added to dryness under a nitrogen atmosphere at a nitrogen atmosphere. THF (40 ml) of 2,2,2-trifluoroethylamine (12 ml, 20 150 mmol). After 1 hour, the reaction was warmed to room temperature and stirred for 18 hours. 231 200836725 The solvent was removed in vacuo and the residue was triturated in Et20 to give a colourless solid (6.2 g). 1H NMR (400 MHz, DMSO-d6): 8.95 (1H, s), 7·75 (1H, dd), 7.36-7.21 (2H, m), 6.85 (1H, s), 3.99-3.84 (2H , m). Step two

The same procedure as in step 18 was followed except that Pd2dba3 and S-Phos were substituted for PdCl2ddpf. After the completion of the aqueous solution, the product was isolated by trituration in petroleum (1.4 g). 1H NMR (400 MHz, DMSO-d6): 8·82 (1H, s), 7.72 (1H, dd), 7·52 (1H, ddd), 7·05 (1H, t), 6.67 (1H, t ), 3·98-3·83 (2H, m), 1.30 (12H, s) · Borate 139 -2-fluoro_5-(4,4,5,5-tetradecyl-"1,3 , 21 diheteropentaborane 15 _2_yl strepamine (2-Fluoro-5-r4,4<t5,5-tetramethvl"ri,3,21dioxaborolan-2-vl>)" phenvl amine)

The same procedure as in Step 18, but without purification, and the crude product was used directly in the next step. 232 200836725 Boric acid 140 - 1-dimethylaminosulfonyl-1H-pyridin-4-boronic acid Step one -4 · Bromo-pyrazole-1-sulfonic acid dimethyl decylamine 5

N-N \ 〇N-NH f) dimethylaminosulfonium (1.611111, 15111111〇1) was added to 4-bromopyrazole (2.20 g, 15 mmol) dissolved in MeCN (15 ml) at room temperature. ) and DABCO (1.85g, 16.5mmol). The reaction mixture was stirred for 20 h, then EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) g). 1H NMR (400 MHz, CDC13): 8.00 (1H, s), 7.70 (1H, s), 2·99 (6H, s). 15 ^ Step 2-1-diamine sulfonamide-1H-pyrazole -4-boronic acid

Methyl lithium (1.6 M in Et2, 12.2 ml, 20 19.5 mmol) was added to 4-bromo-pyrazole-l-sulfonic acid dimethyl amide dissolved in dehydrated THF (40 ml) 233 200836725 (3.18g, 14.9χχίπιο1) and diethylethylate (trimethyl borate, 3.80ml, 22.3mmol) maintained the internal temperature at <_6〇. Hey. After 3 minutes, the reaction temperature was returned to room temperature and continued to be sterilized for 18 hours. The reaction was quenched with 2N EtOAc (EtOAc)EtOAc. The organic extracts were collected, dried (Na 2 SO 4 ), filtered, and the solvent was removed in vacuo. The material was purified by column chromatography to give a colorless gum (2.1 g). MS: [M+H]+ = 220 〇Borate 141 _ 4-(4,4,5,5-tetramethyl-anthracene, 3,21 dioxane $綳--9.-10 base)_ 2 _ 2 chaotic methyl-0 〇 r r r4-(4,4,5,5-Tetramethvl-"l,3,21dioxaborolan-2-vlV2-trifluor omethyl-pyridine)

The same procedure as in Step 18 was carried out without purification, and the crude product was used directly in the next step (1.25 g). 1H NMR (400 MHz, DMSO-d6): 8·93 (1H, s), 8·29·(1Η,d), 7.91 (1H,d),1·34 (12H,s). 20 Boron Acid ester 142 - 5-(4,4,5,5-tetramethyl-"1.3.21 dioxapyridin-2-ylpyridine-2-carboxylic acid decyl ester (5-(4.4,5, 5"Tetramethyl-rU3,21dioxaborolan-2-ylVpyridine-2-carboxvlic acid methyl ester) 234 200836725

The same procedure as in Step 18 was carried out without purification, and the crude product was directly used in the next step (3.1 g). 1H NMR (400 MHz, DMSO-d6): 8.88 (1H, dd), 8. 21 (1H, dd), 8.06 (1H, dd), 3.90 (3H, s), 1.34 (12H, s). Step J1 _ formation of HC1 salt 10 1-(3-{7-"3彳2-amine-ethyl)-molyl 1-oxazole and "1,2_&1 pyridin-3-yl}- stupyl )-3-ethyl-urea diazoxide salt (1 - (3- {7-T3-(2-Amino-ethvl>)-phenvn-imidaz〇ri, 2-alpvridin-3-yl}-phenvl)- 3-ethvl-urea dihvdrochloride salt)

15 l-(3-{7_[3-(2-Amino-ethyl)-phenyl]- propylate dissolved in EtOH (2ml) and [l,2_a] σ ratio 1^ -3- }--phenyl)_3-ethyl-gland (1-(3-{7-[3-(2-Amino-ethyl)-phenyl]-imidazo[l,2-a]pyridin- 235 200836725 3-yl }-phenyl)-3-ethyl_urea, O.Olg) was treated with saturated EtOAc/EtOAc. Stirred until completely dissolved, then concentrated under reduced pressure. MS: [M+H]+ 4〇0 5 Step J2 Step 1.·Γ2-Π-{3-"7-(4·Fluoro-mosyl)-imidazolium "1,2-alpyridin-3-yl 1-Dishyl}-ureido Vethyl 1-aminecarboxylic acid tert-butyl ester (Τ2-Π- n-f7-(4-Fluoro-phenvlVimidaz〇ri.2-alt) vridin-3-vll-phenyl)-ureidoVethyll -carbamic acid tert-butvl ester)

0 C, N 2 shift · Under the environment 'seat m ° sit -1 - base _ (3 H -σ ratio - 3 base) - 曱嗣Cj (Imidazol-l_yl_(3H-pyrrol_3-yl)-methanone, 240mg, Addition of 3-[7-(4-fluoro-phenyl-15-yl)-imidazo[l,2-a]acridin-3-yl]-phenylamine to a stirred solution of THF (10 mL) (3-[7-(4-fluoro-phenyl)-imidazo[l52-a]pyridin-3-yl]-phenyl amine) (450 mg, 1.5 mmol). The mixture was stirred at this temperature for 2 hours and then at room temperature for 3 hours. Transfer half of the reaction mixture to another flask and add (2-amino-ethyl)-carbamic acid tert-butyl ester (320 mg, 5 2 mmol) to (2-amino-ethyl)-amine phthalate acid tert-butyl ester )deal with. The mixture was stirred at room temperature for 16 hours. The residue was purified by vacuum chromatography (2-> 4% 2M NH3-MeOH / CH2C12) to afford compound as the title. (85mg,foam)· MS: [M+H]+ 490. 5 Step 2: 1-(2-Amino)-3-{3-"7-(4_气-采基味°Sit and " l,2-al ^ 比口定 - 3 _基1 - stupid base} - n_(2-Amino-ethvlV3-i3-r7-(4-fluoro-phenvlVimidaz〇rL2-a lpvridin-3-yll-phenvH-urea )

At a temperature of 10 ° C, trifluoroacetic acid (1 ml) was added to [2-(3-{3-[7·(4-fluoro-phenyl)-imidazo[1,] in CH2Cl2 (2 ml). 2-a]Acridine-3-yl]-phenyl}-yl)-ethyl]-amine decanoate ([2-(3- {3-[7-(4-fluoro-phenyl)) -imidazo[l 52-a]pyridin-3-yl]-Cj phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester , 85 mg, 15 0_17 mmo1). After 1 hour, the volatiles were removed in vacuo and the residue was purified using HPLC to give compound (10 mg, solid) as the title: </ br> </ br> </ br> </ br>反 "i,5-alpvrimidine" counter 20 should be flow chart 237 200836725

5 Add 3-aminopyramine (aminopyrazole, 6 g, 37 mmol) to dissolve

EtOH (150 ml) of 2-Bromo- malonaldehyde (12. 8 g, 80 mmol) was then added glacial acetic acid (10 ml). The mixture was refluxed for 4 hours. After cooling, the solid was filtered and evaporated. The residue was separated in 1M NaOH (50 mL) and EtOAc (200 mL). The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The solid was recrystallized from MeOH, filtered hot and washed with MeOH then dried. 238 200836725 MS: [M+H]+ 198 Preparation (or step) K1

F 5 was prepared in the same manner as in the preparation of K (described above), but 2-(4-fluoro-phenyl)-malonaldehyde was substituted for 2-di-propyl 2-bromo- malonaldehyde. Preparation (or step) L · eucalyptus reaction

L) 4-Fluorophenylboronic acid (〇.46g, 3.25mmol) and 2M Na2C03 (10ml) were added to 6-bromo-pyrazolo[l,5-a]pyrimidine (6-Bromo) dissolved in DME (10ml) -pyrazolo[l,5-a]pyrimidine, 〇.5g, 2.5mmol) [with 15 removed by nitrogen gas], followed by tetrakis(triphenylphosphine)palladium (〇) (〇.13〇g, O .llmmol). The mixture was heated at 70 ° C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was triturated with EtOAc (EtOAc)EtOAc. The filtrate was then concentrated under reduced pressure. The product was purified by EtOAc EtOAc (EtOAc) eluting MS: [M+H]+ 214 5 Preparation (or step) Μ -Iodination

V, F 'F Prepare (or step) N-eucalyptus reaction in the third position as described in General Procedure Α Step 2 (Α2)

As described in General Procedure A, Step 3b (A3b), General Procedure 0 Stupid and Sodium (0 benzamidazole) Model Step 01: N-(4-Bromo-2-nitro-phenyl-molyl-1,3 -Diamine 15 (N-(4-Bromo-2-nitr〇&quot;phenyl)-benzene-1,3-diamine)

240 200836725 4_Mid-1 _  -2- phenyl-benzene (1.14 ml, 9.25 mmol), benzene-13-diamine, 1.96 g, dissolved in dry NMP (5 ml). 18.1 mmol) and DIPEA (1.93 ml, 11.1 mm〇l) mixed solution vacuum/filled with N2 (x3) deoxygenated, then stirred and heated to i20 5 °C for 18 hours under nitrogen. After cooling to room temperature, the mixture was separated with EtOAc and 0.5N EtOAc. The organic layer was washed with H 2 〇 (X1 ), brine (X1), dried (MgSCU), filtered, and evaporated. The residue was purified using EtOAc EtOAc (EtOAc (EtOAc) (EtOAc) ·28 (1H, 10 s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 ( 2H,m),5.24 (2H,s). Step 02: N-(4'-Fluoro-3-nitro-Lianmu-4-V-1.3-diamine (N-(4'-Fluoro- 3-nitro-biphenvl-4-vlVbenzene-l diamine)

15 2N Na2C03 (10 ml) was added to PdCl 2dppf (210 mg 5 0. 29 mmol) dissolved in DME (10 ml), N-(4-bromo-2-nitro-phenyl)-benzene-1,3.diamine ( N-(4-bromo-2-nitro-phenyl)-benzene-l, 3-diamine, step 01, 1.8 g, 5.8 mmol) and 4· fluorophenylboronic acid (975 mg, 7·0 mmol). The reaction was devacuated by vacuum/filling 2 (χ3) and scrambled and heated to 90 QC for 18 hours under nitrogen. After cooling to room temperature, the mixture was separated with Et0Ac / H20 and filtered over Celite. The organic 241 200836725 layer was washed with H20 (xl), brine (xl), dried (MgS 4), filtered and evaporated. The residue was purified using EtOAc (EtOAc) (EtOAc) 1H NMR (400 MHz, DMSO-d6): 9.30 (1H, s), 8.32 5 (1H, d), 7.85 (1H, dd), 7·72 (2H, dd), 7·35-7· 24 (3H,m),7.08 (1H,t),6.54 (1H,s),6.47 (2H,t),5·25 (2H,s). Step 03: N*4*-(3-amine -Momo fluoro-Lianmo-3,4•diamine (N*4*-n-Amino-phenvlV4f&quot;fluoro-biphenvl-3&lt;t4-diamine)

N-(4'-Fluoro-3-nitro-biphenyl-4-yl)-benzene-1,3-diamine (N-(4'-Fluoro-3-nitro-biphenyl-) under atmospheric pressure 4_yl)-benzene· 1,3-diamine, step 02, 1.66 g, 5.1 mmol) hydrogenated in EtOH/AcOH (3:1, 40 ml) over 15% 15 Pd/C (300 mg) until hydrogen atom Exhausted. The catalyst was removed by filtration and washed with EtOH. The volatiles were removed in vacuo and the residue was azeotroped in PhMe to give the title compound. This is quickly applied to the next step. 20 Step 04. 3- "5-(4-Fluoro-Zipyl-Momo-imidazol-1-y-phenylamine (3-Fluoro-phenvl Vbenzoimidazol-1 -vll-phenylamine&quot;) 242 200836725

5 10

Lj in the environment of A, N*4*-(3-amino-phenyl)-4,-fluoro-diphenyl-3,4-diamine (N*4*-(3-Amino-phenyl) -4f-fluoro-biphenyl-3,4-diamine, step 〇3, ~5·1 mmol) Dissolved in trimethylorthoformate (30ml) and sandalwood, heated to 120 ° C, 10 hours. The volatiles were removed in vacuo and <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> After cooling to room temperature, the mixture was concentrated to ~2 ml then diluted with water. Add NaHC03 (sat) to reach ~ρΗ7·5. The solid was taken out in CH2C12. The organic layer was dried and evaporated. The residue was purified using celite to give the product (0%-&gt;1%-&gt; 2%, 2M NH3-MeOH/CH2Cl2). The object was triturated in Et20 to give a white solid (890mg) compound as indicated in the title. Step 05: 1_{3-『5_(4-乱·笨基) Stupid-mouth mouth mouth sitting 1 _ base 1 to 15 kibu 3-(2,2,2-digas-ethyl)-pulse Π- l3-r5-(4-Fluoro-phenyl)-benzoimidazol-l-vl1-phenyU -3-( 2,2,2-trifluoro-ethvlVurea) 243 200836725

ΝΚ

<Ν, Ν-

10 3-[5-(4-Fluoro-phenyl)-benzimid-1-yl]-phenylamine (3-[5-(4-fluoro-phenyl)-benzoimidaz〇M-yl]- Phenyl amine, 150 mg, 0·5 mmol) and phenyl 4-nitrochloroformate (i 〇 5 mg, 〇·52 mmol) dissolved in dry THF (5 mL), stirred and heated to 60 ° C under nitrogen Maintain for 3 hours. After cooling to room temperature, DIPEA (250 μl, 1.5 mmol) and 2,2,2-trifluoroethylamine (80 μl, 1.0 mmol) were added and the solution was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue taken in CH.sub.2CI. The hydrazine was eluted with MeOH to remove the phenol and then eluted with 2M NH3-MeOH to give the product. After a small portion of the residue, the residue was triturated in Et20 to give a colorless solid compound (180 mg) as shown in the title 〇ϋ Step 06: Salt formation: 1_Π·Γ5-(4·Oxy-stupyl Rice saliva-1-15 茉茉基丨-3-(2.2.2·Trifluoro-ethyl VM salt 醅n-iS-rS-^-Fluoro-phenvn-benzoimidazol-l-yll-phenvn-Br 2.2.2 -trifluoro-ethvlVurea Hydrochloride) l-{3-[5-(4-Fluoro-phenyl)-benzimidazol-1-yl]-phenyl}-3-(2,2,2·Trifluoro-B The base urea-purine (step 05) was dissolved in MeOH and treated with a 20 EtOAc solution of hydrogenated hydrogen. The solid was collected and dried in vacuo. 244 200836725 General procedure P: IL azabenzamidazole model preparation Pk bromo-3-nitro-pyridin-2-ylmosa-1,3-diamine (N-(5-Bromo-3-nitro-pvridin-2-vlVbenzene-l, 3-diamine)

5-bromo-2-chloro-3-nitro-pyridine (2.4 g, 10.1 mmol), benzene-1,3-diamine (2.7 g, 25 mmol) and DIPEA (5.3 ml, 30 mmol) were dissolved in dry NMP (20 ml) and heated to 120 ° C under nitrogen for 2 h. After cooling to room temperature, the mixture was separated with EtOAc and H20. The organic layer was washed with brine (xl) and dried (MgS〇4), and the mixture was evaporated. The residue was purified using EtOAc (EtOAc) (EtOAc) 1H NMR (400 MHz, DMSO-d6): 9·78 (1H, s), 8.66 (1H, d), 8.60 (1H, 15 d), 7.00 (1H, t), 6.83-6.71 (2H, m) ,6·39 (1H,d),5·13 (2H, s)· Preparation of P2·. N-f5-(4-fluoro-jamma V3·nitro-pyridine_2-yl 1-mol_1, 3-Diamine rN-r5-(4-Fluoro-phenvlV3-nitro-PYridin-2&quot;vll-benzene-1,3-20 diamine) 245 200836725

Br Ο Ο PdCl2dppf (300 mg, 0.4 mmol), N-(5-indol-3- deradyl-acridin-2-yl)-benzene-1,3-diamine (N-(5-bromo-3-nitro -pyridin-2-yl)-benzene-l,3-diamine, preparation Pi, 2.5 g, 8.2 mmol) and 4-fluorophenylboronic acid (1.4 g, 10 mmol) dissolved in DME (16 ml) and 2N In Na2C03 (16 ml), after vacuum/filling with N2 (x3), the mixture was stirred under nitrogen and heated to 80 ° C for 4 hours. After cooling to room temperature, the mixture was separated with EtOAc/H20 and filtered over Celite. The organic layer was washed with brine (xl), followed by drying (MSs 4), filtered and evaporated. The residue was purified by hydrazine chromatography (10-50% EtOAc / pet ether) to afford to give a dark red/brown solid compound (i.Mg) as indicated in the title. 1H NMR (400 MHz, DMSO-d6): 9.85 (1H, s), 8.87 (1H, d), 8.70 (1H, d), 7·82 (2H, dd), 7·33 (2H, t ), 7.02 (1H, t), 6.92_6·81 (2H, 〇m), 6.40 (1H, d), 5·15 (2H, s). 15 Commissioner P3: 3-"6_(4-气- Stupid base) to vomit and "4,5-1) 117 than bite-3_yl 1-stylamine r3-r6-(4-Fluoro-phenvlVimidaz〇r4&lt;t 5-blpyridin-3-yll-phenyl amine ) 246 200836725

Zinc powder (9_3 g, 142 mmol) was added to a stirred solution of N-[5-(4-fluoro-phenyl)·3-nitro-acridin-2- dissolved in AcOH (35 ml) at room temperature. Benzyl-1,3-diamine (N-[5_(4_fluoro-phenyl)-3-nitro-pyridin-2_yl]_benzene_ 5 1,3-diamine) (2.3 g, 7.1 mmol) solution. When the exotherm was over, the mixture was stirred and heated to 60 ° C for 3 hours. The mixture was cooled to room temperature and filtered through Celite - washed with AcOH (~150ml). The filtrate was evaporated and the residue was azeotroped with toluene (x2). The residue was taken up in trimethylorthoformate (50 ml) and refluxed under nitrogen for 1 hour. After cooling to room temperature, the volatiles were removed in vacuo. The residue was taken up in EtOH (100 mL). c.HCl (4 ml) was added and the mixture was heated to reflux for 2 h. After cooling, the mixture was concentrated to ~4 ml and basified with saturated aqueous NaHC. The aqueous mixture was extracted with CH2C12 (x3). The collected extract was dried (MgS04), filtered and evaporated. The residue was purified by EtOAc (15-&gt; 100% EtOAc / pet ether) to afford compound ( s. 86 g) as s s s s s s s s s. (2,2-Dimethyl-Γ1,3Ί二气布瑷-4-yl曱-ylfluoro-benzene-V oxazole and fl,2-alpyridin-3-篡1-molyl丨247 200836725 n -(2,2-Dimethvl-"l,3~ldioxolan-4-vlmethvlV3-{3-r7-(4::j]2i^ o-phenyH-imidazon,2-a1pvridin-3-yl1-phenyl)-urea )

Add CDI (0.054 g, 0.33 mmol) to 3-[7-(4-D-phenyl)-11 methane in CH2C12 (7 ml) and [l,2-a] sigma-3-yl ]-Phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[l52-.a]pyridin-3-yl]-phenyl amine, O.lg, 0.33mmol), at ambient temperature Spoiled for 5 hours. Add (2,2-dimethyl-[1,3]-dioxolan-4-yl)-nonylamine 10 (2,2-dimethyl-[l,3]-dioxolan-4-yl)- Methyl amine, 0.04 ml 0 · 3 3 mmol) to form a precipitate, which was then warmed to 50 ° C overnight. The reaction was washed with EtOAc EtOAc (EtOAc m. 8mg). MS: [M+H]+ 15 461 〇 Step R2: 248 200836725

F

OH

NH ^OH will sit l-(2,2-dimethyl-[1,3]dioxolan-4-ylindenyl)-3-{3-[7_(4_ 乱-phenyl)_啼σ And [l,2_a] ntb e--3-yl]-phenyl}-gland (1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3- {3-[7- (4-fluoro-phenyl)-imidazo[l?2-a]pyridin-3-yl]-phenyl}-urea 3b 0.02 g) EtOAc EtOAc (EtOAc) The mixture was stirred overnight, and concentrated under reduced pressure to give compound (12 mg).

10 Step S 1-(3_{7-"6-Gasyl_1-(3_piperidin-1-yl-propyl)-1,6-diqi_pyridin-3-yl 1-mouth rice mouth And [l,2-al0 is more than -3, keb stupid)-3-(2,2,2-di-Ethylethyl V-hydrochloride (1-Γ3-(7-Γ6-0x0-1 -( 3-piperidin-1 -yl-propyl)-1,6-dihydro-pyr 15 idin-3-vll-imidazofl ,2-alpvridin-3-vn -phenvn-3-(2,2,2-trifl uoro-ethylVurea Hydrochloride) 249 200836725

'General formula A, step A3b uses 1-[3_(4,4,5,5·tetramethyl-[1,3,2]dioxaboropentan-2-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea 5 (l-[3-(4,4,5,5-Tetramethyl_[l,3,2]dioxaborolan-2-yl)-phenyl]-3 -(2,2,2-trifluoro-ethyl)-urea), step A4b uses 2-methoxy-5-pyridine boronic acid. Add ΡΒι·3 (0.174 ml) to l-{3-[7-(6-methoxy-acridin-3-yl)-imidazole [l,2-ap-pyridyl] dissolved in DCE (10 ml) -3-yl]-phenyl}-3-10 (2,2,2-tris-ethyl)-urea (l-{3-[7-(6_Methoxy-pyridin_3-yl)_ Q imidazo[l, 2-a]pyridin_3_yl]_phenyl}-3-(2,2,2_trifluoro-ethyl)-urea, 0.187 g, 0.226 mmol). The reaction was heated to 80 ° C for 3 hours, then separated by EtO Ac and water. The insoluble material was filtered off and dried to give 1-{3_[7-(6-oxy-1,6-dihydrogen). -Acridine-3-yl)-imidazo[l,2-a] 15 11 than sigma-3-yl]•phenyl}-3-(2,2,2-trifluoro-ethyl)- (1- {3-[7_(6-Oxo_l,6-dihydro_pyridin-3-yl)_imidazo[l,2_a]py ridin-3-yl]-phenyl}-3-(2,2,2-trifluoro_ethyl)- Urea, 0.12g) MS: [M+H]+ 428 250 200836725 N-(3-chloropropyl) piperidine hydrochloride, 0.125 g, 0.63 mmol, Cs2C03 (0.32 g) , 0.98 mmol) and Nal (0.095 g, 0.63 mmol) added to l-{3-[7-(6-oxy-1,6-dihydro-pyridin-3-yl) dissolved in DMF (1.5 mL) -imidazole 5 and [1,2_a] σ is more than indole-3-yl]-phenyl}-3_(2,2,2-tris-ethyl)-pulse (1- {3-[7-(6- Oxo-l 56-dihydro-pyridin-3-yl)-imidazo[l ,2-a]py ridin-3-yl]-phenyl}.3-(2,2,2_trifluoro-ethyl)-urea ,〇.12g , 0.63mmol). After the reaction was heated to 80 ° C for 48 hours, it was separated with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by EtOAcqqqqqqqqqq

Step T 15 ΐ-Π-(7-Π-Π-acetamidine-piperidin-4-yl gas V-methyl-l-imidazo[1,2-alpyrrolidin-3-yl}-stupyl) -3-(2,2,2-trifluoro-ethyl V vein (1-Π-(7-r3-n-AcetYl-piperidin-4-vloxv&gt;)-phenyl1&quot;imidaz〇n. 2-a]pvridine -3-vl} -phenvn-B-^^^-trifluoro-ethvD-urea) 251 200836725

ι Add acetamidine chloride (6·3μ1, 82μήιο1) and Et3N (14μ1) to 1-(3-{7_[3-(唆唆-4-yloxy)-phenyl) dissolved in DMF ( 1 Onil) ]-17 m σ sit and [l,2-a] ° than biting-3-yl}-phenyl)-3·(2,2,2-di-ethyl-)- 5 (1-(3) - {7-[3_(Piperidin-4-yloxy)-phenyl]_imidazo[l,2-a]pyrid ine-3-yl}-phenyl)-3-(2,2 52-trifluoro-ethyl)-urea , 50mg, 98μιηο1). The reaction was stirred at rt for 3 h then EtOAc and H20. The aqueous layer was again extracted with EtOAc. EtOAc (EtOAc m. The residue was purified by 10 HPLC to give Compound (17.5 mg).

Halogen-monomer formation U Step U2: 1-(5-Bromo-pyridin-3-yl)-3-ethyl-urea (1 (5-Bromo-pyridin-3-vlV 3-ethyl-urea)

Dissolve EtNCO (1.6ml, 20 mmol) and 5-bromo-252 15 200836725 β-bromo-pyridin-3-yl amine (l〇mm〇l) under nitrogen atmosphere DME (10 ml), stirred and heated to 60 °C. After 2 hours, another portion of EtNCO (1.6 ml, 20 mmol) was added, and the mixture was stirred at 60 ° C for 16 hours. After cooling to room temperature, the mixture was evaporated and the residue was crystallised from EtOAc. The solid was collected by suction <RTI ID=0.0></RTI> to EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjJ ), 8.27 (1H, t), 8.21 (1H, d), 6·39 (1H, t), 3.19-3.05 (2H, m), l·06 (3H, t)· 10 Step U3: 1_(5 _Bromo-pyridin-3-yl V3-(2,2,2_trifluoro-匕^1|^ ri-(5-Bromo-pyridin-3-vn-3-r2,2.2&quot;trifluoro-eihvn&quot;Urea )

5-rhe-dosyl-3-amine (1.73 g, 10 mmol) and 4-nitrobenzoic acid phenyl ester (2.2 g, 11 mmol) were dissolved in dry 15 THF (40 mL). Stir and heat to 60 ° C for 3 hours. After cooling to room temperature, DIPEA (5·2 ml, 30 mmol) and 2,2,2-trifluoroethylamine (1.6 ml, 20 mmol) were added, and the solution was stirred at room temperature for 16 hours. The volatiles were removed in vacuo&apos; then the residue was partitioned from EtOAc & EtOAc. The organic layer was then washed with Ηβ (xl) and brine (χ1) 2 ,, dried (MgS 〇 4), filtered and evaporated. The residue was triturated in CH 2 Cl 2 . The solid was collected, filtered, washed with EtOAc (EtOAc) 1H NMR 000 MHz, DMSO-d6)·· 9·18 (1H, s), 8.49 (1H, d), 8.28 (1H, d), 8.25 (1H, 253 200836725 t), 7·06 (1H , t), 3.99-3.88 (2H, m). Step U4: M2-gas-pyridine-4-yl)_3·(2,2,2-trifluoroethyl)·urea n-(2-Chloro- Pvridin-4-vn-3-(2,2,2-trifluoro-ettivlVurea)

15 4-Amino-2-chloropyridine (2.08 g, 16.2 mmol) was added to phenyl 4-nitroindole (2.91 g, 14.5 mmol) in THF (35 mL). Stir at 60 °C for 2 hours. After cooling to room temperature, 2,2,2-trifluoroethylamine (1.26 mL, 15.9 mmol) and DIPEA (7.5 mL, 43.4 mmol). The reaction was then concentrated in vacuo then EtOAcqqqqqqqqq The organic phase was washed with brine (60 mL)EtOAc. The resulting yellow solid was suspended in CH.sub.2Cl.sub.sub.sub. Step U 5: 1 (4 - gas-to-mouth ratio _ 2 base amine) 3 - B n-(4-Chloro-pyridin-2-yl)-3-ethyl-urea) 254 20 200836725

Cl isocyanate (0·69 ml, 8.69 mmol) was added to 2-amino-4-chloropyridine (1·〇2 g, 7. 9 mmol) dissolved in THF (20 mL) The reaction was heated to 55 ° C for 18 hours. Concentrate the reaction in vacuo. The resulting white solid was suspended in EtOAc (EtOAc) Step U6: 2-(4-Bromo-pyridin-2-ylpropan-2-ol (2-(4-Bromo-pyridin-2-Yl)-propan-2-ol)

A solution of 4-bromo-pyridine-2-carboxylic acid methyl ester (1. 〇8 g, 5 mmol) in dry THF (10 ml) was slowly added to a solution of MeMgBr (3M) in dry THF (20 ml) under nitrogen atmosphere. In Et20, 15 4.21111, 12.6 111111〇1) Stirred solution. After 1 hour, the ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aq. NaHCOs. The aqueous layer was extracted with EtOAc (x2). The collected extract was washed with H20 (xl), brine (xl), dried (Na2S 4), filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc:EtOAc: 4 NMR (400 MHz, CDC13): 8·36 (1H,d),7·60 (1H,d),7.39 (1H,dd),4·52 (1H,s),1·56 (6H,s )· Step U7 - 2-Bromo-"1·3·41 Thiazole (2-Bromo-"l,3,41thiadiazole)

48% aqueous solution of HBr (10 ml) and H20 (10 ml) were added to [1,3,4] ose 0-ylamine ([l,3,4]thiadiazol_2-yl amine, lg, 9.89 mmol) 10 in. After the reaction mixture was cooled to 0 ° C using an ice bath, CuBr (142 mg, 0.99 mmol) was added, followed by dropwise addition of a solution of sodium succinate (0.682 mg, 9.89 mmol) in H20 (10 ml). minute. The reaction mixture was gradually heated to room temperature for more than 30 minutes, and then a saturated bicarbonate solution was added until the pH of the mixed solution reached 8.0. The aqueous layer was extracted with 15 EtOAc (x3). A grayish yellow solid (lg) was obtained which was used directly in the next step. 1H NMR (400 MHz, DMSO-magic): 9·63 (1H, s). Step U8 - 2-Bromo-5-methyl-methyl-"1,3,41 thiazole 20 (2&quot;Bromo-5-methoxvmethyl-n ^^Ithiadiazole)

256 200836725 A stirred solution of 48% aqueous solution of HBr (2.7 ml) and CuBr (20 mg, 0.14 mmol) was cooled to about -7 ° C using an ice/salt bath to give 5-methoxymethyl-[1, 3,4]5-methoxymethyl-[l,3,4]thiadiazol-2-yl amine, 348 mg, 2.4 mmol) and sodium succinate 5 (0.759 g, ll mmol) Part, added to it in more than 30 minutes. The reaction mixture was stirred at -7 ° C for 1 hour and then further stirred at room temperature for 1.5 hours. The mixture was neutralized with 10 M NaOH and treated with a solution of saturated sodium bibisulfite (5 ml) and heated to 6 ° C for 30 minutes and neutralized. The reaction mixture was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) MS: [M+H]+ 209, 211. Step U9 - 2-bromo-4,5-dimethyl-thiazole (2-Bromo-4,5-dimethyl-thiazole)

Bromine (bromine, 6.8 ml, 0.132 mol) was added dropwise to a solution of 4,5-dimethylthiazole (5.00 g, 44.3 mmol) in 2 g of CHC13 (125 ml) at 0 °C. The reaction was warmed to room temperature and stirred for 5 hours before being treated with aqueous sodium thiosulfate solution. It was layered and the aqueous layer was extracted with CHC13. The organic portion was collected, washed with H20, followed by brine (brine), dried (MgSO4), filtered and solvent evaporated. The residue was purified by column chromatography eluting with EtOAc EtOAc. MS: [M+H]+ 192, 194·

General formula V

Step VI - Iodization

As described in General Procedure A, Step 2 (A2). 10 Step V2 -6-Γ4·Fluorine-Methyl V3-(4,4,5,5-tetramethyl-port, 3,21-two-gas 戍Burn-burning _2-base)-------- 1,5-al shouting (V2-6-(4-Fluoro-phenvlV3-(4,4,5,5-tetramethvl-ri,3,2&quot;ldiox aborolan-2-vlVpvrazolof 1,5-a&quot;| Formation of pvrimidine) 258 200836725

Addition of bis(pinacolato diboron, l. 〇3g5 4·07 mmol) and KOAc (0.63g, 6.38 mmol) to 6-(4-fluoro-phenyl)_3_fill_ ϋ ϋ 并 and [i,5_a] cancer bite (6-(4-fluoro-phenyl)_3-iodo-5 pyrazolo[l,5-a]pyrimidine, 〇.69g, 2.02 mmol) of dehydrated DMSO (4 mL) in solution. The reaction flask was filled with nitrogen and PdCl 2dppf (82 mg, 0.11 mm 〇l) was added. The reaction flask was refilled with nitrogen and then heated to 100 ° C for 3 hours. After cooling to room temperature, EtOAc (30 mL) and H20 (30 mL). The filtrate was retained for 10 to separate the organic and aqueous layers. The aqueous layer was re-extracted with EtOAc (25 mL). The collected organic layer was dried with MgS04, filtered, and concentrated in vacuo. The solid was triturated in Et20 to give a brown solid compound (0.35 g). 15 Step V3b · 钤太反应(1-ethylfluoro-mosquito V pyrazole and fl.5-alpyrimidin-3-yl 1-pyridin-4-ylindole • Service (1-Ethyl-3-i2-[ 6-r4-fluoro-phenvlVpvrazol〇ri.5-alpyrimidi n-3-yl1-pyridin-4-vll-urea) 259 200836725

K3P〇4 (640 mg, 3 mmol) of H20 (2 ml) was added to a stirred solution of 6-(4-fluoro-phenyl-5-yl)-3 in dioxane (8 ml) under nitrogen atmosphere. -(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[l,5_a] succinct (6-(4) -fluoro-phenyl)-3_(4,4,5,5_tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazolo[l,5-a]pyrimidine, 330mg, 0.97 mmol) and 1-(2 - Gas-11-p--4-yl)-3-ethyl-pula (1-(2-chloro-pyridin-4-yl)-3-ethyl-urea, step U4, 420 mg, 10 2.1 mmol) mixed solution . The mixture was deoxygenated under vacuum/nitrogenation (x2) and added to PdCl2dppf (40 mg, 0. 05 mmol), and then the mixture was again deoxygenated (x3). The reaction was stirred and heated to 90 °C for 18 hours. After cooling to room temperature, it was then separated by CH2C12/H20. The water soluble layer was extracted with CH2C12 (xl). The collected extract was dried and evaporated. The residue was purified with EtOAc EtOAc (EtOAc) Step W: Heck reaction 5-"7-(4-indole-lamyl imidazolium ri, 2-alpyridin-3-ylpyridin-3-ylamine (5-r7-(4-Fluoro-phenvlVimidaz〇rK2-a1pvridin) -3-vl1-pyridin 260 200836725 -3-vlamine)

-1,4-a, 4-(Fluoro-phenyl)-imidazo 5 [l,2-a]pyridine) (0.1093 g, 0·52 mmol) and 3-amine The base-5-molybdenum is in a solution of 3-amino-5-bromopyridine 0.181 g, 1.05 mmol in DMF (2 mL). The reaction flask was filled with nitrogen and Pd(PPh3)4 (63 mg, 0.055 mmol) was added. The reaction flask was then refilled with air and heated to 120 ° C for 30 minutes. 3-Amino-5 bromopyridine (0.13 g, 0·75 10 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were added, and the reaction was heated to 140 ° C for 1 hour. . The solid was filtered off and the filtrate was concentrated in vacuo. The residue was separated into H20 (20 mL) The collected organic layer was dried over MgS(R) 4, filtered, concentrated in vacuo, and the obtained product was used directly. 15

Step XX (2,2,2-trimethyl acetonitrile) amine wall ))N ((l^^-TrifluoroethvDsulfamovDchloride) 261 200836725 F Ο

F-j^N-|-CI F O A solution of sulfonium (8 ml) in CH3CN (15 ml) was slowly added dropwise to 2,2,2-triethylamine (amine, 3.9 ml, 4.9 mmol). A solid precipitated from the reaction mixture. The reaction was stirred at 42 ° C overnight, and the solid was filtered. 5 The filtrate was concentrated under reduced pressure and then evaporated toluene and used directly. General procedure, ball spit "1,2-(:&gt; synthesis of dense sigma model)

10 Step X - General Preparation of Imidazole H, 2cl Pyrimidine Preparation of XI - Eucalyptus Reaction

A solution of 4-oxophthalic acid (0.7 g, 5.00 mmol) and Κ3Ρ04 (2.87 g, 262 200836725 13.55 mmol) in H20 was added to 6-gas pyrimidine-4-yl group dissolved in dioxane (15 ml). Amine (〇.5g, 3.87mmol). The reaction mixture was deoxygenated, charged with a double dibasic solution (5 4 mg) and the reaction mixture was heated to 50 ° C for 4 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc)EtOAc. The residue was triturated with EtOAc (EtOAc) MS: [M+H]+ 190. Step X2 - Formation of the ring

Step X3 - Potassium Bromination

Br

[1,2-c] 7-(4-Fluoro-phenyl)-imidazo[l,2-c]pyrimidine, 120mg, 0.56mmol) in acetic acid (2ml), followed by bromine (29μ1) , 0.62 mmol) of acetic acid (1 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between EtOAc EtOAc (EtOAc)EtOAc. MS: [M+H]+ 292,294 〇

Follow the procedure of step A3b, but replace DME with THF. Steps for the synthesis of Imidazofl, 2-alpyrazine model by Y-

10

Preparation of Yl-6-(4-fluoro-methyl)-imidazole "l,2_alpyrazine r6-(4-Fluoro-phenyl)-imidaz〇ri, 2-alpyrazine)

264 200836725 Preparation of Y2-6-Γ4-fluoro-moyl)_3_iodo-imidazole fl.2-alpyrazine 5 (6-(4) using 4-fluorophenylboron as described in general procedure A, step A4b -Fluoro-phenvlV3-iodo-imidaz〇n ,2-alpyrazine&quot;)

The method described in General Procedure A, Step 2. Preparation of Y3 _ 1-1346-(4-fluoro-jasmonyl V imidazole "l,2_alpyrazine-3_yl 10 yl}-3-(2,2,2_trisylethyl) Π- n-" 6-(4-Fluoro-phenvlVimidaz〇ri, 2-a~|pvrazjr&gt;-3-vll-phe nvll-3-r2,2,2-trifluoro-ethvl)-urea)

Using the method described in A4b, j^[3_(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan_2-yl)-Pheny1]-3-(2,2,2-trifluoro-ethyl) -urea, and substituting Na2C〇3 for the anti-3?〇4 step Z · 1, M-trifluoro-2-isocvanato-ethane 265 200836725

DPPA (0.47 g, 1.72 mmol) was added to 3,3,3-trifluoro-propionic acid (0.14 ml, 1.56 mmol) in toluene (5 ml), and the mixture was heated before cooling to room temperature. Up to 110 ° C for 2.5 hours. Triethylamine (0.24 ml, 5 1.72 mmol) was added and the mixture was heated to 70 ° C for 18 hours. The reaction solution was used as it was. MS: [M+H]+ 361. Step AA - 1-{3-"7_(411-"1,2,41 triazol-3-yl")-imidazolium "1,2-&amp; 1 pyridyl口定-3-基1-笨基卜 3-(2,2,2-二说-Ethyl 10 Π - Π-Γ7-(4Η-Γ1,2,4~ITriazol-3-vl)-imidaz 〇n ,2-a&quot;lpvridin-3-v 11-phenyll - B-^^^-trifluoro-ethvD-urea) n

266 200836725 a) 3-Γ3-"3-(2,2,2-trisylethyl)-yl 1-stupyl 1 mouth rice mouth and fl,2-alp ratio -7-carboxylic acid decylamine O-HGJJ-trifluoroethvnureidoVphenvliimidazon, 2-al pyridine-7-carboxvlic acid amide)

1-[3·(4,4,5,5_tetradecyl_[1,3,2]disoxaborane-2-yl)-phenyl]-3-(2,2,2 -Trifluoroethyl)-urea (l_[3-(4,4,5,5_Tetramethyl· 10 [l,3,2]dioxaborolan-2-yl)-phenyl]_3_(2,2,2-trifluoro- Ethyl)-urea, 1.2 eq.), 1M Na2C03 (8 eq.) is added to 7· decylamino-3-iodo-imidazo[l,2-a]pyridine (1 eq.) dissolved in DME (using step Α1 and A2, prepared as 4_nonylamino-pyridin-2-ylamine [to remove bubbles via nitrogen gas], followed by tetrakis(triphenylphosphine)palladium(0) (0.05 eq.). The mixture was heated (E.g., EtOAc (EtOAc) EtOAc (EtOAc). Grinding or purification by column chromatography (0-50% Me0H/Et20) 〇20 b) 3_{3-『3_(2,2,2-disorder-ethyl) serving a certain 1 - stupid base}-口米ϋ坐拍 f 1,2-al mouth pyridine-7-carboxylic acid 1_dimethylamino-(E) 甲甲 ai face (3· {3_"3_(2,2,2-Trifluoro -ethyl)_ureidol-phenvl}-imidaz〇ri, 267 200836725 2-a1pyridine&quot;7-carboxvlic acid l-dimethylamino-meth-(EV vlidene amide)

Ν&lt;^ΝΜθ2 Add Bredereck's reagent (25μ1, 0.12mmol) to 3-[3-[3-(2,2,2-trifluoroethyl)ureido]-benzene dissolved in dry 5 DMF (0.5ml) Imidazo[l,2-a]a is more than 唆-7-decanoic acid decylamine (3-[3_[3-(2,2,2-trifluoroethyl)ureido] f, i-phenyl]imidazo[l, The reaction mixture was stirred for 1 hour in 2-a]pyridine-7-carboxylic acid amide (20 mg, 0.053 mmol). Additional Et20 was added and the precipitate was filtered off. The precipitate was redissolved in MeOH, taken to a further flask and solvent was evaporated in vacuo to afford a pale yellow solid (17mg). MS: [M+H]+ 433. c) 1-丨347-(4Η-Γ1 on 41 triazol-3-yl V imidazolium, 2-alpyridine-3-one 1-stupyl 3-(( 2,2,2-tris-ethyl)-pulse ◎ 15 Π]3-"7-(4Η-Γ1,2,41Triazol-3-vlVimidaz〇n,2-alpvridin-3-v H-phenvU-S -^^^-trifluoro-ethyD-urea)

Hydrazine hydrate (5 μΐ, 0.1 mmol) was added to 268 200836725 3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido]- dissolved in acetic acid (〇5 ml) Phenyl}-imidazo[l,2-a]u-pyridyl-7-carboxylic acid 1-dimethylamino-(E)methylene decylamine (3-{3-[3-(2,2) , 2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[l,2-a]pyridine-7-c arboxylic acid l-dimethylamino-meth-(E)-ylidene amide, 5 17 mg, 0.04 mmol). The reaction mixture was heated to 90 QC for 30 minutes before cooling to room temperature. The volatiles were removed in vacuo and the residue was azeotroped with toluene. The residue was triturated in EtOAc (EtOAc) (EtOAc) MS: [M+H]+ 402. 10 Step AB - 1-Γ3-(7-oxazole-5-an-imidazo[n,2-alinridin-3-yl)-phenyl-1-(2,2,2-trifluoro-B Ketourea (l-r3-(7-Oxazol-5-vMmidazo "L2-alpvridin-3-vlVphenvn-3-(2,2,2-trifluoro-ethvU-ureal a)imidazole"1.2-alpyridine-7· I-azo-15 (Imidazofl, 2-alpvridin-7-vl-methanol)

Add NaHC03 (〇.56 g, 6.67 mmol) to (2-aminopyridin-4-yl)-nonanol (0.40 g, 3.3 mmol) dissolved in EtOH, followed by chloroethyl (0.81 ml, 5) .Ommol). The mixture was refluxed for 2 hours. The solvent was removed by vacuum 20 and the crude mixture was separated from EtOAc using water. The aqueous layer was extracted with EtOAc. EtOAc (EtOAc) The residue was purified with EtOAc EtOAc EtOAc EtOAc. 269 200836725 b) (3-iodo-imidazo-fl,2-alpyridine-7-yl)·methanol (r3-Iodo-imidaz〇ri ^-alpyridin-T-vD-methanol)

Use the method as described in step A2. 5 Γ c) 1-"3_(7-Hydroxymercapto-imidazolium "1,2-alpyridin-3-yl V-phenyl-1-(2,2,2-di-ethyl)- nnn-Hvdroxvmethvl-imidazorHalpvridind-vlVphenvl 1-3&quot;r2,2,2-trifluoro-ethvl&gt;)-urea&gt;)

Use the method as described in A3b. 10

Heart 1-"3_(7-Mercapto-imidazolium "1,241 pyridin-3-yl)-phenyl 1-3-(2,2,2-dioxy-ethyl)-gland 15 Π-Γ3 -(7-Formyl-imidazoTl ^-alpyridin-S-ylVphenyll-3-(2,2, 2-trifluoro-ethvlVurea) 270 200836725

〇°C, l-[3-(7-hydroxyindolyl-imidazole [l,2_apbidin-3-yl)-benzene

10-yl]-3-(2,2,2_trifluoro-ethyl)-urea (l-[3-(7-Hydroxymethyl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-3 -(2,2,2-trifluoro-ethyl )-urea, 1.42g, 3.90 mmol) and hydrazine (1·38, 11.7 mmol) dissolved in CH 2 Cl 2 (30 ml) and sieve (3 g), TPAP (0.14 g) , 0.38 mmol) 〇 Before the sieve was removed by filtration, the reaction mixture was warmed to room temperature and stirred for 18 hours. The organic layer was washed with H20 (x2), dried (MgSO4), and solvent was evaporated in vacuo. The residue was purified by column chromatography (EtOAc-EtOAc) MS: [M+H]+ = 363 e) W3V7-oxazol-5-yl-imidazolium fl.2-alpyridine-3-yl V. sulphate 3_3_(2,2,2-trifluoro-ethyl V Urea n-rS-rT-Oxazol-S-yl-imidazon^-alpvridin-B-vlVphenvll-^-15 (2 on 2-trifluoro-ethvlVurea) 271 200836725

F

1-[3-(7-Mercapto-imidazo[l,2-a]pyridin-3-yl)-phenyl]·3_(2,2,2,·di-ethyl)-gland (15 mg, 0.04 mmol), hydrazide (ll mg, 0.08 mmol) and a mixture of TosMic (9.7 mg, 0.05 mmol) were heated to MeOH (2 mL) to EtOAc (EtOAc). The reaction mixture was purified using EtOAc (EtOAc) elute The solvent was removed in vacuo to give the title compound (6 mg). MS: [M+H]+ = 402 10 Step AC - 1-{3-"7-(2Η-tetrazol-5-yl)-imidazolium "l,2-a~K acridine-3-yl stupid基卜3-(2,2,2-二说-ethyl)-脉Π- {3-"2-(2H-Tetrazol-5-vl)-imidaz〇ri J-alpvridin-S-vll-phe nvlU -i^JJ-trifluoro-ethvlVurea) 272 200836725

a) Imidazole and "1,24" than 1? -7-carboxylic acid amide (Imidazo "l j-alpvridine^carboxvlic acid amide"

Prepared as described in Step A1 using 2-aminoisonicotin amide. MS: [M+H]+ 162. ( /10 b). Rice saliva and "l,2-al° 唆-7_萆.篡 (Imidazofl, 2-alpvridine-7-carbonitrile)

Trifluoroacetic anhydride (0.39, 2.83 mmol) was added dropwise to imiban[l,2-a]indole dissolved in CH2C12 (5 ml). Imidazo[l,2-a]pyridine-7-carboxylic acid amide (38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol) were dissolved in 273 200836725. The reaction mixture was stirred at room temperature for 2 h, then washed with MeOH and eluting with 2M NH3 / MeOH. The solvent was removed in vacuo to give the title compound (32 mg). MS: [M+H]+ 143· 5 c) 3-iodo-imidazolium fl, 2-alpyridine-7-cyano (3-Iodo-imidazo "l J-alpvridine-T-carbonitrile)

10 As described in step A2, and using imidazo[l,2-a]pyridine-7-cyano. MS: [M+H]+ 270. (1) 1-"3-(7-Cyano-imidazo"1,241 pyridin-3-yl)-molyl 1-3-(2,2,2-three -ethyl)-gland 15 (l-f3-(7-Cvano-imidazo"l,2-alpvridin-3-vlVphenvl~l-3-(2,2,2-trifluoro-ethyl Vurea)

F

274 200836725 As described in step A3b, 3-iodo-carbazole is used and Tl,2-al p is -7-cyano (3-Iodo-imidaz〇r 1,2-alpyridine-7-carbonitrile) ). Purification by reverse phase HPLC gave the product as a white solid. MS·· [M+H]+ 360. e) 1-丨3-"7·(2Η-tetrazol-5-yl)-imidazolium fl,2-alpyridine_3_yl-1-mollyb 3 -(2,2,2-tris-ethyl) Π-n-r7-(2H-Tetrazol-5-vlVimidaz〇n,2-alpvridin_3-vll-phe nyU-3-(2.2,2-trifluor〇 &quot;ethvn-urea)

1-[3-(7-Cyano-imidazo[l,2-a]acridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (l-[3-(7_Cyano-imidazo[l,2-a] pyridin-3-yl)-phenyl]-3-(2,252-trifluoro-ethyl)-urea, 65mg? 0.18mmol), sodium azide 14 mg, 0.19 mmol) and ammonium sulfate (1 l mg, 15 0.20 mmol) were dissolved in DMF (2 ml) and heated to 90 ° C for 18 hours. After cooling the reaction mixture, the solvent was removed in vacuo and the crude mixture was purified using reverse EtOAc. Thus, the white solid compound (14 mg) shown in the title was obtained. MS: [M+H]+ 403. 275 200836725 Step AE: S-burning three-seat (Alkylated triazole)

Step a) 1-{3-Γ7-(5_Hhenylthio_4_methyl-4Η-Γ1,2,4Ίtriazol-3-yl V imidazolium H,2_alpyrid-3-yl 1-methyl I-3_(2,2,2_trifluoro-ethylurea 5 Π- n-f7-i5-Mercapto-4-methvl-4H-"l,2,41triazol-3-vlVimid az〇rK2-alpvridin-3 -vl1-phenYU-3-(2&lt;t2.2-trifluoro-ethvlVure al

10 Ο 15

1-[3-(7-Mercaptocarbonyl-imidazo[l,2-a]acridin-3-yl)-phenyl]-3·(2,2,2-trifluoroethyl)urea (1-[3-(7-117(11^2111〇〇&amp;1^1)〇11;/1-imidazo [l,2-a]pyridin-3-yl)-phenyl]-3-(2 2,2-trifluoro-ethyl )-urea, 200 mg, 0.51 mmol) and methyl isothiocyanate (37 mg, 0.57 mmol) were dissolved in EtOH (6 ml) and heated at 70 ° C overnight. The reaction mixture was cooled and ice bathed until a precipitate formed. The solid was filtered, washed with EtOAc and EtOAc (EtOAc)EtOAc. (72 mg)· MS: [M+H]+ = 448. 20 Step b) 1-Π-"7-(4-Methyl-5-methylsulfonyl-4H-"1,2,41 triazole-3- 276 200836725 base) - mouth rice mouth and "l , 2_al° 比口定-3-基1_笨基}-3-(2,2,2_三气ethyl 曱 曱 Π - {3-r7-(4-Methvl-5-methvlsulfanvl-4H - "l,2,41triazol-3-vl) -imidazofl .2-a1pvridin-3-yl1-phenvll-3-r2,2,2-trifluoro-ethv 5 l)-urea formate)

KOH (10 mg, 0.18 mmol) and ezine (20 μl, 0.16 mmol) were added to 1-{3-[7_(5-hydroxythio-4-methyl-10-yl-4H-[] dissolved in EtOH (3 ml). 1,2,4]triazol-3-yl)-imidazo[l,2_a]acridine-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l-{3-[7-(5-Mercapto-4-methyl-4H-[l ,2,4]triazol-3-yl)-imidazo[l ^-alpyridin-S-ylj-Ci phenyl} -3 -(2,2 52-trifluoro-ethyl)-urea, 72 mg, 0.16 mmol), the mixture was stirred at room temperature overnight. The reaction mixture was ice bath 15 and a precipitate formed which was then filtered. The precipitate was purified by reverse phase HPLC to give the title compound. (18 mg)· MS: [M+H]+ = 462. Step AF: Triazole 20 Step a) Imidazo-n,2-alpyridine-7-yl-methanol 277 200836725 (Imidazofl.2-a1pyridin-7-yl-methan〇n

Et〇H, then join. Will roll really

The H2N /0HN aqueous layer was extracted with EtOAc and organic layer was concentrated and dried (MgS04). The residue was purified using EtOAc EtOAc (EtOAc:EtOAc) MS: [M+H]+ = 149 °. NaHC03 (0.56 g, 6.67 mmol) was added to (2-Amino-pyridin-4-yl)-methanol (0.40 g, 3.3 mmol). Lml, 5.Ommol). The mixture was refluxed for 2 hours, and the crude mixture was separated from water and EtOAc. 10 Step b) (3-Iodo-imidazolyl &lt;RTI ID=0.0&gt;-a&quot;|pvridin-7-vl)-methanol) ϋ 15

Use the method as described in step A2. Step c) 3-iodo-imidazolium "l,2-a" acridine-7-furfural (3-Iodo-imidaz〇ri, 2-alpvridine-7_carbaldehvde)

3-°C, (3-iodo-imidazolium ri, 2-alpyridine-7-) methizine (i.〇〇g 278 200836725 3.65mmol) and NMO (0.64g, 5.47mmol) were dissolved in CH2Ch (30ml) With sift (3 g), TPAP (0.06 g, 0.18 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours before the sieve was removed by filtration. The organic layer was washed with HW (x2), dried (MgSO4), filtered and solvent evaporated. 5 The residue was purified by column chromatography (0-60% MeOH to EtOAc EtOAc (EtOAc: EtOAc) "l,2-alpyridine_7_)-2_nitro-ethyl 1 (1-(3-Iodo-imidaz〇n,2-a1pyridin-7-vn-2-nitro-ethaiiol)

Nitromethanone (88 μl, 1.63 mmol), diethylamine (6 μl, 0.05 mmol) and sieve (300 mg) were added to 3-iodo-salt and [l,2-a] dissolved in THF (10 ml). It is in the form of -7-carboxylic acid (3_Iodo-imidazo[l,2-a]pyridine-7·carbaldehyde, 150 mg, 0.54 mmol). The reaction 1,15 mixture was heated to 55 ° C for 2 hours before cooling. The sieve was removed by filtration and the solution was separated with EtOAc and H20. The organic layer was separated, dried (MgSO4), filtered and evaporated, MS: [M+H]+= 334· 20 Step e) 3- Moth - 7-((Ε)·2-石基基- B suspected base rice bran and "1,2-alp than mouth (3 -Iodo-7_(TE)-2-nitro-vinvn_imidazo"l,2-alt)vridine) 279 200836725

0.49 mmol) added to 1-(3-iodo-imidazo[1,2-a] 11 to π-den-7-yl)-2·Shi Shaji-Ecluster 5 (l-(3) dissolved in CH2C12 (2 ml) -Iodo-imidazo [l 52-a]pyridin-7-yl)-2-nitro-ethanol, 116 mg, 0.35 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The mixture was then separated with CH2C12 and H20, the organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ = 316. Step f) 3-iodo-7·(3Η-Π.2,31 triazol-4-ylimidazolium fl,2-alpyridine n-IodoKSH-fUJltriazol-^-vlVimidazomalpvridine)

3-iodo_7·((Ε)-2-nitro-vinyl)-imidazo[l,2_a] «Bisidine (3-Iodo-7-((E)-2-nitro_vinyl)-imidazo[ l,2-a]pyridine, 57 mg, 0.17 mmol) and trimethylsilylazide (33 μl, 0.24 mmol) were dissolved in DMF (3 mL) and the reaction mixture was warmed to 50 ° C for 10 min. 280 200836725 Next, a tetrabutylammonium fluoride solution (018 ml, a solution of hydrazine in THF, 0.18 mmol) was added, and the reaction mixture was heated to 50 〇c for 1 Torr. The reaction mixture was cooled, then EtOAc (EtOAc m. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ = 312. -3-yl 1_molyl丨_3-(2,2.2-trifluoro-ethyl V urea 10 n-{3-"7-(3H-"l,2.3&quot;ITriazol-4-vlVimidaz〇n, 2-alpvridin_3-v ll_phenvli-3 彳2-2-2_trifluoro_ethvn-urea)

16 (45 mg, 0.13 mmol) and Cs2C03 (107 mg) were added to 3-iodo-7-(3Η-[1,2,3]triazol-4-yl)-imidazole dissolved in DME (10 ml). ,2-a] 15 pyridine (3-I〇do-7-(3H-[l,2,3]triazol_4-yl)-imidazo[l,2-a] pyridine,34mg,0· 1 Nitrogen to remove bubbles]' followed by tetrakis(triphenylphosphine)palladium (〇) (〇_〇13g, O.Olmmol). The mixture was heated overnight at 80 ° C and directly charged into scx匣, washed with Me0H, And eluted with NH3/MeOH. After the solvent was removed in vacuo, the residue was purified by HPLC to s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 5) a) Imidazolium "1,2-alpyridin-7-carboxylic acid methyl-methyl-decylamine (ImidazoH.2-alpvridine-7-carboxvlic acid methoxv-methvl-amide)

A solution of 2M trimethylaluminum in hexane (3.8 ml, 9.57 mmol) was added to the imidazo[l,2-a]pyridine-7-carboxylic acid methyl ester dissolved in CH2C12 (40 ml) at 10 °C. Imidazo[l,2-a]pyridine-7-carboxylic acid methyl ester, 0.67 g, 3.83 mmol) and dimethylhydroxyl amine (0.93 g, 9.57 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour, then cooled to 0 ° C and quenched with ice. The reaction was filtered through Q then the liquid was separated using CH.sub.2 C.sub.2/H.sub.2. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to afford crude. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ = 206. Step b) 1 mouth 糸g sit "1,2 - a Ί mouth than mouth _ 7 - 2 - ding 1 - 酉 same (l-Imidazo "l, 2-a1pvridin -7-vl-but&gt;2-vn-l - one) 282 200836725

1-propynylmagnesium bromide (0.5 μm in THF, 2.74 ml) was added to the imidazo[l,2-a] 0 ratio in THF (10 ml) at -78 °C. -7-Resorcinated methoxy-methyl decylamine (Imidazo[l,2-a]pyridine-7 5

10 -carboxylic acid methoxy-methyl- amide, 187 mg 5 0.91 mmol). The reaction was warmed to room temperature and stirred for 1.5 hours before being quenched with EtOAc (2 mL). A portion of the aqueous phase was verified using Na2C03 and extracted with CH2CI2. The organic layer was then dried (MgS 4) filtered and solvent was removed in vacuo. The product was obtained (168 mg). MS: [M+H]+ =185 0 Step c) 7-(5-Methyl-isoxazole-3-V-carbazole and H.2-a1pyridine (7-(5-Methvl-isoxazol-3) -vlVimidazo"l ,2-alpvridine)

15 Add triethylamine (0.21 ml, 1.83ππηο1) to 1-imidazo[l,2-a]pyridin-7-yl-2-butyn-1-one (l-Imidazo) dissolved in DMF (10 ml) [l,2-a]pyridin-7-yl-but-2-yn-l-〇ne, 168 mg, 0-91 mmol) and hydroxylamine hydrochloride (94 mg, 1.37 mmol). The reaction mixture was heated to 80 ° C for 18 hours, then separated with EtOAc and H20. The organic layer was separated, dried (MgSO.sub.4), filtered and evaporated and evaporated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ = 200. Step d) 3-iodo-7-(5-methyl-isoxazole-3-V-oxazolidine, 2-a1pyridine 5 n-Iodo-7-(5-methvl-isoxazol-3-ylVimidaz 〇n .2-alpyridine)

Using the method as described in Step A2 (59 mg) ° MS: [M+H]+ = 326 ° 10 Step e) M3-"7-(5-decyl-isoxazol-3-ylimidazolium "1, 2-alpyridine·3_yl 1 -epi-3-(2,2,2-digas-ethyl)-nucleus n-{3-"7-r5-Methvl-isoxazol-3-vl)-imidaz〇 Ri,2-alpvridin-3-vll-phenyl 1-3-(2.2,2-trifluoro-ethvlVurea)

284 =416. 200836725 Step AH: alkylated triazole step a) 1-"3-(7-acetylene-imidazolium "1,2-alpyridin-3-ylphenyl1-3-(2,2, 2-Trifluoro-ethyl V urea 5 Π - "3-(7-Ethvnvl-imi dazo Γ1,2-alpvridin-3-vlVphenvl~1-3-(2,2

2-trifluoro-ethyl)-urea)

Method step SGD4a as described in

10 Step b) 1-{3-"7-Π-Methyl-1H_"1,2,31 triazol-4-yl)-imidazolium "1,2-al p is more than -3-yl 1- Stupid base}-3-(2,2,2-digas-ethyl)-pulse α·(3-Γ7-Π-Methyl-lH-rh2.31Triazol-4-vlVimidaz〇rK2-a1p yridin-S-yll -phenvlI-B-ri.l^-trifluoro-ethylVurea)

15 1_[3·(7-acetylene-imidazo[l,2-a]pyridin-3-yl)-benzene 285 200836725 yl]-3-(2,2,2-trifluoro-ethyl)-urea (i_[3_(7-Ethynyl-imidazo [l,2-a]pyridin_3_yl)-phenyl]-3-(2,2,2-trifluoro_ethyl)-urea, 130 mg, 0.36 mmol) was dissolved in tert-butyl alcohol ( 2 mL) and water (2 mL). Sodium azide (24 mg, 0.36 mmol) was added followed by methyl iodide (0.18 5 mL of a 21V [yield in THF. The reaction was stirred at room temperature for 5 minutes before the addition of copper sulfate (0.02 mL of a 1 M aqueous solution, 〇·〇 2 mm〇i) and sodium ascorbate (7 mg, 0.04 mmol). The reaction was stirred at room temperature for 2 hours. f) The solution is then separated by water and di-methane, dried by a phase separation, and concentrated in vacuo. The residue was purified by HPLC to give white white solid (l. Step AI: Methyl tetrazole 15 Step 1: Imidazo[l,2,a]pyridine-7-carbonitrile

ί; chloroacetaldehyde (~50% in H2 〇, 3.24 ml, 20 26 mmol) was added to the stirred 2-aminoisonicotinonitrile (i.6 g, 3.4 mmol) at room temperature under nitrogen. And a solution towel of NaHC(R) 3 (2.23 g, 26.5 mmol) dissolved in ethanol (20 ml). The reaction was spoiled and heated to 80 ° C for 18 hours. After cooling to room temperature, the volatiles were removed in vacuo and the residue was partitioned EtOAc EtOAc EtOAc. The mixture was filtered and some dark insoluble residue was removed. The solid was washed with MeOH. The aqueous layer was extracted with EtOAc (x2). The collected EtOAc extracts were dried (Na2SO4) and filtered. The MeOH lotion was forceed and the volatiles were removed in vacuo. The residue was purified by column chromatography: EtOAc (EtOAc):咕NMR (400 MHz, DMSO-d6): 8·74 (1H, dd), 8·35 (1H, s), 8·19 (1H, s), 7·86 (1H, s), 7.21 (1H , dd).

10 Step 2: 7-(2H-four-seat -5_base)_ mouth vomit and [l,2-a]0 than mouth (7-(2H-Tetrazol-5-yl)-imidazo[l, 2-a]pyridine)

Sodium azide (97 mg, 1.45 mmol) was added to a stirred solution of NH4C1 (82 mg, 1.53 mmol) in dry DMF (5 mL) at room temperature. a] A solution of imidazo[l,2-a] 15 pyridine-7_carbonitrile, 200 mg, 1.4 mmol. The reaction was stirred and heated to 80 ° C for 10 hours in a sealed can. [3 identical reactions are carried out simultaneously]. After cooling to room temperature, the reaction mixture was collected and diluted with Et20. The solid was collected by filtration and dried to give a bright brown compound (860 mg). [may contain NaCl] 4 NMR 20 (4 0 0 MHz, DMSO-d6): 8.55 (1H, dd), 8.02 (1H, s), 7.94 (1H, s), 7·57 (1H, d), 7 · 54 (1H, dd). Step 3: 7 - ( 2 -Methyl-2 H - 4 ° sitting -5 - base) - Mouth sitting on the sub-[1,2 - a ] ^ ratio σ 287 200836725 (7 -(2-Methyl-2H-tetrazol_5-yl)-imidazo[l,2-a]pyridine) and its isomeric form

Methyl iodide (530 μΐ, 8.4 mmol) was added to a stirred solution of 7-(2H-tetrazol-5-yl)-imidazole in a dry DMF (4 mL) at room temperature. 2-a] is a mixed solution of 7-(2H-tetrazol-5-yl)-imidazo[l,2-a]pyridine, ~4.2 mmol) and K2C03 (1.16 g, 8.4 mmol). After 5 hours, the reaction was separated by Et0Ac/H20. The aqueous layer was extracted with EtOAc (x2). The collected EtOAc extracts were dried (Na2SO4) and filtered.

10 and volatilize. The residue was purified by column chromatography: 1% DCM 4 4% 2M NH3_MeOH / DCM to obtain two regioisomers [regiochemistry based on the results of the nOe study]: 7- (2-methyl-2H-tetrazol-5-yl)-imiphtho[l,2-a] 0 than bite (7_(2-Methyl-2H-tetrazol-5-yl)-imidazo[l,2 -a]pyridine) (more than 15 is not polar): 4 NMR (400 MHz, DMSO-d6): 8.73 (1H,d), 8.19 (1H,s),8·10 (1H,s),7.72 (1H, d), 7.50 (1H, dd), 4·46 (3H5 s). 7-(1-Methyl-1H-tetrazole-5-yl)-imidazo[l,2-a]pyridine (more polar ): 4 NMR (400 MHz, DMSO-d6): 8.78 (lH, dd), 8.18-8.15 20 (2H, m), 7·79 (1H, d), 7·35 (1H, dd), 4.28 ( 3H, s)· Step 4: 3-iodo-7-(2-mercapto-2H-tetrazol-5-yl)-imidazo[l,2-a]pyr. 200836725 pyridine (3-Iodo-7-( 2-methyl-2H-tetrazol-5-yl)-imidazo[l ,2-a]pyridin e)

5 N-Iodo succinimide (300 mg, 1.3 mmol) was added to a stirred solution of 7-(2•methyl- in dry DMF (2 ml) at room temperature under nitrogen. 2H-tetrazol-5-yl)-imidazo[l,2_a]acridine (7-(2-methyl-2H-tetrazol-5-yl)-imidazo[l,2_a]pyridine, 240 mg, 1.2 mmol) mixture. After 5 hours, the reaction was quenched with aqueous sodium thiosulfate / saturated aqueous NaHC03 (1:1, 2 ml). Water (2 ml) was added, and the mixture was stirred at room temperature for 15 minutes. The solid was filtered and dried in vacuo to give compound (360 mg) as a cream. 4 NMR (400 MHz, DMSO-d6): 8.51 (1H, dd), 8.20 (1H, dd), 7.86 (1H, s), 7.65 (1H, dd), 4.47 (3H, s). 15 Step 5: 1_{3-[7·(2·Methyl-2H-tetrazol-5-yl)-imidazo[l,2-a] 11 is determined to be -3-yl]-phenyl}- 3-(2,2,2-trioxy-ethyl)-pulse (l-{3-[7-(2-Methyl-2H-tetrazol_5_yl)-imidazo[l,2_a]pyridin-3 _yl]-phenyl} _3-(2,2,2-trifluoro-ethyl)-urea) 289 200836725

3-Touch-7-(2•methyl-2H-tetrazol-5-yl)-imidazo[l,2-a]°&amp;pyridine (3-iodo-7_(2-methyl-2H-tetrazol) -5-yl)-imidazo[l,2-a]pyridin e, 170 mg, 0·52 mmol), 1-[3·(4,4,5,5-tetramethyl-[1,3,2] Dioxa-5 penopenrol-2-yl)phenyl]_3-(2,2,2-trifluoro-ethyl)-urea (1-[3_(4,4,5,5_Tetramethyl-[l,3 , 2]dioxaborolan-2-yl)_phenyl]_3_(2,2,2_trifluoro-ethyl)_urea,16, 225mg,0·65 mmol) and Cs2C03 (340mg, 1.04 mmol) dissolved in dry DME (2.5ml) Vacuum/nitrogenated (x2) deoxygenation. PdCl2dppf (38 mg, 0.05 mmol) was added, and 10 the mixture was again deoxygenated (x3). The reaction was stirred and heated to 80 ° C for 16 hours. After cooling to room temperature, the mixture was then separated with Et 〇Ac/H20. The aqueous layer was extracted with EtOAc (x2). The collected extract of Et 〇Ac was dried (NazSOO, and filtered, and evaporated. The residue was purified by hplc to give a solid compound (6 mg) as indicated in the title. Step 3 can be carried out as follows in step 3b: 290 200836725 Step AI, step 31 kappa 7-[2·(2,2,2-trifluoro-ethyl)_2H_tetrazol-5-yl]-imidazo[ l,2-a]bite (7_[2-(2,2,2_Trifluoro,ethyl)-2H-tetrazol_5-yl]-imidazo[l,2- a]pyridine)

10

Under a nitrogen atmosphere, sodium hydride (60 mg, 1.5 mmol) was added to a stirred solution of 7-(2H-tetrazol-5-yl)-imidazo[l,2-a]pyrrazole in dry DMF (4 mL). A mixed solution of (7-(2H_tetrazol-5-yl)-imidazo[l,2-a]pyridine, 250 mg, 1.3 mmol). After 1 hour, Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (1.16 g, 5 mmol) was added, followed by 18 - Crown ether-6 (18-crown-6, 260 mg, 1 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with EtOAc (EtOAc). The collected organic extracts were washed with brine (xl), dried (Na.sub.2), filtered and evaporated. Purification by column chromatography (〇·2% 2M NH3.MeOH/CH.sub.2) to afford product (138mg). MS·· [M+H]+ 269.

Step AJ 20 Step 1: 5-Chloro-1,3-dimercapto-1H-[1,2,4]triazole (5-Chloro_l, 3-dimethyl-lH_[l,2,4]triazole) and its isomer Object 291 200836725

5-Chloro-3-methyl-1H-[1,2,4]triazole (1.76 g, 15 mmol), K2CO3 (4.2 g, 30 mmol) and selebrum (Mel, 1.4 ml, 22 mmol): i ^ Stir in acetone (15 ml) at room temperature for 20 hours. After filtration, solid 5 was washed with EtOAc then EtOAc (EtOAc)EtOAc. The CH2C12 layer was separated and added to the aforementioned filtrate. The collected organic extract was evaporated and the residue was taken out with CH2C12. The mixture was then decanted and volatilized to give a mixture of methylated triazoles (1.6 g, brown liquid). 4 NMR (400 MHz, CDC13): 10 3·77 (3H, s), 2.43 (3H, s) [measurement signal only for major isomeric forms]. This material is not purified and can be used directly. Step 2 1-{3-[7-(2,5-Dimercapto-2H-[1,2,4]triazol-3-yl)-imidazo[l,2-a]att*°- 3-yl]-phenyl}-3-(2,2,2-dioxaethyl)-pulse 15 (l_{3-[7-(2,5-Dimethyl-2H-[l,2,4]] Triazol_3_yl)_imidazo[l,2- , a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ure a)

The same preparation method as described in step E3d, but must: 292 200836725 Substituting 4-bromo-1,3-dimethyl-1H-[1,2,4]triazole (and its isomeric form) for 4-bromo -2-methylthiazole. The desired isomeric form was separated by hydrazine chromatography: 100% DCM 6% 2M NH3-MeOH / DCM. Regiochemistry is based on the nOe research theory. 5

Step AK Step 1: 4-iodo-1,5-dimethyl-1Η-imidazole (4-Iodo-l, 5-dimethyl-lH-imidazole) and its isomeric form

10 4-iodo-5-methyMH_imidazole (2.1 g, 10 mmol) and K2C03 (2.1 g, 15 mmol) were dissolved in dry DMF (5 ml) under nitrogen and at room temperature, and stirred with methyl iodide (methyl iodide, 940 μΐ, 15 mmol). After 5 hours, the reaction was stopped with water and then separated with EtOAc / H20. The aqueous layer was extracted with EtOAc (x2) 15 . The collected EtOAc extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography: 60% EtOAc / CH2Cl2-&gt; 80% EtOAc / CH2 C12 - 100% EtOAc, and regioisomer: Regiochemistry is based on the theory of nOe ] 20 4-Iodo_1,5-dimethyl-1H-imidazole (less polar): (contaminated by the ortho-isomers and other unreacted starting materials). 1H NMR (400 MHz, DMSO-d6): 7·58 (1H, s), 3·58 (3H, s), 2.13 (3Η, s)· 293 200836725 5-iodo-1,4·didecyl- 1H-imidazole (more polar): 1H NMR (400 MHz, DMSO-d6): 7·78 (1H, s), 3·51 (3H, s), 2.07 (3H, s). Step 2: 1- {3·[7_(1,5-Dimethyl_111_imidazol-4-yl)imidazo[5,2_a]n is 0-but-3-yl]-phenyl}-3-(2,2 , 2_difluoro^-ethyl)-pulse (1- {3-[7-(1 ?5-Dimethyl-lH-imidazol-4-yl)-imidazo[l ,2-a]py ridin-3- Yl]-phenyl}-3-(252,2-trifluoro-ethyl)-urea) was prepared in the same manner as described in Step E3d except that 4-iodo-1,5-dimethyl-1H-imidazole was substituted 4- Bromo-2-methylthiazole. 10 Steps AL 1_{3-"7_[5-thio-4,5-dihydro-"1,3,41oxadiazole_2-yl)_imidazo"1,2-alpyridine-3-yl 1-phenylindole-3-(2,2,2·trifluoro-ethyl)urea n_{3-"7-i5-Thioxo-4,5_dihvdro-ri,3,41oxadiazol_2-vn-imid azof 1,2 -a&quot;lp vridin-3-νΙΊ-phenyl 1-3-(2,2,2-trifluoro-ethvlVure 15 a}.

L-[3-(7-Mercaptocarbonyl-imidazo[1,2-appyridin-3-yl)-phenyl]-3-(2,2,2-di-ethyl)-gland 20 (l-[3-(7-Hydrazinocarbonyl-imidazo[l,2-a]pyridin-3-yl)-phe 294 200836725 nyl]-3-(2,2,2-trifluoro_ethyl)-urea ) as in Example 332 The same method as described was carried out. Add carbon disulfide (Carbon Disulfide, 22 μl, 0.36 mmol) to l_[3-(7-fluorenylcarbonyl-imidazo[l,2-a]pyridine-3-5-yl)-phenyl dissolved in EtOH (4 ml) 3-(2,2,2-trifluoro-ethyl)-urea (120 mg, 0.30 mmol) and KOH (20 mg, 0.36 mmol). The reaction mixture was heated to 65 ° C, cooled for 3 hours and then ice bath to form a precipitate. The solid was filtered and washed with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ = 435.

Step AM M3-l~7-(5-methylsulfonylhydrazone 1,3,41oxadiazol-2-yl)-imidazolium "1,2-&amp;1 pyridin-3-yl 1-phenyl Indole-3-(2,2,2-trifluoro-ethylurea-{3-"7-(5-Methvlsulfanvl-"l,3,41oxadiazol-2-vl)-imidaz〇r 15 1 ^-alpvridin -S-vlI-phenvH-S-^^^-trifluoro-ethvD-urea)

1-[3-(7-Mercaptocarbonyl-imidazo[1,2&lt;] acridine-3-yl)-phenyl]-3-(2,2,2-tris-ethyl)-pulse ( 1-[7-Hydrazinocarbonyl-imidazo[l,2-a]pyridin-3-yl)-phe 20 nyl]-3_(2,2,2-trifluoro_ethyl)-urea), as described in Example 332 Phase 295 200836725 Prepared by the same method. Carbon disulfide (Carbon Disulfide, 22 μl, 0.36 mmol) was added to 1-[3_(7-fluorenylcarbonyl-imidazo[l,2-a]pyridine-3-5-yl)phenyl) dissolved in EtOH (4 ml). -3-(2,2,2-trifluoroethyl)-urea (120 mg, 0.30 mmol) and KOH (20 mg, 0.36 mmol). The reaction mixture was heated to 65 ° C for 3 hours. Iododecane (20 μl, excess) was then added and the reaction mixture was heated to 65 °C for 1 hour. The mixture was cooled as far as hell until the precipitate formed. The solid was filtered, washed with EtOAc and EtOAc (EtOAc)EtOAc. MS: [M+H]+ = 449.

Step AN

296 200836725 3-Iodo-imidazo[l,2-a]pyridine-7-carboxylic acid hydrazide, 906 mg, 3 mmol ( The method described in the preparation of the procedure of Example 329, 2 was suspended in THF (10 mL). Triethylamine (0.42 mL, 3 mmol) was added, followed by the addition of pivaloyl chloride (0.37 mL, 3 mmol). The reaction was stirred for 2 hours at room temperature. Concentrated sulfuric acid (0.5 mL) was added to the mixture and stirred for additional 1 hour. The reaction was filtered, and EtOAc EtOAc (EtOAc m.醯肼10 (3_Iodo-imidazo[l,2-a]pyridine-7-carboxylic acid N'-(2,2-dimethylpropionyl) hydrazide, 875 mg) 〇 Nitrogen, 3-E-嗤 嗤 [l,2-a] ° than 唆-7-rebel N,-(2,2-dimercaptopropyl hydrazine) 醯肼 (3-Iodo-imidazo[l,2-a] 15 pyridine- 7-carboxylic acid N'_(2,2-dimethylpropionyl) hydrazide, 875 mg, 2.27 mmol) was suspended in dry THF (15 mL). The ratio of the enthalpy to the enthalpy (0.388 mL, 4.76 mmol) and the tosyl L chlodde 518 mg, 2.72 mmol) and the mixture was heated to 70 ° C for overnight. After cooling the reaction, the 20 was separated with EtOAc and 1M EtOAc. The aqueous portion was basified with 2M sodium carbonate solution and extracted with CH2C12. The organic layer portion is dried by one-phase separation and volatilized to a white solid 7-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-3-iodo- Imidazo[l,2-a] °tb bite (7-(5-tert-Butyl_[l,3,4]-oxadiazol-2_yl)-3-iodo-imidazo[l,2-25 a]pyridine,70 Mg) ° 297 200836725 The Suzuki coupling reaction as described in Example 329 was used to synthesize the final product.

Step AO 5

-The formation of fluorop oxadiquinone ^»1 imino-1-0-moth-ethyl sulphate-1,2-di fish, _ 〇 咬 bite-4_ around acid Nf_(2 - gas-12- Imino-1- Π -iodo-vinvl)-1,2-dihvdr〇&quot;pvridine-4-carboxyli £_acid Nf-r2-fluoro-acetyl)-hvdrazide&gt;)

1 〇 EDC (127 mg, 0.66 mmol) and DMAP (5 mg, catalytic) were added to a solution of CH2CI2 (5 ml) in acetic acid (52 mg, 0.66 mniol), and the mixture was stirred at room temperature for 15 min. Add 3-iodo-imidazo[l,2-a]pyridine-7-carboxylic acid hydrazine (as described in Example 329, step ac) (100 mg, 0.33 mmol), and the reaction mixture at room temperature Stir for 18 hours. After the reaction mixture was filtered, the precipitate was washed with Et20 and dried to give crude product (10lmg), and the crude product was used directly in the next step. MS: [M+H]+=363. Gas methyl-"1,3,41^dis-2-yl)-3-break-mouth rice vomiting [1,2-&amp;10 than 〇定CZ-(5-Fluoromethvl-"l,3, 41oxadiazol-2-vlV3-iodo-imidazo『l ^2-alpvridine) 298 200836725

10 2-Imino-1-(1-iodo-vinyl)-l,2-dihydro-pyridine-4-carboxylic acid N'-(2-I-acetyl)-indole (2-Imino) -l-(l-iodo-vinyl)-l,2-dihydro-pyridine-4-carboxylic acid Nf-(2-fluoro-acetyl)-hydrazide, 89 mg, 0.25 mmol), DIPEA (0.24 ml, 1.48 mmol) and Triphenylphosphine (129 mg, 0.49 mmol) was dissolved in MeCN and stirred for 10 minutes. Hexachloroethane (87 mg, 0.37 mmol) was added, and the reaction mixture was stirred for 4 hr. The precipitate formed in the reaction was filtered and rinsed with MeCN. The MeCN solution was concentrated in vacuo and purified by flash column chromatography eluting MS: [M+H]+ = 345 (m.). -Imidazo[1,2-a]吼口定15 (7-(5-Fluoromethyl-[l ,3,4]oxadiazol-2-yl)-3-iodo-imidazo[l ,2-a]pyridine) In it. Step AP ring formation method 20 5-(3-硪-imidazolium "l,2-alpyridine-7-yl"·3Η-"1,3,41oxadiazol-2-one (5-(3- Iodo_imidaz〇ri.2-alpvridin_7-vl)-3H-ri.3,41oxadiazol· 299 200836725 2-one)

Two bases of rice bran (243 mg, 1.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) were added to 3-iodo-imidazo[1,2-a]pyridine 5-7 in THF (10 ml). - 3-Iodo-imidazo[l,2-a]pyridine-7-carboxylic acid hydrazide, 196 mg, 0.5 mmol) (as described in Example 329, step ac), and the reaction mixture Stir for 3 hours. The precipitate formed in the reaction was filtered and washed with Et20, and dried to give the desired product (189mg). MS: [M+H]+ = 329. 10 The same procedure as in step e of Example 329, but using 5-(3-moth-imidazo[l,2-a]pyridin-7-yl)-3Η-[1,3,4]oxadiazole 5-keto-(5-(3-Iodo-imidazo[l,2-a]pyridin-7-yl)-3H-[l,3,4]oxadiazol-2-one) is contained therein.

15 Step AO Step a) 7-(4,4,5,5-tetramethyl-"1,3,21 dioxa haloborane-2-yl)-imidazolium hydrazine 1,2-a1 mouth bite ( 7-(4,4,5,5-TetramethvMl,3,2&quot;ldioxaborolan-2-vlVimidazo"l,2-alpyridine) 300 200836725

7-Chloro-17 m ° and [l,2-a] utb 唆 (7-Chloro-imidazo[l,2-a]pyridine, 2g, 13·1 mmol), double frequency 5

10

Alcohol shed 0^8 mouth 111&amp;(:〇13张〇1)〇1&gt;〇11,48,15.8111111〇1), 1^2(^〇3(2.78,19.5 mmol), Pd(OAc)2 (146mg , 0.63 mmol), tricyclohexylphospine (360 mg, 1.3 mmol) was dissolved in diglyme (20 ml) and water (27 μl) and stirred. The reaction mixture was heated to 100 ° C for 24 hours. After stirring overnight at ambient temperature, the solid was filtered off and washed with diglyme. The residue was suspended in water (25 ml) and dropped for 1 hour 1 'transition'. The solid was washed with water. After sintering and drying, the desired compound (1.48 g) was obtained. MS: [{M-pinacol}+H]+ = 163 Step b) 5-Mimi and fl, 2_al吼唆-7-yl-bite- 2-carboxylic acid methyl ester (5-Imidazo "l, 2-alpvridin-7-vl-pvridine-2-carboxylic acid methyl ester")

Add PdCl2dppf (220 mg, 0.3 mmol) and H20 (55 μl, 3 mmol) 301 200836725 to 7-(4,4,5,5-tetramethyl-[1,3,2]2 dissolved in dry DME (15 ml) Heterooxaborane-2-yl)-imidazo[l,2-a]pyridine (7-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan_2-yl)-imidazo[l,2 -a]pyridine, 732 mg, 3 mmol), 5-bromine "5-bromopyridine-2-carboxylic acid methyl ester (650 mg, 3 mmol) and carbonic acid (2.0 g, 6 mmol) Spoiled in the solution. The reaction mixture was deoxygenated and heated to 80 ° C for 3 hours. The mixture was cooled, then separated with CH2C12/H20 and stirred for 20 min. The solid portion was filtered and washed with MeOH (100 mL). The CH2Cl2 layer 10 was separated, collected with a MeOH wash and the solvent was removed in vacuo. The residue was purified by column chromatography (0-3% 2M NH3.MeOH/CH.sub.2) to afford a dark yellow solid which was used directly in the next step. (492mg)· MS: [M+H]+ = 254. !H NMR d6 DMSO: 9.21 (1H, d), 8.71 (1H,d), 8.44 (1H,dd), 8.20-8.10 (2H,m) , 8.04 (1H, s), 7.69 15 (1H, s), 7.43 (1H, dd), 3.92 (3H, s). Step c) 2 - (5 _ mouth mouth and "1,2 - a 117 Specific ratio _ 7 - base _ 0 ratio q ding - 2 _ ) - C - 2 - one

(2 -(5-Imidaz〇n , 2_alpvridin-7-vl-pvridin-2-vn-propan-2iigLlI

Add decylmagnesium bromide (3M in Et20, 0.5 ml) to 5-imidazo[l,2-a]pyridin-7-yl-acridine-2-carboxylic acid dissolved in dry THF (5 ml). 302 200836725 A solution of 5-Imidazo [l,2-a]pyridin-7-yl-pyridine-2-carboxylic acid methyl ester, 135 mg, 〇.53 mmol). After 1 hour, another portion of methylmagnesium bromide (3M in Et20, 0.5 ml) was added and the mixture was stirred for further one hour and quenched with saturated NH4Cl (aq). The reaction mixture was then separated with Et0Ac/H20, the aqueous layer was extracted with EtO Ac (x2), the organic layer was concentrated, dried (MgSO.sub.4), filtered and solvent removed in vacuo. The residue was purified by column chromatography eluting EtOAc (EtOAc:EtOAc: (44mg). MS: [M+H]+ = 254. lR NMR (4〇〇MHz? CDC13): 10 8·84 (1H,d), 8.27 (1H,d),7.99 (1H,dd), 7·90 (1H, s), 7·74 (1H, s), 7·67 (1H, s) 5 7·53 (1H, d), 7.11 (!H, dd), h62 (6H, s) Step d) 2-[5-Π-iodine-imidazole#pyridine-7-A1-0 ratio-propan-15-2-olΓ2-"5 彳S-Iodo-imidazonj-MpvridinJ-va^rid twist d:yl -pro pan-2-ol)

Use the method as described in step A2. 20 4 NMR (400 MHz, DMSO-d6): 8.97 (1H, d), 8.41 (1H, dd), 8.24 (1H, dd)5 8.05 (1H, s), 7.80-7.76 (2H, m) ,7·49 (1H, dd), 5.30 (1H, s), 1.49 (6H, s). 303 200836725 Step e) 1-(3-Π-Γ6-(1-hydroxy-1-methyl-ethyl Pyridin-3-yl 1-imidazole and "1,2_alp ratio _3_基卜基基)_3_(2,2,2_二就·•ethyl)_脉(1-(3- {7- r6-n-Hvdroxv-l-methvl-ethvl)-pvridin-3-vn-imida 5 ζοΓ 1,2-a1pyridin-3-yU-phenyl)-3-(2,2,2-trifluoro-ethyn-urea

The procedure as described in step B3a was used, but Pd tetrakis was replaced by PdCl2dppf. Step AR - 1-"3-(7_"1,2,41oxadiazol-5-yl-imidazolium "1,2-alpyridine_3_yl)_stupyl 1_3-(2,2,2_ Diox-ethyl) _ pulse - "3-(7-f 1,2,410xadiazol-5-vl-imidazo"l,2-a~lpvridin-3-vl)-15 phenyll-3-(2,2 , l-trifluoro-ethvD-urea) 304 200836725

10 Hydroxylamine, HCl (30 mg, 0.43 mmol) was added to 3-{3_[3-(2,2,2-trifluoro-ethyl)-ureido]-phenyl}-imidazole at room temperature [ 1,2-a] Acridine-7-carboxylic acid 1-didecylamino-(E)-mercaptodecylamine (3 - {3-[3,(2,2,2_trifluoro-ethyl)-ureido] _phenyl}-imidazo[l,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylidene amide, 135mg, 0.3mmol) and 5N NaOH (75μ1, 0.38mmol) of Ac0H/H20 (7 :3, lml) in solution. The reaction mixture was stirred at room temperature for 2 hours before heating to 60 ° C for 7 hours. The reaction mixture was cooled and the volatiles were removed in vacuo. The residue was purified by HPLC to give the desired compound (35 mg). MS: [M+H]+403 ° Step AS - 1-Γ3-(7-"1,2,41 triazole-1-yl-imidazolium,2-alpyridine_3_15-methyl-l-1-3 -(2,2,2-trifluoro-ethyl V urea (1-"3-(7-"1 JjlTriazol-l-vl-imidazofl J-alpvridind-vlVphe nyl1-3-r2, 2.2-trifluoro-ethvl) -urea) Step 1 - 7_"1,2,41 Triazol-1-yl-imidazolium" 1,2_31pyridine (7-"1 JJlTriazol-l-vl-imidazofl J-alDvridine" 305 200836725

Ethylacetate iron (0.94 g, 2.59 mmol), copper (II) oxide (86 mg, 0.86 mmol), 1H-[1,2,4]triterpene (0.90 g, 12.9 mmol), and carbolic acid (5.65 g, 17_3mmol) and 7_ bromo-metamol and [l,2-a] σ is more than 5 (7-bromo-imidazo[l52-a]pyridine5 1.7g, 8.63mmol) dissolved in anhydrous DMF (43ml) Heat to 90 ° C for 30 hours under nitrogen atmosphere. The reaction mixture was cooled, diluted with CH.sub.2 C.sub.2, filtered, The aqueous portion was washed with CH2C12, and the organic portion was concentrated, dried (MgSO4) and solvent was evaporated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. MS: [Μ+Η]+ 1δ5. Step 2 - 3-iodo-7-"1,2,41 triazol-1-yl-imidazolium" 1,241 pyridine O-Iodo-7-oxime, 2,4&quot;|triazol-1 -vl-imidazof L2-alpvridine )

15

Step 3 - 1-Π-(7-"1,2,41Triazol-1-yl-imidazo-fl,2-alpyridin-3-yl)· Stupidin-3-(2,2,2- Tris-ethyl) Π [3-(7-Γ1,2,41 Triazol-1 - vMmidazori,2-alpvridin-3-vl)-phe 20 nvn-3-(2,2,2-trifluoro-ethyl )-urea) 306 200836725

As described in general formula B, step B3a, but using 16 [3-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-phenyl]-3-( 2,2,2-trifluoro-ethyl)-urea as the other half of the coupling.

General SGA

10 Step SGA1 - Formation of imidazole pyridine ring

NaHC03 (2.0 eq.) was added to 4-substituted pyridin-2-ylamine (1.0 eq.) in EtOH, followed by chloroacetaldehyde (1.5 eq.). The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the crude mixture was partitioned from water and EtO Ac. The product is purified by column chromatography, titration, or re-crystallization 307 200836725. RR, product MS: [M+H]+ ch2oh H Imidazo[l,2-a]pyridin-7-yl - methanol 149 ch3 H 7-Methyl_imidazo[l,2-a]pyridine 133 ch2ch3 H 7-Ethyl-imidazo [ 1,2-a]pyridine 147 cf3 H 7-Trifluoromethyl-imidazo[l,2-a]pyri dine 187 〇ch3 H 7-Methoxy-imidazo[l,2-a]pyridine 149 och2ch3 H 7-Ethoxy-imidazo [l,2-a]pyridine 163 ch3 Cl 6-Chloro-7-methyl-imidazo[l ,2-a]pyri dine 167 Step SGA2 - Breaking

Add N·i〇dosuccinimide (1.2 eq.) to 7-substituted imidazo[i,2-a]pyridine (ΐ·〇 equivalent) dissolved in DMF, and mix the solution Stir at room temperature for 2 hours. The resulting thin brown mud was diluted with water, 10% w/v sodium thiosulfate and sodium carbonate (1 M), 10 and extracted with CH2Cl2. The aqueous layer was then extracted with CH2C12. The collected organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give product. If necessary, the product can be purified by pulverization or column chromatography. 308 200836725 RR, product MS: [M+H]+ ch2oh H (3- moth-flavored saliva [l,2_a] mouth ratio n--7-yl)_methanol 275 ch3 H 3-iodo-7-methyl -Imidazo[i,2_a]pyridine 259 ch2ch3 H 7_ethyl-3-break-taste σ sit and [1 j-apit 〇定273 cf3 H 3-A-7-San Dun methyl·m. Sit and [1,2-a]^b σ 313 och3 H 3- moth-7-decyloxy-imidazo[i,2-a]uia 275 OCH2CH3 H 7 -ethoxy-3_carbon ·Smell 11 sits and [1,2-a]n is 0 to 289 ch3 Cl 6-chloro-3_iodo-7-methyl-imidazo[l,2-a]pyridine 293 Step SGA3a - and 1-" 3-(4,4,5,5-tetramethyl, 1,3,21 dioxa haloborane-2-yl Vphenyl 1-3-(2.2.2-trifluoroethyl urea 5 Π Suzuki reaction of 43-(4,4,5,5-Tetramethvl-ri .3,2~ldioxaborolan-2-vn-phenvl &quot;|-3-(2,2,2-trifluoro-ethvl)-urea)

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3_(2,2,2_3 "&lt;ethyl"-pulse 10 (l-[3-(4,4,5,5-Tetramethyl-[l,3,2]di〇xaborolan_2-yl)-plienyl]-3-(2,2, 2_trifluoro-ethyl)-iirea,1·2 when 篁), 1M Na2C〇3 (8 equivalents) is added to 7-substituted iodine-imidazolium dissolved in DME, 2*^]11 than pyridine 309 200836725 (7-subStituted In -3-iod〇-imidazo[l,2-a]pyridine, i equivalent) [removal of bubbles via nitrogen gas], followed by addition of tetrakis(triphenylphosphine)palladium (〇〇5篁). The mixture was heated at 80 CC overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine (bd), dried (MgSO.sub.4) and concentrated. The product was purified by trituration, column chromatography or reverse phase HPLC. Suitably, the product can be dissolved in HCl/dioxane, the solvent removed, and the product recrystallized from Me〇H to give hydrogen chloride. &quot;

310 200836725 ({5-Nitro-pyridin-2-vn-carbamic acid tert-butvl ester)

2-Amino-5-nitropyridine (〇. 70 g, 5 mmol) was added to a solution of sodium hydride (0.20 g, 5 mmol) in dry THF (20 ml). The mixture was heated to room temperature and stirred for 30 minutes. The flask was vented under nitrogen, and a solution of di-tert-butyldicarbonate (1.274 g, 5 mmol) in THF (40 ml). The reaction mixture was stirred for 3 hours before the reaction was quenched with EtOH (1 mL) and separated with CH.sub.2 C.sub.2 and H20. The water-soluble layer was further extracted with CH2C12, and the organic layer was concentrated, dried (MgS04) and evaporated to remove solvent. The residue was triturated with EtOAc EtOAc (EtOAc) MS: [MH]· 238 Step SGB2-(5-Amino-0-q-denyl-2-carboxamidine-reductive guanidine ((5-Amino-pyridin-2-vl&gt;)-carbamic acid tert-butvl Ester)

Add 10% Pd/C (0.08g) to the (5-Nitro) (5-Nitro) dissolved in THF: MeOH (1:1, 80ml) (5-stone-Schottky-° ratio 0-group-2) -pyridin-2-yl)-carbamic acid tert-butyl ester, 0.80 g? 3.4 mmol), and the reaction was placed in a hydrogen atmosphere for 3 hours. 20 catalyzed was filtered off, and the solvent in the organic layer was removed in vacuo to give a white solid compound (0.70 g). MS: [M+H]+ 210 311 200836725 Step SGB3-(5-Mercaptoamino-pyridine-2-ylcarbamic acid tert-butyl ester G5-Metlianesulfonvlamino-t)vridin-2-vl)_carbamic acid tert- Butvl ester)

Pyridine (0.44 ml, 5.68 mmol) was added to p-(5-amino-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester ((5-Amino-pyridin-2-yl)- dissolved in CH2C12 (70 ml) Carbamic acid tert-butyl ester, 0.70 g, 3.36 mmol). The reaction was cooled to 0.degree. C. and sulphur (10. The reaction mixture was then warmed to room temperature and stirred for 18 h. The obtained crude material was subjected to column chromatography (yield: 0-30% MeOH in Et20, gradient) to afford white solid (yel. 43g). MS: [M+H]+ 288 15 Step SGB4_ N-(6-Amino-pyridin-3-Vetamine I(N-(6-Amino-pvridin-3&quot;Vn-methanesulfonamide&gt;) _

4M HCl dissolved in dioxane (20 ml) was added to (5-methanesulfonylamino-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester 20 (((). The reaction was heated to 55 312 200836725 ° C for 18 hours in 5-Methanesulfonylamino-pyridin-2-yl)-carbamic acid tert-butyl ester (0.43 g, 1.48 mmol). The solvent was removed in vacuo, and the crude material was purified eluting with EtOAc EtOAc EtOAc (EtOAc) MS: [M+H]+ 188 5 Step SGB5-N-Imidazole and 1,1,2-alpyridine-6-yl-methyl amide (N_Imidazo "l,2-a1pvridin-6-vl- methanesulfonamide"

Adding gaseous acetic acid (〇3 ml, 2,25 mmol) and sodium bicarbonate (0.25 g, 3111111〇1) to 1 &lt;[-(6-amino-bite bite) dissolved in £1:011 (3〇1111) -3-yl)-methyl 10 sulfonamide (N-(6-Amino-pyridin-3-yl)- methanesulfonamide, 0.28 g, 1.48 mmol). The reaction mixture was heated to 80 °C for 4 hours, then cooled to room temperature and solvent was evaporated in vacuo. The residue was then taken up in EtOAc and H20. The aqueous layer was extracted with EtOAc. EtOAc (EtOAc) The residue was purified with EtOAc EtOAc (EtOAc) elute MS: [M+H]+ 212 Step SGB6·N-(3-iodo-imidazolium Fl,2-alpyridine-6-V-methyl decylamine (N-(3-Iodo-imidazo"l, 2 -alpvridin-6-vlV 20 methanesulfonamide&quot;)

N-iodosuccinimide (70 mg, 313 200836725 〇.31 mmol) was added to N-imidazo[l,2-a]pyridine-6-ylindole dissolved in DMF (3 ml) N-Imidazo [l,2-a]pyridin-6-yl-methanesulfonamide, 61 mg, 0.29 mmol). The reaction was stirred at room temperature for 2 hours and diluted with water, 1% w/v sodium thiosulfate, and 5 sodium carbonate (1M) and extracted with EtOAc. The aqueous layer was then extracted with EtOAc. The organic phase was washed with brine (80 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography (0-»30%MeEtOAc/EtOAc) to yield to crude product C (m), and the crude product was used directly in the next step. MS: 10 [M+H]+ 338 Disc SGB7- 1^(3-{3-"3-(2) 2-Trifluoro-B-)-urea 1-Methylamine-imidazole and "1.2 -alpyridine-6·yl)·methylsulfonamide LN-(3 - i3-"3-(2.2,2-Trifluoro-ethvlVureidol-phenvlamin〇}-i 15 midazo"l ,2-alpvridin-6-vn - methanesulfonamide)

1-(3-(4,4,5,5-tetradecyl-[1,3,2]disoxaborane-2-yl)-phenyl]-3-(2,2,2 - Trifluoro-ethyl)-urea (l-[3_(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan_2-yl)-phenyl 20 ]-3-(2,2,2_trifluoro- Ethyl)_urea, 87mg, 0.25mmol), 1M Na2C03 (2ml) added to N-(3-indole-imidazo[l,2-a] 314 200836725 pyridine-6·yl)-indole dissolved in DME (5ml) N-(3-Iodo-imidazo[l,2-a]pyridin-6_yl)-methanesulfonamide, 72mg, 0·21ηπηο1) [removal of bubbles via nitrogen gas], followed by addition of tetrakis(triphenylphosphine) Palladium (0) (12 mg). The mixture was heated overnight at 80 ° C, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and solvent was evaporated in vacuo. The product was purified using reverse-HPLC to afford white solid (yield: 3.6 g). MS: [M+H]+ 428

Step SGC1 - 6-iodo-7-methyl-imidazolium "1,2-alpyridine (6&quot; Iodo-7-methvl-imidaz〇r 1,2-alpvridine) αχ Like the step in SGA1, but using 5· Iodine-4_Iodo-4-methyl-pyridin-2-yl amine 315 200836725 Step SGC2-6-cyclopropyl-7-methyl-imidazolyl H,2-al Pyridine (6-Cvcl〇pr〇pvl_7-methvl-imidaz〇ri, 2-alpvridine)

5 M3-(4,4,5,5-tetramethyl-"1,3,21 dioxaborane-2- some V stupid_1-3-(2,2,2·_^ _:_Zj_^_^2_ pulse

(l-[3_(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl ( ]-3-(2,2,2-trifluoro-ethyl)-urea, 33mg, 0.39mmol), 1M

Na2C03 (1.6 ml) was added to 10 6-Iodo-7-methyl-imidazo[l,2-a]pyridine (50 mg, 019) dissolved in DME (5 ml) [to remove bubbles via nitrogen gas], followed by addition of four ( Triphenylphosphine) palladium (0) (ll mg). The mixture was heated to 120 ° C for 30 minutes using microwave irradiation, followed by dilution with water and extraction with CH 2 C 12 . The organic layer was washed with brine, dried (MgSO4) and solvent was evaporated in vacuo. The product was purified by column chromatography to give a crude residue, and the crude residue was used directly in the next step Q (34 mg). MS: [M+H]+ 173 Step SGC3-6-Cyclopropyl-3-Moth-7-Methyl-Milingyoup,2-al0 口定定--Cvclopropyl^-iodo-T-methyl-imida ^on^-alpyridine)

As in the step in SGA2, but using 6-cyclopropyl-7-methyl-imidazole 316 200836725 and [l,2-a]pyridine (6-Cyclopropyl-7-methyl-imidazo[l,2-a]pyridine, 165 mg). MS: [M+H]+ 299 Step SGC4 - M3-(6-cyclopropyl-7-methyl-imidazolium "l,2-alpyridin-3-ylaminolamyl 1-3- (2,2,2-trifluoroethyl urea n-r3-(6-Cvcl〇propvl-7-methvl_imidaz〇ri, 2-alpvridin-3-vla mino)-phenyl1-3-(2,2,2 -trifluoro-ethvl&gt;)-urea&gt;)

F

10 as in the step of SGA3a, but using 6-cyclopropyl-3-iodo-7-methyl-imidazo[l,2-a] acridine (6-Cyclopropyl-3-iodo-7-methyl-imidazo[ l 52-a]pyridine5

7mg). MS: [M+H]+ 389 15 General procedure SGD 317 200836725

Step SGDl - Formation of the general imidazole pyridine ring

Add NaHC03 (16.8 g, 200 mmol, 2.0 eq.) to 4-Chloro-pyridin-2-ylamine (12.8 g, 100) dissolved in EtOH (170 ml). In mmol, 1.0 eq., followed by chloroacetic acid (19.0 ml, 150 mmol, 1.5 eq.). The mixture was refluxed for 6 hours. The solvent was removed by a reduced pressure and the crude mixture was separated from EtOAc using water. The organic layer was washed with brine, dried (MgS04), and concentrated under reduced pressure. The product was purified by column chromatography (SiO 2 eluting with 50% EtOAC- petroleum ether) to afford I3. MS: [M+H]+ 153 15 Step SGD2-General Iodization

I

318 200836725 Step A2: N-iodosuccinimide (43_6 g, 194 mmol, 1.05 eq.) was added to 7-chloro-imiline dissolved in DMF (280 ml) and [1] , 2-a] 11 唆 (30.9 g, 186 mmol, 1.0 eq.), and the mixture was stirred at room temperature overnight. The thin brown mud was diluted with water (840 ml), 5 brine (br. The aqueous phase was extracted with EtO Ac (3 X 280 mL). The organic phase was collected, washed with water (2× 280 ml), 10% w/v sodium thiosulphate (280 ml), brine (280 ml), dried (MgS04) and concentrated in vacuo. A brown residue was obtained. The residue was triturated with diethyl ether (200 mL), filtered and evaporated. MS: [M+H]+ 279 Step SGD3 -舆1-"3-(4.4,5,5-tetramethyl--~1.3,21 dioxane borane-2-yl)-stupid 1-3 -(2,2,2-tris-ethyl)-pulse 15 n-"3-(4,4,5,5-Tetramethvl-f l,3»2~|dioxaborolan_2-vlVphenvl l-3-(2 , 2,2-trifluoro-ethyl)-urea)

Step A3b ···l-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]_3·(2, 2,2-Trifluoro-ethyl)urea 20 (l-[3-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan_2-yl)-phenyl 319 200836725 ]-3-(2 , 2,2-trifluoro-ethyl)-urea, 1.2 eq.), 1M Na2C03 (8 eq.) added to 7-ox-3-iodo-imidazo[l,2-a]pyridine (7_chloro-3_iodo) dissolved in DME -imidazo[l,2_a]pyridine, 1 equivalent) [to remove bubbles via nitrogen gas], followed by addition of tetrakis(triphenylphosphine)palladium (〇) (〇·〇5 when 5). The mixture was heated overnight at 80 ° C, then diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried (MgSO4) and evaporated. The crude material was ground in CH2C12 to give a beige solid product. MS: [M+H]+ 389 10 Step SGD4a - Sonagshira reaction 1-[3-(7-acetylene-imidazo[1,2_&amp;]pyridin-3-yl)-phenyl]-3_(2,2, Preparation of 2-dialdehyde-ethyl)-pulse (l-[3_(7-EthynyMmidazo[l,2_a]pyridin-3_yl)_phenyl]-3-(2,2,2-trinuoro-ethyl)_urea)

1-[3-(7·Chloro-flavor. Sit and [l,2_a]σ ratio -3 -3 -yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)- Pulse 20 (l-[3-(7_Chloro-imidazo[l,2-a]pyridin_3-yl)-phenyl]-3_(2,2, 2-trifluoro_ethyl)-urea, 0.59g, 1.6mmol), trimethyl Acetylene Shixia 320 200836725 (trimethylsilylacetylene, 0.92ml, 6.4mmol), carbonic acid unloading (0.44g, 3,2mmol), palladium acetate (0.07g, 0.32mmol) and 2,2'-618 (diphenyl Phosphine-1,1'-1^11&amp;卩111:11&amp;16116 (0.48,0.64111111〇1) was dissolved in toluene (20 ml). The reaction mixture was microwaved (2 x 90 min) to 120 °C, 5 and cooled, then separated with CH2C12 and H20. The water-soluble layer was further extracted with CH2C12, and the organic layer was concentrated, dried (MgS04), and solvent was removed in vacuo. The residue was purified by column chromatography (0-60% MeOH in Et20) to afford solids and used directly in the next step. At 10 ° C, 1 M tetrabutylammonium fluoride (0.09 ml) solution was added to l-(2,2,2-trifluoro-ethyl)-3 dissolved in THF (5 ml). -[3-(7-trimethyldecylamine acetylene-imidazo[l,2-a]pyridin-3-yl)-phenyl]-urea (1-(252,2-Trifluoro-ethyl)-3- [3-(7-trimethylsilanylethynyl-i 15 midazo[l,2-a]pyridin-3-yl)-phenyl]-urea, 25 mg5 0.06 mmol), the reaction mixture was stirred at EtOAc for 1 hour. The reaction mixture was diluted with water and extracted with CH2C12. The organic layer was washed with brine (I), washed, dried (MgS04), and the solvent was removed in vacuo. The residue was purified by reverse EtOAc (EtOAc) MS: [M+H]+ 359 20

Step SGE 321 200836725

Everyone ^NH2

NH, O N^i

NT

N-

Ar

N^i N- Γ Step SGE1-imidazolium n,2-alpyridine-7-carboxylic acid decylamine (Imidaz〇ri.2-alr&gt;vridine-7-carboxvlic acid amide)

NH2 step SGA1, using 2-aminoisonicotinamide MS: [M+H]+ 162. 10 Step SGE2 - Imidazolium 1,2-alpyridine-7-cyano (Imidazofl J -alpvridindcarbonitrile)

Add dropwise trifluoroacetic anhydride (0.39, 2.83 mmol) to the miso dissolved in CH2C12 (5 ml) and [l,2-a] 吼定定-7-decanoic acid decylamine 15 (Imidazo[l, 2 -a]pyridine-7-carboxylic acid amide, 38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol). The reaction mixture was stirred at room temperature for 2 h, washed with MeOH and eluting with 2M NH3 / MeOH before the crude mixture of 322 200836725. The solvent was removed in vacuo to give compound (32 mg). MS: [M+H]+ 144. Step SGE3 - 3-iodo-imidazolium, 2_alpyridine-7-cyano (3-Iodo_imidazo"l J-alpvridine-T-carbonitrile)

10 Step SGA2, using Imidazo[l,2-a]pyridine-7-carbonitrile. MS: [M+H]+ 270. Step SGE4 - l-"3-(7-Cyano-imidazopyridine-3-ylmosamine 15 [3-(2,2,2·2 gas-ethyl pulse n -r3-r7-Cvan〇&quot;imidaz〇ri.2-a1pvridin-3-ylVphenvl1-3-(2,2,2 -trifluoro-ethyD-urea)

F

F 323 200836725 Prepared as in step A3a, but using 3-iodo-imidazo[1,2-a] π than 唆-7- chaotic (3-Iodo-imidazo[l,2-a]pyridine-7_carbonitrile ). Purification was carried out using reverse 5 HPLC to give a white solid product. MS: [M+H]+ 360. Step SGF:

10

(Methyl imidazofl, 2-alpvridine-7-carboxvlate)

Prepared as in the method of step SGA1, but using methyl-2-aminopyridine-4-carboxylate: NaHC〇3 (11.1 g, 132 mmol, 2.0 equivalent) Add EtOH (l50 ml) solution of Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 324 15 200836725 mmol, 1.0 eq.) Then, chloroacetaldehyde (chloroacetaldehyde, 13.0 ml, 99 mmol, 1.5 equivalents) was added. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the crude mixture was separated from EtOAc using water. The precipitate was washed with Et20 5 and crystallized with Me0H/Et20 to give 8.4 g of product. MS: [M+H]+ 177 Step SGF2 - 2 · Imidazolyl H,2_alpyridine_7_A-propan-2-ol (2-Imidazori, 2-a1pvridin-7-vl_pr〇pan-2-ol)

A solution of 1.6 M MeLi in Et20 (5.3 ml) was added to THF (20 mH of methylcarbazole and n,2-a~l pyridine-7-carboxylate {.Methyl imidazo) at -78 °C. [l,2-a]pyridine-7-carboxylate, 0.50 g, 2.84 mmol), then the reaction was warmed to room temperature. The reaction was stopped with water and then layered. The aqueous layer was then extracted with Et20, the organic layer was concentrated, dried (MgSO4), filtered, and solvent was evaporated in vacuo to give product (0.38 g). MS: [Μ+Η]+ 177 Step SGF3 - 2-( 3-iodo-imidazolium fl,2-alpyridine-7-yl V propan-2-ol 20 (2-(3-Iodo-imidaz〇ri.2-a1pyridin-7-vlVpr〇pan-2-〇n)

325 200836725 Prepared as in the method of step SGA2, but using 2-imidazo[l,2-a]pyridin-7-yl-propan-2· drunk (2-Imidazo[l,2_a]pyridin-7-yl_propan -2-ol) 〇MS: [M+H]+ 303. Step SGF4 - 1-{3-"7_Π-hydroxy-1-methyl-ethylimidazolium "1,2-al p is more than -3 -基1·笨基卜3-(2,2,2-digas-ethyl)-pulse (Η3-Γ7-Π-Hvdroxv-1 -methvl-ethvl)-imidazo"l,2-a&quot;lpvridin- 3-vl1-phenvl&gt;-3-(2,2, l-trifluoro-ethvn-urea)

CF.

Prepared as in the method of step SGA3a, but using 2-(3-iodo-imidazo[l,2-a] ° dictate-7-yl)-propan-2-Sf-(2-(3-Iodo-) Imidazo[l,2-a]pyridin-7-yl)-propan-2-ol). Purification by reverse phase HPLC gave the product. MS: [M+H]+ 393. 15

Step SGG 326 200836725

C〇2Et Step SGG1: l-"3-(7-Mercapto-imidazolium "1,2-alpyridin-3-yl)-Cell 5 1-3 - (2,2,2-digas- Ethyl)_脉Π·"3-(7·ΡοηηνΜπιί(1αζοΓ1·2·&amp;1ρνΗ(ϋη-3-νΠ-ρ1ΐ6ην1Ί·3-(2-:2Ί 2-trifluoro-ethvl)-urea&gt;)

TPAP (0.14 g, 0.38 mmol) was added to l-[3_(7-hydroxyindolyl-imidazole [l,2_a]pyridin-3-yl) in 10 CH2C12 (30 ml) at 〇 °C. Phenyl]-3_(2,2,2-trifluoro-ethyl)-urea (l-[3-(7-Hydroxymethyl-imidazo[l?2-a]pyridin-3-yl)-phenyl]-3 -(2,2,2-triluoro-ethyl)-urea, 1.42g, 3.90mmol) (prepared according to step SGA) and NMO (1.38, 11.7 mmol) and containing 327 200836725 sieve (3 g). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours before the sieve was removed by filtration. The organic layer was washed with H20 (x2), dried (MgSO4) and solvent was evaporated in vacuo. The residue was purified by column chromatography eluting EtOAc EtOAc (EtOAc) MS ·· 5 [M+H]+ 363 10 Step SGG2 丨3-[~3-(2 on 2-trifluoro-ethyl V-ureido-l-mom μ taste ρ sit and f 1,2-alρ ratio -7定-7-yl)-propionic acid ethyl vinegar [(Ε)_3·(3- n-r3-(2,2,2-Trifluoro-ethvlVureidol_phenvl}_imid —azo"l,2-a~lt) vridin-7-vlVacrvlic acid ethvl ester)

Γ (; Dissolve Triethylphosphonoacetate (99μ1, 0.5mmol) and lithium chloride (21mg, 0.5mmol) in MeCN (5 ml) and stir. Add DBU (62μ1, 0.41mmol), add l-[3-(7) -Methylmercapto-imidazo[l,2-a] 15 pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (l-[3_(7_Formyl_imidazo[ Before l,2-a]pyridin-3-yl)-phenyl]_3-(2,2,2-trifluoro-ethyl)_urea), the reaction mixture was stirred for a further 15 minutes. Before separating it with EtOAc and H20, The mixture was stirred for a further 1 hour. The aqueous layer was extracted with EtOAc EtOAc (EtOAc m. + 433. Step SGG3 (EV3-(343-"3_(2 义 2-Trifluoro-ethyl V ureido 1-Moum 5 imidazolium, 2-alpyridin-7-yl)-acrylic acid (TEV3-( 3- {3-r3-(2,2,2-Trifluoro_ethvl)-ureidol-phenvll-imid azofl,2-a1pyridin-7-vlVacrvlic acid)

Add 1 M Na2C03 (4 ml) to 10 (E)-3-(3-{3_[3-(2,2,2-trifluoro-ethyl)-ureido group dissolved in EtOH (10 ml); Imidazo[i,2-a] σ ratio &quot;定&quot;7&quot; base)_ethyl acrylate ((E)-3-(3_ {3_[3_(2,2,2_Trifluoro-ethyl)_ureido]-phenyl }-imid azo[l,2-a]pyridin-7-yl)-acryiic ethyl ester,83 mg,

The reaction was heated to 8 ° C for 15 hours in 0.19 mmol. The reaction was neutralized with 1 M 15 HC1 and concentrated. The residue was taken up in hot EtOH, filtered and solvent was evaporated in vacuo to afford product. MS: [M+H广4〇5 _SGG4 @)_1^1^^^(3^3_『3_(2.2.2_三气_乙)_Urea-based stupid base--taste g sitting ratio _ 7_某)·Acrylamide 329 200836725 ((EVN-alkyl-BOn-rB-^^^-trifluoro-ethvn-ureidol-phen yl}-imidaz〇ri, 2-a1pyridin-7-vlVacrvl amide)

Add TBTU (1.5 equivalents) and HOBt (1.5 equivalents) to @)-3-(3-{3_[3-(2,2,2-trifluoro-ethyl)-urea] dissolved in 5 DMF -phenyl}-imidazole [l,2-a] σ ratio °-7-yl)-acrylic acid ((E)-3-(3- {3-[3-(2,252-Trifluoro-ethyl)- In ureido]-phenyl}-imid azo[l,2-a]pyridin-7_yl)-acrylic acid), the reaction mixture was stirred and mixed for 15 minutes. Amine (2 equivalents) was added and the reaction mixture was stirred for 2 10 hours. The crude material was placed in a SCX SPE crucible and the hydrazine was washed with MeOH (x2 column volume) and eluted with 2M NH3 / MeOH (1 column volume). After the solvent was removed in vacuo, the desired product was obtained.

Step SGH 330 200836725

Step SGHl 7-Minkou rice bran and fl, 2-a10 than mouth (7-Bromo-imidaz〇ri, 2-alpyridine)

Prepared as in the method of Step A1, but using 4-bromo-pyridin-2-ylamine. Step SGH2-7-cyclopropyl-m-methane and [1,2- Alp

(7-Cyclopropvl-imidazori, 2-alpvridine)

Add Pd(OAc)2 (0.03g) to 7-bromo-imidazo[l,2-a]pyridine (7-Bromo-imidazo) dissolved in deoxyphenylbenzene (11.36ml) and H2〇 (0.57ml) [l,2-a]pyridine, 0.5 g, 2.53 mmol), cyclopropylboronic acid (0.29 g, 3.29 mmol), K3P〇4 331 200836725 (1.79 g, 8.88 mmol), Pcy3 (0.07 g) , 10 mol%) in solution. The reaction mixture was heated to 100 ° C for 18 hours before being separated with EtOAc and H20. The aqueous layer was washed with EtOAc. EtOAc (EtOAc m. The residue was purified by column chromatography to give the product (yel. 31 g). MS: [M+H]+ = 159 Step SGH3 - 7-cyclopropyl_3_iodo-imidazolium ri,2-alpyridine (7-Cvclopropvl_3_iodo_imidazo"l,2-alp vridine)

Prepared as in the step SGA2 to give the product as a yellow oil. MS: [M+H]+ = 285 Step SGH4 - M3-(7-cyclopropyl-imidazo-1,2-al-azul-3-yl)methyl 1-3-(2,2,2- Trifluoro-ethyl V urea 15 n-"3-(7-Cvclopropvl-imidaz〇ri,2-a1pvridin-3-vl)-phenvll-3 -(2,2,2-trifluoro-ethvl)-urea)

332 200836725 The product is obtained as in the step in SGA3a. MS: [M+H]+ = 375 Step SGI: 1-{3-Γ7彳hydroxyimino-methyl-imidazole and 1,1,2-alpyridin-3-yl 1 -stupyl 3_(2, 2,2_three gas-ethyl) vein 5 Π n-"7-(Hvdroxvimino-methvlVimidaz〇ri, 2-alpvridin-3-vl 1-phenvn-3-(2&lt;t2,2&quot;trifluoro-ethvn-urea0

Addition of hydroxylamine hydrochloride (llmg, 10 0.15 mmol) and triethylamine (21 μl, 0.15 mmol) to l-[3-(7-fluorenyl-imidazo[] in toluene (5 ml) l,2-a; hb pyridine-3-yl)-phenyl]-3-(2,2,2,-trifluoro-ethyl)-urea (50 mg, 0.14 mmol). The reaction mixture was stirred for 1 min; min, then tosic acid (3 mg, &lt;RTI ID=0.0&gt; The precipitate was filtered and washed with EtOAc (EtOAc) to afford product (23mg). MS: [M+H]+ 378. M3-"7-(曱气基亚胺基-methylimidazolium "1.2-alpyridine-3-some 1·cage}-3-(2,2,2 -trifluoro-ethyl)-urea mn-iMethoxvimino-methvlVimidazori, 2-alpvridin-3-vl 20 1-phenyl) -3-Γ2,2.2-trifluoro-ethvlVurea) 333 200836725

The same procedure as above was followed except that hydroxylamine hydrochloride was replaced with methoxy amine hydrochloride. MS: [M+H]+ 392. 334 200836725.荽Φ^Μ 6imlI苳鸯驷》伯友&lt;卜离&gt;铋-拎丧拎wfFT书澳6W叫I苳嫜« [^怜嫁驷]

MS MS: [M+H] + 266 MS: [M+H] + 328 NMR NMR (1H NMR (400 MHz, Me-c/3-OD): 8.49 (1H, d), 8.08 (2H, brs), 7.83 (1H, s)f 7.79 (2H,d), 7.71 (1H,s), 7.53 (2H,t), 7.44 (1H,t), 7.37 (1H, dd). 1H NMR (400 MHz, Me- cf3-OD): 8.72 (1H,d), 8.03 (2H, d), 7.91 (1H, s), 7.84 (2H, d), 7.61-7.43 (7H, m), 2.19 (3H, s). Preparation Step ^ ^ ^ h Cd Record CO II (S electric V 4 private ffl ff士ffl ^ ^ ^ \ W 4 ^5# 运m 0 验 ss 驾德 4. 1 fc, s chemical name 7-phenyl-3 -(1Η^Bizozol-4-yl)-Miso-sit [l,2-a]0 is more than 7-Phenyl-3-( 1 H-pyrazol-4-yl)-imidazo[ 1,2- a]pyridine) IS 91⁄2 ts iti fa ill If 111 ^ 1 Compound IZWT Example No. τ - CNJ 200836725 MS: [M+H]+ 512 MS: [M+H]+ 412 MS: [M+H]+ 413 1H NMR (400 MHz, Me-d3-OD): 8.59 (1H, d), 7.97 (1H, s), 7.79 (1H, s), 7.76-7.66 (3H, m), 7.62-7.49 (2H, m ), 7.45-7.31 (2H, m), 7.13 (2H, d), 3.62 (4H, t), 3.27 (4H, t), 2.19 (3H, s), 1.51 (9H, s). 1H NMR (400 MHz, Me-c/3-OD): 8.79 (1H, d), 8.20 (1H, s), 8.15 (1H, s), 8.13 (1H, s), 7.91 (2H, d), 7.87 (1H, Dd), 7.66 -7.58 (2H, m), 7.52-7.44 (1H, m), 7.25 (2H, d), 3.62 (4H,t), 3.43 (4H,t), 2.20 (3H, s). 1H NMR (400 MHz , Me-cf3-〇D): 8.59 (1H, d), 7.99 (1H, s), 7.80 (1H, s), 7.78-7.47 (5H, m), 7.39 (2H, t), 7.10 (2H, d), 3.87 (4H, t), 3.26 (4H, t), 2.19 (3H, s). 趑f 3 a sneak abuse 5 ^ ^ h ^ f Alkali province cn: Dan I — job 7 do dl cA聋械械-^ ^ ^ | #铝叫省2旦参1膳 K午砩锘tO蟛$ Μ #1^4 &lt;硪£ 1婳Κ 4-{4-[3-(3-Ethylamino)- Phenyl)-imidazo[1,2-a]σ is more than -7-yl]-phenyl}-Nymidine-1 - tert-butyl carbonate. (4- {4-[3-(3-Acetylamino-) Phe nyl)-imidazo[ 1,2-a]pyridin-7 -yl] -phenyl} -piperazine-1 -ca rboxylic acid tert-butyl ester) I Ν-{3-[7-(4-piperazine-1 -yl-phenyl")-σ米σ sit [1,2-a]σ than bite_-3 -yl]·* phenyl}-acetamide hydrochloride (Ν- {3-[7-( 4-Piperazin-l-yl-p henyl)-imidazo[ 1,2-a]pyridin -3-yl]-phenyl} -acetamide hydro-chloride salt ^43⁄4 i'll ti pi rj . Ri 〇° 〇&gt; rT K/V )~A_/ZV WVz CO 寸 ΙΟ VO m 200836725 MS: [M+H]+ 329 MS: [M+H]+ 346 MS: [M+H]+ 358 1H NMR (400 MHz, Me-d3-OD): 8.75-8.64 (3H, m), 8.09 (1 H, s), 8.01 (1H, t), 7.93-7.85 (2H, m), 7.82 (1H, s ), 7.62-7.53 (2H, m), 7.50-7.39 (2H, m), 2.19 (3H, s). 1H NMR (400 MHz, Me-d^OD): 8.64 (1H, d), 7.99 (1H ,t), 7.88-7.79 (3H, m), 7.75 (1H, s), 7.59 (1H,d), 7.54 (1H,t), 7.42 (1H, d), 7.35 (1H, dd), 7.31- 7.21 (2H, m), 2.19 (3H, s). 1H NMR (400 MHz, Me-c/3-〇D): 8.63 (1H,d), 8.28-8.16 (1H, m), 7.99 (1H, t), 7.89 (1H, s), 7.84-7.73 (2H, m), 7.69 (1H, d), 7.58 (1H, d), 7.56-7.48 (2H, m), 7.42 (3H, dd), 4.73 (2H, s), 2.19 (3H, s). Λ 4 (l/ tO 举罗阳&lt;&lt;Νλ 彐4地1 domain 2 ά ^ ^ Φν ϊ ιΛ ^ -^ &lt;Ν &lt; ^ ^ V ^ I meal C base tO ^ BP &lt;&lt;3 Λ W硪鳊 drive 4 1 meal Tuo tO every time: J 辕:S Η -4^ &amp;- 萆面d I meal K N-[3-( 7-Pyridin-4-yl-imidazole [1,2-&amp;]0-indol-3-yl)-phenyl]-acetamidamine (N-[3-(7-Pyridin-4-yl-imidaz 〇) [1,2-a]pyridin-3-yl)-phenyl] -acetamide) N-{3-[7-(4-fluoro-phenyl)-mi-[1,2-&amp;]° ratio ^^-3-yl]-phenyl}-acetamidamine (N- {3- [7-(4-Fluoro-phenyl)-i midazo[ 1,2-a]pyridin-3-yl]-p henyl} -acetamide) N-{3-[7-(3-hydroxyindolyl-phenyl) )-M. 0 sits [1,2-&]11 than indole-3-yl]-phenyl}-acetamidamine (N- {3-[7-(3-Hydroxymethyl-phenyl)-imidazo[ 1, 2-a]pyridi n-3-yl]-phenyl}-acetamide) CD 00 200836725 MS: [M+H]+ 427 MS: [M+H]+ 427 MS: [M+H]+ 386 1H NMR (400 MHz, Me-c/3-〇D): 8.64 (1H,d), 7.99 (1H,t),7.88 (1H,s), 7.80 (1H, s), 7.74 (1H,s), 7.72 (1H, d), 7.59 (1H, d), 7.57-7.47 (2H, m), 7.43 (2H, t), 7.38 (1H, dd), 3.73 (4H, t), 3.65 (2H, s), 2.54 (4H, t), 2.19 (3H, s). 1H NMR (400 MHz, Me-c/3-OD): 8.89 (1H,d), 8.27 (1H, s), 8.24 (2H, s), 8.08 (2H, d), 7.90 (1H, dd), 7.83 (2H, d), 7.67-7.56 (2H, m), 7.54-7.46 (1H, m), 4.51 (2H, s), 4.08 (2H, Br s), 3.83 (2H, br s), 3.43 (4H, br s), 2.20 (3H, s). 1H NMR (400 MHz, Me-Gf3-OD): 8.65 (1H,d),7_99(1H , t), 7.90 (1H, s), 7.80-7.66 (3H, m), 7.60 (1H, d), 7.56-7.48 (2H, m), 7.47-7.35 (3H, m), 3.74 (2H, s), 2.19 (3H, s). 3 r $4 私更 w ^ -砩寸Λ ^ l膳c难tO ^ s\ ώ ^ ^ toi? ^ c gs in i &lt;蚪;f gallium 4 . 1 meal c a few tO ^ M +4 v ^ l li E # J21 tft- 1 . 1 〇 ' lit ^ls£l| : 3⁄4 砩έ 砩έ g Jin 苜Ν-{3-[7-(4-? Phenyl-4-ylmethyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenylethylidene hydrochloride (N- {3-[7-(4-Morpholin- 4-yl methyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -acet amide hydro-chloride salt) {3-[3-(3-Ethylamino-phenyl)- ϋ ϋ [l,2-a]0 than 唆~7-yl]-phenyl}-acetic acid ({3-[3-(3-Acetylamino-phen yl)-imidazo[ 1,2-a]pyridin- 7-yl]-phenyl}-acetic acid) 〇o 200836725

MS: [M+H]+ 382 MS: [M+H]+ 375 MS: [M+H]+ 362 MS: [Μ+Η]+ 375 &amp; Parts 9 J S-ίΤ- ω χ ^ χ X Eco χ |〇6^ n:co ^ x* ν! X ^ 2 T- r- CD _Γ ^SS2&amp; 1H NMR (400 MHz, Me-cf3-〇D): 8.63 (1H, d), 8.21 (0.5H, s), 7.86-7.70 (5H, m), 7.52-7.40 (2H, m), 7.38-7.19 (4H, m), 3.07 (6H, s)· 1H NMR (400 MHz, DMSO-d6 ): 9.97 (1H, s), 8.80 (1H, d), 8.15 (2H, d), 8.00 (3H, dd), 7.89 (1H, d), 7.76-7.67 (1H, m), 7.57 (1 H, t), 7.49-7.37 (4H, m), 4.05 (2H, s)· 1Η NMR (400 MHz, Me-cf3-〇D): 8.59 (1Η, d), 8.24 (0.5Η, s), 7.88-7.68 (5Η, m), 7.43 (1H,t), 7.38-7.17 (5H, m), 3.27 (2H, q), 1.18 (3H,t). 4 Gallium 1 ts 11 ffl f Js w硪誊Exhaustion: 窠蚪Cd to 1 issi S κ 5 _ , I 12 |g|S| lUtl i 11 Aluminium 砩K Cd .gl ^ E 3 5|l « ® ^ tf stomach ' private ^ ψ rA aluminum 碥κ il蚪 per £ ^ pq ^ : remainder $' this obv beer ^ ^ i)© s«|S ^ f cA 5 aluminum 硪C Cd N-{3-[7-(4_fluoro-phenyl)-imidazole [1,2-&]0 is more than -3-yl]-phenyl}-methanesulfonate (N- {3-[7-(4-Fluoro-phenyl)-i midazof 1,2- a]pyridin-3-yl]-p henyl} -met Hanesulfonamide formate salt) 3-{3-[7-(4-fluoro-phenyl)-imiphthene[1,2-a] 0-bite-3-yl]phenyl}-1,1-dimethyl- Urea formic acid (3-{3-[7-(4-Fluoro-phenyl)-i midazo[ 1,2-a]pyridin-3-yl]-p henyl} -1,1 -dimethyl-urea formate salt) .X Ϊ Ϊ 云 云 · 自 f ^ 名今 1 〇-|g imi! 〇| ^ Ifl 9 π 士 B 舌 5 Mei 3 砩 9 ^ Li. 0 :f Q Ί CVJ &lt;ζ&gt; ΙΟ MS : [Μ+ΗΓ 362 MS: [M+H]+ 411 MS: [M+H]+ 332 MS: [M+H]+ 456 1H NMR (400 MHz, Me-c/3-〇D): 8.58 (1H, d), 8.19 (1H, s), 7.88-7.69 (5H, m), 7.47 (2H, d), 7.42-7.17 (4H, m), 3.78 (3H, s). 1H NMR (400 MHz , Me-d3-〇D): 8.59 (1H, d), 8.15 (1H, s), 7.93-7.74 (4H, m), 7.58-7.47 (2H, m), 7.45-7.20 (5H, m), 2.85 (6H, s)· 1H NMR (400 MHz, Me-c/3-OD): 8.59 (1H, d), 7.88-7.76 (3H, m), 7.73-7.63 (1H, m), 7.39-7.20 (4H, m), 6.92-6.82 (2H, m), 6.76 (1H, dd), 3.20 (2H, q), 1.34-1.19 (3H, m). 1H NMR (400 MHz, Me-d3-OD) : 8.67 (1H, d), 8.33 (1H, s), 7.92-7.80 (3H, m), 7.75 (2Hf t), 7.57-7-34 (5H, m), 7.29(1 H,d), 3.81 -3.71 (6H, m), 3.28 (2H, q), 2.64 (4H , d), 1.19 (3H,t). κ 5 ^ s OT n ^ VET s « 录-ft 曹 m S ^ 〇蕻^ HE趑〇l蚪 every 2 even" 2 volumes · lm ffl ^ ^ ψ W Haha Office «1 ^ ψ cA Aluminum 碥 ee 1 2 2 PQ ® ^ Age 5 stomach - L ^ m 毽 pigeon ^ f cA 碥 \ \ \ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ - + 许cd g '早呤£给一个m ^ ^ ^ 1 ^ ^ S f ^ ^ ^ 荽m毽tO 1 4 #录琴潜{3-[7-(4-气-phenyl)-咪嗤[1,2-3^~β-3-yl]-phenyl}-carbamoic acid methyl ester formate ({3-[7-(4-Fluoro-phenyl)-imi dazo[ 1,2 -a]pyridin-3-yl]-phe nyl}-carbamic acid methyl ester formate salt) 1,1-dimethyl-3-{3-[7-(4-fluoro-phenyl)-flavored saliva [1 ,2-a] ° than 唆-3-yl]-phenyl hydrazide 醯 醯 urea salt (1,1 -dimethyl-3- {3-[7-(4-flu oro-phenyl)-imidazo[ 1 ,2-a]p yridin-3-yl]-phenyl} -sulfony lurea formate salt) Ethyl-{3-[7-(4-gas-phenyl)-mouth rice saliva^^-^^ than 唆- ^-Butyl-phenyl}-amine formate (Ethyl-{3-[7-(4-fluoro-pheny l)-imidazo[ 1,2-a]pyridin-3-yl ]-phenyl}-amine formate Salt) 1-ethyl-3-{3-[7-(3-oxalin-4-ylmethyl-phenyl)-flavor 0 sitting [1,2-&amp;]0-pyridin-3-yl] -phenyl}-urea Acidate (1-Ethyl-3-{3-[7-(3-morphol in-4-ylmethyl-phenyl)-imida zo[ 1,2-a]pyridin-3-yl]-pheny 1}-urea formate Salt) xy^z u. fp P (D 00 σ > 200836725 MS: [Μ+Η]+ 329 MS: [M+H]+ 355 MS: [M+H]+ 360 MS: [M+H] + 346 900 .χ f^EJ ixx^. • v- to 卜|$t iiSsS i od 卜·1H NMR (400 MHz, Me-rf3-〇D): 8.65 (1H,d), 8.35 (1H,d ), 8.05 (1H, t), 7.88-7.74 (6H, m), 7.74-7.68 (1H, m), 7.62 (1H, d), 7.34 (1H, dd), 7.28-7.20 (2H, m), 6.58 (1H, t). 1H NMR (400 MHz, Me-c/3-〇D): 8.59 (1H,d), 8.17 (1H, s), 7.90-7.72 (4H, m), 7.70-7.51 ( 3H, m), 7.49-7.33 (2H, m), 7.26 (2H, t), 4.48 (2H, s), 2.03 (3H, s). 1H NMR (400 MHz, Me-cfa-OD): 8.61 ( 1H, d), 8.18(0.5H, s), 8.09 (1H, s), 7.90 (1H,d), 7.87-7.74 (5H, m), 7.67 (1H, t), 7.34 (1H, d), 7.25 (2H, t), 2.98 (3H, s). ss ^ 黢余¥ 靖毽ψ twa +硪— ®(10) ^ ^ &quot;Σ a 4 m 1 Κ S S S &amp;·蝣m ffl BS iw^ + ^ — 5 ® ^ S Μ ί } f 驾 4 5 ώ lc 余午工cd '械 S w ^ Ψ ^ • ^ private oi? ^ ^ 茫f 4 4- 4 C PQ $4 ^ 窠 4 times I i ^ # 5 Every φ\办cd &quot; m « m ^ 余镓鸽 ^ • ^ ^ Qt s^is 5-[7-(4-fluoro-phenyl)-carboxazole [l,2-a]pyridine each]]- 1H-carbazole (5-[7-(4-Fluoro-phenyl)-imid azo [ 1,2-a]pyridin-3 -yl] -1 Hi ndazole) 7-(4-say-phenyl)-3 -(3-σΛσ sitting-1-yl-phenyl)-imidazole [l,2-a]pyridinium (7-(4-Fluoro-phenyl)-3-(3-py razol-1 -yl-phenyl) -imidazo[ 1 ,2-a]pyridine) 丄χ^? f fr- ^ g «a ^;ii '今B弓晋1 ΦΙΪίέΙ $令铯3 g 士έ dt〇έ a I s 3 g ^ il. # % ^ cn JSSIfl lHll U. $ py^zc ^ . Seven ^ i inch ε 200836725

MS: [M+H]+ 463 MS: [M+H] + 328 MS: [M+H]+ 470 1H NMR (400 MHz, Me-c/3-OD): 8.62 (1H, d), 7.89 (1H, s), 7.84-7.68 (3H, m), 7.62-7.54 (2H, m), 7.54-7.42 (3H, m), 7.42-7.33 (2H, m), 3.73 (4H, t), 3.65 (2H, s), 3.07 (3H, s), 2.54 (4H, t). 1H NMR (400 MHz, Me-of3-OD): 8.55 (1H, d), 7.86-7.72 (4H, m), 7.72 -7.56 (3H, m), 7.50 (1Hfd), 7.35-7.19 (3H, m), 4.04 (2H, s). 1H NMR (400 MHz, DMSO-c/6): 10.26 (1H, s), 8.68 (1H, d), 8.12 (1H, s), 8.07 (2H, brs), 7.99 (1H, s), 7.87 (1H, s), 7.83 (1H, s), 7.81-7.72 (2H, m), 7.54-7.43 (2H, m), 7.43-7.34 (2H, m), 3.66-3.54 (6H, m), 2.47-2.36 (4H, m), 2.11 (3H, s). * ^ K ί ^ ^ S Hey! ;趑5 « &lt; ^ ^ fl 4 灭余琴一 a ^ ^ 11^ • 6- ^ ^ pq(9) tight 1 c黢毽 each umbrella sf general formula H; steps HI, H2 and H3 N-{3-[ 7-(3-morpholin-4-ylindenyl-phenyl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-indolesulfonamide (N- {3-[7- (3-Morpholin-4-yl methyl-phenyl)-imidazo [1,2-a]pyridin-3-yl]-phenyl}-met hanesulfonamide) {3-[7-(4-fluoro-phenyl)-flavor [l,2-a]indol-3-yl]-phenyl}-acetonitrile ({3-[7-(4-Fluoro-phenyl)-imi dazo [ 1,2-a]pyridin-3 -yl ] -phe nyl}-acetonitrile) 4 ^ S ·ν 殳ΐ ? f ^ Σ1 ά v V ^ g S ^ ^ ^ J ά 11 o ¢- ^ &lt;: 〇11 cn ^ ^ C,p, 6 1 P 0 〇Uo 0 (f , 么 \ z / Vv ^xy^z 2^^XO 200836725 Γ

MS: [Μ+ΗΓ 440 MS: [M+H]+ 452 MS: [M+H]+ 485 1 NMR (400 MHz, Me-c/3-〇D): 8.63 (1Η, d), 7.98 ( 1H, s), 7.87 (1H, s), 7.78 (1 H, s), 7.73 (1 H, s), 7.70 (1H, d), 7.58 (1H, d), 7.56-7.46 (2H, m) , 7.45-7.39 (2H, m), 7.36 (1H, dd), 3.66 (2H, s), 2.57 (8H, brs), 2.32 (3H, s), 2.19 (3H, s). 1H NMR (400 MHz , DMSO-d6): 10.45 (1H, s), 8.71 (1H, d), 8.12 (1H, t), 8.08 (1H, t), 8.01 (1H, brs), 7.94 (1H, s), 7.88 ( 1H,t), 7.82-7.72 (2H, m), 7.49 (1H,t), 7.44-7.35 (2H, m), 3.67-3.54 (6H, m), 2.47-2.36 (4H, m), 2.13 ( 3H, s)· 1H NMR (400 MHz, Me-cf3-〇D): 8.76 (1H, d), 7.89 (1H, d), 7.85 (1H, s), 7.77 (1H, s), 7.74 (1H ,s), 7.70 (1H, d), 7.60-7.38 (4H, m), 7.34 (2H, dd), 3.66 (4H, m), 2.63 (8H, s), 2.38 (3H, s), 1.25 ( 3H, t). cs ^ ;婳s ^ CO PQ cd l轵琴口 A Sis 轵祀酴a ¥ S Distillation Fermentation Thickness I s Driving&lt;I遛2Building t〇5璁毽PQ毽毽爸爸私埒Κ g -硪趑·2 PQ ^ cs .2 aluminum se roll: Meng 趑 趑 N-(3-{7-[3-(4-methyl-piperazin-1-ylindenyl)-phenyl ]-Imidazole [l,2-a] σΛσ-3-yl}-phenyl)-ethinamine (N- (3-{7-[3-(4-Methyl-piper azin-1 -ylmethyl)-phenyl]-im idazo[ 1,2-a]pyridin-3-yl} -ph enyl)-acetamide) N-{ 3-cyano-5-[7-(3-morpholin-4-ylindenyl-phenyl)-imidazole [l,2-a] hydroxypyrimidin-3-yl]-phenyl}-ethylamine (N- {3-Cyano-5-[7-(3-morph olin-4-ylmethyl-phenyl)-imi dazo[ 1,2-a]pyridin-3-yl]-phe nyl}-acetamide) N- [3-(7-Acridine-4-yl-imidazole [l,2-a]° ratio -3-yl)-phenyl]-acetamide (N-[3-(7-Pyridin-4-) Yl-imidaz 〇[ 1,2-a]pyridin-3-yl)-phenyl] -acetamide) (f. 〇〆 \ ( CNJ 83 200836725 %f / / rtv

MS: [M+H]+ 442 MS: [M+H] + 541 MS: [M+H]+ 401 1HNMR (400 MHz,Me-d3-OD): 8.60 (1H, d), 7.83 (1H, t ), 7.78 (1H, s), 7.75-7.65 (3H, m), 7.46 (1H, t), 7.43-7.31 (2H, m), 7.28 (1H, d), 7.11 (2H, d), 3.88 ( 4H, t), 3.31-3.24 (6H, m), 1.19(3H, t). 1H NMR (400 MHz, Me-d3-〇D): 8.60 (1H, d), 7.83 (1H, t), 7.77 (1H, s), 7.76-7.63 (3H, m), 7.46 7.40-7.31 (2H, m), 7.27 (1H, d), 7.12 (2H, d), 3.67-3.56 (4H, m), 3.30- 3.21 (6H, m), 1.51 (9H, s), 1.19 (3H, t). • · ^ -r Specialist inch - 〇^CO S-DO&gt; 0)^:^ Z 7 τΓ Bu rc〇^ ^ ^ ^ &lt; ^ ^ ^ Ha 1 province minus 22 E-- g • 5苎v win, c stroll ^ K-character ^ ^ ^ 4 , 1 1 yeast 窠 h U, , ^ fTT&gt; t S? oJ $ 1 gallium driving 1-ethyl-3· {3-[7-(4-morpholin-4-yl-phenyl)-imidazole [1,2-*pyridin-3-yl]-phenyl} -urea hydrochloride (l-Ethyl-3-{3-[7-(4-morphol in-4-yl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -urea Hydro-chloride salt 4-(4-{3-[3-(3-ethyl-glycol)-phenyl]-imidazo[1,2-a]acridin-7-yl}-phenyl)-peri 4-(4-{3-[3-(3-Ethyl-ureido)-phenyl]-imidazo[1] ,2-a]pyridi n-7-yl}-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester) 4- {3-[3-(3-ethyl- phenylphenyl)-imidazole [1, 2-a] ton pyridine-7-yl}-benzoic acid (4- {3-[3-(3-Ethyl-ureido)-ph enyl]-imidazo[ 1,2-a]pyridin-7-yl} -benzoic acid) i〇„0° VcT L·, i/. CO 寸 ε MS: [M+H]+ 414 MS: [M+H]+ 444 1 MS: [M+H]+ 454 MS: [M+H]+ 470 1H NMR (400 MHz, Me-d3- OD): 8.69 (1H, d), 8.17 (2H, d), 7.96 (1H, s), 7.91 (2H, d), 7.85 (1H, s), 7.77 (1H, s), 7.48 (1H, t ), 7.43 (1H, dd), 7.39 (1H, d), 7.30 (1H, d), 3.28 (2H,q), 1.19 (3H, t) 1H NMR (400 MHz, Me-rf3-OD): 8.66 (1H,d), 7.87(1 H,s), 7.86-7.83 (1H, m), 7.81 (4H, s), 7.75 (1H,s), 7.47 (1H,t), 7.41 (1H,dd) , 7.37 (1H, d), 7.29 (1H, d), 4.09 (2H, s), 3.53 (3H, s), 3.27 (2H, q), 1.19(3H, t). 1 1H NMR (400 MHz, Me-c/3-OD): 8.66 (1 H,d), 7.88 (1 H,s),7_84 (1H,s), 7.79 (1H,s), 7.73 (2H, d), 7.55-7.34 ( 5H, m), 7.29 (1H,d), 3.64 (2H, s), 3.28 (2H, q), 2.52 (4H, brs), 1.70-1.61 (4H, m), 1.52 (2H, brs), 1.19 (3H, t). 1H NMR (400 MHz, Me-^-OD): 8.68 (1H, d), 7.93 (2H, d), 7.89-7.81 (2H, m), 7.76 (1 H, s), 7.65 (1H,t), 7.55-7.49 (1H, m), 7.47 (1H, d), 7.43-7.33 (2H, m), 7.30 (1H, d), 3.71 (8H, d), 3.27 (2H, q), 1.19(3H, t). I (4) if谰jK cn υπι in rrt VEI ^ fX, } 驾 driving c 参 g潜1 more aluminum af I &lt;N +4 , Λ or? cti— 1 f_g &lt; ^ s 4 μ I driving &lt;1 to q 1 lt ^ Ί private I ^ ^ g ^ » 2 f I r &lt;叽5德.^ ^ i-4 &lt; ^ E... W exhausted: 礒^ &amp;-1 gallium slave I ^ iift .Kef &lt; ^ ^ ^ c 1 黢琴蜇l-{3-[7-(3-dimethylaminomethyl-benzene嗤米嗤[l,2-a]n比唆_3_基]phenyl}-3-ethyl-脉(1 - {3-[7-(3-Dimethylamino methyl-phenyl)-imidazo[ 1,2 -a]pyridin-3-yl]-phenyl} -3-et hyl-urea) ^«ιΐΊι _ 议安越|!| 宁窆荅? II! U Ip 3^1121 ::L/ \ .彳t/ 〇.〇200836725 MS: [Μ+ΗΓ 366 MS: [M+H]+ 425 MS: [M+H]+ 457 1H NMR (400 MHz, Me-of3-〇D): 8.39 (1H, d), 7.75 (1H, t), 7.51-7.37 (2H, m), 7.35-7.26 (1H, m), 7.21 (1H, d), 6.92 (1H, dd), 6.78 (1H, d), 3.88 (4H, t), 3.31 (4H, t), 3.26 (2H, q), 1.18 (3H,t). SS .ί 巧 δ 1 'r' itb-work t !讥1 2 E 03⁄4 od od N- 1H NMR (400 MHz, Me-of3-〇D): 8.65 (1H, d), 7.89-7.81 (2H, m), 7.77 (2H, d), 7.72 (1H, s), 7.55-7.42 ( 3H, m), 7.41-7.33 (2H, m), 7.29 (1H,d), 3.70 (3H, s), 3.27 (2H,q), 1.64 (6H, s), 1.19 (3H, t). ' λ @2 — ί &lt; to s • BE cd &lt; ί ^ E 1 t driving ^ 1 ^|5I ^ $4 ^ ^ 淞a T a ^ ^ c3 Jj c I 丨t driving A ^ ' &lt;N $4 $奋 5硪? &lt; S Gallium A襃® Record ¥ 4-:3⁄4二^ K «5 w Μ 6- nl ^ c ^ ^ rn ^ I黢驾&&quot; V硪1-ethyl-3-[3-(7 - 惊吓^-4-基_ 口米°Sitting [1,2-3&gt;]|1 to 11--3-yl^)-phenyl]-urea (1 -Ethyl-3 - [ 3 -(7 -morpholin-4-yl-imidazo[ 1,2-a]pyridin_3 -yl)-phenyl] -urea) 1 -ethyl-3-(3- {7-[3-(1Η-tetrazole•5-yl) )·Phenyl]-imidazole [l,2-a] phenanthrenyl}-phenyl)-urea formate (1 -Ethyl-3-(3- {7-[3-(lH-tetr azol) -5-yl)-phenyl]-imidazo[ 1 ,2-a]pyridin-3-yl} -phenyl)-ur ea formate salt) 2-(4-{3-[3-(3-ethyl-mai) )-phenyl]-imidazole [l,2-a]acridin-7-yl}-phenyl)-2-indolyl-propionic acid methyl ester (2-(4- {3-[3-(3) -Ethyl-ureido)« phenyl] -imidazo [ 1 ?2-a]pyridi n-7-yl} -phenyl)-2-methyl-pr opionic acid methyl ester) o )=° xb^? c〇200836725 Ο

MS: [Μ+Η]+ 440 MS: [M+H]+ 415 MS: [M+H]+ 400 ΊΗ NMR (400 MHz, Me-dr〇D): 8.64 (d, J = 7.3 Hz, 1H ), 7.89-7.85 (m, 1H), 7.83 (t, J = 2.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.72 (s, 1H), 7.51 (d, J = 7.8 Hz) , 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.5, 2.1 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 3.73 (s, 2H), 3.27 (q, J = 7.3 Hz, 2H), 2.69-2.56 (m, 4H), 1.92-1.80 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H). 1H NMR (400 MHz, Me-c /3-OD): 8.66 (1H, d), 8.38 (1H, s), 8.15 (2H, d), 7.98-7.87 (3H, m), 7.84 7.76 (1H, s), 7.46 (1H, t) , 7.42-7.32 (2H, m), 7.28 (1H, d), 3.96 (3H, s), 3.27 (2H, q), 1.19 PH, t). 1H NMR (400 MHz, Me-c/3-OD ): 8.55 (1H,d), 7.75 (2H, s), 7.62 (1H,s), 7.56 (2H,d), 7.41-7.33 (2H, m), 7.33-7.14 (4H, m), 3.17 ( 2H, q), 2.92 (2H, t), 2.82 (2H, t), 1.08 (3H, t). Φν l φ ^ ^ ^ ^ ^ 5 ^ •昍&amp; ¢- &lt;汔桊 domain^ I 4 , in frr&gt; -^ CJ $1^1 &lt;i ^ S aluminum &lt; alkali 1 gallium aluminum I rn - mechanical J ', yang Cd _ E drive &lt; 汔桊 &amp;&gt; 1 窠C umbrella office 1 · 1 gallium drive feed 1-ethyl-3-{3-[7 -(4-pyrrolidin-1-ylindenyl-phenyl)-anthracene [1,2-3^ than -3-yl]-phenyl}-pulse (1-Ethyl-3- {3- [7-(4-pyrrolidi η-1 -ylmethyl-phenyl)-imidaz 〇[ 1,2-a]pyridin-3-yl]-phenyl }-urea) 4-{3-[3-(3-ethyl -pulse)-phenyl]*imidazole [l,2-a]吼唆-7-yl}- benzoic acid methyl ester formate (4- {3-[3-(3-Ethyl-ureido)-ph Enyl]-imidazo[ 1,2-a]pyridin-7-yl}-benzoic acid methyl ester formate salt) til ^ ^ ^ d ή 4 g cA ϋ tO £2, S λ Si... i/ IZi〇^ o 5 200836725 Ο

MS: [M+H]+ 388 MS: [M+H]+ 429 MS: [M+H]+ 388 1H NMR (400 MHz, Me-d3-〇D): 8.66 (1H, d), 8.58 ( 1H, d), 8.12 (1H, dd), 7_84(2H, s), 7.73(1 H, s), 7.47 (1H, t), 7.41-7.31 (2H, m), 7.29 (1H, d), 6.96 (1H, d), 4.00 (3H, s), 3.28 (2H, q), 1.19 (3H, t). 1H NMR (400 MHz, Me-d3-OD): 8.68 (1H, d), 8.16 ( 2H, d), 7.96 (1H, s), 7.90 (2H, d), 7.84 (1H, t), 7.77 (1H, s), 7.47 (1H, t), 7.43 (1H, dd), 7.41-7.34 (1H, m), 7.30 (1H,d), 3.24 (2H,t), 1.61-1.50 (2H, m), 1.50-1.37 (2H, m), 0.99 G3H, t)· 1H NMR (400 MHz, Me-c/3-〇D): 8.69 (1H, d), 8.27 (1H, d), 8.01 (1H, s), 7.86 (1H, t), 7.79 (1H, s), 7.48 (1H, t ), 7.44-7.34 (3H, m), 7.29 (1H, d), 7.22 (1H, s), 4.00 (3H, s), 3.27 (2H, q), 1.19 (3H,t). I (N $ Is ^ K c3 &lt;: from S wrong &lt; 6-1 gamma Μ ^ ^ 4 Λ L κ κ &lt; | 趑 ill 4 f1 (four) to n ^ ^ ^ δ: 1 aluminum c &lt; ^ t硪1 11峨.§靛电IA collapse&lt; 1 f .BE λ 4 &lt;!E per drive&lt;ί给¢-\ Λ 1-ethyl-3-(3-{7-[3-(1Η -tetrazol-5-yl)-phenyl]-imidazole [l,2-a] than 0-but-3-yl}-phenyl)-carboxylate (l- Ethyl-3-(3-{7-[3-(lH-tetr azol-5-yl)-phenyl]-imidazo[ 1 ,2-a]pyridin-3 -yl} -phenyl)-ur ea formate salt) 4-{3-[3-(3-Butyl-urea)-phenyl]-imidazo[1,2-a]acridin-7-yl}-benzoic acid (4- {3-[3-(3- Butyl-ureido)-ph enyl] -imidazo [ 1,2-a]pyridin-7-yl}-benzoic acid) Μ ^ $ 碥1呤t:|li/ i / xzt〇5 ΙΟ 200836725

MS: [Μ+ΗΓ 374 MS: [M+H]+ 379 MS: [M+H]+ 301 1 NMR (400 MHz, Me-Gf3-〇D): 8.93 (1H,d), 8.28 (2H, d), 8.05 (1H, t), 7.83 (1H, dd), 7.70 (1H, d), 7.57 (1H, t), 7.41 (1H, dd), 7.36 (1H, d), 7.04 (1H, d ), 6.91 (1H, dd), 3.28 (2H, q), 1.19 (3H, t). 1H NMR (400 MHz, Me-of3-OD): 8.44 (2H,d), 7.87 (1H,t), 7.67 (1H, s), 7.46 (1H, t), 7.34 (1H, dd), 7.23 (1H, d), 7.15 (1H, dd), 6.90 (1H, d), 3.58 (4H, t), 3.26 (2H, q), 2.83 (4H, t), 2.52 (3H, s), 1.18 (3H, t). 1H NMR (400 MHz, DMSO-cf6): 8.70 (1H, s), 8.55 (1H, d ), 7.83 (1H, d), 7.81-7.70 (2H, m), 7.42 (2H, d), 7.17 (1H, dt), 7.05 (1H, dd), 6.10 (1H, q), 2.66 (3H, d). Electric IA music '二疋驾2鲁i every i-K cd &lt; ^ aluminum&lt;; give ¢- Q 1 gallium exhaust: Shu l 2 · · _ fu, ^ J -K cd &lt; ^ IZ 51 Record 51 s 1-ethyl-3-{3-[7-(2-oxy-1,2_二戴τσ ratio -4- base)-ν米σ sit [1,2-a]ϋ唆-3-yl]-phenyl}-pulse (1 -Ethyl-3-{3-[7-(2-oxo-1,2-dihydro-pyridin-4-yl)-imidaz 〇[ 1,2 -a]pyridin-3-yl]-phenyl }-urea) 1-ethyl_3-{3-[7-(4-indolyl σ-Q- 1 -yl)- miso [1,2-a]0 is more than 唆-3-yl]-phenyl}-carbamate (1 -Ethyl-3-{3-[7-(4-methyl-p iperazin-1 -yl)- Imidazo [ 1,2-a] pyridin-3-yl] - phenyl} -urea formate salt) l-[3-(7-chloro-imidazo[l,2-a]acridin-3-yl)-phenyl ]-3-methyl-pulse (1 -[3-(7-Chloro-imidazo[ 1,2-a]pyridin-3 -yl)-phenyl] -3 -me thyl-urea) W7 seven v&lt;? &gt ;° 0 xy^z (D N. σ\ MS: [Μ+ΗΓ 379 MS: [M+H]+ 361 MS: [M+H]+ 373 1H NMR (400 MHz, DMSO-c/6): 8.71-8.63 (2H, m), 8.57 (1H, d), 8.18 (1H, s), 8.09 (1H, dd), 7.95 (1H, s), 7.80 (1H, s), 7.77-7.70 (1H, m), 7.45-7.33 (3H, m), 7.24-7.15 (1H, m), 6.97 (1H, d), 6.24 (1H, t), 3.73 (4H, t), 3.55 (4H, t), 3.18 -3.08 (2H, m), 1.07 (3H, t). 1H NMR (400 MHz, DMSO-d6): 8.74 (1H, s), 8.62 (1H, d), 8.17 (1H, s), 7.99 (1) H, s), 7.96-7.87 (2H, m), 7.85-7.74 (2H, m), 7.46-7.29 (5H, m), 7.25-7.16 (1H, m), 6.13 (1H,q), 2.67 ( 3H, d). 1H NMR (400 MHz, Me-d3-〇D): 8.91 (1H, d), 8.57-8.47 (2H, m), 8.29 (1H, s), 8.24 (1H, s), 8.06 (1H,t), 7.84(1H,dd), 7.56 (1H, t), 7.44-7.38 (1H,m), 7.35 (1H,d), 7.26 (1H, d), 3 .28 (2H, q), 1.19 (3H, t). ^ r^l X ^ 1 ^ ^ ^ ^ 5 5 -Γ &lt;N ^ Ψ ^ .C cd &lt;E 3姣1 Lifting the private s\ record - the potential of the tank is 7 tg哼荠蝣. Zhu Xi (7) "Yang Yang ^ 燧 3 4 dances · every inch inch Λ惫 4 job test: ^ ί1^ 1 # t-? Ω private I 4丨j age ^ 1 ^ ί t ^ 5 ^ ^ w &lt; t ^ ^ cd ^ 1 黢 耩 耩; ^ 1-ethyl-3^3-[7-(6^马 啉-4-yl-〇 咬 bite) 3-base ^)- 〇 〇 sit [1,2 -3·] pyridin-3-yl]-phenyl}-carbamate (l-Ethyl-3-{3-[7-(6-morphol in-4-yl-pyridin-3 -yl)-imidaz 〇[ 1 ?2-a]pyridin-3-yl]-phenyl }-urea formate salt) 1 - {3-[7-(4-Fluoro-phenyl)-Minami [l,2-a]吼Pyridin-3-yl]-phenyl}-3-methyl-urea citrate (1- {3-[7-(4-Fluoro-phenyl)-i midazo [ 1,2-a]pyridin-3 - Yl] -ρ henyl} -3 -methyl-urea formate salt) 1 1-{3-[7-(6-gas-porto-but-3-yl)_imidazole[1,2-a]acridine -3 -yl]-phenyl}-3-ethyl-urea hydrochloride (1 - {3-[7-(6-Amino-pyridin-3 -yl)-imidazo[ 1,2-a]pyridin- 3-yl]-phenyl} -3-ethyl-urea hydro-chloride salt) x 〇ir^ xy^zi/ s 200836725 MS: [Μ+ΗΓ 540 MS: [M+H]+ 396 MS: [M+H ] + 407 1H NMR (400 MHz, Me-d3-〇D): 8.65 (1H, d), 7.89-7.81 (2H, m), 7.80-7.69 (3H, m), 7.48 (3H, t), 7.42 -7.33 (2H, m), 7.29 (1H, d), 4.21- 4.09 (2H, m), 3.63 (1H, d), 3.47 (1H, d), 3.27 (2H, q), 3.09 (1H, d), 2.78-2.70 (1H, m), 2.21- 2.06 (2H, m), 1.94 (1H, d ), 1.83-1.74 (1H, m), 1.67-1.60 (1H, m), 1.25-1.17 (6H, m), 1.13 (3H, s)· _ 1H NMR (400 MHz, Me-c/3-OD ): 8.40 (1H, d), 7.77 (1H, d), 7.51 (1H, s), 7.48-7.16 (3H, m), 6.97 (1H, dd), 6.80 (1H, d), 4.08 (1H, Dd), 3.86-3.60 (6H, m), 3.26 (2H, q), 3.02-2.89 (1H, m), 2.79-2.66 (1H, m), 1.18 (3H, t). 1H NMR (400 MHz, Me-of3-〇D): 8.38 (1H,d), 7.76 (1H,t), 7.48 (1H, s), 7.41 7.34-7.25 (1H, m), 7.19 (1H,d), 6.91 (1H, d), 6.78 (1H, s), 3.84-3.68 (4H, m), 3.46-3.36 (2H, m), 3.36-3.34 (2H, m), 3.26 (2H, q), 2.18 (3H, s) , 1.18 (3H, t). Haia do 2 ^ 1 ^ S β ^ K Λ S * Λ I 1 t ^ Ha l _ 2 ^ &lt; Exhaustion: SI gallium driving electricity l two r 'BE c ^ J ^ 轵(7)T · ^ W. α φ ^ E . Lu 1黢 n3 l-(4-{3-[3-(3-ethyl-puls)-phenyl]-imidazole [1,2-a]吼Acridine_7_yl}-benzyl)-3-methyl-negative-3-carboxylic acid ethyl ester (l-(4-{3-[3-(3-Ethyl-ureido)-phenyl]-imidazo [ 1,2-a]pyridi n-7-yl} -benzyl)-3-methyl-pi peridine-3-carboxylic acid Ethyl ester) 1-ethyl-3-{3-[7-(2-methyl-methyl)--------------------------------------------------- -Phenylbuzone hydrochloride (1-Ethyl-3-{3-[7-(2-hydroxymethyl-morpholin-4_yl)-imid azo[ 1,2-a]pyridin-3-yl]-phen yl }-urea hydro-chloride salt 1-{3-[7-(6-alkyl-°bi- -3-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl }-3-ethyl-urea hydrochloride (l-{3-[7-(6-Amino-pyridin-3 -yl)-imidazo[ 1,2-a]pyridin-3-yl] -phenyl} - 3 -ethyl-urea hydro-chloride salt) i/ ) Bu. &quot;-Λ (five). I〇 S 5 200836725

MS: [M+H]+ 442 MS: [M+H]+ 470 1H NMR (400 MHz, Me-c/3-OD): 8.69-8.61 (2H, m), 8.46-8.39 (1H, m) , 8.09 (1H, dd), 7.88 (1H, t), 7.82 (1H, s), 7.73 (1H, s), 7.47 (1H, t), 7.38-7.26 (3H, m), 7.08 (1H, d ), 3.91 (3H, t), 3.27 (2H, q), 1.19 (3H, t). 1H NMR (400 MHz, Me_c/3-OD): 8.53 (1H, d), 7.72 (2H, s), 7.66-7.56 (3H, m), 7.35 (1H, t), 7.29 (2H, d), 7.24 (2H, dd), 7.17 (1H, d), 3.63 (4H, t), 3.15 (3H, q) , 2.84-2.76 (2H, m), 2.61-2.53 (2H, m), 2_48(4H,t),1.07(3H,t)·electric i # $ I -1 ? st &lt; ^ ^ ^ g 锲&lt Give A _ work l gallium aluminum 4 alkali 砩...胪π to ^ 5 4 &quot;f ^ ^ its - Residual electricity (7) Γ 2g - K «3 inch: take. ' ^ S ^ 窠 &lt; give ώ nickel work 1 t ^ 4 Μ ^ 1-ethyl-3-{3-[7-(6-Brigade-qin-1-yl-σ ratio β--3-yl)嗤米嗤[1,2-a] 比 -3--3-yl]-phenyl benzoate formate (1 -Ethyl-3- {3-[7-(6-piperazi η-1 -yl-pyridin -3-yl)-imidazo [1,2-a]pyridin-3-yl]-phenyl} -urea formate salt) 1-ethyl-3-(3-{7-[4-(2-morpholine- 4-yl-ethyl)-phenyl]-imidazole [1,2-a] 0-indol-3-yl}-phenyl)-hyperate hydrochloride (1-Ethyl-3-(3- {7- [4-(2-morp holin-4-yl-ethyl)-phenyl] -imi dazo[ 1,2-a]pyridin-3-yl} -phe nyl)-urea hydro-chloride salt) Β iB 200836725 MS: [M+H]+ 441 MS: [M+H]+ 441 MS: [M+H]+ 429 1H NMR (400 MHz, Me-d3-OD): 8.82 (1H, d), 8.12 (2H, d), 8.05 (1H, t), 7.91 (2H, d), 7.86 (1H, dd), 7.55 (1H, t), 7.42-7.30 (2H, m), 7.25 (2H, d) , 3.62 (4H, t), 3.43 (4H, t), 3.28 (2H, q), 1.19 (3H, t). 1H NMR (400 MHz, Me-c/3-〇D): 8.62 (1H,d ), 8.52 (1H, d), 7.97 (1H, dd), 7.83 (1 H, t), 7.77 (1 H, s), 7.69 (1H, s), 7.46 (1H, t), 7.40-7.24 ( 3H, m), 6.94 (1H, d), 3.70-3.61 (4H, m), 3.27 (2H, q), 1.79-1.63 (6H, m), 1.19 (3H, t) 1H NMR (400 MHz, DMSO-c/6): 8.97 (1H, s), 8.62 (1H, d), 7.99 (1H, brs), 7.96-7.87 (2H, m), 7.81-7.78 (2H, m), 7.47-7.44 (2H, m), 7.41-7.31 (3H, m), 7.31-7.23 (1H, m), 6.85 (1H,t), 4.01-3.89 (2H, m). Contains ·13⁄43⁄4宁^铋§卜办i Λ 5 5 V per C Hh 2L ^ ^ ^ ^ X Driving a few α ^ 1骖锘h Μ芊Q φν ii ^ IS | (4) Fen gallium &lt; ^ ε x residual aluminum &lt; Give 7. 1黢锘球送M cn Ph ^ ^ ^ κ 5 &lt; ^ ^ .. ^ ^ ^ ^ 锘A ^磕舞毽 I 3 ^ u! Fortunately 1-ethyl-3-{3-[7-( 4-α-Chenazine-1-yl-phenyl)-imidazole [l,2-a]npyridin-3-yl]-phenyl}-urea hydrochloride (1-Ethyl-3- {3-[ 7-(4-piperazi η-1 -yl-phenyl)-imidazo [ 1,2-a ]pyridin-3-yl]-phenyl} -urea hydro-chloride salt) 1-(4-{3-[3- (3-ethyl-pulp)-phenyl]-imidazole [l,2-a]acridin-7-yl}-benzyl)-3-methyl-pyridine-3-deconazole ethyl ester ( 1 -(4- {3 - [3 -(3 -Ethyl-ureido)-phenyl]-imidazo[ 1,2-a]pyridi n-7-yl} -benzyl)-3-methyl-pi peridine-3- Carboxylic acid ethyl ester) l-(4-{3-[3-(3-ethyl-pula)-phenyl]- phloem [1,2-a] ° 〇定-7-yl}-benzene Mercapto)-3-methyl-transformation-3-acidic ethyl ester (1 -(4- { 3 - [3 -(3 -Ethyl-ureido)-phenyl]-imidazo[ 1,2-a]pyridi N-7-yl}-benzyl)-3-methyl-pi peridine-3-carboxylic acid ethyl ester) Ύ Q xy^z ίο s κε 200836725

Example 59A 1-{3-Γ7-(4-Fluoro-carboxylimidazo, 2-alpyridin-3-yl 1-phenylindole-3-(2,2,2-trifluoro-ethylurea) Nn-"7-(4-Fluoro_phenvl)-imidazo"l,2-alpvridin-3-vn-ph 5 envl}-3-(2,2,2-trifluoro-ethvl)-urea hydrochloride) o

o Step (a): 1-Π-bromo-mosa V3-(2,2,2-trifluoro-ethyl)-urea n-n-Bromo-phenvlV3-r2,2,2-trifluoro-ethvlVurea&gt;)

10 (^c, 3-Bromophenyl isocyanate, 21.12 g, 107 mmol) was slowly added to a mixture of 2,2,2-trifluoroethylamine (2, under nitrogen). 2,2-trifluoroethyl amine, 15 40 ml, 0.5 mol) was dissolved in THF (100 mL) and rinsed with THF (25 mL). The reaction was slowly warmed to room temperature and maintained at this temperature for 16 hours. The volatiles were removed under reduced pressure to give a solid compound (31.6 g). NMR (400 MHz, DMSO-d6) δ 8.94 (1H, s), 7.80 (1 Η, t), 7.31-7.24 ( 1Η, m), 7.20 (1Η, t), 7.16-7.08 (1Η, 20 m), 6.83 (1H, bt), 3.98-3.85 (2H, m)· 354 200836725 Step (b): l-“3彳4.4.5,5-tetradecyl-"l·3·21 dioxa borane-2-yl>)-stupyl l-3-(2,2-2·trifluoro-ethyl)urea N-r3-(4,4.5.5-Tetramethvl-ri,3.21dioxaborolan-2-vl)-phen yn-3-(2,2.2-trifluoro-ethvl)-urea&gt;)

^ 1-(3-Bromo-phenyl)·3_(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-phenyl)-3-(2,2,2- Trifluoro-ethyl)-urea) (3 1.6g, 106 mmol), double-linking, bis (pinacolato diboron, 54g, 212 mmol) and KOAc (31.3 g, 319 mmol) dissolved in dry 10 Deoxygenated (x3) in DMSO (110 mL) via vacuum/re-nitrogenation. PdCl2ddpf (7.78 g, 10.6 mmol) was added, and the mixture was again deoxygenated (Χ3) and stirred, and heated to 10 ° C for 100 minutes under nitrogen. The reaction was cooled to room temperature, diluted with EtOAc EtOAc m. The collected organic extracts were washed with water (320 mL), brine (1 mL (320 mL), dried (MgSO4), filtered and evaporated. Solid compound (37.4g). 4 NMR (400 MHz, CDC13) δ 7.63 (1H, s), 7.58 (1H, d), 7.46 (1Η, d), 7.34 (1Η, t), 6·65 (1Η ,brs),5·21 (1Η,brs), 3.99-3.86 (2H,m),1·33 (12H,s). Step (c): 7-Gas-carbazole and 1,2,2-alpyridine (7-Chloro-imidaz〇n ,2-alpyridine) 355 200836725 h2n

C Add NaHC03 (32·7 g, 0.389 mol) to a solution of 4-chloro-pyridin-2-ylamine (25.0 g, 0.194 mol) in EtOH (250 mL) Then, a solution of 50% chloroacetic acid dissolved in water (37 5 mL, 0.292 mol) was added. The mixture was refluxed for 6 hours. The solvent was removed under reduced pressure and the crude mixture was diluted with water (250 <RTIgt; The concentrated organic layer was washed with brine (50 mL), dried (MgSO4), and evaporated. 4 NMR (400 MHz, CDC13) δ 8·06 (1H,d), 10 7.64 (2Η, d), 7.56 (1H, s), 6.79 (1H, dd). Step (d): 7-(4- Fluorine-stupyl--- 4-Fluoro-phenvl Vimidaz〇n (2-alpyridine)

7-Chloramizolo[l,2_a]pyridine (15.0 g, 98.6 mmol), 4-fluorophenylboronic acid (16.55 g, 118.3 mmol), potassium carbonate (81.5 g, 590 mmol) were dissolved in the indole-furfuryl alcohol- In ethanol·water (1:1:1:1, 800 mL), nitrogen gas was filled with 20 gas to remove gas, and bis(tri-tert-butylphosphine)palladium (O) ((bis(tri-tert-butylphosphine) palladium ((bis(tri-tert-butylphosphine))) 0), (400 mg). After degassing the mixture, it was added to 80 and 18 hours. The mixture was then cooled to ambient temperature, transferred to a separating funnel and separated. The organic fraction 356 200836725 was reduced in reduced pressure. The residue was extracted with di-methane. The methylene methane extract was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give the compound 17.3 g (83%) as the title compound. hNMRMOOMHz, CDC13 ) δ 8.22 (1H, d), 7·87 (1H, s), 7.71 (1H, s), 7.69-7.58 5 (3H, m), 7.20 (2H, t), 7·11 (1H, d) Step (eV. 7-(4-Fluoro-stupyl V3-iodo-imidazole "1,2-alpyridine nM-Fluoro-Ohenvm-iodo-imidazorU-alpvridine")

Add N-iodosuccinimide (14. 5 g, 64·4 mmol) to 7-(4-fluoro-phenyl)-imidazole [l,2-a]pyridine (7_(4) -Fluoro-phenyl)-imidazo[l,2-a]pyridine) (13.0 g, 61.3 15 mmol) in N,N-dimercaptocaramine (100 mL), stirred at ambient temperature under nitrogen . The reaction mixture was stirred for 2 hours and water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration. After washing with water, it was placed on a filter paper and dried in the air. The solid was triturated in diethyl ether, filtered, collected and dried in vacuo at 50 °C. The resulting solid 20 was separated with water and EtOAc. The organic layer was washed with brine, dried (MgSO4). The solid obtained was partitioned with aqueous sodium thiosulfate and EtOAc. The organic layer was washed with brine, dried (MgSO4) The product was triturated with EtOAc (EtOAc)EtOAc. 1H NMR (400 MHz, CDC13) δ 8.23 (1H, d), 7.91 (1H, s), 7.78 (1H, s), 7.67 (2H, dd), 7.28 (1H, d), 7·22 (2H, t). Another product containing a secondary impurity can be obtained by pulverizing the filtrate under reduced pressure, grinding in petroleum ether / EtOAc, and collecting by filtration. 5 Step W3-"7-(4-Fluoro-methyl)-imidazolium 1,2-α1pyridin-3-yl 1-benzene}-3彳2.2,2-trifluoro-ethyl)-urea- Ι3-Γ7-Γ 4-Fluoro-phenyl)-imidaz〇rK2-a1pyridin-3-vl1-ph envl}-3-r2.2,2-trifluoro-ethvlVurea) Ο

7-(4-Fluoro-phenyl)-3-iodo-imidazole [l,2-a] oxidine (7-(4-Fluoro-phenyl)-3-iodo-imidazo[l,2-a]pyridine 15 (lO.lg, 29.8 mmol), 1-(3-di-phenyl)-3_(2,2,2·tris-ethyl)-urea (1 - (3-Bromo-phenyl)_3_( 2,2,2-trifluoro-ethyl)-urea) (12.3g, 35.8mmol) and 2M sodium carbonate (120 mL) were dissolved in dimethoxyethane (595 mL), via vacuum/re-nitrogenation (χ3) Deoxidation. Tetrakis(triphenylphosphine)palladium (1.72 g, 1.49 mmol) was added, and the mixture 20 was again deoxygenated (x3) and heated to 8 ° C overnight under nitrogen. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude mixture was diluted with water 358 200836725 (100 mL), EtOAc (100 mL) and DCM (100 mL). After the obtained slurry was filtered, EtOAc was evaporated. 4 NMR (400 MHz, DMSO-A) δ 8.98 (1H, s), 8.61 (1H, d), 7.99 (1H, s), 7.96-7.87 (2H, m), 5 7·79 (2H, s), 7·45 (2H, d), 7·41-7·30 (3H, m), 7.30-7.23 (1H, m), 6.87 (1H, bt), 4·00-3·89 (2H , m)· MS: [M+H]+ 429 Step (g): Fluoro-lamyl)-imidazolyl H,2-alpyridin-3-yl 1-mollyb 3-(2,2,2· Tris-ethyl)- sulphate sulphate 10 (1 _ n-F7-(4-Fluoro-phenvlVimidaz〇ri , 2_a1pvridin_3-vll-ph envl}-3-(2-trifluoro_ethvn-urea hydrochloride salt) Add 4M hydrogen chloride/dioxin (10 mL) to 1-{3·[7-(4·fluoro-phenyl)-mouth σ sit and [1,2 a]σ ratio _3-3-]-benzene }}-3-(2,2,2-diox-ethyl)-urea (1 -{3-[7-(4-fluoro-phenyl)-imidazo[l,2-a]pyridin-3-yl a solution of -15 phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, 9.8 g) and methanol (100 mL). The solution was stirred at room temperature for 90 min then concentrated under reduced pressure The compound (11.lg) was obtained as the title: b NMR (400 MHz, DMSO-A) δ 9·47 (1H, s)5 8.81 (1H,d),8·41 (1H,s), 8 ·24 (1H, s), 8·03 (3H, dd), 7·95·7·82 (2H, m), 7.60-7.51 20 (2H, m), 7.50-7-39 (3H, m), 7.37-7.28 (1H, m), 7·14 (1H, t) 5 4.03-3.42 (7H, m), 3.17 ( 3H5 s). 359 200836725 -- ^rff\ 011 is 09苳鸯« MS MS: [M+H] + 470 MS: [M+H] + 367 MS: [M+H] + 427 NMR data 1R NMR ( 400 MHz, Dioxane): 9.13 (1H, d), 8.50 (1H, s), 8.44 (1H, s), 8.29 (1H, s), 8.22-8.05 (3H? m), 7.91-7.74 (3H, m ), 7.68-7.56 (2H, m), 4.36 (2H, d), 4.10 (2H, t), 3.87 (2H, d), 3.81-3.74 (2H, m), 3.54-3.48 (6H, m), 1.42 (3H, t). lR NMR (400 MHz, Me-^-OD): 8.64 (1H, d), 7.99 (1H, s), 7.88 (1H, s), 7.82-7.72 (3H, m), 7.62-7.32 (6H, m), 4.03 (2H, s), 2.19 (3H, s). 'H NMR (400 MHz, Me-rfj-OD): 8.64-8.52 (2H, m), 8.05-7.93 ( 2H, m), 7.79 (1H, s), 7.70 (1H, s), 7.62-7.47 (2H, m), 7.40 (1H, d), 7.32 (1H, dd), 6.97 (1H, d), 3.69 (4H, t), 2.64 (4H, t), 2.41 (3H, s), 2.19 (3H, s). Preparation steps 辛s丨^ . Two ' K g S ^ $5 f 4 H 221 two two % alt aluminum &lt; 参ώ襻工1录铝4 u砩^ f &lt;3办^ ^ ^ ά ig aluminum 硪K鮏\ ή Sill ® in (N 40/ do i &lt; ^ s 1 more s ^\v \ ^ ' &lt;rT ^ 砩κ V砕1 Wall from the name of the chemical name 1-ethyl-3-(3-{7-[3-(2-morpholin-4-yl-ethyl)-phenyl]- Imidazo[l,2-a]acridin-3-yl}-phenyl)-urea hydrochloride (1 -Ethyl-3 -(3 - {7-[3 -(2-morpholin-4-yl-ethyl) )-phenyl] -imidazo [ 1,2-a] pyridin-3 -yl} -phenyl)-urea hydro_chloride salt) fi|莩^ 9 CN ^ slgfi :Z; 二〇·? ^ f . , α Forced IQ 2^ 6 + S 8 f*g|; ά 硪 compound \2 Example j No. ε9ε 200836725 Γ MS: [Μ+Η] + 304 MS: [M+H] + 360 MS: [M+H] + 418 lR NMR (400 MHz, EtOD): 6.39 (1H, d), 5.68-5.57 (3H, m), 5.46 (1H, s), 5.16-5.01 (4H, m)? 4.80 (1H, t), 4.76 (1H, d), 4.68-4.59 (1H, m). lR NMR (400 MHz, Me-^-OD): 8.64 (1H, d), 8.01 (1H, t), 7.88-7.78 (3H, m ), 1.1 A (1H, s), 7.59 (1H, d), 7.53 (1H, t), 7.41 (1H, d), 7.35 (1H, dd), 7.31-7.22 (2H, m), 2.46 (2H , q), 1.25 (3H, t). lR NMR (400 MHz, Me-i/j-OD): 8.53 (1H, d), 7.94 (1H, s), 7.79-7.62 (4H, m), 7.62 -7.44 (2H, m), 7.36 (1H, d), 7.27 (1H, dd), 7.09 (2H, d), 4.14 (1H, dd), 4.09-3.97 (2H, m), 3.79-3.64 (2H , m), 2 .18 (3H, s). 4 « K recorded every ‘s s毽 镏锲 1 i4 ^ Ϊ ^ ,. « s ^ f余f灭^ it% W孽cA per l i4 ^ £ K f cA . ^ fr 2 i eDonkey A = Umbrella - &lt; vi 卞C shout 1 - ' ^ - Aluminium 硪 K ^ ^ 1 meal趑酴B 1 1| i '11 1—1 ^ Ϊ |1 t名^ ίΐΗ tII 1 1 rA ^ ? 11 ^ 13⁄4 ¥ I f sl^ Φ好|ϊ v ?*g 子涂rd:| έ ^ έ s *a Ν-(3-{7-[4.(2,3-dihydroxy-propoxy)-phenyl]-imidazole [l,2-a]-piperidin-3-ylphenyl)- Acetamine (N -(3 - {7-[4-(2,3 -Dihydroxy-propo xy)-phenyl]-imidazo[ 1,2-a]pyridin -3 -yl} -phenyl)-acetamide) LL 0 V &gt;§ ί h\/Y y\/2Y xy^ s 3 200836725 MS: [M+H] + 374 MS: [M+H] + 361 MS: [M+H] + 402 兮2 Magic KN Ilfas ^ * 〇s ^ r〇ai :3⁄4 O inch y inch®2So?S !_ . ffi ^ —Γ目啼田 I· _ * ώ f tube ^ oo CG ®15SS igsa g K ffi ^ ^ k S k VO v〇rn t〇Jr* od t&gt; cn 4 « ^ K 余1 «3 '. S SS|? Recording Yu Qin II.硪 ^ ^ ^ l i4^ £ 4 Aluminium and ember ί ! 41 Each: 毽 2 open • rq sgf ^φίί Aluminium $4 ^ Helmet “ 1 “ pq &lt; Fan t0 4 s pigeon « s| Gallium gallium cA A '峨ο «if ^ 窠域阳 i ^ ^ N- {3_|; 7-(4-fluoro-phenyl)·imidazole [1,2-a] 17 than -3-yl]phenyl bbutyramide (N-{3 -[7-(4-Fluoro-phenyl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -butyramide) 2-amino-N-{3-[7-( 4-fluoro-phenyl)-imidazole [l,2-a]n-pyridin-3-yl]-phenyl}-acetamimidate (2-Amino-N- {3 -[7-(4) -fluoro-phen yl)-imidazo[ 1,2-a]pyridin-3 -yl] -ph enyl}-acetamide formate salt) lilt ΣΙ^Χ% bring 1 翠笞ίϊ3|Ι &amp;ss^l '- V-^ eS Ns^/ rH 〇V ff xy^zi/ ο\β VO s 200836725

MS: [M+H] + 318 MS: [M+H] + 328 MS: [M+H] + 329 MS: [M+H] + 289 NMR (400 MHz, Me'-OD): 8.30 ( 1H, s), 8.21 (1H, s), 8.04 (1H, d), 7.88 (1H, s), 7.82-7.76 (2H, m), 7.74 (1H, d), 7.70 (1H, s), 7.62 (1H, dd), 7.43 (1H, d), 7.34 (1H, dd), 7.26 (2H, d), 2.16 (3H, s). !H NMR (400 MHz, Me-i/3-OD ): 8.65 (1H, d), 7.96 (1H, s), 7.88 (4H, d), 7.64 (1H, d), 7.50 (1H, d), 7.39 (2H, d), 7.30 (2H, t) , 6.61 (1H, s). ϋί - ε k Q 〇ji .^ v〇ii boast I \〇€, § ^ i fun | Uut P οό^ S £ 4 . Old 碥 I ^ ^ f- 4 S d 〇 Slg 二镏嗲 ^ Wt w嘁A l ^ ^ 4 « iScL K Jun 2. « s ^ AJfiC &lt;u 9 ψ ^ w ^ 1 i4 ^ ' Inch CQ 5黢Cd ο ^ &lt;N PQ PQ Gallium Gallium Dioxide ω ff ^ i4 ml ^ ^ 3-[7-(4-Fluoro- Phenyl)-imidazole [l,2-a]acridin-3-yl]~4_methyl-phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[l,2-a] Pyridin-3 -yl]-4-methyl-phenyl amine) 7-(4-fluoro-phenyl)-3-(lH-indol-5-yl)-imidazole [l,2-a]indolecarboxylic acid Salt (7-(4-Fluoro-phenyl)-3 -(1 H-indol-5 -yl)-imidazo [ 1,2-a]pyridine formate salt) 6-[7-(4-fluoro-phenyl) -imidazole [l,2-a]»pyridin-3-yl]-1H-indazole (6 - [7,(4-Fluoro_phenyl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -1 H-indazole) J If & SB i II $ || $ _ έ # 埼毽J戾0 0 d 0 Q ,Q rf χχ^ζ py^z Cr^ $ O MS: [M+H] + 347 MS : [M+H] + 469 MS: [M+H] + 346 MS: [M+H] + 328 ..s /^SG &gt;s—^ Q 〇ffi S Sod C — 3 O «&gt; l&gt Iss^S ^ isis ^ r^ VO Hpl inch 乂 (N · Yin od points K 2 Q 〇6 cn /«-N ^ §〇e ^ p fresh g| sS^3% • 9S , ps^t ® 2 Od ^ r&gt; s 1 lU NMR (400 MHz, DMSO-J5): 10.16-10.10 (1H, m), 8.59 (1H, d), 7.98 (1H, s), 7.95-7.86 (2H5 m), 7.78 ( 3H,d),7·6 3 (2H, d), 7.40-7.29 (3H, m), 2.10 (3H, s). !H NMR (400 MHz, Mc-d3-0O): 8.59 (1H, d), 8.30 (1H, s) , 7.90-7.79 (3H, m), 7.77 (1H, d), 7.72 (1H, s), 7.66 (1H, s), 7.39 (1H, d), 7.33 (1H, d), 7.31-7.20 (3H , m), 6.57 (1H, d). fs per electric i 苎 2 ί4 w PQ 硪 gallium arsenide. .麻f «潜' ^ w ^ 1 i-4 ^ ^ CN ttir ^ 趑&lt; wu 5 umbrella s 7 do Yang PQ office ^ every 1 record cd · electric s system S毽W ^ ^ ^ ^ ^S^ Csi4 絮«硪1 4 黢 黢 ^ Ϊ -5 -5 : : : : : -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 2 2 2 2 CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN ^ Ψ 窠蝣K 1 ^ ^ 智二穿额g力^ ^ | .a ^ ftm 义1 Sslll 1~II 1 1 &lt;D fA ^ ε 4-{3-[7-(3-morpholine-4 -mercapto-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-2,4-dihydro-[1,2,4]triazole-3-thione (4 - {3 -[7-(3 -Morpholin-4-ylmethyl-phenyl)-imidazo[ 1,2-a]p yridin-3-yl]-phenyl} -2,4-dihydro-[ 1,2,4 ]triazole-3-thione) ? |琴^ 13⁄4 hfl with a key 1 ge! f!l. 7-(4-gas-phenyl)-3_(111-° 丨 ° °-6-yl)-imidazole [ 1,2-a] 4-(Fluoro-phenyl)-3-(lH-indol-6-yl)-imidazo[ 1,2-a]pyridine formate salt), 』 °v ^ %ί LL § \〇^z Li. I cn jn V〇200836725 MS: [M+H] + 404 MS: [M+H] + 457 MS: [M+H] + 483 • · rH 一办# 〇〇 〇〇 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 ^): 10.11 (lH, s), 8.64 (lH, d), 7.97 (1H, s), 7.82 (1H, s), 7.78-7.73 (2H, m), 7.51-7.45 (2H, m), 7.40 -7.36 (2H, m), 7.33 (1H, t), 6.93 (1H, dd), 3.83 (3H, s), 3.63-3.55 (6H, m), 2.41 (4H, s), 2.08 (3H, s lR NMR (400 MHz, Me-^-〇D): 8.69 (1H, d), 7.99-7.90 (2H, m), 7.90-7.82 (2H, m), 7.76 (1H, s), 7.65 ( 1H, t), 7.55-7.25 (5H, m), 4.01-3.52 (2H, m), 3.35-3.30 (2H, m), 3.28 (2H, q), 2.64 (4H, s), 2.44 (3H, s), 1.19 (3H,t). 5 shoots "δ « PQ 〇录酴:| 朱 s Zhu S i ° ά 1 wff W硪cA 窠蚪K鮏\ ^ ψ Sii £ ^ l :;弩κ硪B々A食^ ^ G/ tO Driving out of the wrong 1 旷鮏趑 i i , · cA wearing r 3 distillation K _ jf 5 ^ gallium gallium 硪 m? ^ 1 -λ ^τ1 &lt; ψ 1 Driving B·鮏7 J; | 1 13⁄4 I-1 OSI Z^N ΰ f goods iji $fi § i § Φ^ j|'i Cl rA V ? .3⁄4 ^ ^ έ NO 13⁄4 ffl f 吉ε; 8 si III m^I|1 1-ethyl-3-(3-{7-[3-(4-indolyl-piperazine carbonyl)-phenyl]-imidazole [l,2-a]pyridine-3- -1 -Ethyl-3 -(3 - {7-[3 -(4-methyl-pip erazine-1 -carbonyl)-phenyl] -imida zo[ 1,2-a]pyridin- 3 -yl} -phenyl)-ure a) sv 4^ xy^z ο xy^z °s ::L^ p- 〇〇 On 200836725

f G MS: [M+H] + 400 MS: [M+H] + 483 1 MS: [M+H] + 426 ..gf S · Si--j _ · mm |S^g^ ^ 00 t&lt ; ^ &amp;ss^; SK Ciq X 13⁄43⁄4 isl?!s lisstg lR NMR (400 MHz, Me-i/j-OD): 8.63 (1H, d), 7.89-7.81 (2H, m), 7·76 (2H,d),7·72 (1H,s), 7.51-7.40 (3H, m), 7.40-7.23 (3H, m), 3.72 (2H, s), 3.38 (4H, t), 3.27 (2H q), 2.24-2.11 (2H,m), 1.19 (3H,t). ^ ' »1 ?T ''祀q &lt;ti^ iws .SE ^ 5 f &lt; ^ EV ^ S^IISs 1 Gallium Aluminium.M砩t.' ί 0 ^ ^Ιϊ5! ^ t4 5 S ^ ISjp 5!il Turn to &amp; to inquire a 1 yeast drive I^VS〇&lt;; every E $ drive n%nt A , ,rB ^ Jz Ιά^ s^ ill %n ^?额|百身'vl士同2夸竿石ψψψψ f|I « f S*r ^ έΐ Ip II Iff A 死 t[I荖ά^Φ1 | 2 spoons, C fe N 1? i^i If 呤¥ i| f:S if? fresh l,2 ? ά§Λά|| t/, i/ § oo 99ΓΠ 200836725 Γ

MS: [Μ+Η] + 431 MS: [M+H] + 396 MS: [M+H] + 481 Η NMR (400 MHz, Me-i/j-OD): 8.65 (1Η,d),7.89 -7.80 (2Η,m), 7.73 (1H,s),7.52-7.41 (2H,m), 7.41-7.32 (4H,m), 7.29 (1H,d), 7.04 (1H, dd), 4.29-4.20 (2H, m), 3.86-3.77 (2H, m), 3.47 (3H, s), 3.30-3.21 (2H, m), 1.19 (3H, t). XH NMR (400 MHz, Me-^-OD) : 8.67 (1H, d), 7.89 (1H, s)5 7.85 (1H, t), 7.82-7.76 (2H, m), 7.74 (1H, s), 7.57 (1H, t), 7.52-7.42 (2H , m), 7.42-7.33 (2H, m), 7.29 (1H, d), 4.04 (2H, s), 3.27 (2H, q), 1.19 (3H, t)_ lR NMR (400 MHz, Me-i /j-OD): 8.67 (1H, d), 8.14 (2H, d), 7.94 (1H, s), 7.91-7.80 (3H, m), 7.76 (1H, s), 7.48 (1H, t), 7.45-7.35 (4H, m), 7.32 (1H, d), 7.13-7.03 (2H, m), 4.42 (2H, s). ^ 1 ^ ill -K cd ^ s II 黢 drive S -K cd &lt ; ^ Ε硪诏&lt; 参硪1黢壤叫^ IS ij 5 ^ S ^ &lt;J t}· 3* ^ '绪 K官 4 • K cj 2 趑&lt; ^ ^ Aluminum&lt; Umbrella w Gallium 1 Gallium aluminum feed 轵 It £1 φΙ !ii si s: season 1 〇,.S 1-{3-[7-(3-cyanomethyl-phenyl)-isoxazole [l,2-a] Acridine-3-yl]phenyl}-3-ethyl-urea (1 - {3 -[7-(3 -Cyanomethyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-pheny 1}-3-ethyl-urea) 4-(3-{3- [3-(4-Fluoro-benzyl)-urea]-phenylimidazole [l,2-a]acridin-7-yl)-benzoic acid (4-(3 - {3 -[3 - (4-Fluoro-benzyl)-urei do]-phenyl} -imidazo[ 1,2-a]pyridin -7-yl)-benzoic acid) / 1/ y\_/zY W~Vz w/Vz OO S OO 200836725 fu MS: [M+H] + 374 MS: [M+H] + 394 MS: [M+H] + 394 !H NMR (400 MHz, Me-rfj-OD): 8.64 (1H,d), 8.12 (lH, dd), 7.95 (1H, d), 7.85 (1H, t), 7.80 (1H, s), 7.73 (1H, s), 7.47 (1H, t), 7.39-7.32 (1H, m) , 7.28 (2H, d), 6.71 (1H, d), 3.28 (2H, q), 1.19 (3H, t). 'Η NMR (400 MHz, Me-^-OD): 8.52 (1H, s), 8.41 (1H,d), 7.82 (1H, t), 7.56 (1H, s), 7.44 (1H, t), 7.31 (1H,d),7·22 (1H,d),7·01 (1H, Dd), 6.78 (1H?d), 4.26-4.16 (2H, m), 3.49 (2H, dd), 3.27 (2H, q), 3.17 (2H, dd), 1.32 (6H, d), 1.18 (3H , t). Ο ^ Λ CV 1-1 + 弋 琴 S S — 1 α &gt; vd ^ ffi ^ 0 r&gt; 〇w ^ 〇 Sc? Iz; 〇t&gt; Κ-Γ ^ ΙηΗ Λ Λ w 00 . 00 ^C(T: &lt;N electric 1 A umbrella, K Gallium &lt; ^ J f -K cd &lt;;^ PlI &lt;Blasting g Driving&lt;;To Ω ^ 1 ^ c ^ Ξ \l 3(4)| ^ 1 g ^|I ' cn Private Can ^ K id &lt;i ^ Ξ M Aluminium &lt; Umbrella S 1 Gallium Aluminum S ή , SI § 1? \〇ι_ι Μ /-^-s Ε| ^11 άί^τίΐ 352:^13⁄4 二穿砩ά S茇23⁄4 riiJ U §||1 _ Discussion 11!!! l-{3-[7-((2R,6S)-2,6-Dimercapto-morpholin-4-yl)-11 m e sitting [1,2- a] ° 比石定-3 -yl]-phenyl}-3-ethyl-urea formate (l-{3-[7-((2R56S)-256-Dimethyl-m orpholin-4-yl) -imidazo[ 1,2-a]pyrid ine-3-yl]-phenyl} -3-ethyl-urea formate salt) \ χ 〇xv° 00 00 oo9£ 200836725 MS: [M+H] + 542 MS: [ M+H] + 456 MS: [M+H] + 537 1H NMR (400 MHz? Me-d3-OD): 8.88 (1H, d), 8.63 (1H, d), 8.41 (1H, dd), 8.22 (2H, d), 8.10-8.04 (1H, m), 7.87 (1H, dd), 7.56 (1H, t), 7.42-7.33 (3H, m), 3.88-3.79 (4H, m), 3.73-3.65 (4H, m), 3.28 (2H, q), 1.52 (9H, s), 1.19 (3H, t). 'H NMR (400 MHz, DMSO-^): 8.74 (lH, s), 8.63 (lH, d), 8.17 (0.5H, s), 8.06 (1H, brs), 7.96 (1H, d), 7.88 (1H, s), 7.84-7.79 (2H, m), 7.60 (1H, t), 7.48- 7.40 (4H, m), 7.25-7 .19 (1H,m), 6.13 (1H,q), 3.64 (4H, brs), 3.32 (4H, brs), 2.67 (3H, d). lH NMR (400 MHz, Me-^-OD): 8.65 (1H, d), 8.32 (1H, s), 7.86 (2H, s), 7.83-7.71 (3H, m), 7.59-7.44 (3H, m), 7.44-7.32 (4H, m), 7.30 (1H , d), 7.08 (2H, t), 4.41 (2H, s)5 3.69 (3H, s), 1.63 (6H, s). ^^二^ 51^ t ItitH φν ^ . ψ ^ &lt; ^ E ^ ^ 驾&lt;1 _ ιΛ ^ φ 1 more aluminum enjoy nickel province ί K辕 two f irrigation ^ S g 5 &lt;3 ^ 1碥U » electric 蚪岑 SE gallium 4 ^ ^ ^ ^ a 151® ^ ^ -- ^ S ^ f ^ ^ B«tc p K v 3 % hammer § ^ ^ s ^ ^ £ ®- a 1砩4 S $ 0硪4-(5-{3-[3-(3-ethyl- Urea)-phenyl]-micron sitting [1,2 -a] 0 than bite-7-yl} · bite-2 -yl ►)-piperazine-1-carbonate tert-butyl ester hydrochloride (4-( 5 - {3 -[3 -(3 -Ethyl-ureido)-phen yl]-imidazo[ 1,2-a]pyridin-7-yl} -py ridin-2-yl)-piperazine-1 -carboxylic acid tert -butyl ester hydro-chloride salt 1-methyl-3-(3-{7-[3-(?-lin- 4-yl)-phenyl]-imidazole [l,2-a]acridine-3 -yl}-phenyl)-urea citrate (1 -Methyl-3 -(3 - {7-[3 -(morpholine -4-carbonyl)-phenyl]-imidazo[ 1,2-a]pyridin-3 -y 1} -phenyl) -urea fo Rmate salt) 2-[4-(3-{3-[3-(4-fluoro-phenylhydrazino)urea]-phenyl}•imidazole [l,2-a]acridin-7-yl)-benzene 2-methyl-propionic acid methyl ester decanoate (2-[4-(3 - {3 -[3 -(4-Fluoro-benzyl)-u reido]-phenyl} -imidazo[ 1, 2-a]pyri din-7-yl)-phenyl]-2-methyl-propio nic acid methyl ester formate salt) V 〆P xy^z 1/ s. 5; 69ΓΠ 200836725 MS: [M+H] + 512 MS: [M+H] + 523 'H NMR (400 MHz, Me-i/3-OD): 8.67 (1H, d), 8.27 (2H, s), 7.90 (33⁄4 d), 7.86 (1H, t), 7.76 (1H, s), 7.68 (2H, d), 7.47 (1H, t), 7.43-7.32 (2H, m), 7.28 (1H, d), 4.43 (1H, d), 4.20 (1H , d), 3.57-3.42 (2H, m), 3.27 (2H, q), 3.01-2.87 (lH,m), 2.13-1.84 (4H, m), 1.49-1.34 (1H, m), 1.25-1.10 (6H,m). !H NMR (400 MHz, Me-i/j-OD): 8.65 (1H, d), 7.90-7.82 (2H, m), 7.77 (2H,d),7·73 (1H ,s),7·57 (2H, d), 7.54-7.44 (1H, m), 7.39 (4H, dd), 7.31 (1H, d), 7.13-7.02 (2H, m), 4.42 (2H, s ), 1.62 (6H, s). Step D2 as in Example 52 l_(4-{3-[3_(3_ethyl-urea)phenyl]-carboxazole [l,2-a]pyridine-7-yl }-Benzyl)-3-methyl-piperidine-3-carboxylic acid formate (1 - (4) - {3 -[3 -(3 -Ethyl-ureido)-phen yl]-imidazo[l ,2-a]pyridin-7-yl} -be nzyl) -3 -methyl-piperidine-3 -carbo xylic acid formate Salt) III ρ ill mmi 200836725 MS: [M+H] + 361 MS: [M+H] + 388 MS: [M+H] + 484 1H NMR (400 MHz, DMSO-d6): 8.66-8.50 (2H , m), 8.35 (1H, s), 8.07 (1H, s), 7.86 (1H, s), 7.81-7.73 (1H, m), 7.68 (1H, s), 7.45-7.33 (2H, m ), 7.29-7.15 (2H, m), 6.19 (lH, d), 3.90 (3H, s), 3.18-3.08 (2H, m), 1.19-1.02 (3H, m). lR NMR (400 MHz, Me -i/j-OD): 8.62 (1H, d), 8.24 (1H, d), 8.05 (1H, dd), 7.84 (1H, t), 7.79 (1H, s), 7.71 (1H, s), 7.46 (1H, t), 7.39-7.31 (1H, m), 7.27 (2H, dd), 6.71 (1H, d), 3.70 (3H, s), 3.27 (2H, q), 1.19 (3H, t) ^ NMR (400 MHz, Me-禹-OD): 8.66 (1H, d), 7.92-7.83 (2H, m), 7.75 (3H, d), 7.52-7.31 (5H, m), 7.27 (1H, d), 3.88 (4H? t), 3.27 (2H, q), 3.14 (4H, s), 3.08-2.98 (2H, m)5 2.79 (2H, t), 2.16-2.03 (2H, m), L19 (3H,t). /Privately dive $黢5械1毛令C砩f兹一奸&lt; ^ κ 1录芟二砩E t! ί n ^ ^ $4 $办勹5 Sllr &lt; ^ Ξ s ^ a ^ ^ E 1 gallium aluminide · M ^ ^ ^ ^ -® Cd inch • '褎 趑Ξ 1 趑Ξ sheep, race 1 gallium aluminum 4 Μ砩 1-ethyl-3-{3·[7-(1-methyl -1H-pyrazol-4-yl)-imidazo[1,2-a]pyridine-3-yl]-phenyl}-urea (1 -Ethyl-3 - {3 -[7-( 1 -methyl-1) H-py razol-4-yl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -urea) 1-ethyl-3-{3·[7-(1-methyl-6 -oxy-1,6-diaza 0 to ind-3-yl]-phenyl}-nuclear (1 -Ethyl-3 - {3 -[7-( 1 -methyl-6-oxo-1,6- Dihydro-pyridin-3-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -urea) 1-ethyl-3-(3-{7-[3-(3-morpholine) 4-yl-propyl)-phenyl]-imidazo[1,2-a]acridin-3-yl}-phenyl)-urea citrate (1-Ethyl-3 -(3 - { 7- [3 -(3 -morpholin-4-yl-propyl)-phenyl] -imidazo[ 1,2-a]pyridin-3-yl} -phenyl)-urea formate salt). λ 〉 /z^f° o / ,} λ K&lt;y K/V -t; QT \=/Vi O-ti P; 200836725

C

MS: [M+H] + 356 MS: [M+H] + 291 MS: [M+H] + 367 MS: [M+H] + 358 1H NMR (400 MHz, Me-d3-OD): 8.71 (1H? s), 8.10 (1H, s), 7.77-7.67 (3H, m), 7.58-7.50 (2H, m), 7.46-7.35 (2H, m), 7.29-7.18 (2H, m), 6.98 (1H, dd), 3.88 (3H, s), 2.17 (3H, s). 1H NMR (400 MHz, Me-d3-0D): 8.47 (1H, s), 8.28-7.92 (2H, m), 7.73 -7.63 (3H, m), 7.41 (1H, t), 7.28-7.17 (2H, m), 6.99 (1H, dd)? 3.88 (3H, s). 1H NMR (400 MHz, Me-d3-0D) : 8.43 (1H, s), 8.19 (1H, br s), 7.98 (1H, br s), 7.71-7.62 (3H, m), 7.48 (2H, d), 7.44-7.21 (6H, m), 7.06 (1H, dd), 5.19 (2H, s). 1H NMR (400 MHz, DMS0-d6): 10.12 (lH, s), 8.64 (lH, s), 8.14 (1H, s), 7.99 (1H, s ), 7.81-7.71 (2H, m), 7.71-7.65 (2H, m), 7.65-7.56 (2H, m), 7.49 (1H, t), 7.40 (1H, d), 7.10-7.01 (2H, m ), 3.81 (3H, s), 2.09 (3H, s). rA黢5 CJ硪lit T ^ ^ U ^ t0 Aluminium ί·4 κ 1砩IQ f ^ 2 ^ 〇rT trl 巅Gallium 3 A 1 4 v1 mm mm 〇' m: • m -a ca m ^ $4 4 ^ 窠砩K耱Φ懋j ~1 gallium S SE 0 m\, every 1Λ @ · iH ^ S? G/ u L remaining ^ r7 Lv U ^ N-{3-[6-(3- Methoxy-phenyl oxime [l,2-a]e is more than indole-3-yl]-phenyl}-ethanoamine (N- {3-[6-(3-Methoxy-phenyl)-imi Dazo[ 1,2-a]pyridin-3-yl]-phenyl} -a cetamide) i 6-(3-Dimethoxy-phenyl)-3-(lH"pyrazol-4-yl)-imidazole [l,2-ap 碇(6-(3 -Methoxy-phenyl)-3 -(1 H-pyr azol-4-yl)-imidazo[ 1,2-a]pyridine) 6-(3-phenyl Oxy-phenyl)-3-(lH-carbazole•4-yl)·imidazole [l,2-a]pyridinium (6-(3-Benzyloxy-phenyl)-3-(1 H-py razol- 4-yl)-imidazo[ 1,2-a]pyridine ) N-{3-[6-(4-Dimethoxy-phenyl)-imidazo[l,2-a]pyridin-3-yl]- Phenylacetate (N-{3 -[6-(4-Methoxy-phenyl)-imi dazo[ 1,2-a]pyridin-3-yl]-phenyl} -a cetamide formate salt) J b-&lt;i ON O 200836725

MS: [M+H]&lt;+&&&&&&&&&&&&&&&&&&&&&&&&& , s), 8.85 (1H, s), 8.57 (1H, d), 8.33 (1H, d), 8.09 (1H, s), 7.87-7.68 (4H, m), 7.56 (1H, d), 7.49 ( 1H, t), 7.43 (1H?d), 3.94 (3H, s), 2.08 (3H, s). 1H NMR (400 MHz, Me-d3-0D): 8.78 (1H, s), 8.12 (1H, s), 7.80-7.67 (4H, m), 7.67-7.49 (4H, m), 7.47-7.40 (1H, m), 7.34 (1H, dt), 2.18 (3H, s). 1H NMR (400 MHz, Me-d3-OD): 8.71 (1H, s), 8.09 (1H, s), 8.00-7.91 (2H, m), 7.81-7.76 (3H, m), 7.67 (1H, dd), 7.56-7.49 ( 2H, m), 7.47-7.41 (3H, m), 2.16 (3H, s). 1H NMR (400 MHz, Me-d3-0D): 8.72 (1H, s), 8.05 (2H, d), 7.70 ( 1H, s), 7.68-7.46 (5H, m), 7.40 (1H, dt), 6.94-6.86 (1H,m),2· 19 (3H, s). m feed tO test d ^ Ψ w. fis Latent 1 eradication W "Working 锘" 〇 \ \ ° 5 ° ^ Γ ^ ^ 〇 ^ t〇 ^ f ά ^ m 1 Φ back κ 〇 ^ Every gallium 褎 A private blessing, gallium alkali &lt; · wall l ^ c Ν-{3-[6-(5-Dimethoxy-acridin-3-yl)-imidazole [l,2-a]acridin-3-yl]-phenylethylideneamine (N - {3 -[6-(5 -Methoxy-pyridin-3 -yl )-imi Dazo[ 1,2-a]pyridin-3 -yl]-phen yl}-acetamide) N-{3-[6-(3-trifluoromethoxy-phenyl)-isoxazole [1,2-a ]pyridin-3-yl]-phenyl}-acetamidamine (N-{3 -[6-(3-Trifluoromethoxy-phe nyl)-imidazo[l ,2-a]pyridin-3-yl]-p henyl } -acetamide) liJl Λ tO g A ^ ^ o 蝣 ; § § ijts Sfllf v ^ XII :έ d:^•目工吏 and 苕芩百I fill •S&lt;J ΓΛ /&quot;ν/γ K/ V Κ /ΖΎ \=yV2 fH oss rH 200836725 Γ:

MS: [Μ+Η] + 328 MS: [M+H] + 434 MS: [M+H] + 361 1 NMR (400 MHz, Me-d3-OD): 8.76-8.69 (1Η, m), 8.07 (1H, s), 7.79-7.65 (5H, m), 7.61-7.38 (6H, m), 2.18 (3H, s). 1H NMR (400 MHz, Me-d3-OD): 8.68 (1H, s) , 8.16 (1H, s), 7.73 (3H, d), 7.52 (2H, d), 7.46 (2H, d), 7.40-7.27 (6H, m), 7.23 (1H, d), 7.03 (1H , dd), 5.16(2H, s), 2.13 (3H, s). 1H NMR (400 MHz, DMSO-d6): 8.66-8.58 (2H, m), 7.90-7.77 (3H, m), 7.56-7.49 (1H, m), 7.45-7.37 (2H, m), 7.24-7.14 (2H, m), 6.64-6.58 (1H, in), 6.19 (1H, t), 4.00 (3H, s), 3.18-3.08 (2H,m), 1.14-1.02 (3H,m) General C4 $4 g; Latent cA ff 趑3蚪〇l\ ft硪〇摩OY蚪ά 窠砩阳1灭田9艺二3宁®奴1硪难难碎难S訾i ϋ ώ 1! im S办ίϋΐ Ν-{3-[6-(3-Benzyloxy-phenyl)-imidazole [l,2-a]w than bite-3 -基]-本基}-Ethylamine (N-{3 -[6-(3 -Benzyloxy-phenyl)-i midazo [ 1,2-a]pyridin-3 -yl] -phenyl }-acetamide) 1 -ethyl-3-{3-Γ7-(2-mercapto-2H-pyrazol-3-yl)-flavor 0 sitting [1,2-3]'° than biting-3-yl]-phenyl} -urea (l-Ethyl-3-{3-[7-(2-methyl) -2H-py razol-3 -yl)-imidazo [ 1,2-a]pyridin-3-yll-phenyl} -urea) s 1—H r-H i-H 200836725

MS: [M+H] + 420 MS: [M+H] + 486 1H NMR (400 MHz, Me-d3-OD): 8.39 (1H, d), 7.75 (1H, t), 7.51-7.39 (2H , m), 7.34 (1H, dd), 7.25 (1H, d), 6.91 (lH, dd), 6.78 (lH, d), 3.95 (2H, q), 3.88 (4H, t), 3.30 (4H, t). 1H NMR (400 MHz, DMSO-d6): 9.54-9.30 (1H, m), 8.58-8.48 (2H, m), 7.93-7.80 (3H, m), 7.70 (1H, s), 7.44- 7.29 (3H, m), 7.15 (1H, d), 7.09-6.92 (1H, m), 6.72 (1H, t), 6.62 (1H,d), 3.60 (4H,t),3·44 (2H, t), 3.16-3.06 (2H, m), 2.43 (4H, s), 1.06 (3H, t). lR NMR (400 MHz, CDC13): 8.57 (1H,d), 8.52 (1H,d),8.02 (1H, s), 7.97 (1H, s), 7.75-7.63 (2H, m), 7.60 (1H, d), 7·49 (1H, dd), 7.31 (1H, d), 7.27-7.18 (2H , m). 4 , op CN 竣5 more than £ ί. 1 Shu two 砩芑 g dive 2. 5 f ^ ^ c —5 swallow 5s辕: 黢筚Glow pigeon. -K Si n3 鮏&lt;from E硪tight 1黢aluminum嚷毽^ fl 二阳f ^ PQ - age rn a? St ί ^ ^ Iff 1 -[3 -(7-morpholine·4·yl-imidazole [ 1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -[3 -(7 -Morpholin-4- Yl-imidazo [ 1 ,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride salt 1-ethyl_3-(3-{7 -[6-(2-?)---4-yl-ethylamino>&gt;-pyridin-3-yl]-imidazole [l,2-a]acridin-3-yl}-phenyl)- Urea hydrochloride (1 -Ethyl-3 -(3 - { 7-[6-(2-morpholin-4-yl-ethylamino)-pyridin-3-yl]-imi dazo[ 1,2-a]pyridin- 3 -yl} -phenyl)-u rea hydro-chloride salt) 3 -(2-gas-° than 唆-4-yl)-7-(gas-phenyl)-i mouth rice mouth [1,2- a] n-(2-Chloro-pyridin-4-yl)-7-(fluoro-phenyl)-imidazo[ 1,2-a]pyridine) Ο U. ξ g 1—Η sri O lH彝 φ^^麦 f W inch II is called III military 驷铋 驷铋. Funeral w? FT-ffi 妩 911 ^ 1111 ¥ marry ^ η 200836725

MS MS: [M+H]+ 376 W cn ..T oo go ¢, m MS MS: [Μ+Η ]+ 428 NMR data 1H NMR (400 MHz, Me-d3-OD): 9.15 (1H, d ), 8.92 (1H, d), 8.57 (1H, s), 8.16 (1H, t), 7.86-7.75 (3H, m), 7.38-7.26 (4H, m), 3.28 (2H, q), 1.20 ( 3H, t). 1H NMR (400 MHz, Me-d3-OD): 9.18 (1H, d), 8.95 (1H, d), 8.59 (1H, s), 8.09 (1H, t), 7.92 (1H, d), ! 7.87-7.78 (2H, m), 7.43 (1H, t), 7.35-7.28 (2H, m), 7.23-7.18 (1H, m), 3.05 (3H, s). 1Η NMR (400 MHz , DMSO-d6): 9.55 (1Η, d), 8.99 (1Η, d), 8.89 (1H, s), 8.73 (1H, s), 8.49 (1H, d), 8.40 (1H, d), 8.19 ( 1H, t), 7.99 (1H, br s), 7.69 (1H, dt), 7.43-7.31 (2H, m), 7.09 (1H, d), 6.80 (1H, t), 4.02-3.90 (2H, m Preparation steps gallium i people _ A ^ ^ cA ^ recorded 4 off two $, 1 a ^ ^ tear r 4 test inch Λ @ two 0 ^ gallium 襻鍩 人 l everyone «7 cT 2 ^ ^ Λ 黪ι swallow: r and “1. Φν s ^ ^ ^ ή g = inch: π π X t 黪芩襃 remaining q 2 φ\々&lt; Take V硪邑 chemical name 1 1-ethyl-3- {3-[6-(4-Gas-phenyl)-indolozolo[1,5-a]pyrimidin-3-yl]-phenyl}-urea (1 -Ethyl-3 - {3 -[6 -(4-fluoro-pheny l)-pyrazolo[ 1,5 -a]pyrimidin-3 -yl] -phenyl}-urea) Diet 2 ^ 1? ft lit I|| sg芩晋1 Pregnancy il τ〇ε 1 - {3 -[6 -(6-amino-σ is more than 唆-3 -yl)-σ than saliva [l,5-a] aceto-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea hydrochloride (1 - {3 -[6-(6-Amino-pyridin-3 -yl)-pyrazolo [ 1,5 -a]pyrimidin-3 -yl] -p henyl} -3- (2,2,2-trifluoro-ethyl)-u rea hydrochloride salt) Compound vr2^ (Υ&gt;- Ν-Ν\^( QF UL U. gas i Example number τ·Η rH rH CN rH m rH iH 200836725

MS: [M+H]+ 374 1 MS: [M+H]+ 356 MS: [M+H]+ 290 1H NMR (400 MHz, Me-d3-OD): 8.97 (1H, d), 8.76 ( 1H, d), 8.42 (1H, s), 8.21 (1H, d), 8.02 (1H, s), 7.77 (lH, dd), 7.66-7.62 (lH, m), 7.27-7.16 (2H, m) , 6.64 (lH, d), 3.15 (2H, q), 1.08 (3H, t). 1H NMR (400 MHz, Me-d3-OD): 8.64 (1H, d), 8.16 (1H, s), 7.98 (1H, dd), 7.94 (1H, s), 7.87 (1H, t), 7.80 (1H, s), 7.66 (1H, dd), 7.61 (1H, dd), 7.57-7.49 (1H, m), 7.47 (1H, d), 7.41-7.33 (lH,m), 7.29 (lH,d), 3.27 (3H, q), 1.19(3H,t) 1H NMR (400 MHz, DMSO-d6): 8.93 (1H , d), 8.71-8.61 (2H, m), 8.17 (1H, d), 8.03 (1H, s), 8.00-7.87 (3H, m), 7.60 (1H, dd), 7.39-7.32 (3H, m ) Ά Ά “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ 々砭 々砭 K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K Indole base 1-{3-[6-(6-amino:-mouth ratio -3-yl)-mouth-azolo[l,5-a]pyrimidin-3-yl]-phenyl-3-ethyl Base-urea hydrochloride (1 - {3 -[6-(6-Amino-pyridin-3 -yl)-pyrazolo[ 1,5-a]pyrimidin-3 -yl] -p henyl} -3 -ethyl- Urea hydrochloride salt) 1-ethyl-3-[3-(7-thia -3-yl-imidazole [l,2-a]n than indole-3-yl)-phenyl]-urea citrate (1-Ethyl-3 - [3 -(7-thiophen-3 -y 1 - i midazo[l ,2-a]pyridine-3-yl)-phe nyl]-urea formate salt) 7-(4-fluoro-phenyl)-3-pyridin-3-yl-imidazole [l,2-a ] Dtfc» 7-(4-Fluoro-phenyl)-3 -pyridin-3 -yl-imidazo[ 1,2-a]pyridine) : zi. # xy^z LL· 1—Η rH rH v〇TH rH 200836725 Example 117 Ν·丨3-『6-(4-Fluoro-stupylpyrazole "1,5-alpyrazin-3-yl 1 -Phenyl K oxime (N-{3- r6-(4-Fluoro-phenvl, -pvrazol〇n.5-alpvrazin-3-v11-p 5 henyll- acetamide&quot;) Step 1: 2-Bromo-5- Trimethyl decylamine acetylene-pyrazine r2-Bromo-5-trimethylsilanylethYnvl-pyrazine&gt;) 2-bromo-5-iodo-pyrazine, 1 · 14 g, 4.0 mmol ) and cuprous iodide (copper (I) iodide, 80 mg, 〇·42 C / 10 mmol) dissolved in DMF/Et3N (2:1, 24 ml), deoxygenated via vacuum/re-nitrogenation (x3). Add acetylene After adding Ethnyl-trimethyl-silane (680 μl, 4.8 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol) was added and the mixture was deoxygenated (xl) again. The reaction was given at room temperature. After being mixed for 16 hours, it was separated with Et20/H20. The organic layer was washed with water (xl), brine (15 ml), dried (MgS04), filtered and evaporated. The residue was purified by chromatography (2 - 4%) Et20/Petrol) to give the compound as shown in the title (850 mg, wax solid), which is a single couple of ~3:1 Mixed q with double coupling. 1H NMR (400 MHz, CDC13): 8·63 (1H, d), 8.43 (1H, d), 0·25 (9H, s), [double coupled product: 8.60 (s), 0·25 (s)]. This material can be used directly without purification. Step 2: 6-Bromo-2·trimethyldecylamine-pyrazolo-H,5-alpyrazine ( 6-Bromo-2-trimethYlsilanvl-pyrazol〇n ,5-alpyrazine&quot;)

378 25 200836725 (O-(Mesitylenesulfonyl)hydroxyl amine, 680mg, 3.2 mmol) 2-bromo-5-tridecylamine acetylene-pyrazine (2) added to 0 °C and dissolved in CH2C12 (3 ml) -bromo-5-trimethylsilanylethynyl-pyrazine5 Step 1, 3 5 mmol) solution. The mixture was stirred at 〇 ° C for 30 minutes, at room temperature for 4 hours, and then evaporated. The N-amine adduct can be used without further processing. K2C03 (410 mg, 3 mmol) was added to a solution of the above-mentioned N-aminopyrazine (N_aminopyrazine) dissolved in dry 10 DMF (5 ml) in a nitrogen atmosphere at room temperature. After 6 hours the mixture was separated with EtOAc / H20. The organic layer was washed with saturated brine (x2) and then evaporated. The residue was taken up in CH2C12 and passed through a phase. The filtrate was evaporated, and the residue was purified EtOAcjjjjjjjjjj MS: [M+HJ+ 270/272. 15 Step 3: 6-(4-Fluoro-Methylpyrazolofene, 5-alpyrazine (6-(4-Fluoro-phenvn-pyrazol〇ri, 5-alpyrazine)

In a microwaveable bottle, 6-bromo-2·trimethyldecylamine-pyrazolo 20 [l,5-a] °tb (6-bromo-2-trimethylsilanyl_pyrazolo[l,5-a]pyrazine , 60 mg, 0.23 mmol), 4-n-benzoic acid (40 mg, 0·29 mmol), and PdCl 2dppf (10 mg, 0.014 mmol) dissolved in CH3CN (1 ml) and 2N Na2C03 (aq, 1 ml) Deoxidize for 20 seconds. The bottle 379 200836725 was sealed, stirred and heated in a microwave for 150 ° C for 20 minutes. After cooling, the reaction mixture was separated with CH 2 C 12 /H. The mixture was passed through a phase separation. The organic layer was evaporated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjh 9.15 (1H, d), 8.75 (1H, s), 8.06 (1H, d), 7·98·7·92 (2H, m), 7.24-7.14 (2H, m), 6.84 (1H, d)· Step 4: 6-(4-gas base)-3 ang-mouth ratio 1 "1,5- mad 1 mouth than mouth Qin Ο 〇 6 f6-(4-Fluoro-phenvl)-3-iodo-pvrazolo "l,5-alpvrazine"

I

15 ϋ 20 N-iodosuccinimide (13mg, 0.06 mmol) was added to a stirred solution at room temperature under nitrogen atmosphere in dry DMF (0.5 ml) 6- A solution of (4-fluoro-phenyl)-pyrazolo[l,5-a]pyrazine (6-(4-fluoro-phenyl)-pyrazolo[l,5-a]pyrazine5 1 lmg, 0.05 mmol). After 30 minutes, another portion of a solution of N-iodosuccinimide (13 mg, 0.06 mmol) dissolved in DMF (0. 2 mmol) was added. After a further 30 minutes, the mixture was heated to 50 ° C for 90 minutes at room temperature. After cooling to room temperature, the reaction was quenched with aqueous sodium thiosulfate / saturated NaHC.sub.3 (l:l,l). The mixture was stirred at room temperature for 1 hour and then separated with CH2C12 /H20. The mixture was passed through a phase separation. The organic layer was evaporated to give the title compound (13 mg, solid). 4 NMR (400 MHz, CDC13): 9·01 (1H, d), 8.69 (1H, d), 8.05 (1H, s), 8.00-7.90 (2H, m), 7.24-7.14 380 200836725 (2H , m) 〇Step 5: N-(3-f6-(4-fluoro-phenyl)-pyrazole and "1.5-alpyrazin-3-yl-1-yl}-acetamide 5 (N- n -f6-(4-Fluoro-phenvn-pvrazolof 1.5-a1r&gt;vrazin-3-vll-p henvll- acetamide&quot;)

In a microwaveable bottle, 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[l,5_a]pyridazine 10 (6-(4-fluoro_phenyl)-3-iodo_pyrazolo[l, 5_a]pyrazine, 13 mg, 0·04 mmol), 3-acetamidophenylboronic acid (14 mg, 0. 08 mmol) and PdCl 2dppf (3 mg) were dissolved in CH3CN (1 ml) and 2N Na2C03 (aq, 1 ml) Nitrogen gas was bubbled for 20 seconds to deoxidize. The bottle was sealed, stirred and heated in a microwave for 150 ° C for 30 minutes. After cooling, the reaction was mixed and the hydrazine I5 was separated as CH2Cl2/H2. The mixture was passed through a phase separation. The organic layer was evaporated, and the residue was purified by HPLC to afford compound (6 mg, solid). ^ NMR (400 MHz, Me-d3-〇D): 9.46 (1H,d),9·08 (1H,d),8·38 (1H,s),8·15·8·09 (3H,m ), 7.56-7.44 (3H, m), 7.31-7.21 (2H, m), 2.20 (3H, s). 381 20 200836725 EXAMPLES Inscription Compounds Chemical Name Method NM-R·Data MS 117 ^aF N-{3-[6-(4-Fluoro-phenyl)-e-pyrazolo[l,5-a] ° ratio Indole-3-yl]-phenyl}-ethnamine as in the above single example NMR (400 MHz, Me-d3-OD): 9.46 (1H, d), 9.08 (1H, d), 8.38 (1H , s), 8.15-8.09 (3H, m), 7.56-7.44 (3H, m), 7.31-7.21 (2H, m), 2.20 (3H, s). MS: [M+H]+347 Example 118 3-"4-Fluoro-jammapyrazolofl.5-alpyridin-3-yl 1-molly i 5 (3-F6-(4-Fluoro-phenvlVpvrazol〇ri,5-a&quot; |pvridin-3-vll-phen vl amine) Step 1: 3-(4-Galy-indolyl Vpyridine r3-(4-Fluoro-phenvn-pyridine) 3·Bromide (2.5 g, 15·8 mmol) And a solution of 4-fluorophthalic acid 10 (2.8 g, 20.0 mmol) dissolved in DME (20 ml) and 2N Na2CO3 (aq, 20 ml), deoxygenated via vacuum/re-nitrogenation (x2). PdCl2dppf (600 mg, 0.8 mmol), and the mixture was deoxygenated again (χ3). The reaction was heated to 80 ° C for 16 hours under nitrogen. After cooling to room temperature, the mixture was separated with Et0Ac/H20. Extraction. 15 concentrated extracts to saturate The aqueous solution was washed with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjj ,oil).咕NMR (400 MHz, CDC13): 8.83 (1H,brs),8·61 (1H,brs), 7.85 (1H,d),7·54 (2H,dd),7.39 (1H,brs ), 7.18 (2H, t). 20 Step 2: - Stupid base) - The mouth is more than squat and f 1,5-alp is more than -3 -acidic methyl group (6-(4-Fluoro-phenvlVpvrazolo" l ,5-alpvridine-3-carboxylic 382 200836725 acid methyl ester)

(O-(Mesitylenesulfonyl)hydroxyl amine, 3.5g, 16.2 5 mmol), 0, in a nitrogen atmosphere, once added to the scrambled mixture and dissolved in dryness

A solution of 3-(4-fluoro-phenyl)-pyridine (2.8 g, 16 mmol) of CH2C12. After 30 minutes, the ice bath was removed and the reaction was stirred at room temperature for 16 hours. The volatiles are removed in vacuo and the N-aminopyridine can be used directly without further purification. K2CO3 (4.4 g, 32 mmol) was added to the N-aminol ratio (~16 mmol) solution in the above-mentioned mixture at room temperature under nitrogen, followed by 2- in dry DMF (48 ml). A solution of 2-benzenesulfonyl-3_dimethylamino-acrylic acid 15 methyl ester (4.3 g, 16 mmol). • After 3 hours, the reaction was heated to 100 ° C for 2 hours at room temperature. After cooling to room temperature, the mixture was separated with EtOAc / H20. The aqueous layer was extracted with EtOAc (x2). The concentrated extract was washed with water (xl), saturated brine (xl), dried (MgS04), filtered and evaporated. The residue was purified by trituration in CH2C12 / pet. 4 NMR (400 MHz, CDCI3): 8.68 (1H, s), 8.42 (1H, s), 8.22 (1H, d)5 7.63 (1H, dd), 7·60·7·51 (2H, m), 7.23-7.14 (2H,m),3.94 (3H,s). 383 200836725 Step 3: 644-Fluoro-Mal-V-pyrazole, 5^Pyll (6-(4-Fluoro-phenvl)-pvrazol 〇n .5-alpvridine)

6-(4-Fluoro-phenyl)-pyrazolo[l,5-a]pyridine-3·carboxylic acid decyl ester 5 Ο 10 15 Ο 20 (6-(4-fluoro-phenyl)-pyrazolo [ l, 5-a]pyridine-3-carboxylic acid methyl ester, 1.08g, 4 mmol) and a mixed solution of NaOH aqueous solution (2n, 4ml) and EtOH (16ml) were stirred, heated to 85 °C, 30 under nitrogen hour. The reaction was cooled to room temperature then ice bath. 2N hydrochloric acid (5 ml) was slowly added. Filter to collect the solids, rinse with Et20 and dry in vacuo. The acid can be used directly without further processing. The above acid was suspended in polyphosphoric acid (~15 ml) under a nitrogen atmosphere and scrambled and heated to 150 °C. After 3 hours, the reaction was cooled to room temperature and poured carefully into ice water. Filtration The solid was isolated and dissolved in CH2C12. The solution was passed through a separate phase and then evaporated to give the compound ( 582 mg, solid). 4 NMR (400 MHz, CDC13): 8.66 (1H, s), 7·98 (1H, s), 7·63-7·51 (3H, m), 7.34 (1H, d), 7·17 (2H ,t),6·55 (1H, s)· Step 4: 6-(4-Fluoro-Momo V3-Break-pyrazolopyridine (6-(4-Fluoro-phenvlV3-iodo-pvrazolo"l i5- A1pvryjn—e)

384 200836725 N N-iodosuccinimide (630 mg, 2·8 mmol) was added to a 6-(4-fluoro-) mixture under nitrogen at room temperature. A solution of phenyl)-lazolo[l,5-a]acridine (6-(4-fluoro-phenyl)-pyrazolo[l,5-a]pyridine 5 500 mg, 2.4 mmol) in dry DMF (6 mL). After 45 minutes, the reaction was stopped with a saturated aqueous solution of sodium thiosulfate/saturated NaHC03 (1:1, 40 ml). The mixture was stirred at room temperature for 15 min then separated with EtOAc /EtOAc. The organic layer was washed with water (xl), saturated brine (xl), dried (MgSO4), filtered and evaporated. The residue was purified by trituration in petroleum to give the compound ( </ br> !H NMR (400 MHz, CDC13): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (lH, dd), 7-22-7.13 (2H, m) · Step 5: 3-"6-(4- gas-stupyl)-11 is more than fluorenyl, 5-alpfep--3-yl-phenylamine 15 (3-"6-(4-Fluoro-phenvl)- Pvrazol〇ma1pvridin-3-vll-phen vl amine)

6-(4-Gas-phenyl)-3-A-ϋ 并[1,5-a] (定(6,(4-fluoro-phenyl)-3_iodo-pyrazolo[l,5-a]pyridine , 20 140 mg, 0.41 mmol) and 3-aminophenylboronic acid pinacol ester (120 mg, 0.5 mmol) dissolved in a mixed solution of DME (2 ml) and 2N Na2C03 (aq, 2 ml). And deoxidized via vacuum / re-nitrogenation (x3). After the addition of PdCl2ddpf 385 200836725 (15 mg, 0·02 mmol), the mixture was again deoxygenated (χ2). The reaction was stirred and heated to 90 ° C for 24 hours under nitrogen. After cooling to room temperature, the mixture was separated at ch2ci2 / h2o. Use a split phase to layer. The organic layer was evaporated and the residue was purified mjjjjjjjjjjjj Example 119 1-Ethyl-3-indole-3-indolene 6-fluorene 4-fluoro-stylpyrazolo-[1,5-alpyridin-3-yl 1-phenyl}-urea oxime 10 (1-Ethvl-3 - {3-Γ6-i4-fluoro-phenvl)-pvrazol〇ri,5-alpvridin- 3-yll-phenvU-urea)

3_[6_(4_Fluoro-phenyl)-oxazolo[l,5-a;h-pyridin-3-yl]-phenylamine (3_[6-(4-fluoro-phenyl)-pyrazolo[ l J-abyridin-S-yU-iS phenyl amine) (Example 118, 50 mg, 0.16 mmol), Et3N (45 pL, 0.32 mmol), and ethyl isocyanate (26 pL, 0.32 mmol) It was stirred in dry DME (2 ml) and heated to 60 ° C for 24 hours under nitrogen [7 hours, then ethyl isocyanate (30 μM) was added. The reaction mixture was evaporated and dried in vacuo to give Compound (55 mg, solid) as shown in the title 20. iNMR (400 MHz, DMSO_d6): 9·09 (1 Η, s), 8.53 (1 Η, s), 8.36 (1 Η, s), 8.02 (1 Η, d) , 7.93-7.83 (3H,m),7·72 (1H,dd),7.38-7.29 (3H,m), 386 200836725 7·27·7·22 (2H,m),6·15 (1H,t ), 3.19-3.09 (2H, m), 1·08 (3H, t). Example No. Compound Chemical Name Preparation Procedure NMR Data (400 MHz, DMSO-4) MS 118 ^.nh2 3-[6-(4 -qi-phenyl)"pyrazolo[l,5-a]pyridin-3-yl]-phenylamine (3-[6-(4-Fluoro-phenyl)-pyrazolo[l,5-a]pyridi N-3 -yl] -phenylamine) The example "H NMR: 9.06 (1H, s), 8.28 (1H, s), 7.99 (1H, d), 7.93-7.81 (2H, m), 7.66 (1H, dd), 7.40-7.29 ( 2H,m), 7.11 (lH,t), 6.95 (1H, t), 6.85 (lH,d), 6.51 (lH,dd),5.14(2H,s). MS: [M+ H]+ 304 f, 387 200836725 \i/ ci •(5cn)ooOTtffiCN) 60.ε-6Γε X5I) SIVOxsfficss.卜丨ss first s 6ΓΖΓ8ΓΓ(ΡΡ worsl卜·/Λεffi£) eoo.ZTs·卜effiI) SOOXSKI) 9E00XS MI)rosooxsffiI) 60·6ώιι (SJn-{lx§qd •[J^-cn-u*»-Hppxd[03»AI]or-HozceIxd,(lx sqd-OJ Js-9)di ei,w· I) Tourmaline- (硪蚪-^-inch)-9]-two-£-硪0_1

82^031苳鸯驷 611

MS MS: [M+H]+ 456 MS: [M+H] + 390 NMR (400 MHz, Me-rfj-OD): 8.62 (1H, d), 7.86 (1H, t), 7.83-7.67 (4H, m), 7.46 (1H, t), 7.38-7.31 (2H, m), 7.28 (1H, d), 7.13 (2H, d), 4.76-4.65 (1H, m), 3.34-3.31 (2H , m), 3.28 (2H, q), 3.09-2.96 (2H, m), 2.22-2.08 (2H, m), 1.98-1.84 (2H,m), 1.19 (3H,t). (400 MHz, Me -d3-OD): 8.62 (1H, d), 7.90-7.75 (4H, m), 7.71 (1H, s), 7.46 (1H, t), 7.37 (1H, ddd), 7.33-7.22 (4H , m), 3.35-3.32 (2H, m), 2.82 (2H, t). Preparation step for 3-le^TsnSiS f Ξ 4 ^ T $4 ^ • f 4 half N &lt;蚪κ御1 3芟潜化学The name 1-ethyl-3-(3-{7-[4-(piperidinyloxy)-phenyl]-imidazole [l,2-a]pyridin-3-ylphenyl)-urea ( 1 -Ethyl-3 -(3 - {7-[4-(piperidin-4-y loxy)-phenyl]-imidazo[ 1,2-a]pyri din-3-yl} -phenyl)-urea) 1- (2-Amino-ethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-gland (1 - (2-Amino-ethyl)-3 - {3 -[7-(4-flu oro-phenyl)-imidazo[ 1,2-a]pyridi n-3 -yl] -phenyl} -urea) , 5 Examples No. fH CM T-H οοοοε 200836725

MS: [M+H]+ 404 MS: [M+H]+ 430 MS: [M+H]+ 359 (400 MHz, Me-d3-OD): 8.61 (1H, d), 7.85-7.77 (4H ,m),7.71 (1H,s),7·46 (1H,t),7·36 (1H, ddd), 7.33-7.19 (4H,m), 3.34-3.32 (2H,m),2·78 (2H,t), 1.79-1.70 (2H,m). (400 MHz, DMSO-d6): 9.51 (1H, s), 9.02 (1H, s), 8.85 (1H, s), 8.71 (1H, s ), 8.14 (lH, s), 8.01-7.90 (2H, m), 7.70 (1H, d), 7.50-7.29 (4H, m), 6.75 (1H, t), 4.03-3.90 (2H, m). (400 MHz, DMSO-d6): 9.75 (lH,d), 9.13 (lH,d), 8.76 (1H, s), 8.74-8.68 (2H, m), 8.54 (1H, s), 8.10 (1H, s), 8.01-7.93 (2H, m), 7.64 (1H, d), 7.46 (1H, d), 7.31 (lH,t), 6.15 (lH,t), 3.19-3.09 (2H, m), 1.08 (3H, t). Take the tear I I loose: jujube i 黢毽 $ $ 4 &lt; 3 硪 毽 C 硪 aluminum A 黢% 趑 province ^ 2 ^ gallium sf ^ S 邾 s ^ ^ H: S - ^ in ^ Ci 7 W ^ cA e Yu Liu, 1 14 Ning $ « , f ^ ^ Si κ gallium d, ^ aw QG difficult to identify two inches λ 5 a, 铋硪: 3⁄4 1-(3-amino -propyl)-3-{3-[7-(4-fluoro-phenyl)-imidazole [1,2-a] «pyridin-3-yl]-phenyl}-nuclear (1 -(3 - Amino-propyl)-3 - {3 -[7-(4-fl uoro-phenyl)-imidazo[ 1 2-a]pyrid in-3 -yl] -phenyl} -urea) l-{3-[6-(4-fluoro-phenyl)pyrazolo[l,5-a]pyrimidin-3-yl]- Phenyl}-3-(2,2,2-triethyl)-urea (1 - {3 -[6-(4-Fluoro-phenyl)-pyraz olo[l,5-a]pyrimidin-3-yl ]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea) 1-ethyl-3-[3-(6-e-base-e ratio 0 sits and [l,5-a] Pyrimidin-3-yl)-phenyl]-urea (1 -Ethyl-3 -[3 -(6-pyridin-4-yl-pyra zolo[ 1,5 -a]pyrimidin-3 -yl)-phenyl ]- Urea) w xy^z ia r—H τ-Η H 200836725

MS: [M+H]+ 360 \ MS: [M+H]+ 360 (400 MHz, DMSO-d6): 9.90 (1H, d), 9.48 (1H, d), 9.35 (1H, d), 8.84 -8.75 (2H, m), 8.72 (1H, d), 8.54 (1H, s)5 8.08 (1H, t), 7.64 (1H,d),7·49 (1H,d), 7.32 (lH,t ), 6.14 (lH,t), 3.18-3.09 (2H,m), 1.08 (3H,t). (400 MHz, DMSO-d6): 9.96 1 (1H5 d), 9.41 (1H, d), 9.33 ( (1H, d) , d), 7.32 (lH,t), 6.15 (lH,t), 3.19-3.09 (2H, m), 1.08 (3H, t). ft 4 Μ绔3 G #宁击砩起Q又^ V ^ ¥ t ^ ^ a (M ^ ^ ^ ^ ^ ^ ^ A A _ t〇苎砩^ Λ rl, ^ CA 鹓硪 every 0褎t U &lt;N Ί ^ will be if 4; ^ ψ ―cd P&gt ;-» 5 μ ί 呤目;g U·目 lf!| ,譬古爸s 〇A咛巧• rr-H 1 H —1~1 &gt;&gt;» PJ 〇r § 200836725 Γ: Ο

[Μ+Η] + 416 [M+H] + 415 1HNMR (400 ΜΗζ, DMSO-d6): 9.44 (1 Η, m), 9.87 (lH, m), 8.89 (lH, m), 8, 61 (1H, s), 8.38 (1H, s), 8.11 (2H, s), 7.67 (1H, dd), 7.43 (1H, dd), 7.33 (lH, t), 6.80 (lH, t), 3.97 (2H, m ), 3.93 (3H, s) lHNMR (400MHz Me-d3-OD): 8.58 (1H, d), 8.21 (2H, m), 8.02 (1H, s), 7.85 (1H, s), 7·80 ( 1H, s), 7_76 (1H, s), 7.50 (1H, t), 7.40 (1H, dd), 7.36 (lH, dd), 7.30 (lH, dd), 3.98 (3H, s), 3.96 (2H ,m). —二 A · ^ &lt; A 2Ϊ|Ι|ί|〇^ ?褊笆 every 4 ί 5 gallium; 糠会之硪,硪tl ^ ^ &lt;N 〇cT i ^ ιΛ ^ 'Ί 〇 ^ SS 5 ^ ^ ^ ? lit jSf |l§ 1-{3_[7_(1_methyl-1H-pyrazol-4-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl }-3-(2,2,2-Trifluoro-ethyl)-ureacarboxylate (l-{3-[7-(l-Methyl-lH-pyrazol-4-yl)-imidazo[ 1,2 -a]pyridin-3-yl]-p henyl}-3-(232,2-trifluoro-ethyl)-ur ea formate) (NH 200836725

[M+H] + 358 [M+H] + 358 [M+H] + 347 [M+H] + 308 1H NMR (400 MHz, CDC13): 8.68 (1H,d),8·67 (1H, d), 8.46 (1H, d), 8·28 (1H, s), 7.90 (1H, s) 5 7·76 (1H, s), 7·69 (1H, s), 7.51 (1H, d) , 7.50 (1H, d), 7.34 (2H, d), 7.14-7.11 (lH, m), 7.08 (1H, dd), 5·86 (1H, s), 3.33 (2H, qt), 1.18 (3H) , t) 1H NMR (400 MHz, CDC13): 8.87 (1H, d), 8.63 (1H, dd), 8.46 (1H, d), 8.12 (13⁄4 s), 7.96-7.88 (1H, m), 7· 84 (1H, s), 7.67 (1H, t), 7.65 (lH, s), 7.45-7.31 (3H, m), 7.11 (lH, d), 7.08 (lH, dd), 5.77 (lH, s) , 3.32 (2H, qt), 1.18 (3H, t) 1H NMR (400 MHz, Me-d3-OD)·· 8.55 (1H,d),8-12 (1H,s), 7.80 (1H, t) ,7·74 (1H, s), 7.67 (1H, s), 7.65 (1H, t), 7.45 (lH, t), 7.36 (lH, d), 7.26 (2H, dd), 7.01-6.93 (1H , m), 3.27 (2H, q), 1.19 (33⁄4 t). 1H NMR (400 MHz, Me-d3-OD): 8.82 (13⁄4 d), 8.36 (1H, d), 8.08 (1H, s), 7·91 (1H, s), 7.89-7.81 (2H, m), 7.70 (1H, dt), 7·49 (1H, s), 7.46 (1H, dd), 7.34-7.23 (2H, m ). &lt ;s ' ^ 1 boast ball ginseng, I ^ &lt; \ 1 electric 镏芟 ί ^ $ ^ &lt; \ 1 electric 镏 &lt; i &lt; t l l Ξ cA Ί Record today cd 4 &lt;N s -祀5 f + 1趑S # 1-ethyl-3-[3-(7-pyridin-4-yl-imidazo[l,2-a]acridin-3-yl)-phenyl]-urea (1 - Ethyl-3 -[3 -(7-pyridin-4-yl-imid azo[ 1 ?2-a]pyridin-3 -yl)-phenyl]-ur ea) 1-ethyl-3-[3-(7 -pyridin-3-yl-imidazo[l,2-a]acridin-3-yl)-phenyl]-urea (1 -Ethyl-3 -[3 -(7-pyridin-3 -y 1-imid azo [ 1 ? 2-a]pyridin-3 -yl)-pheny l]-ur ea) eg 2 4 5 J 〇^ ^ r—4 tH O ^ L—JN cd 7-(4-gas-phenyl) -3-(2-gas) ratio 1,4--4-)-imidazole [l,2-a] fluorene (7-(4-Fluoro-phenyl)-3-(2-fluoro-pyridin-4-yl) )-imidazo[ 1 ?2-a]pyridi ne) \ \ \ LL· iH cn iH CN mt-H 200836725 [M+H] + 374 [M+H] + 393 [M+H] + 362 1HNMR (400 (M,,,,,,,,,,,,, , 7.52-7.42 (2H, m), 7.36 (1H, dd), 7.30 (1H,d),3·27 (2H,q), 1.19(33⁄4 t). 1HNMR (400 MHz, DMSO-d6): 9.12 (1H, s), 8.80 (1H, d), 8.38 (lH, s), 8 .23(13⁄4 s), 8.06-8.00 (2H, m), 7.92 (1H, s), 7.85 (1H, dd), 7.53-7.50 (2H, m), 7.46 (2H, t), 7.31 7.27 (1H, m), 6·65 (1H, t), 4·47 (2H, dt), 3.42 (2H, dq). lHNMR (400MHz, DMSO-d6): 9·44 (1H, dd), 8.95 (1H, dd), 8.60 (lH, s), 8.50 (1H, s), 8.38 (1H, s), 8.12 (1H, s), 8.06 (lH?t), 7.60 (13⁄4 dd), 7.45 (lH, dd), 7.29 (lH, t), 6.11 (13⁄4 t), 3.92 (3H, s), 3.13 (2H, m), 1.08 (3H, t) &lt; 5 J i&amp;N ^ &lt; ιβ, \ m ^ 1 ‘琴 &lt; ‘ Cui 1 避 I have 0 褎 Ξ 镓 二 Λ f ^ f 5 (five) about? . f W 蝙私硪9硪5 乐44硪々π 1 κ “ ω — ΙΦΚΛ but inch” _ f ^ G , 宁娜味&lt;7 γ办1-ethyl-3-{3-[7-(l -oxyl~4~yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-mai (1-Ethyl-3 - {3 -[7-( 1 -oxy-pyridin -4 -yl)-imidazo[ 1,2-a]pyridin-3-yl]-p henyl}-urea) 1-(2-fluoro-ethyl)-3-{3-[7-(4-fluoro -phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-urea hydrochloride (1-(2-Fluoro-ethyl)-3 - {3 -[7-(4-flu) Oro-phenyl)-imidazo[ 1,2-a]pyridi n-3-yl]-phenyl} -urea Hydrochloride) i- 1-ethyl-3-{3-[6-(l-methyl-1H- Pyrazol-4-yl)-ntb σ sits and [1,5-a] shouts 3-amino]-phenyl}-urea (1 -Ethyl-3 - {3 -[6-( 1 -methyl-) 1 H-py razol-4-yl)-pyrazolo[ 155-a]pyrimi din-3 -yl]-phenyl} -urea) 'V % Li. \ % 1 , 1 1 cn m 200836725

[M+H] + 374 [M+H] + 442 [M+H] + 412 [M+H] + 370 1HNMR (400 MHz, Me-d3-OD): 8.81 (1H, s), 8.70 (lH , d), 8.39 (lH, d), 8.09-8.01 (2H, m), 7.85 (lH, t), 7.80 (lH, s), 7.69 (1H, dd), 7.47 (1H, t), 7.41-7.31 (2H,m), 7.28 (1H,d), 3.27(2H,q), 1.19(3H,t). 1HNMR (400 MHz, DMS0-d6): 8.96 (1H, s), 8.59 (1H , d), 8.41 (lH, d), 8.05 (1H, dd), 7.91 (1H, s), 7.78 (2H, d), 7.48-7.38 (2H, m), 7.35-7.22 (2H, m), 6.85 (1H, t), 6.52 (1H, d), 4.01-3.89 (2H, m), 3.55 (3H, Λ_ 1HNMR (400 MHz, DMS0-d6): 9.51 (1H, s), 9.02 (1H, s ), 8.79 (1H, s), 8.71 (1H, s), 8.12 (1H, s), 8.00-7.90 (2H, m), 7.68 (1H, d), 7.50-7.29 (4H, m), 6.50 (lH,t),6.08 (lH,t), 3.63-3.49 (2H, m). 1HNMR (400 MHz, DMS0-d6): 9.60 (1H,d), 8.88-8.82 (1H,m),8.71 (2H, s), 8.06 (1H, s), 7.64 (1H, d), 7.46 (1H, d), 7.34 (lH, t), 6.74 (1H, t), 4.01-3.89 (2H, m). CN stomach residual β 硪 毽 $ &lt; ^ ^ K 1 1 毽 $ ^ ^ ^ ^ f ϊ: ^ Ω buckle gallium two two Electric two-^砩砩Kq «μ ^ ^ 1 tO ^ ^ ^ S ΐά J 5 ^ 3 S ^ i4 ^ v ^ ^ ve ^ shout a v〇1 HH (N · ^ κ ^ vS S Φ 铋 铋蛱一:ζ; 铋 bond gallium 1-ethyl-3-{3-[7-(1-oxy-η-pyridin-3-yl)-imidazole [1,2-a] 咐 pyridine-3- -1 -Ethyl-3 - {3 - [7-( 1 -oxy-pyridin-3 -yl)-imidazo [ 1,2-a]pyridin-3 -yl] -p henyl} -urea) 1-{3-[7-(1-indolyl-6-oxy-1,6-dihydro-σ~^^-3-yl)-flavors[1,2-a] ΐI Ratio t^-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(1 -Methyl-6-oxo-1, 6-dih ydro-pyridin-3 -yl)-imidazo[ 1,2-a] pyridin-3 -y 1] -phenyl} -3 -(2,2,2-trif luoro-ethyl)-urea) 1 - (2,2-difluoro-ethyl)-3 - {3-[6-(4-fluoro-phenyl)-oxazolo[l,5-a]pyrimidin-3-yl]-phenyl} -pulse (l-(2?2-Difluoro-ethyl)-3-{3-[6-(4-fluoro-phenyl)-pyrazolo[ 1,5-a]py rimidin-3 -yl] -phenyl} - Urea) 1-[3·(6-chloro-pyrazolo[l,5-a]pyrimidin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1 -[3 -(6-Chloro-pyrazolo[ 1,5-a]py rimidin-3 -yl)-phenyl] -3 -(2,2,2-trif luoro-ethyl)-urea) % &gt; =〇V工 v· v〇m 卜m rH 〇〇m fH On m rH 200836725 [M+H] + 394.12 [M+H] + 455 1 [M+H] + 459 lHNMR (400MHz? DMSO_d6): 9.51 (lH, s), 9.02 (1H, s ), 8.74-8.64 (2H, m), 8.10 (1H, s), 8.01-7.90 (2H, m), 7.66 (1H, d), 7.50-7.35 (3H, m), 7.32 (1H, t), 6.41 (lH,t),4·48 (2H, dt), 3.43 (2H,dq). 1HNMR (400 MHz, Me-d3-0D): 8.81 (1H,d), 8.15 (lH,s), 8.13 -8.01 (2H,m), 7.82 (1H,dd),7.58 (1H, t),7.52-7.35 (4H,m),7.06 (1H,d),6.11 (2H, s), 3.96 (2H, q 1HNMR (400 MHz, Me-d3-OD): 8.86 (1H, d), 8.19 (2H, d), 8.07 (1H, t), 7.87 (1H, dd), 7.66-7.55 (2H, m) , 7.55-7.28 (4H,m),4.04 (3H,s), 3.96 (23⁄4 q). 铋β S襃毽^ ^ Λ砭琶Μ - 5 difficult mii ^ $^4- Jh 'πγ1 ^ 3 θ + &lt; 厶 厶 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 -Fluorol phenyl carbazolo[l,5-a]pyrimidin-3-yl]-phenyl}-urea (1 -(2-Fluoro-ethyl)-3 - {3 -[6-(4- Flu oro-phenyl)-pyrazolo[ 1 ?5-a]pyrim idin-3-yl]-phenyl} -urea) 1-Ρ-(7-benzo[1] 3] Dioxol-5-yl-imidazo[l,2-a]acridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea Hydrochloric acid (l-[3-(7-Benzo[l,3]dioxol-5-yl-i midazo [ 1,2-a]pyridin-3 -yl)-pheny l]-3-(2,^,2 -tri0uoro-ethyl)-urea Hydrochloride) l-{3-[7-(4-Fluoro-3-dimethoxy-phenyl)-imidazole [l,2-a]acridin-3-yl]-benzene }}-3-(2,2,2-tris-ethyl)-urea hydrochloride (1 - {3 -[7-(4-Fluoro-3 -methoxy-ph enyl)-imidazo[ 1,2-a ]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea Hydrochloride) LL \ °Λ°工z&gt;=〇LL· or—K 2 200836725

[M+H] + 429 [M+H] + 426 1 [M+H] + 405 1HNMR (400 MHz, Me-d3-OD): 8.87 (1H, d), 8.21 (1H, s), 8.20- 8.16(13⁄4 m), 8.09-8.01 (lH,m), 7.85 (1H, dd), 7.79-7.53 (4H,m), 7.49-7.38 (2H, m), 7.38-7.28 (1H,m),4.03 -3.89 (2H,m). 1HNMR (400 MHz, Me-d3-OD): 8.85 (1H?d), 8.69 (lH,d), 8.19-8.13 (3H,m), 7.95 (1H,s), 7.91-7.75 (2H,m), 7.56-7.44 (2H,m), 7.41 (2H, dd), 7.33 (1H,d),3·96 (2H,q), 2.62 (3H, s). 1HNMR ( 400 MHz, DMSO-d6): 9.51 (1H, d), 9.01 (1H, d), 8.69 (1H, s), 8.57 (1H, s), 8.08 (1H, s), 7·95 (2H, dd ), 7·64 (1H, d), 7.46 (1H, d), 7.40 (2H, t), 7.30 (lH, t), 6.20 (1H, t), 3.23-3.10 (2H, m), 2.61 ( 2H, t), 1.58-1.48 (2H, m). &lt;NJ Block 0 S ^ ^ ^ £ f5 f 灭德1轵二i硪硪K r&lt;m^ f ^ t ψ 4 Ηζ &lt;N ^ &quot ; ^ f ig ^ v »1 硪 ^ ^ ^ 人 轵鹓蚪 砩 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3 -[7-(3 -Fluoro-pheny l)-imida zo[l ,2-a]py Ridin-3-yl]-phenyl} -3-( 2,2,2-triiluoro-ethyl)-urea Hydrochloride) l-{3-[7-(6-methyl-pyridin-3-yl)-imidazole [ l,2-ap ratio -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea formate (1 - {3 -[7-(6-Methyl) -pyridin-3 -yl)-i midazo[ 1,2-a]pyridin-3 -yl] -pheny 1} -3 -(2 tri 2-triiluoro-ethyl)-urea Formate) 1 -(3 -amino- Propyl)-3 - {3 - [6-(4-Gas-phenyl)-oxazolo[l,5-a]pyrimidin-3-yl]-phenyl}-urea (1 -(3 - Amino) -propyl)-3 - {3 - [6-(4-fl uoro-phenyl)-pyrazolo[ 1,5-a]pyri midin-3 -yl]-phenyl} -urea) work z xz&gt;=〇% LL IZ LL· %工, fH 200836725

[M+H] + 491.16 [M+H] + 347 [M+H] + 391.13 1HNMR (400 MHz, DMSO-d6): 9.51 (1H, d)? 9.02 (1H,d), 8.69 (1H, s ), 8.64 (1H, s), 8.10 (1H, s), 7.95 (2H, dd), 7·64 (1H, d), 7.49-7.35 (3H, m), 7.31 (lH, t), 6.87 ( lH, t), 6.27-6.18 (lH, m), 3.21-3.10 (2H, m), 3.08-2.98 (2H, m), 1.40 (9H, s). 1HNMR (400 MHz, DMSO-d6): 8.90 (1H5 s)5 8.72 (1H,d), 8.51 (2H, s), 8.31 (1H, s), 8.09 (1H, s), 7.92 (1H, s), 7.83 (1H, d), 7 · 48 (2H, d), 7.25 (1H, d), 6.36 (lH, s), 3.13 (2H, d), 1.07 (33⁄4 t). 1HNMR (400 MHz, DMSO-d6): 9.50 (1H, d ), 9.00 (1H, d), 8.77 (1H, s), 8.67 (1H, s), 8.11 (lH, s), 7.94 (2H, dd), 7.65 (1H, d), 7.49-7.34 ( 3H,m), 7.30(lH,t),6.38(lH,s), 3.26-3.15 (23⁄4 m), 2.80-2.69 (2H, m). 4 J ^ ^ K¢-铋人蛱_ β 3褎硪鹓^ ^ ιΛ Ο , 5 ^ 丄Η ^ ^ # f ® Λ ^ ^ h 铋蚪cs ν硪潜^ j ; c 5 household wf test ^ 5 fv ^ ^ Γ袒 umbrella 4; two j bow drive κ丨ί会_ ^ &lt; \ ^ ^ ^ Driving gallium · 聋 3 and gallium 1 轵毽 &lt; 彳砩淞 4窆地 l 4 钟钟 I Z Z遂人' per β 0 f硪, ^ ^ ιΛ ^ κ3 ^ Μ ·莩秾f {g 铋蚪e V硪潜乐[2-(3-{3-[6- (4-Fluoro-phenyl)-hydrazino-[l,5-a]pyrimidin-3-yl]-phenyl}-urea)-ethyl]-carbamic acid tert-butyl ester ([2-(3- {3 -[6-(4-Fluoro-phenyl)-py razolo[ 1 ?5-a]pyrimidin-3-yl]-phen yl}-ureido)-ethyl]-carbamic acid tert-butyl ester) 1-B 3-(3-[7-(1Η-pyrazol-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-urea hydrochloride (1-Ethyl-3 - { 3-[7-( lH-pyrazol-4-yl )-imidazo[ 1 ?2-a]pyridin-3-yl]-phe nyl}-urea Hydrochloride) 1-(2-Amino-ethyl)-3- {3-[6-(4-Fluoro-phenyl)-oxazolo[l,5-a]pyrimidin-3-yl]-phenyl}-yl (1-(2-Amino-ethyl)-3 - {3 -[6-(4-flu oro-phenyl)-pyrazolo[ 1 ?5-a]pyrim idin-3 -y 1] -phenyl} -urea) u. \z xzr2^ U. τ-H 200836725 [ M+H] + 411 [M+H] + 524 [Μ+Η] + 444 1HNMR (400 MHz, Me-d3-OD): 8.91*8.83 (1H, m), 8.19 (2H, s), 8.06 ( lH, s), 7.91 (3H, dd), 7_68-7.54 (4H, m), 7.50-7.37 (2H, m), 4.02-3.91 (2H, m). 1HNMR (400 MHz, Me-d3-OD) : 8.90 (1H, d), 8.23 (2H, d), 8.11-7 .95 (3H, m), 7.90 (1H, dd)5 7.78-7.70 (1H, m), 7.70-7.54 (2H, m), 7.50-7.37 (2H, m), 3.96 (2H, q), 3 · 77 (6H, s), 3.60-3.49 (2H, m). 1HNMR (400ΜΗζ, DMSO-d6): 9.65 (1Η,d),9·14 (2H,s),9.06 (1H, d),8.86 (1H, s), 8.74 (lH, s), 8.16 (lH, s), 7·69 (1H, d), 7.45 (1H, d), 7.35 (1H, t), 6.74 (lH, t), 1 23 5 二 二 二 二 二 二 二 二c ¥ 1 _[3-(7-phenyl-imidazole [1,2-a]. Bispin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -[3 -(7-Phenyl-imidaz0[ 1,2-a]py Ridin-3 -yl)-pheny 1] -3 -(2?2?2-triflu oro-ethyl)-urea Hydrochloride) 1-(3-{7-[3-(? )-phenyl]_imidazole [l,2-a]acridin-3-ylphenyl)-3-(2,2,2-tris-ethyl)-urea hydrochloride (1 -(3 - { 7-[3 -(Morpholine-4-carbon yl)-phenyl]-imidazo[ 1,2-a]pyridin -3 -yl} -phenyl)-3 -(2,2,2-trifluoro-e thyl)- Urea Hydrochloride) ^{346-(2-Dimethoxy-pyrimidin-5-yl)-pyrazolo[l,5-a]pyrimidin-3-yl]-phenyl}-3-(2,2, 2-Trifluoro-ethyl)-urea (1 - {3 -[6-(2-Methoxy-pyrimidin-5 -yl)-pyrazolo[ 155-a]pyrimidin-3 -yl]-phenyl}-3-( 2,2,2-trifluoro-ethyl )-urea) % o ZEZ^. 2jr/ ? Os τ—Η in 200836725 [M+H] + 427 [M+H] + 412 [M+H] + 414 1HNMR (400 MHz, DMSO-d6): 9.99 (1H, d), 9.26 (lH , d), 9.04 (lH, s), 8.91-8.82 (2H, m), 8.48 (1H, s), 8.38 (1H, d), 8.22 (1H, s), 7.70 (1H, d), 7.45-7.31 (2H, m), 6.92 (lH, t), 4.03-3.89 (2H, m), 2.78 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 9.28-9.21 (1H, m), 9.03-8.96 (1H, m), 8.62 (1H, s), 8.22 (1H, s), 7·83 (3H, d), 7.64-7.47 (3H, m), 7.40 (2H, d) , 3.99 (2H, q). 1HNMR (400 MHz, DMS0-d6): 9.76 (1H, d), 9.36 (2H, s), 9.28 (lH, s), 9_13 (lH, d), 8.91 (1H, s), 8.78 (1H, s), 8.17 (lH, s), 7.70 (lH, d), 7.46 (1H, d), 7.35 (lH, t), 6.79 (13⁄4 t) 5 4.01-3.91 (23⁄4 m ). »1 ^ 4 ^ f ^ ^ ig hit a gallium &lt; dive, 1 _ electric ® VO A ^ iS 毽w 趑 5 truss one gallium &lt;1 ^ . &quot; f 5 ® ^ m ξp ^ ^ W Ψ 13⁄4 1-{3-[6-(2-Methyl-pyridin-4-yl)-oxazolo[l,5-a]0 crypt-3-yl]-phenyl}-3-( 2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3 -[6-(2-Methyl-pyridin-4-y 1)-pyrazolo [ 1 ? 5 -a] pyrimidin- 3 -y 1] -ph enyl} -3 -(2,2?2-trifluoro-ethyl)-ure a Hydrochloride) 1-[3-(6-Phenyl-oxazolo[l,5-a]pyrimidine 3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-nuclear (1 -[3 -(6-Phenyl-pyrazolo[ 1,5-a]py rimidin-3 -yl)-pheny 1] -3 -(2,2,2-trif luoro-ethyl)-urea) l-[3-(6-pyrimidin-5-yl-oxazolo[l,5-a] shout 3-yl)-phenyl]-3-(2,2,2-difluoro-ethyl)-urea (1 -[3 -(6-Pyrimidin-5 -y 1-pyrazolo [ 1,5-a ]pyrimidin-3 -yl)-phenyl]-3 -( 2,2?2-trifluoro-ethyl)-urea) rr\^F q % X〇iX % ^〇iX CN ?! 5; 200836725

[M+H] + 402 [M+H] + 429 [M+H] + 304.08 1HNMR (400 MHz, DMSO-d6): 9·48 (1H,d),9.02 (1H,d),8.91 (1H ,s), 8.69-8.59 (1H,m),8·33 (2H,s),8.17-8.09 (13⁄4 m), 7.67 (1H, d), 7.47-7.38 (lH,m),7.33 (lH, t), 6.85-6.75 (1H, m), 4.02-3.90 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9·49 (1H,d), 8.98 (1H,d),8.88 (1H) , s), 8·78 (2H, s), 8.68 (lH, m), 8.13 (lH, s), 7.68 (1H, d), 7.44 (1H, d), 7.34 (1H, t), 7.10 ( 2H, br), 6.77 (1H, t), 3·98 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.52 (1H, s), 8.01 (1H, s), 7·78 (2H) , dd), 7.68 (1H, d), 7.62 (1H, d), 7.37-7.20 (3H, m), 6.84 (1H, s), 6.76 (13⁄4 d), 6.68 (1H, d), 5.52 (23⁄4 s). ^ G 5 Record M ^ κ ^ ^ - a More than S 4 to do κ e flavor \ 余卜 arsenic. Pigeon gallium private S domain; =; "Half half \ now destroy ^ Ψ A 5 ® 硪阳 $盘绪 f ^ ^ 余2Ning 轵 _ a gallium C毽〇^ gallium.3⁄4 λΚ m private ball _ _ _ 1邾邾1-{3-[6-(1Η-ηBizozol-4-yl)-η-biazo[l,5-a]pyrimidin-3-yl]-phenyl}-3-( 2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3 -[6-( 1 H-Pyrazol-4-yl)-pyraz olo[l?5-a]pyrimidin-3-yl] -phenyl} -3 -(2,252-trifluoro-ethyl)-urea Hydrochloride) l-{3-[6-(2-Amino-pyrimidin-5-yl-carbazolo[l,5-a]pyrimidine-3- ]]-phenyl}-3-(2,2,2-di-ethyl-hydroxy)-hydrochloride (1 - { 3 - [6-(2-Amino-pyrimidin-5 -yl )-pyrazolo [1, 5-a]pyrimidin-3 -y 1]-phenyl} -3 -(2,2,2-trifluoro-ethy 1)-urea Hydrochloride) 3-[5-(4-Gas-phenyl)-Ben 11 1-1-yl]-phenylamine (3-[5-(4-Fluoro-phenyl)-benzoimi dazol-1 -yl]-phenylamine) \ gas y ZZZ LL h2n^n u_ \ in VO rH 200836725 [M+H] + 443 [M+H] + 375.12 [M+H] + 611 1HNMR (400 MHz, DMSO-d6): 9·41 (1H, s), 8.95 (1H, s), 8.84 ( lH, s), 8.68 (1H, s), 8.39 (lH, s), 8.15 (lH, s), 8.00 (13⁄4 d), 7.68 (lH, d), 7.42 (lH, d), 7.34 ( lH,t), 6.80-6.70 (1H,m),6·56 (1H,d),4.04-3.89 (2H,m),3·55 (3H,s). 1HNMR (400 MHz, DMSO-d6) : 9·26 (1H, s), 9.03 (1H, s), 8.09 (1H, s), 8.07-7.99 (1H, m), 7.87-7.76 (4H, m), 7.52 (lH, t), 7.43 (lH,d), 7.34 (2H,t),7·27 (1H,d),6.39 (1H, s), 3.13 (2H, q), 1.07 (3H,t). 1HNMR (400 MHz, DMSO- D6): 9.54 (1H, d), 9.04 (lH, d), 8.85 (lH, s), 8.72 (lH, s), 8.15 (lH, s), 7.70 (lH, d), 7.53-7.40 (4H , m), 7.34 (1H, t), 7.07 (lH, d), 6.76 (lH, t), 4.79-4.71 (1H, m), 4.02-3.91 (2H, m), 3.77-3.66 (2H, m ), 3.22 (2H,t), 1.98 (2H,d), 1.63-1.51 (2H,m),1.42 (9H,s)· ^ ^ ^ 0 0 &gt;0 ^ ^ ^ 5 1 — S j 〇^ Ph - one AM β soil hit one ember _ 1-{3-[6-(1-methyl-6-oxy-1,6-dihydro-0 ratio bite ~3 -yl)-° ratio σ Sodium [1,5-a]-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 - [6-( 1 -Methy l) -6-oxo-1,6-dih ydro-pyridin-3 -yl)-pyrazolo[ 1,5-a ]pyrimidin-3-yl]-phenyl}-3-(2?2?2 -trifluoro-ethyl) -urea) 1-ethyl-3-{3-[5-(4- defeat- Phenyl)-benzimidazole-1-(yl)-phenylphenylurea hydrochloride (1 -Ethyl-3 - {3 - [5 -(4-fluoro-phenyl)-benzoimidazol-1 -yl]-phenyl} - Ur ea Hydrochloride) 1 1 1 4-[3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)]-phenyl}-atba sits and [l,5-a ][-[3-(3-{3-[3-(2,2,2-Trifluoro-ethyl))]-[Phenyl]-phenoxy]-piperidine-1-carbonate tert-butyl ester -ureido]-phenyl} -pyrazolo[ 1,5-a]pyrimidin-6-yl)-phenoxy]-piperi dine-1-carboxylic acid tert-butyl ester) V LL % 〇0,o °x oo ON s 200836725

[M+H] + 359 [M+H] + 361 [M+H] + 511 1HNMR (400 MHz, DMSO-d6): 9.77 (1H, d)5 9.38 (1H,d), 8.79-8.70 (2H , m), 8.52 (lH, s), 8.22 (lH, d), 8.07 (13⁄4 s), 7.99 (lH, t), 7.65 (lH, d), 7.53-7.42 (2H, m), 7.31 (lH , t), 6.13 (lH, t), 3.20-3.08 (2H, m), 1.08 (3H, t). 1HNMR (400 MHz, DMSO-d6): 8.88 (1H?s), 8.71 (1H, d) , 8.l (lH, s), 7.95 (1H, s), 7.90 (1H, s), 7.75 (1H, d), 7.53-7.41 (3H, m), 7.28-7.20 (1H, m), 6.43 (1H,d), 6.34 (1H, d), 3.18-3.08 (2H, m)5 2.44 (3H? s), 1.07(33⁄4 t). ! 1HNMR (400 MHz, DMSO-d6): 9.54 (1H , d), 9.09-9.02 (1H, m), 8.89 (1H, s), 8.75-8.69 (13⁄4 m), 8.65-8.55 (2H, m), 8.18 (lH, s), 7.71 (1H, d), 7.56-7.44 (3H, m), 7.41-7.31 (2H, m), 7.10 (lH, d), 6.80 (1H, t)5 4.86-4.80 (1H, m), 4.01-3.91 (2H, m), 3.31 (2H, brm), 3.17-3.07 (2H, m), 2.22-2.12 (2H, m), 1.94-1.83 (2H, m). u ^ ^ m df ϊ &lt;N ^ ^ KK Zhao Salary per ^ ^ ^ ^ 硪^ 4Φ &lt; ^ ^ m ^ &lt; 1 ^ 1 Φν ^ ^ '1 ^ 4v '1 S s S ^ ^ I £ $min s g ¥ $录^ 5 ^ - ί 铋德轵黢b, 丨定1-ethyl-2-yl-σ ratio 0 sits and [l,5-a]pyrimidin-3-yl)-phenyl]-urea (1 -Ethyl-3 -[3 -(6-pyridin-2-yl-pyra zolo[ 1,5-a]pyrimidin-3 -yl)-phenyl ]-urea) 1-ethyl-3-{3- [7-(5-Mercapto-furan-2-yl)-imidazole [l,2-a] bite &gt; 3-yl]-phenyl phenylurea (1-Ethyl-3 - {3 - [7- (5 -methy 1-furan-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl}-urea) 1-(3-{6-[3-(piperidin-4- Benzyl)-phenyl]-oxazolo[l,5-a]pyrimidin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -(3 - {6-[3 -(6)(Piperidin-4-yloxy)-p henyl]-pyrazolo[ 155-a]pyrimidin-3 -yl} -pheny 1)-3 -(2,2,2- Trifluoro-et hyl)-urea hydrochloride salt) % l % CH^ZI Fly. iX s 1 &lt; ss rH 200836725 [M+H] + 461 [M+H] + 525 1HNMR (400 MHz, DMSO-d6): 13.55 (13⁄4 s)? 9.41 (1H, s), 8.45 (13⁄4 d) , 8.02 (13⁄4 s), 7.84 (1H? s)? 7.49 (2H, m), 7.35-7.20 (2H, m), 7.11(lH,t), 6.88 (1H,d),3·95 (2H, q), 3.84-3.69 (4H, m), 3.50-3.27 (4H, m), 2.18 (3H, s) 1HNMR (400 MHz, DMSO-d6): 9.58 (1H,d), 9.06 (1H,d) , 8.89-8.82 (1H, m), 8.73 (1H, s), 8.14 (1H, s), 8.03-7.90 (2H, m), 7.75-7.58 (2H, m), 7.47 (2H, dd), 7.35 (lH,t), 6.75 (1H,t), 4.03-3.90 (2H,m),3.59 (8H,brs). ^ Λ ή. ^ a « 必铋ul ® Recording A.私私 vo t4 口 « « ^ ^ Μ 3? ^ f pq ώ -115 1 黢 · · 硪 & & & & NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 7-(4-Ethyl-piperazin-1-yl)-imidazole [l,2-a]acridin-3-yl]phenyl}-3-(2,2,2-tri-H-ethyl )-urea hydrochloride (1 - {3 -[7-(4-Acetyl-piperazin-1 -y 1) -imidazo[l,2-a]pyridin-3-yl]-phen yl} -3 -( 2,2,2-triduoro-ethy l)-urea hydrochloride salt) 1 -(3 - {6 - [3 -(?)-4-phenyl)-phenyl]_pyrazolo[l,5-a Pyrimidine-3-ylphenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1 -(3 - { 6-[3 -(Morpholine-4-carbon yl)-phenyl ] cone pyrazolo[ 1,5-a]pyrimi din-3-yl}-phenyl)-3-(2,2,2-trifluor o-ethyl)-urea) Q &gt;=〇IEZ Q production&quot;C eight o, 〇r Iz^ U· s 1-H yr\ vo 200836725

[M+H] + 611 [Μ+Η] + 305.03 [M+H] + 430 1HNMR (400 MHz, DMSO-d6): 9·44 (1H,d), 9.01 (1H,d), 8.90 (lH , s), 8.68 (1H, s), 8.13 (1H, s), 7.82 (2H, d), 7·69 (1H, d), 7.45 (1H, d), 7.34 (1H, t ), 7.15 (2H, d), 6.81 (1H, t) 5 4.71-4.65 (13⁄4 m), 4.01-3.91 (2H, m), 3.74-3.64 (2H, m), 3.28-3.16 (2H, m) , 1.95 (2H, s), 1.62-1.51 (2H, m), 1.42 (9H, s). 1HNMR (400ΜΗζ, DMSO-d6): 8·82 (1Η, s), 8.71 (1Η, d), 8 ·45 (1Η,d),7·85 (2Η, dd), 7.35 (2Η,t), 7.23 (1Η,t), 7.14(lH,t),6.97(lH,d),6.66 (1H,d ), 5·47 (2H, s). 1HNMR (400 MHz, Me-d3-OD): 10.41 (1H, d), 9.88 (1H, d), 9.72 (13⁄4 s), 9.55 (13⁄4 s), 8.95 (1H, s), 8.69-8.55 (2H, m), 8.51 (lH, d), 8.41 (lH, q), 8.27 (1H, d), 8.21-8.08 (2H, m), 7.62 (1H, t ), 4.81-4.71 (2H, m). mitk w pen each time ^ ^ '1, ^ 铋M singular A β φ preparation P3, μ埏_ gallium _ Cheng V 〇 private A, ^ KS {g ^ ^ ^ sgg § 'stpll Slpfil i«Write 11 4 鋈硪S ^ II II! 1 IS Off S § -SS呤vA 1-{3-[6-(3-Fluoro-phenyl)"-pyrazolo[l,5-a]pyrimidin-3-yl]-phenyl}-3-(2,2,2-trifluoro -ethyl)-urea (l-{3-[6-(3-Fluoro-phenyl)-pyraz 〇1〇[ 1 ?5-a]pyrimidin-3 -yl]-phenyl} -3 -(2,2 ,2-trifluoro-ethy l)-urea) f&gt;Cny〇αΝΗ Li. ΰ &gt;〇Q ο Λ 〇$ν V // / \^/ LL τ—^ VO 〇〇VO 1-H 200836725 π·9 Bu ε .(5ε)ΟΟΙΟΊ xbKIe [H+w] ui JΚΙ)8Γ9 Χ6κε) ΙΓ 卜 -CN inch./z?ffiCN)CN17«&gt;4s.Bu XppffiCN) 98t&gt;xsffiI) 90OOXP ffiooorooxpffiIHZ/ooxsffiI)sooxsffiI) 96oo:(9p-osp\ta NHSOOs^MNm ει inch.(εΚΊ&lt;ΝΙ)&lt;ΝΙ6·ε-Ι0·5ΚΊι) avdl tH+s】offiI) 9ΓΖ/6ffie inch inch·卜二S·卜xpffil) IZ/ z/effiI) 96^-800xsffiI)&lt;NIooxpffiI) εΓοοe ffiz) 9//8 xsffiI)oosooeffiI)6ε°1(ρffiI) a.6 :(9p-ossa nhpmoos^wnhi § •βΊΚΊαςότχδΚΊζ) tH+w】οο0 ΖΓ0Γ5κΙ) ι rzz(pffiCN) inch sz/(pffil)CN8.z/(sffil)&lt;N6r-·xsffie) 300XsffiI) 6ε00χρρffiOISooxpffil) 6900XPffil)sv(sffit) 6 inch·6 :(9p-oswa ^DAIOOsiNffil c /L· (SJ?{JXU &lt;l&gt;l!d-[ JyirA-.sp-cyidfq-giozcdpjfmx &gt;, Jd-OJ Js-9]-e}ΓΑ-&gt;,Ψ3-1) 矾-{硪^-[硪-£-^麦[9^寸] fi# -(^i4-¥s-9)d -£-硪0丨一

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[M+H] + 511 ! [M+H] + 377.12 [M+H] + 430 1HNMR (400 MHz, DMSO-d6): 9.45 (1H, s), 9.02 (1H, s), 8.89-8.73 ( 3H,m),8.68 (1H,d),8·15 (1H,s),7·85 (2H, d), 7.70 (1H, d), 7.46-7.28 (2H, m), 7.18 (2H, d), 6.86 (1H, m), 4.77 (1H, m), 4·04-3·89 (2H, m), 3·27 (2H, m), 3·11 (2H, m), 2.15 ( 2H,m), 1.89 (2H,m). 1HNMR (400 MHz, DMSO-d6): 9·56 (1H,d), 9.13-9.03 (2H,m), 8.81 (lH,s), 8.34 (lH , d), 8.3l(lH,d), 7.97 (2H,dd),7.51 (1H,dd),7.41 (2H,t),6·29 (1H,t),3.23-3.09 (2H,m) , 1.09 (33⁄4 t). 1HNMR (400 MHz, Me-d3-OD): 8.74-8.62 (2H, m)? 8.44-8.33 (1H, m), 7.97-7.83 (2H, m), 7.78 (1H, s), 7.50 (1H, t), 7.46-7.20 (4H, m), 3.96 (2H, q) 4 ·-Caf $f 5Ha γ ^ KAS 余4 z 鍩,鍩考: 谂 谂 谂^s Step V3b Yang t〇^ &lt;inch丨1 _巴矿驾d 3 into human 04 1 二硪κ 1·(3-{6-[4-(piperidin-4-yloxy)-phenyl ]-吼11 sits and [1,5-&amp;] shouts 唆-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1 -(3 - { 6-[4-(Piperidin-4 -y loxy)-p henyl]-pyrazolo[ 155-a]pyrimidin-3-yl} -phenyl)-3 -(2,2,2-trifluoro-et hyl)-urea) 1·ethyl-3-{ 2-[6-(4-Ga-phenyl)-0 is more than squat and [1,5-&amp;] acetophenone-3-yl]pyrimidin-4-yl}urea (1-Ethyl-3 - { 2-[6-(4-fluoro-phenyl)-pyrazolo[ 1,5-a]pyrimidin-3-yl]-pyridin-4-yl} -urea) 1 - {3-[7-(6-fluoro- Acridine-3-yl)-imidazole [l,2-a]nbipyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - { 3 - [7-(6-Fluoro-pyridin-3 -yl)-i midazo[ 1 ?2-a]pyridin-3-yl]-pheny l}-3-(2,2?2-trifIuoro-ethyl) -urea)工Z^)-〇\u. % IZX B Li. 04 cn y 嗜rH 200836725 f ο [M+H] + 429.08 [M+H] + 457 [M+m + 511 lHNMR (400MHz, DMSO -d6): 9.12 (13⁄4 s), 8.61 (1H, s), 8.04 (1H, s), 7.91 (1H, t), 7.85-7.76 (2H, m)5 7.72 (1H, d), 7.65 (lH , dd), 7.52 (lH, t), 7.44 (1H, d), 7.37-7.24 (3H, m), 6.91 (lH, t), 4.03-3.89 (2H, m). 1HNMR (400 MHz, DMSO- D6): 9.03 (1H, s), 8.47 (1H, d), 8.03 (1H, s), 7.86 (1H, s), 7.44 (2H, m), 7.34 (1H, dd), 7.21-7.13 (lH,m), 6.95 (lH,d), 6.44 (1H,t),3·64 (4H,s) , 3.37 (4H, m), 3.16-3.06 (4H, m), 1.25 (3H, t) 5 1.06 (3H, t). 1HNMR (400 MHz, DMSO-d6): 9.37 (1H, s), 8.47 ( (1H, d) (lH,d), 4.01-3.87 (2H,m), 3.64 (5H,s),3·38 (4H,s), 3.14 (2H, q), 1.25(3H,t). Step 05 from gallium 4 broken.兰^ 福福ί £ Electric building ^ 4 w.趑GA VO 蚱' 〇^ f ξ ^ ^ -3 « ^ # cA J ^ ο Λ ώ ^ ^ A i 二 S 二 7硪硪l_{3-[5-(4-Fluoro-phenyl)_Benzene Imidazolium 1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-puls (l-{3-[5-(4-Fluoro-phenyl)-benzo imidazol-1 -yl]-phenyl} -3 -(2,2,2-tr ifluoro-ethyl)-urea) 1-{3-[7-(4-Ethracite yellow base)-imidazole [l,2- a] acridine-3-yl]-phenyl}-3-ethyl-urea hydrochloride (1 -{3-[7-(4-Ethanesulfonyl-pipera zin-1 -yl)-imidazo[ 1,2 -a]pyridin-3 -yl]-phenyl} -3 -ethyl-urea hydrochloride salt) l-{3_[7_(4-Ethylene sulphate-piperazine-1_yl)-flavor[1,2 -a] ^Bist-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3-[7-(4-Ethanesulfonyl-) Pipera zin-1 -yl)-imidazo[ 1 ?2-a]pyridin-3 -yl]-phenyl}-3-(2?2,2-trifluoro-eth yl)-urea hydrochloride salt) u. °0 z xz&gt;=〇a) IQ TH VO r- 200836725 [M+H] + 402 [M+H] + 430.05 [M+H] + 416 [M+H] + 376 1HNMR (400 MHz, DMSO-d6) : 12.79 (lH?brs), 9.50 (1H, d), 9.21 (13⁄4 d), 8.89 (1H, s), 8.71 (lH, s), 8.09 (1H, s), 7.68 (1H, d) , 7.53 - 7.38 (2H, m), 7.35 (lH, t), 7.19-7.11 (1H, m), 6·77 (1H, t), 4.02-3.91 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9·11 (1H, s), 8.90 (1H, s), 8.73 (1H, d), 8.48 (1H, d), 8.09 (1H, s), 7·86 (2H, dd), 7.57-7.43 (3H, m), 7.36 (2H, t ), 6.86 (1H, t), 4.02-3.89 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9.30 (1H, d), 9.00 (1H, d), 8.85 (lH, s), 8.67 (1H, s), 8.10 (lH, s), 7.67 (lH, d), 7.44 (lH, d), 7.34 (lH, t), 7.12 (1H, d), 6.75 (1H, t), 6.32 ( 1H, d), 4.02-3.90 (2H, m), 2.40 (3H, Λ_ 1HNMR (400 MHz, DMSO-d6): 9.80 (1H, s), 8.61 (1H, d), 8.03-7.97 (1H, m ), 7.93 (2H, dd), 7.81 (2H, d), 7.56-7.44 (2H, m), 7.42-7.28 (4H, m), 4.16 (2H, q), 1.27 (3H, t). State 2 Frame two. Private f shouting; z; g 〇ε 〇鹓3 vo J Λ h ^ ^ 2 ^ ¢-gas 黢 f A _ SKK gallium ^^ 轵 "gallium c 毽 frame 谂 electric gallium f 4 private post ^ CN +4 ^ 2 £硪崔QQ检你寸私簦旺X » f起避避&lt;砩次 l潜铝机械pq . ¢-1鲈黢毽 base 1-{3-[6-(1Η-imidazole 1-2-yl )·pyrazolo[l,5-a]pyrimidin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3 -[6- ( 1 H-Imidazol-2-yl)-pyra zolo [ 1 ? 5 -a] pyr imidin-3 -y 1] -phenyl } -3 -(2,2,2-trifluoro-ethyl)-urea Hydrochloride) -{3-[6-(4-fluoro-phenyl)-imidazole [4,5-b] σ 唆-3-yl]-phenyl}-3-(2,2,2-digas-B -1 - {3 -[6-(4-Fluoro-phenyl)-imida zo [4,5 -b] py r idin-3 -y 1] -phenyl} -3 -(252?2- Trifluoro-ethyl)-urea) 1_{3-[6-(5-methyl-furan-2-yl)-oxazolo[l,5-a]°^^-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-pulse (1 - {3 - [6-(5 -Methy l-furan-2-yl)-py razo Ιο [ 1 ? 5 -a] pyrimidin -3 -y 1] -phen yl} -3 -(2,2,2-trifluoro-ethy l)-urea) {3-[7-(4-fluoro-phenyl)-imidazole [l,2-a Acridine-3-yl]-phenyl}-carbamic acid ethyl ester hydrochloride ({3-[7-(4-Fluoro-phenyl)-imidazo [1] 2-a] pyridin-3-y I] -phenyl} -carb amic acid ethyl ester Hydrochloride) Vz ENGINEERING LL u. LL \ oo On t-H § 00

[M+H] + 417 [M+H] + 491 [M+H] + 510 1HNMR (400 MHz, DMSO-d6): 9.52 (1H, d), 9.05 (lH,d), 8.85 (lH, s ), 8.72 (lH, s), 8.14 (lH, s), 7.70 (lH, d), 7.46 (lH, d), 7.35 (lH, t), 6.75 (1H, t), 4.02-3.91 (2H, m). 1HNMR (400 MHz, Me-d3-OD): 8.39 (1H, d)5 7.76 (1H, s), 7·49 (1H, s), 7·44 (1H, t), 7.39-7.30 (1H, m), 7·25 (1H, d), 6.93 (1H, dd), 6.80 (1H, d), 4.19 (2H, q), 3.95 (2H, q), 3.68 (4H, s), 3·54·3·36 (4H,m),1.31 (3H,t). ^ oo w ^ W ^ A ^ ffi ώ Q s inch·- cs ^ «a &quot;V 蟛5襃蚪μ 2 5 gas I S from the truss... Gallium &lt;; «1 ^ 1 ϊ! &quot;' S* 2 Mine. S芯赵5 1 〇S ^ v ^ ^ K tO CN _ 竞^颂&quot;1趑A 2 Ϊϊ|ΐϊ|ί1 l-[3-(6-d5-phenyl-carbazole[l,5- a] pyrimidine-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1 -[3 -(6-d5 -Pheny l-pyrazolo[ 1,5 -a ]pyrimidin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea) 4-(3-{3-[3-(2,2,2-trifluoro- Ethyl)-urea]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-piperazine-1-carboxylic acid ethyl ester (4-(3-{3-[3-(2? 2?2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[ 1,2-a]p yridin-7-yl)-piperazine-1 -carboxyl ic acid ethyl ester) 1-{3-[7-( 3-morpholin-4-ylmethyl-phenyl)-imidazole [1,2-decaderidin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)- Urea hydrochloric acid (1 - {3 -[7-(3 -Morpholin-4-ylmethy 1 -phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-3-(2,2?2 -trifluoro-eth yl)-urea Hydrochloride) 〇QQ. r° °) /~v /-2 O % s S t-H 200836725

[M+H] + 376 [M+H] + 461 [M+H] + 421 [M+H] + 403 1HNMR (400 MHz, Me-d3-OD): 8·65 (1H,d), 8.54 (1H,d), 8.46 (lH,d),8·39 (1H, t), 7.91-7.79 (4H,m),7.39 (1H, dd), 7.28 (2H,t), 3.29 (2H,q ), 1.20 (3H, t). 1HNMR (400 MHz, Me-d3-OD): 8.65 (1H, d), 7.88-7.80 (4H, m), 7.73 (1H, s), 7.48 (1H, t) , 7.40-7.23 (5H, m), 4.31-4.24 (lH, m), 4.09 (1H, dd), 3.74 (1H, dd), 3.52-3.42 (2H, m), 1.45 (3H, s), 1.39 -1.33 (3H,m). 1HNMR (400 MHz, Me-d3-OD): 8·65 (1H,d), 7.88-7.78 (4H, m),7·73 (1H,s), 7.47 (1H , t), 7.42-7.22 (5H, m), 3.80-3.71 (1H, m), 3.57 (2H, d), 3.49-3.42 (2H, m). 1HNMR (400 MHz, Me-d3-OD): 8.65 (1H, d), 7.88-7.77 (4H, m), 7.73 (1H, s), 7·47 (1H, t), 7.40-7.21 (5H, m), 3.07 (2H, d), 1.88-1.77 (1H,m), 0.98 (6H,d). Ξ 铋 铋 1 4 K Ξ s ut « ψ ^ ^ Driving PQ gallium 1 bat recording private f S private diving K male ω ψ _ two aluminum ί· 4 » Gallium 1 灭 ♦ ♦ (4) Thermal s? It Electric Potential BE W ^ Ψ ^ ^ Aluminum 蚪 "Gallium 1 褊 Gallium 1-ethyl-3-{5·[7 -(4-Ga-phenyl)-ρ米吐[1,2-a]π ratio bit-3-yl]-σ ratio 唆-3 -yl} Hydrochloric acid (1 -Ethyl-3 - {5 -[7 -(4-fluoro-phenyl)-imidazo[ 1 ?2-a]pyridin-3-yl]-pyri din-3-yl}-urea Hydrochloride) l-(2,2-dimercapto-[1,3 Dioxocyclopentan-4-ylmethyl)-3-{3-[7-(4-fluoro-phenyl)-isoxazole [l,2-a]acridin-3-yl]-phenyl} -urea (1 -(2,2-Dimethyl-[ 1,3]dioxolan-4-y lmethy 1)-3 - {3 - [7-(4-fluoro-phen yl)-imidazo[ 1,2-a ]pyridin-3-yl]-p henyl}-urea) 1-(2,3-dihydroxy-propyl)-3-{3-[7-(4-i-fluoro-phenyl)-imidazole [1, 2-Tepyridin-3-yl]-phenylpyrazine hydrochloride (1 -(2,3 -Dihydroxy-propyl)-3 - { 3 -[ 7-(4-fluoro-phenyl)-imidazo[ 1 ?2 -a ]pyridin-3 -y 1] -phenyl} -urea Hydrochloride) Sf ii d 砩X 1 殳1 iii | ί | g g.s J 鲴〇 鲴〇 SS \ I 1) LL \ LL \ Li. \ zV m 00 VO 00 ss t-H 〇〇00 rH 200836725 US · (£ffilCNIurcnlxsCHS) ffis "sffies.5ffis06·ε 丨 inch 0, inch ancient ffiCN) inch inch · inch offiI) CN8.9 CHI) $ε·ζ /(ρffiI) inch inch. Bu, sffi£) 657,4////(51) 1000 effi&lt;N) orooxsKI) inch/;ooxs ffiI) 96·°°,(ρffio inchΓ°1(ρκϊ)6S _°1(SffiI)&lt;Nrn:(9p0swaNHsoospiHNm 3 .(6ΚΊΙ) tH+w](Ν9·Ι-(Νζ;Γεκ£) 06Ί-60Τxppffi&lt;N)CN inch·'ΦΚΙ) 6//ε X 曰ΙΙ)98·εώ6·εχεκΙ) οο6·ε-οο0·inch zgκε) ΙΓΖΓ(Νε·ζ, ΧρΚζ)9ε5ffilu inch·biffiI) inchb.^effisoorb-600·b•(pffiI) 59°°(αο -ερ·01ΑΙ NHWOOspiWNffil

If gallium ^Μ^(ΙΙ)^-ί·4鸯-CN-(^ pigeon 14)-,3^3⁄4^^3⁄4^A s-.ςν inch)-ev inch K^q inch v gallium 淞s遛毽孽K^N electric shock. A f Φ Ν.缕4 (&lt;υρμο2οΟΙΡΧΜ«3(ι&gt;δι(Ι^Ρ(υ—OJOnsJvCNcsroivrn-ohsqd^x-cn-uipJ6*cxd[B^一]oozsxd-(&gt;&gt;§qd-^.qpuqx-inch -.solldlos- ε)-9]-ε } l) 丨(硪蚪-硪I硪-inch-举喾-£)-9]-£}-1 (9PJJOs0OJPXH SJn 丨(^IPQUIJX-CN-usa- OJPXlls^vrn- {Jksqd-fJXrA-.sp^dfBnIJOZBPIf UI*T(IX§qd-OJOnE-s-/J-rn} _ l -4r)i Potential iH^A^c^—^^· Alkali gvz ^^-DfCA-^ffql】 1^^ι(^ί4.^4).Α】ΓΑΗ·$

200836725

+ + 5c ± O [M+H] + 552 1HNMR (400 MHz, DMSO-d6): 9.67-9.59 (1H, m), 8.61 (1H, d), 8.29 (2H, s), 7.99 (1H, s ), 7.92 (2H, dd), 7.84 (1H, s), 7.78 (lH, s), 7.51-7.30 (6H, m), 7.22 (1H, d), 3.03 (2H, d), 2.59 (2H, s), 0.92 (6H, s). 1HNMR (400 MHz, Me-d3-OD): 8·63 (1H, d), 7·88·7·80 (4H, m), 7.74 (1H, s) , 7.54 (2H,d), 7.41-7.33 (2H,m), 7.30-7.24 (2H, m), 4.72 (2H, q). 1HNMR (400 MHz, DMSO-d6): 12.85-12.59 (1H, m ), 8.97 (lH, s), 8.61 (lH, d), 8.14 (1H, s), 8.03 (1H, s), 7.80 (2H, s), 7.50-7.35 (5H, m), 7.32-7.24 ( 13⁄4 m), 7.09-7.01 (1H, m), 6.86 (1H, t), 4.85-4.77 (1H, m), 4.01-3.83 (3H, m), 3.76-3.66 (1H, m), 3.43-3.22 (2H,m),2.08-1 ·98(4Η,ιη), 1.94(lH,s),1.71-1.50 (2H,m). 二JJ ® 2 ^ 1 蝙余毽碥4轵鑀1|έϊ « ψ ^ ^ ^ ^ ^ 2 钡i4 gallium \ ^ 1 . 2 ^ ^ 1 Ί 1 ^ &lt;$5S?s Ϊ ping i5S 1竺v each 1-(3-amino-2,2-didecyl- Propyl)-3-{3-[7-(4-carbo-phenyl)-imidazo[l,2-a]acridin-3-yl]-phenylpyrazine (1 -(3 -Amino-2?2-dimethy 1-propyl )-3 - { 3 - [7-(4-fluoro-pheny l)-imida zo[ 1,2-a]pyridin-3 -y 1 ] -phenyl} -ur ea Hydrochloride) f 'Ί 1 专-SL, i 〇3 cd ¥ ^ |1 § is til 33⁄4 l.iS ^ iS E 3 ri .智^:二is l-(3-{7-[3-(l-Ethyl-piperidin-4-yloxy)-phenyl]-imidazole [l,2-a]acridine·3- }--phenyl)-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (1 -(3 - { 7-[3 -(1 -Acetyl-piperidin-4-yloxy)) -phenyl]-imidazo[ 1,2-a]pyr idin-3-yl}-phenyl)-3-(252,2-trifluo ro-ethyl)-urea Formate) LL \ 〇k LL o Q. r° i-H ON S T-H 200836725

[M+m + 465 [Μ+Η] + 419 [M+H] + 444 1HNMR (400 MHz, Me-d3-OD): 8·59 (1H,d), 7.90-7.72 (4H, m), 7.60-7.47 (2H, m), 7.37 (2H, t), 7.32-7.20 (3H? m), 3.71 (2H, q). 1HNMR (400ΜΗζ, Me-d3-OD): 8.85 (1Η,d), 8·16 (2H, s), 8·03 (1H, s), 8.01-7.91 (2H, m), 7·83 (1H, dd), 7.69-7.51 (1H, m), 7.45-7.30 (4H , m), 3.56-3.47 (1H, m), 3.44-3.37 (43⁄4 m), 3.26-3.11 (1H, m), 1.19 (3H, d). 1HNMR (400 MHz, Me-d3-OD): 8.85 (1H, dd), 8.16 (2H, s), 8.01-7.88 (3H, m), 7.82 (1H, d), 7.68-7.54 (23⁄4 m), 7.47-7.31 (3H, m), 4.78-4.69 ( 1H,m),4.04 (1H,d),3.52-3.36 (3H,m),3.17-2.92 (lH,m), 2.03-1.52 (6H, m). SS $? wElectric distillation κ 2Do not PQ ψ Every remaining 叟 ^ ί4 ω - OQ Meng * do. s f !丨卜 酴 also "7 &lt; N. Driving Lin PQ Yu® 1 Bat Gallium — 4 Gallium 5 ^ ^ κ ^ « f ^ 5 p? ^ λ 2 ^ Driving ω Gallium A ^ l 4 more ‘硪Q ? ^ Poor? Teach π &quot;丨.§安^ 5-. is| f 3 ||j ^ 2 %Ψ41 mtk ^ ^ t〇w Ν (Ν S (士)-1-{3-[7-(4-Fluoro- Phenyl)-imidazo[l,2-a]indol-3-yl]•phenyl}-3-(2-dimethoxy-propyl)-urea hydrochloride ((±)-l-{3 -[7-(4-Fluoro-phenyl)-im idazo[l,2-a]pyridin-3-yl]-phenyl} -3 -(2-methoxy-propy l)-urea Hydrochloride) (士)-l -{3-[7-(4-D-phenyl)-sodium [l,2-a] acridine-3-yl]-phenyl}-3-piperidin-2-ylindenyl-urea hydrochloride ((±)-l-{3-[7-(4-Fluoro-phenyl)-im idazo[ 1 ?2-a]pyridin-3 -yl]-phenyl} -3 -piperidin-2-ylmethy 1-urea Hydrochloride) Ύ: % LL LL \ Li. i—i tH 200836725

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[M+H] + 404 [M+H] + 390 [M+H] + 448 1HNMR (400 MHz, Me-d3-OD): 8.34 (1H,d), 7·78-7·70 (1H, m), 7.44 (1H, d), 7.40 (1H, d), 7.33 (1H, d), 7.26-7.21 (lH, m), 6.71-6.63 (1H, m), 6.37 (1H, s), 4.00 -3.88 (2H, m), 3.48-3.40 (4H, m), 2.15-2.04 (4H, m). 1HNMR (400 MHz, Me-d3-OD): 8.31 (1H, d), 7.74-7.68 (1H , m)5 7.46-7.37 (2H,m), 7.37-7.25 (1H,m), 7.25-7.10(13⁄4 m), 6.43-6.34 (1H,m),6·24 (1H,s),4.01 ( 4H, t), 3.94 (3H? q), 2.51-2.37 (2H, m). 1HNMR (400 MHz, Me-d3-OD): 8.47 (1H, s), 8.39 (1H,d),7·88 (1H, s), 7.66 (1H, s), 7.50 (lH, t), 7.39 (lH, d), 7.27 (lH, d), 7.17 (lH, d), 6.84 (1H, s), 3·95 (2H,q),3·74 (1H, d),3·52 (4H,m), 3.41 (3H,s), 2.09-1.86 (2H,m),1·71 (2H,d ). ^ S tB- ^ 趑 is more gl铋鳊^ AW w\ ® &lt; gas A. ^ ^ J ^ ^ PQ 5 — &lt;N B. 1宇趑嘁硪硪^(N ^ w SV ^ ^ t神. • Driving S 3蚪宁S fe 毒碥ά今 1 ^ SB ^ ^ K ♦ 0 ^ &lt;N " 刍s ^ iu.' Gallium ^ &lt;N ^ ® ^ qi, • «气3耩, w硪 per inch:: "two. 2 ^ gv ^ 83⁄4 driving l PQ ba ^ people into 1 cA gallium two" "T1 砩 l-[3- (7-吼-r-butyr-1-yl-imidazole [l,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)·urea hydrochloride (1 -[3 -(7-Pyrrolidin-1 -yl-imidazo[ 152-a]pyridin-3 -yl)-phenyl]-3 -(2,2 52-trifluoro-ethyl)-urea Hydrochloride) CN —A la ρ L| 5l III 匕ill (soil)-1-{3-[7-(3-dioxaoxy-piperidin-1-yl)imidazo[l,2-a]acridin-3-yl]-benzene }}-3-(2,2,2-trifluoro-ethyl)-urea ((±)-1 - {3 - [7-(3 -Methoxy-piperidi n-1-yl) imidazo[ 1,2 -a]pyridin-3 -yl]-phen y 1} -3 -(2,2,2-trifluoro-ethy l)-urea) Q h xz^z ^ % P 0, H 202 s CN 200836725 :/ [ M+H] + 377 [M+H] + 420 [M+H] + 523 1HNMR (400 MHz, DMSO-d6): 9.59 (1H, d), 9.16 (lH, s), 9.12 (lH, d) , 8.80 (lH, s), 8.22 (2H, d), 8.17-8.11 (1H, m)? 8.02-7.92 (2H, m), 7.68 (lH, dd), 7.41 (2H, t), 3.24-3.21 (2H, m), 1.12 (3H, t). lHNMR (400MHz, Me-d3-OD): 8.45 (1H? s), 8.41 (1H, d)5 7.89 (1H, s), 7.66 (1H, s), 7.50 (lH, t), 7.41 (lH,d), 7.27 (1H, d), 6.94 (1H, d), 6.53 (1H, s), 4.62 (1H, s), 3.94 (2H, q), 3.73-3.52 (3H , m), 3.45 (1H?d), 2.31-2.08 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9.01 (1H, s), 8.63 (1H, d), 7·99 (1H, s), 7.84-7.71 (5H, m), 7.54-7.43 (3H, m), 7.39 (2H, dd), 7·28 (1H, m), 6.90 (1H, t), 3.95 (2H, m) , 3.65 (2H, s), 3_18 (2H, m), 2.97 (2H, s), 2.62 (2H, m). φ\ W 1 2 gallium 3 ^ gallium three private slaves wf: 2 music f will S3 4 ^ Record / _ γ -^ V ^ A, Sissggi ^ ^ ^ VAA 1 cA轵趑硪砩硪Ϊ _ S $ 5 5 ul ^ ^ or ^ &lt;N 1 ^ V硪砩1-ethyl-3-{4 -[6-(4-disorder-phenyl)-n is more than [l,5-a]pyrimidin-3-yl]-pyridin-2-yl}-urea (1-Ethyl-3 - {4-[ 6-(4-fluoro-phenyl)-pyrazolo[ 1,5-a]pyrimidin-3-yl]-pyridin-2-y 1} -urea) l-{3-[7-(3-hydroxy-pyrrolidine) -1-yl)·imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-difluoro-ethyl)-gland (1 - {3-[ 7-(3 -Hydroxy-pyrrolidin-1 -yl)-imidazo[ 1,2-a]pyridin-3- Yl]-p henyl} -3 -(2?2,2-trifluoro-ethyl)-ur ea) 1-(3-{7-[3-(3-oxy-pyrene-1-ylmethyl) -phenyl]-imidazole [l,2-a]acridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1 -(3 - {7 -[3 -(3 -Oxo-piperazin-1 -yl methyl)-phenyl]-imidazo[ 1,2_a]py ridin-3 -y 1} -pheny 1)-3 -(2,2,2-triflu oro -ethyl)-urea) u. 工工2&gt;=〇\X s Factory/_ΛΖ工Ο 204 s CN 206 91寸200836725 Γ [Μ+Η] + 401 ! [M+H] + 553 [M+H ] + 482 1HNMR (400ΜΗζ, Me-d3-OD): 8·57 (1Η, d), 7.86 (1H, s), 7.81 (1H, s), 7.71 (1H, s), 7.70-7.65 (1H, m)5 7.49 (1H, t) , 7.41 (1H, d), 7.36 (1H, dd), 7.3 l(lH,d), 7.01 (lH,d), 6.62 (1H,dd),3·95 ( 2H,q). 1HNMR (400 MHz, Me-d3-OD): 8.63 (1H, d), 8.27 (1H, d), 8.05 (1H, dd), 7.86 (1H, s), 7.80 (1H, s ),7·73 (1H,s), 7.49 (1H,t),7·39 (1H,d), 7.35-7.25 (2H,m),6·71 (1H,d), 4.17 (2H,t ), 3.95 (2H,q), 2.53-2.38 (6H,m),2.11-2.01 (2H,m),1.67-1.56 (4H,m), 1.48 (2H, s). 1HNMR (400 MHz, DMSO- D6): 9.32 (1H, s), 8.83 (1H,d),8·41 (1H,s), 8.21 (1H, s), 8.07 (1H,d),7·92 (1H,s), 7.88-7.77 (33⁄4 m), 7.60-7.49 (3H,m),7·45 (1H,d),7.38-7.30 (1H,m),7.05 (lH,t),3·95 (2H, m),3·54 (2H,s), 2.64 (3H,d). K t ^ (N ^ ^ ^ ^ &lt; cr ^ &lt;N 5 ^ 5 -: &lt; - inch: difficult to combine.窠二3 a 5常1 SY硪砩Step S ' • 2 褎π &lt;&lt; 3 巧录铝 cA耩2 g 1 SU硪矾 Gallium 1-[3-(7-furan-2-yl-imidazole [l,2-a]n °-3-yl)-phenyl]-3-(2,2,2-tris-ethyl)-urea (1 -[3 -(7-Furan-2) -yl-imidazo[ 1,2-a ]pyridin-3-yl)-phenyl]-3-(2?2?2-tri fluoro-ethyl)-urea) l_(3-{7_[6-oxy- 1-(3-Piperidine-l-yl-propyl)-1,6-dihydro-pyridin-3-yl]-imidazole [l,2-a] 吼子&gt;3-kibphenyl)- 3-(2,2,2-trifluoro-ethyl)-hydrochloride (1-(3-{ 7-[6-Oxo-1 -(3 -piperidin-1 -y 1-propyl)-1,6 -dihydro-pyridin-3 -yl]-imidazo[ 1 ?2-a]pyridin-3-yl} -p henyl)-3-(252,2-trifluoro-ethyl)-ur ea Hydrochloride) N-methyl- 2-[3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-a]»pyridin-7-yl) -phenyl]-acetamidamine hydrochloride (N-Methyl-2-[3-(3-{3-[3-(2?2,2-trifluoro-ethyl)-ureido]-phenyl}-imi dazo[ 1,2-a]pyridin-7-yl)-phenyl]-acetamide Hydrochloride) 〇3 \ :11⁄2 \ 〇207 208 209 200836725 [M+H] + 434 [M+H] + 430 [Μ+Η] + 512 1HNMR (400 MHz, DMSO-d6): 8·98 (1H, s), 8.32 (1H, d), 8.17 (2H, s), 7 · 69 (1H, s), 7.52-7.45 (1H, m), 7.44-7.33 (2H, m), 7.21-7.12 (1H? m), 6.96-6.83 (2H, m), 6.71 (1H, d) , 3.94 (2H, dd), 3.72-3.54 (3H, m), 2.94-2.81 (1H, m), 2.77-2.65 (1H, m), 1.90 (1H, d), 1.84-1.72 (lH, m) , 1.61-1.46 (lH, m), 1.44-1.31 (lH, m). lHNMR (400MHz, Me-d3-OD): 8.68 (1H, d), 8.32 (lH, d), 8.19 (lH, s) , 8.08 (lH, s), 7·86 (1H, s), 7.82 (1H, s), 7·74 (1H, d), 7.57-7.45 (2H, m), 7.45-7.35 (2H, m) , 7·32 (1H, d), 3.96 (2H, q). 1HNMR (400ΜΗζ, Me-d3-OD): 8.68 (1Η,d), 8.24 (1Η, d), 8.06-7.96 (1Η,m) , 7.86 (1H, s), 7.80 (1H, s), 7.50 (1H, t), 7·46·7·29 (4H, m), 7.20 (1H, s), 5.30 (1H, m), 4.05 -3.91 (4H, m), 3.71-3.56 (2H, m), 2.18-2.04 (2H, m), 1.88-1.74 (2H, m). gallium gallium 1 ^ ^ έ ^ ^ L field tO each way VO ^ s ^ ΐ | ^ ^ B - 辛 Sqin cn i 灭 $验 « ^ ^ ^ ί s: 淼 '4 &lt;15 1 (NS ^ V ^ K 〇2 ^ ^ ^ ^ 余 | β1 &lt; s '1 55115 1 sv ^ ^ l-{3-[7-(3-Hydroxy-piperidin-1-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl }-3-(2,2,2-trifluoroethyl)-urea phthalate (1 - {3 -[7-(3 -Hydroxy-piperidin-1 -yl)-imidazo[ 152-a]pyridin- 3-yl] -p henyl} -3 -(2,2,2-trifluoro-ethyl)-ur ea formate) l_{3-[7-(2-fluoro-pyridin-4-yl)-imidazole [l, 2-a]»Bipyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 - {3 -[7-(2-Fluoro-pyridin) -4-yl)-i midazo[l,2-a]pyridin-3-yl]-pheny 1} -3 -(2,2-trilluoro-ethy l)-urea Hydrochloride) 1-(3-{7 -[2-(Four Wind-〇比喃-4-基&gt;oxy^)-° than bite-4-yl]-flavor 0 sits [1,2-a]ϋ 咬-3-yl}- Phenyl)-3-(2,2,2-difluoro-ethyl)-urea (1 -(3- {7-[2-(Tetrahydro-pyran-4-y loxy)-pyridin-4-yl] -imidazo[ 1,2-a ]pyridin-3 -yl} -phenyl)-3 -(2,2,2-tri fluoro-ethyl)-urea) % P § % o-^o % \ 210 ^Η ( Ν 212 200836725

[M+H] + 447 [M+H] + 454.1 [M+H] + 400 1HNMR (400 MHz, Me-d3-OD): 8.41 (1H, d), 7.78 (1H, s), 7·55 (1H, s), 7.49-7.39 (1H, m), 7.35 (1H, d), 7.24 (1H, d), 6.94 (1H, d), 6·76 (1H, s), 4·00 (2H, s), 3.99-3.91 (2H, q), 3.80-3.62 (2H, m), 3·58 (2H, d), 3.06 (3H, s). 1HNMR (400 MHz, DMSO-d6): 9.29 (1H, s), 8.71 (1H, d), 8.02 (1H, d), 8.00-7.89 (5H, m), 7·78 (1H, t), 7.44-7.31 (3H, m), 7· 10 (1H, t), 4.02-3.91 (2H? m). 1HNMR (400 MHz, Me-d3-OD): 8.61 (1H, d), 8.01 (1H, s), 7.85-7.75 (5H, m) , 7.59 (1H, s), 7.35 (1H, d), 7.25 (2H, t), 3.28 (2H, q), 1.20 (3H, t). VO ^ ^ ^ \»i 每 ^ ^ per age ^ 1 S ^ f ϊ Ϊ ^ ^ •咿S 3 , 5 ^ Τ V ^ i-4 ^ | ri S ri V ^ ^ ^ cs ίο i-4 Λ PQ r' is ^ ^ ^ S ^ t4 ^ ^ ^ Aluminium®; a few -1 of 4 gallium. M shovel ^ a domain remaining 1 4 gallium 々 "鲤l-{3-[7_(4-methyl-3-oxo-piperazine-1·yl)-imidazole [l,2-a] acridine- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ureamic acid m (1 - {3 -[7-(4-Methy 1-3 -oxo-piperaz in -1 -yl)-imidazo[ 1 ?2-a]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-eth yl)-urea Formate) l-{3-Actyl- 5-[7-(4-Fluoro-phenyl)-°-mazole [l,2-a]indol-3-yl]-phenyl}-3-(2,2,2·sandon-ethyl --urea (l-{3-Cyano-5-[7-(4-fluoro-pheny 1)- imidazof 1,2-a]pyridin-3 -yl]-phen yl} -3 -(2,2, 2-trifluoro-ethy l)-urea) r H3-cyano-5-[7-(4-fluoro-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}- 3-ethyl-urea (1 - { 3 -Cy ano-5 - [7-(4-fluoro-pheny l)-imidazo[ 152-a]pyridin-3 -yl]-phe nyl}-3-ethyl- Urea), T, uT^ LL % z % m iH 214 tn H CN 200836725 [Molecular ion] + 405 [M+H] + 459 [M+H] + 430 1HNMR (400 MHz, DMSO-d6): 8.68- 8.58 (2H, m), 7·98 (1H, d), 7.92 (2H, dd), 7.80 (lH, s), 7.39-7.3 l (3H, m), 7.28 (1H, s), 7.16 (lH , t), 6.77 (13⁄4 dd), 6.18 (lH, t), 3.81 (3H, s), 3.19-3.06 (2H, m), 1.07 (3H , t). 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.64 (1H, d), 7.99 (1H, s), 7.92 (2H, dd), 7.81 (1H, s), 7.42 -7.31 (33⁄4 m), 7.29 (lH, s), 7.18 (lH, s), 6.90-6.79 (2H, m), 4.02-3.88 (2H, m), 3.82 (3H, s). 1HNMR (400 MHz , DMSO-d6): 9.18 (1H, s), 8.68-8.59 (2H, m), 8.51 (1H, d), 8·24 (1H, t), 8.03 (1H, s), 7.97-7.91 (3H , m), 7.40 (1H, dd), 7.35 (2H, t), 7.08 (lH, t), 4.02-3.91 (2H, m). s ^ 2 ^ Driving & Willow 1 4 Gallium 邾 22 δ Ξ ^ f ^ free of a 1 4 gallium 邾 s -f per; cA 鋈 aluminum 酴ά 3 and θ 1 4 Φν V ^ ^ 1-ethyl-3-{3-[7-(4-gas- Phenyl)-° rice bran sits [l,2-a]n-pyridin-3-yl]-5-dimethoxy-phenyl}-urea (1-Ethyl-3 - {3 -[7-( 4-fluoro-pheny 1 )-imidazo[ 1,2-a]pyridin-3-yl]-5_m ethoxy-phenyl} -urea) 1 - { 3 - [7-(4-fluoro-phenyl)-imi [1,2-a] 比pyridin-3-yl]-5-dimethoxy-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 - [7-(4-Fluoro-phenyl)-imida zo [ 1,2-a] pyridin-3 -y 1] -5 -methoxy-phenyl} -3 -(2,2,2-trifluoro-ethy 1)- Urea) 1 - { 5-[7-(4-Ga-phenyl)- ^Sit [1,2-a] 0 than bite-3 -yl]-β is more than -3 -yl} -3 -(2,2,2-trifluoro-ethyl)-urea (1 - {5- [7-(4-Fluoro-phenyl)-imida zo [ 1,2-a]pyridin-3 -yl]-pyridin-3 -y 1} -3 -(2,2,2-trifluoro-ethy l)- Urea) LL \ xz &gt;=〇% LL 216 217 218 200836725

[M+H] + 441 [M+H] + 537 [M+H] + 440 1HNMR (400 MHz, Me-d3-OD): 8.63 (1H?d)5 7.84 (2H,d),7·78 (1H, s), 7·72 (1H, s), 7.68 (1H, d), 7.61-7.27 (6H, m), 4.73 (2H, s), 3.96 (2H, q). 1HNMR (400 (M,,,,,,,,,,,,,,,,,,,,,, t), 7.45-7.36 (2H,m),7·34 (1H,d), 3·96 (2H,q),3.83 (2H,s),3.57 (2H,s),2.53 (4H,d) , 2.36 (3H, s). 1HNMR (400 MHz, DMSO_d6): 8·88 (1H, s), 8.62 (1H, d), 7.99 (1H, s), 7.95-7.90 (2H, m), 7.79 ( (2H,m) 2.87 (2H, t). •昍O cA ^ ^ ^ K β ^ 1 Ί1 ^ ^ ^ PT ^ &lt;N ^ S ^ JV ^ ^ &lt; su sT&lt;^ 1 s Y硪砩缌K ^ ^ ^ r ^l • A ' Γ0 ^ 5 仓雀ί15- 1二υ硪硪κ丨1毽m Competition "i铋,襃&lt; ^ W 〇^ gallium" six_a蚪 private a 3^ fs25li l-{3- [7-(3-Hydroxymethyl-phenyl)-imidazole [1,2-a] ° 唆-3 -yl]-phenyl} -3 -(2,2,2-tris-ethyl) - (1 - {3-[7-(3-Hydroxymethyl-phen yl)-imidazo[ 1,2-a]pyridin-3 -yl]-p henyl} -3 -(2,2?2-trifluoro-ethyl) -ur ea) 1-(3·{7-[3-(4-indolyl-pyridinyl-l-l-wei)-phenyl]-imidazole [l,2-a] 吼-3-yl} -phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1 -(3 - {7-[3 -(4-Methyl-piperazine-l-carbonyl)-phenyl]-imidazo [l,2-a]pyridin-3 -yl} -phenyl)-3 -(2,2,2-t rifluoro-ethyl)-urea) 1-(3-Amino-2,2-difluoro-propyl )_3-{3-[7·(4·Fluoro-phenyl)-isoxazole [l,2-a]acridin-3-yl]-phenyl}-urea (1 -(3 - Amino-2? 2-difluoro-propyl) -3- {3 -[7-(4-fluoro-phenyl)-imidaz 〇[ 1 ?2-a]pyridin-3 -yl]-phenyl} -ure a) % §工z&gt; =〇, LL \ VZ CM L 219 220 ▼—H 200836725 [M+H] + 389 [M+H] + 403 [M+H] + 403.15 1HNMR (400 MHz, DMSO-d6): 8.61 (1H, d), 8.49 (1H, s), 7.99 (1H, d), 7.93 (2H, dd), 7.79 (2H, s), 7.46-7.29 (5H, m), 7.21 (1H, dt) , 6.09 (1H, d), 3.84-3.73 (1H, m), 1.12 (6H, d). 1HNMR (400 MHz, DMSO-d6): 9.24 (1H, s)5 8.83 (1H,d), 8.32 ( 1H, s), 8.27 (1H, s), 7.85 (1H, s), 7.54 - 7.50 (2H m), 7.47 (1H, d), 7.35-7.25 (1H, m), 7.01 (1H, t)5 4.02-3.87 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.60 (13⁄4 d) 5 8.44 (1H, s), 7·99 (1H, s), 7.92 (2H, dd), 7.78 (1H, s), 7.73 (1H, s), 7.45-7.29 (5H, m), 7.19 (13⁄4 dt),6.07(lH,s),1.31(9H,s). l κ S ^ m ^ ^ , $ 3Ϊ1|3?5 1 A φ\ 二《&quot;τ··办办阳私cs i硪KI ^ ^ ^ 5 ΐ -3⁄4 w ^ ^ 1 4 琴琴畹_带琳I戈2^11? &§£^| rH 〇NC/3 1-(2,2,2-Trifluoro 1 -ethyl)-3-[3-(7-trifluoromethyl-imidazo[l,2-a]« butyl-3-yl)-phenyl]-urea hydrochloride (1-(2,252-Trifluoro-ethyl) )-3-[3-(7-trifluoromethyl-imidazo[ 1,2-a]pyr idin-3-yl)-phenyl]-urea Hydrochloride) 1 1-tert-Butyl-3-{3-[7- (4-fluoro-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-urea (1-tert-Butyl-3 - {3 -[7-(4-fluoro-) Ph eny l)-imidazo [ 1,2-a]pyridin-3 -y 1] _ phenyl}-urea) % V 222 CN 224 200836725 [M+H] + 349 [M+m + 295 [M+H] + 469 1HNMR (400 MHz, Me-d3-OD): 8.38 (1H, d), 7.73 (1H, s), 7.56 (lH, s), 7.41 (13⁄4 d), 7·35 (2H, d), 7·21 (1H,d), 6·78 (1H, dd), 3.94 (2H, q), 2.41 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.46 (1H,d), 7.80-7.72 (1H,m) , 7.59 (1H, s), 7.49-7.41 (1H, m), 7.39 (1H, s), 7·34 (1H, d), 7·23 (1H, d), 6·87 (1H, d) ,3·26 (2H,q), 2.46 (3H, s), 1.18(33⁄4 t). 1HNMR (400 MHz, Me-d3-OD): 8·63 (1H,d),7.84 (2H,s) ,7·77 (1H,s),7.74-7.64 (2H,m),7.54-7.38 (3H,m), 7.38-7.31 (2H,m),7.27 (1H,d), 3.66 (2H,s) ,3·27 (2H,q),2.63 (8H,brs),2.39 (3H,s),1.19 (3H,t). BC tO ί辔私Y 2 溪溪 y ^ ri aa As 1 A γ γ Do a bombardment 3 4. IMS g ^ f ^ Vd S蚪to Ϊ every gas fg 1 PQ Ph .52 l-[3-(7-methylimidazo[l,2-a]acridin-3-yl)phenyl]-3- (2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -[3-(7-Methyl-imidazo[ 1 ?2-a]py ridin-3 -yl)-phenyl] -3 -(2 ,2,2-triflu oro-ethyl)-urea Hydrochloride) ill fn frt r—η C ^ 1-ethyl-3-(3-{7·[3-(4-methyl-piperazinyl) )-phenyl]-imidazole [l,2-a]n-pyridin-3-yl}-phenyl)-urea (1 -Ethyl-3 -(3 - { 7- [3 -(4-methyl-pip) Erazin-1 -ylmethyl)-phenyl]-imida zo[ 1,2-a]pyridin-3 -yl} -phenyl)-ur ea) Z &gt;=〇h&gt; Z- (N 226 227 200836725 69ε .( εffilCNI) tH+w] 88·ε-οο&gt;οκΙ)ςοο.^(ρρκϊ) so«&gt;c?pffiI) inchΓζ/(εffiCN) 0 inch·丨丨CNsisffiI) U·丨丨Rz/(s ffiI α·ζ/(ρρ®ι) inch 8.LXPffiI) ssoozsffiI) S6oo&quot;(9p-oswa.Ni oos.wiffi- π inch·?!ffile 卜寸.ε-δ·ε tH+s) will ffiI) 90.SKI) 8Z/9CS ffiI) 9&lt;N ΙΑε·ζ/(ηΗΓ&lt;ι) s inch·/zg ffi&lt;N)0S.ZT9sl&gt;epffiI) inch 8.//(5 κι) 16·// (日ΪΚ)ooAzroooooxs ffil) εΓοοβκοοοεοοχρffiI) 08°°.(saI) Oorsl6 :(9p-oswa .Ni 91 inch _ ΐ. tH+wl__lffi&lt;N) 68·ε-0σ'(^Ηε) inch r inchΧ5Ι) 68·9 xpffiIurz/s κ(Ν)^ΤΓοο^;ζ/ (ρ®Ι)Ις·ζ, xsffil) 9 卜 AXSffiI) Ιοοκ with WI) 60ΟΟΧΡΚ1)sooxsffiI) inch/;°°.(s CHI) 66oo&quot;(9p-ossa.NioosigK- Ning (wd ' McizCNH-^ 1(3⁄4 砩ls-s-1 inch SCAH 91^^qcnv gallium - &lt;5- § ss 5^ d'Mcvd:-e-[^i4-ct 砩10-slnv inch)-εΗ K^qs , s recorded.潜褎硪机械褊-inch昍 ^^PQt^. «&lt;锘1 HV gallium ΦΝ

(SJn-(JyfIP8J οηυμνζ^ζνε-Ι^δψκΙΧΓΑέφμ xd[BciIoZB3UI*vOJOso-/&gt;eH) i ^ ,ε-^ffnI 】^f-^6CAH

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Ββ 200836725 [M+H] + 361 [M+H] + 595 1HNMR (400 MHz, DMSO-d6): 8.60 (1H,d), 7.97 (1H, s), 7.95-7.84 (2H,m), 7.73 (1H, s), 7.45-7.23 (5H, m), 7.12 (1H, s), 6.88 (1H, d), 6.83 (1H, s), 6.64 (lH, dd), 6.13 ( lH,t), 3.68 (2H, d). 1HNMR (400 MHz, Me-d3-OD): 8.60 (1H,d),7.83 (1H,s),7·78 (1H,s),7.75-7.66 (3H, m), 7.49 (1H, t), 7.40 (1H, d), 7.37-7.30 (2H, m), 7_13 (2H, d), 3.96 (2H, q), 3·62 (4H, s ), 3.26 (4H, t), 1.51 (9H, s) · Art S to record: ι 喊 1 4 昍 gallium 5 S '1' ^ ^ f 2 s 5 ^ ^ ^ ^ d 黢; 1 q &lt; CA ^ ffi ^ Jh 2: A 5 ^ cn 1 ^ s B 2|l| |ΓίΙ and 丄旦玄SSIs. sHai (N ^ w N § 4-[4-(3-{3-[3-(2 , 2,2-trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-a]npyridin-7-yl)-phenyl]piperazine-1-carbonate tert-butyl ester (4 -[4-(3 - {3 -[3 -(2,2,2-Trifluoro-eth yl)-ureido]-phenyl} -imidazo[ 1,2-a ]pyridin-7-yl)-phenyl]piperazine -1-carboxylic acid tert-butyl ester) b ^ p LHQ, °x 232 200836725

[M+H] + 495 [M+H] + 443 1HNMR (400 MHz, Me-d3-OD): 8.81 (1H, d), 8.14 (1H, s), 8.12 (lH, s), 8.07 (1H , t), 7.91 (2H, d), 7.87 (1H, dd), 7.58 (1H, t), 7.45-7.37 (2H, m), 7.25 (2H, d), 3.96 (2H, q), 3.64- 3.60 (4H, m), 3.43 (4H, t). 1HNMR (400 MHz, Me-d3-OD): 8.59 (1H, d), 7.84 (1H, t), 7.70 (1H, s), 7.48 (1H , t), 7.44 (1H, s), 7.38 (1H, d), 7.31 (1H, d), 6.98 (lH, dd), 3·95 (2H, q), 3.81 (3H, s), 2.36 ( 3H, s), 2.29 (3H, s). ^ , 4 4 Office 11 韬二q人5砩&lt;砩魈1 n3 gr 言2 ^ κ λ f \ s V ^ ^ -r fr- ^ 1 - {3 -[7-(4-Bell-1)-yl-phenyl)-°m e[l,2-a]acridin-3-yl]-phenyl}-3-(2,2, 2-trifluoro-ethyl)-urea hydrochloride (1 - {3-[7-(4-Piperazin-1 -yl-phenyl)-imidazo[l ,2-a]pyridin-3-yl]-phe nyl} -3-(2,2,2-trifluoro-ethyl)-urea Hydrochloride) 1-(2,2,2-Trifluoro-ethyl)-3-{3_[7_(l,3,5-tridecyl- 1H-pyrazol-4-yl)-imidazole [l,2-a]acridin-3-yl]-phenylicarbazide (1-(2,2,2-Trifluoro-ethyl)-3-{3- [7-(1,3,5-trimethyl-1 H-pyrazol-4-yl)-imidazo [ 1,2-a]pyridin-3 -yl] -phen yl}-urea) Q % 234 200836725 [M+H] + 305 [Μ+Η] + 375 [M+H] + 433.13 1HNMR (400 MHz, DMSO-d6): 8.70 (1H,d), 8.05 (1H,d),8.02 (1H ,s),7·94 (3H, dd), 7.41 (1H,dd),7·36 (2H,t), 6·83 (1H,d),6·77 (1H,s),6.08 (2H , s). lHNMR (400MHz, Me-d3-OD): 8.57 (1Η, d), 7.87-7.77 (3H, m), 7.66 (1H, s), 7·36 (1H, t), 7.33-7.21 (3H,m), 6.99 (1H,d), 6.84 (1H,s),6.71 (1H,dd),3·83 (2H,s),2·79 (3H, Λ_ 1HNMR (400 MHz, DMSO- D6): 8.66-8.57 (2H,m), 8.00 (1H,s), 7.97-7.88 (2H,m), 7.82 (1H,s),7·41 (1H,dd), 7.39-7.30 (2H, m),7·24 (1H,t), 7·15 (1H,t),6.73 (lH,s), 6.19 (1H, t), 4.69-4.59 (1H, m), 3.19-3.06 (2H, m), 1.31(6H,d), 1.07(3H,t). ^ ϋδΙ SH \ 4 ^ 4 W =3 tO ^ S f 4 I f ^ ^ frame d Xiongdian A ® f with ffi s 1 ^ Silts 1 cA襃璁4-[7-(4-fluoro-phenyl)-imidazole [l,2-a] 吼-3-yl]-吼 bit-2-yl-gas (4-[7-(4) -Fluoro-phenyl)-imidazo[l52-a]pyridin-3-yl]-pyridin-2-yla mine) 2-{3-[7-(4-fluoro-phenyl)-imidazole [l,2-a ] »Biidine-3 -yl]-anilino}-N-methyl-acetamidamine (2-{3-[7-(4-Fluoro-phenyl)-imida zo[ 1 ?2-a]pyridin-3 -yl]-phenylami No} -N-methyl-acetamide) 1·Ethyl-3-{3-[7-(4-Gas-phenyl)·^σ[[,2-a] Acridine-3-yl]-5 -Isopropoxy-phenylurea (1-Ethyl-3 - {3 -[7-(4-fluoro-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-5-is opropoxy -phenyl} -urea) % , u. \ U- \ ^Τ) 236 237 200836725 [M+H] + 487.15 [M+H] + 552 [M+H] + 402 1HNMR (400 MHz, DMSO-d6) : 8.93 (1H, s), 8.61 (1H, d), 7.98 (13⁄4 d)? 7.96-7.86 (2H, m), 7.80 (1H, s), 7.42-7.28 (3H, m), 7_24 (1H, t), 7.17 (1H, t), 6.84 (lH, t), 6.81-6.75 (1H, m), 4.72-4.60 (1H, m), 4.02-3.87 (2H, m), 1.32 (6H? d) 1HNMR (400 MHz, Me-d3-OD): 8·67 (1H, d), 8.16 (2H, s), 7.97-7.63 (5H, m), 7.60-7.36 (5H, m), 7.32 (1H , d), 4·37 (2H, s), 3·96 (2H, q), 2.94 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.61 (1H, d), 8.35 ( 1H, s), 7.92 (1H, s), 7.82 (1H, s), 7_74 (2H, d), 7.48 (lH, t), 7.40 (1H, d), 7.35 (1H, d), 7.30 (lH,d) , 3.95(2H,q). nr» - WlC f ^ ^ r Λ &lt; vS: forged ^ aluminum 畹毽 tear 1毽K 1 A 孽邾 base from tO cn SJ Ϊ ^ 3 ^ ^ ^ 5 gr J ^ &lt ;sm srm step AB sl|fp^ill ^ u| J ^ V s^Sv|| N-[3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-mai ]-phenyl}_tT m e sits [1,2-a]吼唆-7-yl)-benzyl]-methanesulfonamide (N-[3-(3-{3-[3-(2,252) -Trifluoro-et hy l)-ureido]-phenyl} -imidazo[ 1,2 -a]pyridin-7-yl)-benzyl]-methanes ulfonamide) 1 l-[3-(7-oxazole-5-yl) -imidazole [l,2-a]pyridin-3-yl)-phenyl]-3·(2,2,2-trifluoro-ethyl)-urea (Η3 - (7-Oxazol-5-yl -imidazo[ 1,2_ a]pyridin-3 -yl)-phenyl] -3 -(2,2,2-tr ifluoro-ethyl)-urea) c工 c OO 239 〇200836725

[M+H] + 375 1 [M+H] + 596 [M+H] + 496 1HNMR (400 MHz, DMSO-d6): 9.22 (1H, s), 8.75 (1H,d), 8.30 (1H, d), 8.06 (1H, s), 8.04 (2H, s), 8.00-7.91 (2H, m), 7.79 (1H, s), 7.48 (1H, dd), 7.36 (2H, t), 7.29 (1H , dd), 3.27-3.16 (2H5m), 1.12 (3H,t). Λ C\ 2^5 e 〇〇 · f ancient ffi nf swallow ffi will be 5 bar SSw gas sg 〇 od W ^ ^ K; ' m Sg'O ffi p $2 ww ^ Yi-rr-ovovo^ K $ S〆气气. A. »—* ψ^, co Γ&quot;^ CO &lt; 1HNMR(400 MHz, Me-d3-OD): 8.62 (1H, d)? 8.57 (1H,d),8·01 (1H,dd),7.83 ( 1H, s), 7.79 (1H, s), 7.71 (1H, s), 7.49 (lH, t), 7.40 (lH, d), 7.33 (2H, dd), 6.97 (1H, d), 3.96 (2H, q), 3.64 (4H, t), 2.99 (4H, t)· Sl^l! K tO &lt;N JD ^ ..1 ^ VX tii±uU ls ^ 4 '1 ^ 晏cs ^ op ^ ^ ^ Le: r two: J5 △ a few g 1 1-ethyl-3-{4-[7-(4-fluoro-phenyl)-imi "sit [1,2-a] ϋ bite-3 -yl]-11 than 唆-2-yl}-pulse (1-Ethyl-3-{4-[7-(4-fluoro-phenyl)-imidazo[ 1 ?2-a]pyridin-3-yl]- Pyri din-2-yl}-urea) 4-[5-(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea]-phenyl}-imidazole [1,2 -a]pyridin-7-yl)-pyridin-2-yl]-piperazine-1-carbonate tert-butyl ester (4- [5 -(3 - {3 -[3 -(2?2?2-Trifluoro-) Eth yl)-ureido]-phenyl} -imidazo[ 1,2-a ]pyridin-7-yl)-pyridin-2-yl]-pipera zine-1-carboxylic acid tert-butyl ester) 1 - {3 - [ 7-(6-派嘻-1 -yl-17 than bit-3-yl)-imidazole [1,2-a]pyram-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1 - {3 -[7-(6-Piperazin-1 -yl-pyridin -3 -yl)-imidazo[ 1,2-a]pyridi N-3-yl] -phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) u. °h^. b % )fZ zx &lt;&lt;N 200836725

[M+H] + 510 [M+H] + 509 [M+H] + 443.14 1HNMR (400 MHz, Me-d3-OD): 8.61 (1H, d), 7.84 (1H, s), 7.79 (1H, s), 7.77-7.68 (1H, m), 7.49 (lH, t), 7.40 (1H, d), 7.36-7.29 (2H, m), 7.26 (1H, t), 7.09-6.98 (2H , m), 6.76 (1H, dd), 4·07-3_89 (4H, m), 3.69-3.48 (3H, m), 2.11-2.00 (2H, m), 1.62-1.47 (2H, m). 1HNMR (400 MHz, DMS0-d6): 9·24 (1H, s), 8.56 (1H, d), 7·87 (1H, s), 7·79 (1H, s), 7.77-7.69 (3H, m ), 7.49-7.39 (2H, m), 7.39-7.30 (1H, m), 7.29-7.21 (1H, m), 7.21-7.12 (1H, m), 7.06 (2H, d), 4.00-3.88 (2H , m), 3.27-3.19 (4H, m), 2.49-2.45 (4H, m), 2.24 (3H, s). 1HNMR (400 MHz, DMS0-d6): 8.70 (1H, s), 8.62 (1H, d), 7.99 (1H, s), 7.96-7.87 (2H, m), 7.83-7.74 (2H, m), 7.51-7.41 (2H, m), 7.41_7.31 (3H, m), 7.31-7.23 (lH,m), 6.86 (1H,d),4.61-4.48 (1H,m), 1.30 (3H,d). K tO § 蚪§ ^ 1 u| ^ ^ ^ 15 14 15望 S录涂1 η , ί; B ^ l S v ^ ^ cA ^ ^ 1 4 2 equipment ^ ί | nl ^ 0 | «iilllL &lt;€Λf Si read lv 砩硪1 ^ # 蟛^ ^ ®械余今 a 2 驾4 Z摩3二ι κ κ 1-(3-{7-[3-(tetrazole-pyran-4-ylamino)-phenyl]-imidazole [l ,2-a]Acridine-3-yl}-phenyl)-3-(2,2,2-Triton-ethyl)-urea (1 -(3 - { 7-[3 -(Tetrahydro-pyran) -4-y lamino)-phenyl]-imidazo[ 1,2-a]py ridin-3 -yl} -phenyl)-3 -(2,2,2-triflu oro-ethyl)-urea) l-(3 -{7-[4-(4-Methyl-piperazin-1-yl)-phenyl]-imidazole [l,2-a]acridin-3-ylphenyl)-3-(2,2 ,2-trifluoro-ethyl)·Ureaacetic acid (1-(3-{7-[4-(4-Methyl-piperazin-1 -yl)-phenyl]-imidazo[ 1,2-a]pyridi n- 3 -yl} -phenyl)-3 -(2,2,2-trifluoro-ethyl)-urea Acetic acid) a^1 ip f ^ Suining 1 i — JO % work, LL %, 244 245 CM

[M+H] + 468 [Μ+Η] + 405.16 [M+H] + 490 1HNMR (400 MHz, Me-d3-OD): 8.72-8.57 (1H, m), 8.19 (3H, s), 8.01 -7.70 (5H,m), 7.61 (1H,t),7.54-7.42 (2H,m), 7.39 (lH,d),7.30 (lH,d),3.96 (2H, q), 2.98 (3H, s 1HNMR (400ΜΗζ, DMSO-d6): 8.66-8.57 (2Η,m), 8.00-7.89 (3Η,m), 7.76 (1Η,s), 7.69 (1H,s), 7.40-7.31 (4H,m ), 7.14 (lH, s), 6.17 (lH, t), 5.25 (lH, t), 4.55 (2H, d), 3.17-3.09 (2H, m), 1.07 (33⁄4 t). 1HNMR (400 MHz, DMS0-d6): 8·99 (1H, s), 8.70 (lH, d), 8.30 (lH, s), 8.18_8.05 (3H, m), 7.90-7.77 (3H, m), 7.72 (lH , t), 7.51 - 7.43 (4H, m), 7·41 (1H, dd), 7.34 - 7.25 (1H, m), 6.88 (1H, t), 4.02-3.89 (2H, m). K tO 褎1 S v硪砩cA毽tnpj mtU 1 Q &lt;N ^ ^ Private/Fail 9 Call 353151 l S v ^ ^ ^ III , "宁宁目目 4ass|| ^ έ 4 ά ^ i ^ t〇^ έ ο 1-ethyl·3-{3-[7-(4-fluoro-phenyl)-imidazole [l,2-a]npyridin-3-yl]-5-hydroxyindenyl-phenyl}-urea (1 -Ethyl-3 - {3 -[7-(4-fluoro-phenyl)-imidazo[ 1,2-a]pyridin-3 -y 1] -5 -hy Droxymethyl-phenyl} -urea) ίέ? 121 〇^ § 占占^^ 31 si| ri gas ϋ q S g sSIgill ο~] LL· \工% 0: φ:〇247 248 249 200836725 [M+H] + 523 [M+H] + 489 [M+H] + 387 i $ ?* κ § 06 K ^ ffi I Ώ ^ 8 ^ 1H NMR (400 MHz, Me-d3-OD): 8.67 (1H, d), 8.33 (1H, s), 8.26-7.92 (5H, m), 7.92-7.71 (3H, m), 7.54-7.41 (2H, m), 7.38 (13⁄4 d), 7.31 (1H, d), 3.96 (2H5 q ) 5. 3. 3. (3H, s). (1H, dd), 7·55 (1H, ddd), 7.35 (1H, t), 7.06 (1H, dd), 6.87 (1H, t), 4.00-3.86 (2H, m). 5 ,94 Έιΐήΐ&quot;|ι NS!s_ Aluminium Two Hearts Q 1 SV砩砩h V蝣黢ee ov jjcJ ii ΓΠ ^ 3 ^ K 5 ig _1 Each gallium Ψ ^ β f 1 • Inch Λ M cn 验 /^ 1 Nothing硪硪^ 5 S ^ ^ in ^ ^ fu| g ^ ^ &lt; J 2 IQ &lt;N 〇1-(3-{7·[3-(piperazin-1-carbonyl)-phenyl]-imidazole [ l,2-a]Acridine-3-ylphenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -(3 - {7-[3 -(Piperazine-) 1 -carbony l)-phenyl]-imidazo[ 1,2-a]pyridin-3-yl}-phenyl)-3-( 2,2,2-trifluoro-et hyl)-urea hydrochloride) 1-{3-[7-(3-methylsulfonyl-phenyl)-imidazole [l,2-a]acridin-3-yl] -phenyl}-3-(2,2,2-tris-ethyl)-urea phthalate (1 - {3 -[7-(3 -Methanesulfonyl-phe nyl)-imidazo[ 1 ?2-a ]pyridin-3 -y 1]-phenyl} -3 -(2,2,2-trifluoro-ethy 1)-urea formate) l-[3-(7-gas-imidazole [l,2-a] acridine -3-yl)-4-a-phenyl]-3-(2,2,2-disorder-ethyl)-urea (1 -[3 -(7-Chloro-imidazo[ 1 ?2-a]] Py ridin-3 -yl)-4-fluoro-phenyl] -3 -(2, 2?2-trifluoro-ethyl)-urea) work =&gt;=. °ψ〇b U. 250 251 252 § 200836725 [M+H] + 447.1 [M+m + 447 [M+H] + 389.16 1HNMR (400 MHz, DMSO-d6): 8.97 (lH, s), 8.31 ( 1H, dd), 8.01 (1H, s), 7.97-7.88 (2H, m), 7.81 (1H, s), 7.71 (1H, dd), 7.54 (1H, ddd), 7.42-7.30 (4H, m) , 6.85 (1H, t), 4.00-3.87 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.62 (1H, d), 8.18 (13⁄4 s), 7.85 (1H , s), 7·81 (1H, s), 7.74-7.64 (2H, m), 7.51-7.41 (3H, m), 7.35-7.24 (2H, m), 6.85 (lH, t), 4.02-3.89 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.60 (1H, d), 8.23 (1H, s), 7.98 (1H, s), 7.93 (2H, dd), 7.79 (1H, s), 7.74 (1H, s), 7.43-7.27 (4H, m), 7.18 (1H, dd), 6.63 (lH, t), 3.21-3.08 (2H, m), 2.27 (3H, s), 1.09 (3H,t). ^ ^ it t imtu face l KS v ^ ^ ίζ; K tO Λ # ? ^ fm: • inch I耩, sonar, &lt; S褎^ a β $4 skew l ν ^ ^ Ί Ι|έ2ί- Mo. v彳录1 υ3 a 5 slip l-{4-fluoro-3-[7-(4-fluoro-phenyl)-imidazole [l,2-a]«pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea (1 - {4-Fluoro-3 -[7-(4-fluoro-phenyl)-imidazo[ 1,2-a]pyridin-3 -yl]-p henyl} -3 -(25232-trifluoro-ethyl)-ur ea) 1-{3-[7-(3,5-Difluoro-phenyl)-isoxazole [l,2-a] Acridine-3-yl]-phenyl}-3-(2,2,2-tris-ethyl)-urea (1 - { 3 -[7-(3 5 5 -Difluoro-pheny l)-im Idazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-ethy l)-urea) 1-ethyl-3-{5-[7-(4 - gas-phenyl)- miso sitting [l,2-a] 吼-3-yl]-2-mercapto-phenyl}-urea (1 -Ethyl-3 - {5-[7-(4 -fluoro-phenyl )-imidazo[ 1 ?2-a]pyridin-3-yl]-2-m ethyl-phenyl} -urea) work ^〇A work z&gt;=〇V LL. CN 254 3 200836725 [Μ+ Η] + 443 [M+H] + 430 [M+H] + 459.16 1HNMR (400 MHz, DMSO-d6): 8·98 (1H, s), 8.53 (lH, d), 8.40 (lH, s) , 8.18(0.5H, s) , 8·09 (1H, s), 7.87 (1H, s), 7.77 (1H, s), 7.70 (1H, s), 7.48-7.39 (2H, m), 7.30- 7.20 (2H, m), 6.89 (lH, t), 4.10 (2H, t), 4.02-3.88 (2H, m), 1.91-1.79 (2H, m), 0.8 8 (3H, t). 1HNMR (400 MHz, Me-d3-OD): 9.48 (13⁄4 d), 8.28-8·18 (2H, m), 8.02 (1H, s), 7.90 (1H, d), 7·79 (1H, s), 7.52 (1H, t), 7.47-7.36 (2H, m), 7.26 (2H? t), 3.96 (2H, q). 1HNMR (400 MHz, DMSO-d6): 8 ·96 (1H, s), 8.62 (1H, d), 7·99 (1H, s), 7.97-7.87 (2H, m), 7.78 (1H, s), 7.67 (1H, s), 7.42 (1H, s), 7.40-7.32 (3H, m), 7.21 (lH, s), 6.82 (lH, t), 5.28 (lH, t), 4.56 (2H, d), 4.03-3.88 (2H, m ). It -s flag f S ^ few, 1 ΐ ? i 4 i ^ inch 〇〇 K ^ &lt;N ^ # Υ 4 S &lt;νλ秘录 ί' 1 Q &lt;N ^ ^ l-{3 -[7-(l-propyl-1H-pyrazole-4.yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-tri Fluoro-ethyl)-urea formate (1 - {3 -[7-(1 -Propyl-1 H-pyrazol-4-yl)-imidazo[ 1,2-a]pyridin-3 -yl] -p Henyl} -3 -(2,2,2-trifluoro-ethy l)-ur ea formate) 1-{3-[7-(4-defy-phenyl)-imida[l,2-c]pyrimidine- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-gland (1 - {3 -[7-(4-Fluoro-pheny l)-imida zo[ 1,2 -c]pyrimidin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) f1 3 1 § i .-H i 砩 i i i i i i i n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n DMSO-d6): 8·59 (1H,d), 8.19-8.08 (2H,m), 7.98 (1H,s), 7·97·7·88 (2H,m),7·76 (1H,s ), 7.43-7.30 (4H, m), 7.30-7.20 (2H, m), 4.04-3.93 (2H, m), 2.29 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.71 ( 1H5 d), 8.19 (1H, s), 7.86 (2H, d), 7.67 (1H, dd), 7.51 (lH, t), 7.44 (lH, d), 7·35 (1H, d), 3.96 ( 2H,q), 3.25 (2H, q), 1.50 (3H, t). 1HNMR (400 MHz, Me-d3-OD): 8.66 (1H,d), 8.20 (2H,d),8.02-7.72 (5H , m), 7.61 (1H, t), 7.54-7.42 (2H, m), 7.39 (1H, d), 7.3l (lH, d), 3.96 (2H, q), 3.54-3.41 (2H, m) , 1.28 (3H, t). Chicken _ ^ ^ V ' ^ κΐ ^ ^ 2 cA \ ^ ^ Λ ^ ^ ^ ^ ^ (N ^ 4\ rrr, ^ ^ ^ W 4 ^ tO g| ^ 1 s鲈轵子^ ί ί Hi ^ g ^ 驾二Q人人 tO m lsv ^ ^ ^ 5 ill ¥ It?1 Itmi turns miscellaneous l-{3-[7-(5-ethyl-[1,3, 4]thiadiazol-2-yl)-imidazole [l,2-a]lpyr-3-yl]-phenyl}-3-(2,2,2-tri-ethyl)-pulse (l -{3 -[7-(5-Ethyl-[l,3,4]thiadiazo l-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl ]-phenyl} -3-(2,252-trifluoro-ethyl ) -urea) uj ^ ® S11 atf Na 5呤|^晋1 g tO έ 2 2 LL \工z Vi I i 259 260 r—4 200836725

[M+H] + 508.09 • [M+H] + 512 [M+H] + 494 1HNMR (400 MHz, DMSO-d6): 9.01-8.96 (2H?m), 8.62 (lH, s), 8.57 ( lH,d),8.16 (1H,s),7·79 (1H,s),7·77 (1H, s), 7.49-7.41 (3H, m), 7.31-7.22 (1H, m), 6.87 ( 1H, t), 4.02-3.88 (2H, m)3 2.92 (6H, s). 1HNMR (400 MHz, Me-d3-OD): 8.67 (1H, d), 8.26 (1H, s), 8.02-7.88 (3H,m), 7.85 (1H, s), 7.76 (1H, s), 7·63 (1H, t), 7.50 (1H, t), 7.46-7.37 (2H, m), 7.34 (1H, d ), 3.96 (2H, q), 3·63 (4H, s), 3.42 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.68 (1H, d), 8.05 (1H, s) , 7.99-7.93 (1H, m), 7.92 (1H, s), 7.86 (lH, t), 7·77 (1H, s), 7·74-7_67 (1H, m), 7·64 (1H, t) , 7.50 (lH, t), 7.46-7.37 (23⁄4 m), 7_35 (lH, d), 4.47 (2H, t), 4.27 (2H, t), 3.96 (2H, q), 2.48-2.38 ( 2H, m). &lt; BE 5 5 s ^ 〇1 S v ^ ^ w K θά, private 2 base V 2铤•inch;;绻, gallium硪&lt; S Μ KO cn , ^ ^ ^ K ^ ^ ^ ^ SS ^ ^ ^ &lt;! S '1 3 ^ ^ ^ Aluminium II q 人叉竑" 1 s V ^ έ Β ^ 4-(3·{3-[3-(2,2,2-Three Gas -ethyl)- ]-phenyl}-imidazole [l,2-a]acridin-7-yl)-吼σ sitting-1-sulfonicacid dimethylamide (4-(3 - {3 -[3 -(2,2, 2-Trifluoro -ethyl)-ureido]-phenyl} -imidazof 1 ,2-a]pyridin-7-yl)-pyrazole-1 -sulf onic acid dimethylamide) Ν·(2-dimethoxy-ethyl)- 3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-appyridin-7-yl)-benzamide Amine (N-(2-Methoxy-ethyl)-3 -(3- {3-[3 -(2,2?2-trifluoro-ethyl)-ureido]-phe nyl} -imidazof 1,2-a]pyridin -7-yl)-benzamide) 1-(3-{7-[3-(azetidin-1-yl)-phenyl]-imidazole [l,2-a]indole-3-yl} -phenyl)-3_(2,2,2-trifluoro-ethyl)-urea (1 -(3 - {7-[3 -(Azetidine-1 -carbonyl )-phenyl]-imidazo[ 1,2- a]pyridin-3 -yl} -phenyl)-3 -(2,2,2-trifluoro-eth yl)-urea) workerz&gt;=〇' K 262 s CN 264 200836725 卜 6 inch.as tH+s SCNT χεffieUT-08T^ffiCN) βό.^βΜεϊ, οοΓΖΓό inch·//(51) 09·ζ/(ί I) 9z/z/(pffiI) S6. Bu XPtcCN) 60ooeΉϊ) inchΓ8 Xs KI) inch&lt; N°°.(sffiI) εεοο^ffil) oo inch ooeffiI)soo&quot;(aoCAp-ow .Nffis 00s 5

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L9Z 200836725 [M+H] + 454 j [M+H] + 447 [Moleculai ion] + 431 1HNMR (400 MHz, Me-d3-OD): 8·69 (1H,d),8.32 (1H,s) 5 8.04-7.92 (3H, m), 7.86 (1H, s), 7.76 (1H, s), 7.65 (1H, t), 7.50 (1H, t), 7.46-7.38 (2H, m)? 7.35 (1H , d), 3.96 (2H, q). 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.64 (1H,d),7·88-7·73 (4H,m), 7.51- 7.38 (33⁄4 m), 7.33-7.23 (2H, m), 7.20 (1H, d), 6.86 (1H, t), 3.95 (2H, m). 1HNMR (400MHz, DMSO: 9.11 (1H, s), 8.54 (1H,d),8·22 (1H, s), 7.78 (2H, s), 7.75 (1H, s), 7.55 (1H, d), 7.49-7.40 (2H, m), 7.31 7.21 (2H,m),7.02 (1H,t), 6.93-6.86 (lH,m),4.01-3.87 (23⁄4 m). § ί 1 u| ^ ^ 11 1 ^ lsv ^ ^ ^ K tO A -ψ μ Ϊϊ|552 1 s ν ^ ^ '1 1 &lt; a Ί ^ ^ 3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-mai]_phenylimidazole [l,2-a]Acridine-7-yl)-benzamide (3 -(3 - { 3 -[3 -(2?2?2-Trifluoro-ethy 1) -ureido]-phenyl} - Imidazo[ 1 ?2-a]p yridin-7-yl)-benzamide) 1-{3-[7-(2,4-Difluoro-phenyl)-carbazole [l,2-a]acridine- 3-yl]-phenyl}-3 -(2,2,2-digas-ethyl)-pulse (1 - {3 -[7-(2,4-Difluoro-phenyl)-im idazo[ 1 ?2-a]pyridin-3 -yl] -phenyl} -3 -(252,2-tri£luoro-ethyl)-urea) l-{3-[7-(5-methyl-nonphen-2-yl)-imidazole [l,2-a]吼Pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (1 - {3 -[7-(5-Methyl-thiophen-2-yl) ) -imidazo[ 152-a]pyridin-3 -yl]-phen y 1} -3 _(2,2,2-tri0uoro-ethy l)-urea formate) \ 〇z eg工&gt;=〇u. % 268 ii 1 269 270 200836725

[Fragment] + 441 [M+H] + 447 [M+H] + 445 1HNMR (400 MHz, DMSO-d6): 8.95 (1H, s), 8.59 (1H, d), 7.92 (1H, s ), 7.82 (2H, d), 7·78 (1H, s), 7.76 (1H, s), 7.45 (2H, d), 7·36 (1H, dd), 7.32-7.23 (1H, m), 7.08 (2H,d), 6.85 (lH,t), 3.95 (2H,m),3.83 (3H, s). 1HNMR (400 MHz, DMSO-d6): 8·97 (1H, s), 8.62 (1H , d), 8.12-7.99 (2H, m), 7.85-7.71 (33⁄4 m), 7.62-7.53 (1H, m), 7·49·7·37 (3H, m), 7.32-7.24 (1H, m ), 6.86 (lH, t), 4.01-3.90 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.96 (1H, s), 8.63 (1H, d), 8.04 (1H, s), 7.91 (2H, d), 7.80 (2H, d), 7·57 (2H, d), 7.46 (2H, d), 7.39 (1H, dd), 7.31-7.24 (lH, m), 6.85 (lH, t ), 3.95 (23⁄4 m). BE tO S ^ 超Λ ^ 4 A early super C ^ f ^ 1 SssisS? 1 s 7砩花硪 K tO &lt; ^ | u,i ^ ^ or &lt;N _〇 , inch r music, 亨毽1 S v硪砩UKO 4 ^ | i 1 • inch: difficult private &lt; s Μ drive - 3 people 蚪 1 S ν 办 4 ^ {347-(4-dimethoxy -phenyl)-imidazole [1,2-a]σ ratio 1¢-3 -yl]-phenyl-p-3-(2,2,2-trifluoro-ethyl)- (1 - {3 -[7-(4-Methoxy-phenyl)-imi dazo[l,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethy l) -urea) l-{3-[7-(3,4-Difluoro-phenyl)-imidazo[l,2-a]acridin-3-yl]-phenyl}-3-(2,2, 2-triethyl)-urea (1 - {3 -[7-(3?4-Difluoro-pheny l)-im idazo[ 152-a]pyridin-3 -yl]-phenyl} -3 -(2,252- Trifluoro-ethyl)-urea) ^{347-(4-Chloro-phenyl)-imidazole [l,2-a] σ than -3-yl]-phenyl}-3-(2,2,2- Dioxo-ethyl)-urea (1 - {3 -[7-(4-Chloro-phenyl)-imida zo[ 1,2-a]pyridin-3 -yl]-phenyl} -3 -( 2,2 ,2-trifluoro-ethyl)-urea) ? \ LL 〇\ H. 〇272 rn &lt;N 200836725

[M+H] + 428 ! [M+H]. 430.06 1HNMR (400 MHz, Me-d3-OD): 8.66 (1H, d), 8.41 (1H, s), 8.37 (1H, d), 7.85 (1H, s), 7·83 (1H, s), 7.74 (1H, dd), 7.50 (lH, t), 7.46-7.38 (13⁄4 m), 7.38-7.31 (lH, m), 7.28 (13⁄4) d), 3.96 (2H, q). 1HNMR (400 MHz, DMSO-d6): 9·57 (1H, s), 8.76 (1H, d), 8.63-8.57 (1H, m), 8.35 (1H, d ), 8.07 (2H, s), 7.97 (2H, dd), 7.80 (1H, s), 7.49 (1H, dd), 7.42-7.3 l (3H, m), 4.14 - 4.03 (2H5 m).今 A襃”1 ^ ¥ 1 5β g硪&lt; X « V ^ ^ Private two π硪-5 a 5 q蚪_ per &lt; ^ d ^ T3 ^汔碥硪,s aluminum c tsp gallium 1 gallium EI途" ' Φ ψ # ^ 二-_ 鳘 ^ ^ ^ ^ 毽智智媸wg沄1 1-{3-[7-(2-气基-咬咬-4-基)-σ米0坐[l ,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-tris-ethyl)-pulse (1 -{3-[7-(2-Amino-pyrimidin-- 4-yl )-imidazo[ 1,2-a]pyridin-3 -yl]-phe nyl} -3 _(2,2,2-trifluoro-ethyl)-urea ) l-{4-[7-(4 -fluoro-phenyl)-isazole [l,2-a]pyridin-3-yl]-pyridin-2-yl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {4-[7-(4-Fluoro-phenyl)-imida zo[ 1,2-a]pyridin-3 -yl]-pyridin-2- y 1} -3-(2,252-trifluoro-ethyl)-urea) % rz CM % LL· 274 m CN 200836725

[M+H] + 483 [M+H] + 551 1HNMR (400 MHz, Me-d3-OD): 8.70 (1H, d), 8.41 (2H, s), 7.92-7.86 (1H, m), 7.86 -7.79 (2H,m), 7.51 (1H, t), 7.47-7.37 (1H, m), 7.34 (lH,d), 7.20(lH,dd), 6.91 (1H, s), 4.08 (3H, s ), 4.02-3.88 (2H, m). t lHNMR (400MHz, Me-d3-OD): 8.91 (1H, d), 8.29 (1H, s), 8.22 (1H, s), 8.13-8.04 (3H, m), 7.90 (1H, dd), 7.80-7.67 (2H, m), 7.64-7.54 (1H, m), 7.49-7.37 (2H, m), 4.01-3.91 (2H,m), 3.73-3.64 ( 8H,m), 1.42 (3H,t). 0 ^ -6- ^ 2 ^ '1' ^ i ^ Inch: Destroy each aluminum; ^ S 2 2,, J β W 1 丨丨硪 carboxy 93⁄4 5 · 9 萏Ή gallium s 砭 s ^ f ® ^ # 5^355131 1 S cA # 4 1-{3-[7-(2-methyl-5-trifluoromethyl-2H-port ratio 0 sitting -3 -基)-味°[1,2-a]吼σ定-3-yl]-phenyl}-3-(2,2,2-di-o-ethyl)-urea (1 - { 3-[7-(2-Methyl-5 -trifluoromet hyl-2H-pyrazol-3-yl)-imidazo[ 1,2 -a]pyridin-3-yl]-phenyl} -3-(2,2,2 -trifluoro-ethyl)-urea) 1 -(3 - {7-[3 -(4-ethyl-pyrene-1 -yl)_phenyl]-imidazole [l,2-a]acridine-3 - kibphenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -(3 - {7-[3 -(4-Ethyl-piperazine-) 1 -carbonyl)-phenyl]-imidazo[ 1,2-a] pyridin-3-yl} -phenyl)-3 -(2,2,2-trif luoro-ethyl)-urea Hydrochloride) 276 277 200836725 [M+ H] + 445 [M+H] + 441 [M+H] + 463 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.62 (1H,d), 8.09 (1H, s),7 · 95 (1H, s), 7.89-7.75 (3H, m), 7.60-7.37 (5H, m), 7.28 (1H, m), 6.86 (1H, t), 4·02-3·88 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.96 (1H?s), 8.61 (1H, d), 8.03 (1H, s), 7.84-7.76 (2H, m), 7.50-7.35 (6H, m ), 7.32-7.24 (lH, m), 7.05-6.96 (1H, m), 6.85 (1H, t), 3_95 (2H, m), 3.87 (3H, s). 1HNMR (400 MHz, DMSO-d6) : 8.97 (1H, s), 8.63 (1H, d), 8.14 (lH, s), 8.01 (1H, dd), 7.87-7.67 (4H, m), 7.50-7.39 (3H, m), 7.28 (1H , m),6·85 (1H,t),4.01-3.89 (2H, m). cation tO A per _arsenite BE ^ pr W (N ^ electric G9 gallium SS515S 1 s 5 硪硪 alkali ^ | i 1 Y5 $4 continued 1 g ^ K 〇4 gallium Ψ &lt; r{芟1 gamma machine" l-{3-[7-(3-chloro-phenyl)-imidazole [l,2-a] σ ratio淀-3-yl]-phenyl}-3-(2,2,2-di-o-ethyl)-urea (1 - {3 - [7-(3 -Chloro-pheny l)-i Mida zo[ 1 ?2-a]pyridin-3 -yl]-phenyl} -3 -( 2,2,2-trifluoroethyl)-urea) _ l-{3-[7-(3-dimethoxy- Phenyl)-p-m[beta][l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l-{3- [7-(3-Methoxy-phenyl)-imi dazo[ 1,2-a]pyridin-3-yl]-phenyl}-3-(252,2-trifluoro-ethyl)-urea) 1-{3-[ 7-(4-Chloro-3-gas-phenyl)-°米〇[1,2-a]吼β定-3-yl]-phenyl}-3-(2,2,2-trifluoro -ethyl)-urea (l-{3-[7-(4-Chloro-3-fluoro-phenyl)-imidazo[l,2-a]pyridin-3-yl]-p heny 1} -3 - (2,2,2-trifluoro-ethy l)-ur ea) % Workers. % 〇 , Λχ ο OO CN 279 280 200836725

[M+H] + 468 [M+H] + 447.09 1HNMR (400 MHz, DMSO-d6): 9.12 (1H, s), 8.64 (1H,d),8·55_8·50 (1H,m),8.10 (1H, s), 7.98 (4H, s), 7.86-7.78 (2H, m), 7.50-7.41 (3H, m), 7.31-7.25 (1H, m), 7.05-6.99 (1H, m), 4.00 -3.90 (2H,m), 2.82 (3H,d). 1HNMR (400 MHz, DMSO-d6): 8·80 (1H,d), 8.55 (1H,d), 8.41 (1H,dd),7· 99 (1H, d), 7.97-7.88 (2H, m), 7.77 (1H, s), 7·46-7·24 (6H, m), 4.06-3.93 (2H, m)· I^Sa:| S • 'inch, record ^ 闺 温 Si temperature ^ 4 PQ inch: (four) β 〇 ci γ a few 3 1 4 private 4 pigeons:!趑g lull vl-s 1·{2·Fluoro-5-[7-(4-fluoro-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-( 2,2,2-trifluoro-ethyl)-urea (1 - {2-Fluoro-5-[7-(4-fluoro-phenyl)-imidazo[ 152-a]pyridin-3-yl]-p Heny 1} -3 -(2,2?2-trifluoro-ethyl)-ur ea) % Ό^〇xz s X2 工z&gt;=〇LL· S (N 200836725

[M+H] + 537 [M+H] + 463 [M+H] + 442 ffi ηηλ On S ^ 2 N*' rH ^ ^ CN §^κ^κ2κ sh ε gώ茭SSffi茭κ 2 S «&gt ; i&gt;Sc-; G, lHNMR (400MHz, DMS0-d6): 8.96 (1H, s), 8.62 (lH, d), 8.13 (lH, dd), 8.09 (lH, s), 7.91 (1H, m ), 7·82 (1H, s), 7.80 (lH, s), 7.56 (lH, t), 7.51-7.37 (3H, m), 7.28 (1H, m), 6.85 (1H, t), 4.02- 3.89 (2H, m). 1HNMR (400 MHz, DMS0-d6): 8.97 (1H, s), 8.64 (1H, d), 8.28 (1H, d), 8.22 (1H, s), 7.86 (1H, s ), 7.80 (1H, s), 7.52 (1H, dd), 7.49-7.42 (3H, m), 7.35-7.24 (2H, m), 6.85 (1H, t), 4.02-3.88 (5H, m). K tO S 樾# jLtJ 丨1 *—* 1 sister? ^Sd:gsS^H • inch:: a few, f G耩w噌^ώηδ short sg霄f. S 93⁄4鈇s K 〇cA &lt; 5'( ΪΪΒ 55? 1 sv ^ ^ ^ tO ^ *m4i ^ ^ ^ &lt;褎&lt;N 5 S ^ I ^ ^ S ^ ^ ^ V # f &lt;;丨^ ώ g: ¢4 ^ ^ lsv ^ ^ Ί 1_(3-{7-[3-([1,4]diazepine carbonyl)-phenyl]-imidazole [l,2-a] Acridine 3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1-(3-{7-[3-([l,4] Diazepane- L-car bonyl)-phenyl]-imidazo[ 1,2-a]pyr idin-3 -yl} -phenyl)-3 -(2,2,2-trifluo ro-ethyl)-urea Hydrochloride) ^{347- (3-Oxo-4-fluoro-phenyl)-imiphate [1,2-a] ° ratio biting 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl) -urea (1 - {3-[7-(3-Chloro-4-fluoro-phen yl)-imidazo[ 1,2-a]pyridin-3 -yl]-p henyl}-3-(2?2, 2-trifluoro-ethyl)-ur ea) l-{3-[7-(2-Dimethoxy-pyridin-4-yl)-imidazole [l,2-a]acridin-3-yl]-benzene -3-}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(2-Methoxy-pyridin-4-yl)-imidazo[ 1,2-a]pyridin -3 -yl]-phe nyl}-3-(2,2,2-triiluoro-ethyl)-urea ) 0. \ X〇iX 〇Λ工z工2&gt;=〇S3 (N 284 ^r\ 00 &lt ;N 200836725 /L· [M+H] + 479 [M+H] + 496 [M+H] + 471 Weeping first g iimi face g €^百0 &amp; HNMR (400 MHz, DMSO-d6): 9.01 (1H5 s), 8.57 (lH, d), 7.88 (lH, s), 7.82-7.71 (4H, m), 7.44 (2H, d), 7.35 ( 1H, dd), 7.31-7.22 (lH, m), 7.07 (2H, d), 6.91 (1H, t), 4.02-3.89 (2H, m), 3.82-3.72 (4H, m), 3.24-3.15 ( 43⁄4 m). 1 1HNMR (400 MHz, 1 DMSO-d6): 9.02 (1H, s), 8.58 (1H, d), 8.18 (0.5H, s, formate), 8.00 (lH, s), 7.81 (lH , s), 7.77 (1H5 s), 7.50-7.35 (5H? m), 7.27 (1H, m), 7.08 (1H, d), 6.92 (1H, t), 4.03-3.86 (5H, m), 3 ·82 (3H, s). Yang ο ^ Λ ή ^ in late ^ Pr ^ cn £ ss recorded S &lt; 5 fssll^ 昍tO ^ ^ S ^ ^ i4 aluminum two 3 people! E 1 vo 4 ^ tO go ^ ^ S ^ 5 111 | ^ ^ ί vi ^ -&lt; ^ ^ $4 &lt; S »1 Aluminium 2 3 α人 ι \ sv ^ ^ Ί si &amp;|? ill f|f ll% 33⁄4宁l|! Turn S_! l-{3-[7_(4-morpholin-4-yl-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (1 - {3-[7-(4-Morpholin-4-yl-pheny l)-imidazo[ 1,2-a]pyridin-3 -yl]-phe nyl } -3 -(2,么2-triiluoro-ethyl)-urea ) i 1_ Γ 1-{3-[7·(3,4-Dimethoxy-phenyl)-isoxazole [l,2-a N-pyridin-3-yl ]-Phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (l-{3-[7-(3,4-Dimethoxy-phenyl)-imidazo[ 1,2 -a]pyridin-3 -yl]-phen yl}-3-(2,2,2-trifluoro-ethyl5-urea Formate) :\ Q \ ZEZjZ U. &gt;=〇% 〇s 1 286 287 〇〇〇 〇cs in inch inch 200836725

[M+H] + 489 [M+H] + 418 [M+H] + 479 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.68 (1H, d), 8.21-8.11 (33⁄4 m), 8.04 (2H,d),7·86 (1H,s),7·81 (1H, s),7.51-7.42 (3H,m),7.34-7.25 (1H,m),6.86 ( 1H,t), 4.02-3.89 (2H,m)· 1HNMR (400 MHz, DMS0-d6): 9.28 (1H,d),8.96 (1H,s),8·63 (1H,d),8·45 (1H, d), 8.27 (1H, s), 7.80 (1H, s), 7.78 (1H, s), 7.64 (1H, dd), 7.50-7.42 (2H, m), 7.32-7.24 (lH , m), 6.86 (lH, t), 4.01-3.90 (2H, m) · 1H NMR (400 MHz, DMS0-d6): 8.98 (1H, s), 8.65 (1H5 d), 8.24-8.13 (3H, m ) 5 7.87-7.71 (4H, m), 7.52-7.42 (3H, m), 7.33-7.24 (1H, m), 6.86 (1H, t), 4.02-3.89 (2H, m). ttO &lt; S »1 5έ3ϊΐ| 1 γ 硪 硪 4 Private tO recorded 1 1 iK Yunna fe, 丨丨 3 temple test ^ (N 2 !i 1 recorded two γ to do wmo § ^ | ^ 锘 2 3 people a 3 1 v ^ ^ cA l-{3_[7-(4-Methanesulfonyl-phenyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2 -Tris-ethyl)-urea (1 - {3 -[7-(4-Methanesulfonyl-phe nyl)-imidazo [ 152-a]pyridin-3 -y 1]-phenyl} -3 -(2,2 , 2-triflu Oro-ethyl)-urea) 1-{3-[7-thiadiazol-4-yl)-imidazole [l,2-a]oxa-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (1 - {3 -[7-Thiazol-4-yl)-imidazo[ 1, 2- a]pyridin-3 -y 1] -phenyl} -3 -(2 ,2,2-trifluoro-ethyl)-urea) 1 -(2,2,2-tris-ethyl)-3 {3 -[7-(3-trifluoromethyl-phenyl)- miso[ 1,2-a]Acridine-3-yl]-phenyl}-pulse (1-(2,2,2-Trifluoro-ethyl)-3-{3-[7-(3-trifluoromethyl-phenyl)- Imidaz 〇[ 1 ?2-a]pyridin-3 -yl]-phenyl} -ure a) % 'Οί,Ρ jjS d, C〇&quot;^2: V % LI. 289 290 iH 200836725 [M+H] + 495 [M+H] + 480.11 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.64 (1H, d), 8.05 (1H, s), 8.03-7.96 (2H, m), 7 · 82 (1H, s), 7.80 (1H, s), 7.55-7.42 (4H, m), 7.40 (1H, dd), 7.33-7.24 (1H, m), 6.85 (1H, t), 4.02-3.89 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9.30 (1H, d), 8.98 (1H, s), 8.70 (1H, d), 8.57 (1H, dd), 8.30 ( 1H,d),8.03 (1H,d), 7.88 (1H,s),7·83 (1H,s),7.52 (1H, dd), 7.50-7.42 (23⁄4 m), 7.34-7.25 (1H,m ), 6.87 (1H, t), 4.03-3.88 (2H? m). 2 i '1' ^ f 1 VO ^ 4 K , 9 2 U| per 硪 2 κ 3 a cardiac S How to 辕莩 辕莩 懋 二 q q q q 人 人 人 人 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ' ' ' ' ' ' (2,2,2-trifluoro-ethyl)-3-{3-[7-(4-trifluoromethoxy-phenyl)-flavored saliva [l,2-a[ than indol-3-yl ]-phenyl}-gland (1 -(2,2,2-Trifluoro-ethy 1)-3 - { 3 - [7-(4-trifluoromethoxy-phenyl)-imid azo[ 152-a]pyridin-3 - Yl]-phenyl}-u rea) 1-(2,2,2-trifluoro-ethyl)-3-{3-[7-(6-trifluoromethylpyridin-3-yl)-imidazole [ 1,2-a]npyridin-3-yl]-phenylurea (1 -(2,2,2-Trifluoro-ethy 1)-3 - {3 -[7-(6-trifluoromethyl-pyridin- 3-yl)-i midazo[ 1,2-a]pyridin-3 -yl]-pheny l}-urea) u. LL+O κ L·- o CN 293 200836725

. /IV

[M+H] + 504 [M+H] + 533 [M+H] + 495 lHNMR (400MHz, DMSO-d6): 9.89 (1H, s), 8.98 (1H, s), 8.66 (lH, d) , 7.92 (1H, s), 7.81 (1H, s), 7.79 (1H, s), 7.65-7.55 (2H, m), 7.54-7.41 (3H, m), 7.34-7.23 (3H, m), 6 ·87 (1H,t), 4.02-3.89 (2H,m), 3.08 (3H?s). 1HNMR (400 MHz, Me-d3-OD): 8·65 (1H,d), 7.89-7.80 (2H ,m),7·74 (1H,s), 7.63 (1H,s),7.55-7.37 (4H,m), 7.37-7.27 (3H, m)? 3.96 (2H, q), 2.85 (6H, s 1HNMR (400 MHz, Me-d3-OD): 8.67 (1H, d), 8.50 (1H, s), 7.92-7.83 (4H, m), 7.79-7.72 (1H, m), 7_61 (2H, d), 7.50 (1H, t), 7·43-7_29 (3H, m), 4.12 (1H, dd), 3.96 (2H, q), 3.53-3.25 (3H, m), 3.25-2.98 (3H, m). 5 · 4 ά老^ ^ S - S ^ ^ a ^ 1 S v砩硪i tl_ ^ cA FT ^ ^ ^ 1 S &quot;r砩砩巴铬取tO黢# g ^ ^ ^ ul ^ S ^ s Avoid 1 ^ ^ v ^ ST N_[3-(3_{3-[3-(2,2,2-Trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-a] Acridine-7-yl)-phenyl]-methanesulfonamide (N-[3-(3-{3-[3-(2,252-Trifluoro-et hyl)-ureido]-phenyl}-imidazo[ 1, 2 -a]pyridin-7-yl)-p Henyl]-methanes ulfonamide) 1-{3-[7-(3-[Ν,Ν-dimethylaminesulfonylamino]phenyl]imidazole [l,2-a]«bipyridine-3- ]]-phenyl}-3-(2,2,2-tris-ethyl)-urea (l-{3-[7-(3-[N,N-dimethylsulfam oylamino]phenyl)-imidazo [ 1 ,2-a] pyridin-3-yl]-phenyl} -3 -(2,2,2-trif luoro-ethyl)-urea) l-{3_[7-(4-pipeh-2-yl-benzene Imidazo[l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (l-{3-[7- (4-Piperazin-2-yl-phenyl)-imidazo [ 1,2-a]pyridin-3 -y 1] -phe nyl} -3 -(2?2,2-trifluoro-ethyl)-urea hydrochloride) z&gt;〇, 294 295 (N 00 inch inch 200836725 [M+H] + 495 ! [M+H] + 453 [M+H] + 486 1HNMR (400 MHz, DMSO-d6): 8·98 (1H, s ), 8.64 (lH, d), 8.12 (lH, s), 7.94 (lH, d), 7.88 (1H, s), 7.83 (1H, s), 7.81 (lH, s), 7.65 (lH, t) , 7.51-7.39 (4H, m), 7.33-7.24 (lH, m), 6.87 (lH, t), 4.03-3.88 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.98 (1H, s ) 5 8.62 (1H? d), 7.99 (1H, s), 7.84-7.76 (2H, m), 7.72 (1H, s), 7.66 (1H, d), 7.50-7.36 (4H, m), 7.36-7.24 (2H, m), 6. 86 (lH,t), 4.02-3.89 (2H,m), 3.06-2.96 (1H,m), 1.29 (63⁄4 d). 1HNMR (400 MHz, DMSO-d6): 8·98 (1H, s), 8.63 (1H,d), 8.41 (1H,d),8.08-7.97 (3H,m),7.81 (lH,s), 7.80 (1H, s), 7.50-7.36 (4H,m),7.32-7.24 ( lH,m), 6.87 (lH,t), 4.01-3.89 (2H,m),2.83 (3H,d). hlht &lt; SM lv K tO ^ # 11 1 &lt; S Μ 3 . ¢4 2 φ ^ 44 ^ ^ Pin two 3 people z vg: 1 Napa spider K tO 4 褎 AtJ 1 1 § ί 1 ^ ^ ^ or W (N 5 fi ♦ / S $ 黪| &gt; i-i 353Ϊ5? 1 v1 "潜, f ? P ji! # ils spill ί 41111 Si?£j|? 1-{3-[7-(3-isopropyl-phenyl)-imidazole [l,2-a] acridine-3 -yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l-{3-[7-(3-Isopropyl-phenyl)-imi dazo [ 1,2-a ]pyridin-3 -y 1] -phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) 31 slf ¢1411 As ό 3 N nu Today 2 s s * with u u_ 0-1-u -%工z&gt;=〇LI. 297 CN 299 200836725 [M+H] + 426 [M+H] + 479 [M+H] + 454 1HNMR (400 MHz, DMSO-d6): 9.31 (1H, s) , 8.64 (1H, d), 8.55 (lH, d), 8.31 (13⁄4 s), 8.17 (1H, s), 7.84 (2H, s), 7.77 (1H s),7·67 (1H,d), 7.52-7.40 (3H,m),7·27 (2H,d), 3.82 (2H,m),2·58 (3H,s). 1HNMR (400 MHz , DMSO-d6): 8.98 (1H, s), 8.63 (1H,d), 8.18 (lH,d),8.14 (1H, s),7·89 (1H,dd),7·84 (1H,s ), 7.80 (lH, s), 7.76 (lH, d), 7.50-7.39 (3H, m), 7.32-7.24 (1H, m), 6.86 (1H, t), 4.02-3.89 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.66 (1H, d), 8.28 (lH, s), 8.14 (1H, d), 8.10-8.01 (lH, m), 7.98 (1H , d), 7·89 (1H, s), 7.82 (1H, s), 7.55-7.41 (3H, m), 7.34-7.25 (lH, m), 6.86 (lH, t), 4.02-3.88 (2H , m). 田tO ί 11 ή 11 f 疋tO, $ ^ | _i per tlu% :g few today f late c S »1 ^ SsgllS lv ^ ^ '1 Tian tO 4 ^ 5 ^ ^ ϊ •' inch How many. Private $ 驾 ηί5 丨 5; 5 Υ硪硪缄 l-{3-[7-(2-methyl-pyridin-4-yl)-imidazole [l,2-a]«pyridin-3-yl] -phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylic acid hydrazine (1 - {3 -[7-(2-Methyl-pyridin-4-yl)-i midazo[ 152 -a]pyridin-3 -y 1] -pheny 1}-3-(2,2,2-triijuoroethyl)-urea Formate) l-{3-[7-(3,4-di-phenyl)- Imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(3,4) -Dichloro-phenyl)-i midazo[ 1,2-a]pyridin-3 -y 1] -pheny 1} -3 -(2,252-trifluoro-ethyl)-urea) 1-{3-[7-(4- Cyano-3-fluoro-phenyl)-isazole [l,2-a]tt than -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(4-Cyano-3-fluoro-pheny l)-imidazo[ 1,2-a]pyridin-3 -yl]-phe nyl} -3 -(2,2,2- Trifluoro-ethyl)-urea ) % 〇o % 〇&gt;〇% lL I 300 〇cn s cn 200836725 [M+H] + 436 [M+H] + 415 [M+H] + 490 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.66 (1H, d), 8.18 (lH, s), 8.10 (2H, d), 8.02-7.93 (3H, m), 7.86 (1H, s), 7 · 80 (1H, s), 7.46 (3H, d), 7.33-7.25 (lH, m), 6.86 (lH, t), 4.01-3.89 ( 2H,m)· 1HNMR (400 MHz, Me-d3-OD): 8.68 (1H, d), 8.39 (1H, s), 7.91 (1H, s), 7.84 (1H, s), 7.81 (lH, s ), 7.51 (lH, t), 7.43 (lH, d), 7.35 (2H, t), 7.30 (lH, s), 7.15 (lH, s), 4.02-3.89 (5H, m). 1HNMR (400 MHz , DMSO-d6): 8.97 (1H, s)5 8.67 (1H,d), 8.13 (1H,s),8·08 (2H, d),7·94 (2H,d),7_85 (1H,s ), 7.81 (1H, s), 7.51-7.40 (5H, m), 7.33-7.25 (lH, m), 6.85 (lH, t), 4.02-3.89 (2H, m). K tO 4 ^ ^ S i ^ 窠二3人5砩1 s γ硪硪佑电 tO 余蚩^ ii obi wJLi ^ s〇15 ^ s ϊ 1-1 iw ^ · Take HE $揲...J today ^ ^ ^ Ji l gallium two v硪硪SK t 〇4 * ^ 11 1 ^ • inch:; several 蛉: clock &lt;3 S ^ 1 g hand 砩硪鍩 feeding 1-{3-[7-(4-cyano-phenyl)-imidazole [ l,2-a]nbipyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (l-{3-[7-(4) -Cyano-phenyl)-imida zo [ 152-a]pyridin-3 -yl]-phenyl} -3 -( 2,2,2-triiluoro-ethyl)-urea formate) 1- {3-[7-(l -Methyl-1H-imidazole 1-2-yl)-imidazole [l,2-a]a than benzyl-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl) -urea phthalate (1 - {3-[7-( 1 -Methyl-1 H-imidazol- 2- yl)-imidazo[ 1 ?2-a]pyridin-3-yl]-phenyl} -3-(2?2,2-trifluoro-ethyl)-urea formate) 4- (3-{3-[3·(2,2,2-Trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-a]acridin-7-yl)-benzene (4-(3 - {3 -[3 -(2,2,2-Trifluoro-ethy 1) -ureido]-phenyl} -imidazo[ 1 ?2-a]p yridin-7-yl)-benzenesulfonamide) 2&gt;=〇% 303 304 sm 200836725 [M+H] + 442 [M+H] + 415 [M+H] + 477 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.70 (1H , d), 8.62 (1H, d), 8.23 (1H, dd), 8.03 (1H, s), 7.79 (2H, s), 7.49-7.42 (2H, m), 7.40 (1H, dd), 7.32-7.23 (1H, m), 6.96 (lH, d), 6_86 (lH, t), 4.02-3.88 (5H, m). 1HNMR (400 MHz, Me-d3-0D): 8.60 (1H, d) , 7.98 (1H, s), 7.81 (1H, s), 7.73 (1H, s), 7·69 (1H, d), 7.57-7.46 (2H, m), 7·43 (1H, d) , 7.32 (1H, d), 6.82 (1H, d), 4.03-3.89 (5H, m). 1HNMR (400 MHz, DMS0-d6): 9·19 (1H, s), 8.75 (1H, d), 8.66 (1H, d), 8.29 (2H, s), 8.18 (lH, s), 7.97-7.88 (1H, m)5 7.87-7.76 (43⁄4 m), 7.64 (1H, t), 7.49 (1H, dd), 7.48-7.42 (2H, m), 7.33-7.24 (1H, m), 7.10 (lH, t), 6.60 (lH, t), 4.02-3.87 (2H, m). tO ^ ^ ^ ^ ^ K - inch: 襻,来 s々尨β蚪辕赫1 s ^ U Private tO余# ^ 1 1 tK wjd 余vo g 1 3 W 二^ κ ^ ^ x 5 ^ ^ ^ sn ^ ^ 1 Gallium 2 v硪硪S訾昍tO , ^ ^ W. Λ Ιά|3^ίΙ 1 s 硪硪1-{3-[7-(6-Dimethoxy)pyridin-3-yl)-imidazole [ l,2-a]Acridine-3·yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(6-Methoxy-pyridin) -3 -yl )-imidazo[ 1,2-a]pyridin-3 -yl]-phe ny 1} -3 -(2,2,2-仕ifluoro-ethy l)-urea ) l-{3-[ 7-(l-Methyl-1H-pyrazol-3-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea (1-{3-[7-(1 -Methyl-1 H-pyrazol-3 -yl)-imidazo[ 1,2-a]pyridin-3-yl]-p henyl} -3 » (2,252-trifluoro-ethyl)-ur ea) 1-{3-[7-(3-ηBizozol-1-yl-phenyl)-imidazole [l,2-a]acridin-3-yl]- Phenyl}-3-(2,2,2-trifluoro-ethyl)-urea phthalate (1 - {3-[7-(3-Pyrazol-1 -yl-phenyl)-i midazo[ 1 ? 2-a]pyridin-3 -yl]-pheny 1} -3 -(2,2,2-triiluoro-ethyl)-urea formate) ? :fa ' i 307 gm 200836725 [M+H] + 428 [M+H] + 433 [M+H] + 470 1HNMR (400 MHz, DMSO-d6): 11.97 (1H, s), 8.95 (1H, s), 8.54 (lH, d ), 8.05 (1H, dd), 7.97 (1H, d), 7.90 (1H, s), 7.78 (lH, s), 7.75 (lH, s), 7.49-7.39 (2H, m), 7.31 ( 1H, dd), 7.28-7.21 (1H, m), 6.84 (1H, t), 6.47 (1H, d), 4.02-3.88 (2H, m). 1HNMR (400 MHz, DMSO-d6): 8.98 (1H , s), 8.68 (1H, d), 8.23 (1H, s), 7.91 (1H, s), 7.77 (1H, s), 7.60 (1H, dd), 7.56-7.42 (2H, m), 7.30 (1H,d), 6.86 (1H, t), 4.02-3.88 (2H, m), 2.82 (3H, s). 1HNMR (400 MHz, DMS0-d6): 8·98 (1H, s), 8 ·57 (1H,d), 8.22 (1H,d),8.04-7.94 (2H,m),7.84 (1H,s),7.77 (1H, s), 7.50-7.35 (3H,m),7·26 (1H, d), 6.88 (lH, t), 6.52 (lH, d), 5.18-5.08 (lH, m), 4.02-3.89 (2H, m), 1.42 (6H, d). 5 · ^ 11 η : 12 mhC 1田&amp;硪硪"Gas tO Record ^ ii iK 5 ^ fe '1' § ^ ^ &lt; cA 2, a A ^ ^ l ^ ^ v 4 S v 5 . ^ ϋ巧旧·] &lt ; 3 ^褎A a孽裟 gallium early &lt; ri芟铋® 轵 3 Hz ί 哼 哼 ' ' ' ' ' 々 々 々 々 々 々 々 々 々 々 々 々 々 々 々 々 々 ά ^ ^ ^ ^ 1 S 5硪硪M Gallium 1-{3-[7-(6-oxy-1,6-di-rho-!7-specific-3-yl)-imidazole [1,2 -a] acridine-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(6-Oxo-156-dihydro- Pyri din-3-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-eth yl)-urea) l-{3-[7 -(5-methyl-[1,3,4]-thiadiazol-2-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (l-{3-[7-(5-Methyl-[l,354]-thiadia zol-2-yl)-imidazo[ 1 ?2-a]pyridin-3 -yl]-phenyl}-3-(2,252-trifluoro-eth yl)-urea) 1 l-{3-[7-(l-isopropyl-6-oxy-1,6-diaza ratio bite- 3 -based)-°m σ sits [1,2-a]σ 唆-3-yl]-phenyl}-3-(2,2,2-trisyl·ethyl)-urea (1- {3-[7-(1 -Isopropyl-6-oxo-1,6-d ihydro-pyridin-3 -yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3 -( 2,2,2-t rifluoro-ethyl)-urea) B Sr) Xi&gt;: O work z&gt;=complex z&gt;=〇〇1 309 310 m 200836725 [M+H] + 470 [M+H] + </ RTI> </ RTI> </ RTI> <RTIgt; 8.01 (1H, s), 7.79 (2H, s), 7 .45 (2H,d),7·39 (1H,dd), 7.31-7.23 (lH,m), 6.92-6.81 (2H,m),5.38-5.28 (1H,m), 4.01-3.89 (2H, m), 1.34 (6H, d). 1HNMR (400 MHz, Me-d3-OD): 8·67 (1H, d), 8.54 (1H, s), 8.32 (1H, s), 7.82 (1H , s), 7·79 (1H, s), 7.70 (1H, d), 7.53-7.48 (1H, m), 7.44 (1H, d), 7.34 (1H, d)5 3.96 (2H, q). 1H NMR (400 MHz, DMSO-d6): 8.96 (1H, s), 8.69 (1H, d), 8.22 (1H, s), 7·86 (1H, s), 7·74 (1H, s), 7.63 (1H,d), 7.52 (1H,d),7·47 (1H,t), 7.29 (lH,d), 6.85 (lH,t),4.01-3.90 (2H, m). 5 · Θ Τ' Φιή Λ ^ ^ w C3 C玄襃 ja ¥絮^ . ^ H: &lt; ^ ^ ••inch: 耱, 々 A ^ ag $4 ^ ^ ^ 1 S 5硪砩M t Gallium Step AA Step AC l- {3-[7-(6-isopropoxy-° ratio 0 -3-yl) _ mouth rice 0 sitting [1,2-&amp;]° than -3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(6-Isopropoxy-pyridin-3 -yl)-imidazo[ 1,2-a]pyridin-3 -yl ]-p henyl} -3 -(2,2,2-trifluoro-ethy l)-ur ea) l-{3-[7-(4H-[l,2,4]triazol-3-yl)- Imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (l_{3-[7-(4H-[l,2,4]Triazol-3-yl)-imidazo[ 1,2-a]pyridin-3 -yl] -phen y 1} -3 -(2,2?2-trifluoro-ethyl)-urea) j 1-{3-[7-(1Η-tetrazol-5-yl)-imidazole [l,2-a; Hb pyridine-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l-{3-[7-(lH-Tetrazol-5-yl)-imida zo [ 1,2-a]pyridin-3 -yl]-phenyl} -3 -( 2?252-trifluoro-ethyl)-urea) % % %x O 312 m cn 314 200836725

/-V

[M+H] + 416 [M+H] + 392 [M+H] + 378 1HNMR (400 MHz, Me-d3-OD): 8.60-8.50 (2H,m), 8.47 (1H,s),8 · 37 (1H, s), 8.30-8.20 (13⁄4 m) 5 8.20-8.14 (1H, m), 8·04-7·96 (1H, m), 7.81 (lH, s), 7.78 (lH, s ), 7.32 (1H, d), 4.04-3.90 (5H, m). 1HNMR (400 MHz, Me-d3-OD): 8.54 (1H, d), 8.21 (1H, s), 7.80 (lH, s) ,7·74 (1H, s), 7.70 (lH, s), 7.49 (lH, t), 7.42 (2H, d), 7.l (lH, d), 4.00 (3H, s), 3.95 (2H, q). 1HNMR (400 MHz, Me-d3-OD): 8·55 (1H, d), 8.20 (1H, s), 7.84-7.79 (1H, m), 7.77 (1H, s), 7.71 (1H , s), 7.55-7.45 (2H, m), 7.43 (1H, d), 7.32 (1H, d), 3.95 (2H, q). ss|3 ^ - 2 s ^ ^ Step SGI using methoxyamine salt The acid salt step SGI uses hydroxylamine hydrochloride l-{5-[7-(l-methyl-1H-pyrazol-4-yl)-mouth miso[1,2-a] 唆-3-yl] -11 唆-3 -yl}-3-(2,2,2-triethyl)-urea (1-{5-[7-(1 -Methyl-1 H-pyrazol-4-yl)-imidazo [ 1,2-a]pyridin-3-yl]-p yridin-3 -y 1} -3 -(2,2,2-trifluoro-eth yl)-urea) 1-{3-[7-(A Oxyimido-indenyl--salt [l,2-a]acridin-3-yl]-benzene }-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(Methoxy imino-methy 1)-imidazo[ 1,2-a]pyridin-3 -yl] -phen yl} -3 -(2,2,2-trifluoro-ethy l)-urea) l-{3-[7-(hydroxyimino-indenyl)-imidazole [l,2-a]acridine -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 - [7-(Hydroxy imino-methy 1)-imidazo[ 1,2- a]pyridin-3 -yl] -phen y 1} -3 -(23252-trifluoro-ethy l)-urea) 315 316 317 200836725 [M+H] + 415 [M+H] + 459 [M+H] + 429 1HNMR (400 MHz, Me-d3-OD): 8.65 (1H, d), 7.91-7.85 (lH, m), 7.83 (lH, s), 7·77 (1H, s), 7.74 (1H, s), 7.50 (1H, t), 7.40 (1H, d), 7.37-7.29 (2H, m), 7·20 (1H, dd), 4.02-3.86 (5H, m). 1HNMR (400 MHz, Me -d3-OD): 8.74 (1H,d), 8.28 (1H,s),7.93-7.88 (1H,m), 7.88-7.82 (1H,m),7·63 (1H,d), 7.52 (lH , t), 7.44 (lH, d), 7.35 (1H, d), 3.96 (2H, q), 1.55 (9H, s). 1HNMR (400 MHz, Me-d3-OD): 8.68 (1H, d) , 7.85 (2H, d), 7.80 (1H, s), 7·51 (1H, t), 7·43 (1H, d), 7.38-7.28 (2H, m), 6.92 (1H, s) ,3·95 (2H,q), 3.79 (3H s), 2.36 (3H, s). -^ &quot;7 Length gl ^ ^ ^ Gallium A "砭A鲢阳^ ^ ^ 5,v〇3 · n Aluminum 3 m 盏w, i3 κ孑a 5酴硪Every c shouting every si ^ ^ ^ ψ ^ 3^ $4 E ik 3, ^ s ^ ^ w ^ iA fs ώ l-{3-[7-(3-mercapto-3H-imidazole 1-4 -yl)-imidazole [l,2-a]«pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7 -(3 -Methyl-3 H-imidazol-4-yl)-imidazo[l52-a]pyridin-3-yl]-phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) 1- {3·[7-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]acridin-3-yl]-phenyl}- 3-(2,2,2-tris-ethyl)-urea (1 - {3 -[7-(5 -tert-Butyl-[ 1,3,4]oxad iazol-2-yl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-3-(2?2,2-trifluoro-et hyl)-urea) 1_{3-[7-(1,5-dimethyl-1Η -imidazole 1-2-yl)-imidazole [l,2-a]«pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l_{ 3-[7-(l55-Dimethyl-lH-imida zol-2-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -3 -(25252-tri£Iuoro-eth yl) -urea) ί工&gt;= Completion 2&gt;=〇OO m 319 1 200836725 [M+H] + 456.1 [M+H] + 429 [M+H] + 429 1HNMR (400 MHz, DMSO-d6): 9.23 (1H , d), 9.07 (1H, s), 8.70 (lH, d), 8.46 (1H, dd), 8.26 (lH, s), 8_15 (lH, d), 7·88 (1H, s), 7· 83 (1H, s), 7.52 (1H, dd), 7.50-7.42 (2H, m), 7.34-7.25 (1H, m), 6.95 (1H, s), 4.02-3.89 (2H, m). 1HNMR ( 400 MHz, Me-d3-OD): 8·66 (1H,d), 7.90-7.76 (3H,m), 7.50 (1H,t), 7·43 (1H,d),7.33 (2H,d) , 7.02-6.95 (1H, m), 3·95 (2Η, q), 3·86 (3H, s), 2.26 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.54 (1H , d)? 7.93 (1H, s), 7.80 (1H, s), 7_67 (1H, s), 7.60 (lH, s), 7.48 (lH, t), 7.41 (lH, d), 7.36 (13⁄4 d) ), 7.31 (1H, d), 3.95 (2H, q), 3.71 (3H, s), 2.46 (3H, s). S 3 s § I S black 91 £ ? ^ ^ V ί Ϊ: ^ • inch: Difficult 5 early domain 1 S ν ^ ιΛ # ^ &lt; 2 1 gallium two V 硪砩 private tO recorded 3 G ^ ^ | o SliplI:! 2, l gallium: Tv硪硪S and β road 5- (3-{ 3-[3-(2,2,2-tris-ethyl)-urea]-phenyl}-imidazo[1,2-a]acridin-7-yl)-« than carbo-2-oxoic acid 5-(3-{3-[3-(2,2?2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[ 1,2-a]py ridin-7-yl)-pyridine-2-carboxylic Acid l-{3-[7-(l, 4-Dimethyl-1H-imidazole 1-2-yl)-imidazole [l,2-a]npyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-B -1-[3-[7-(1,4-Dimethyl-1 H-imida zol-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl}-3 -(252,2-trifluoro-eth yl)-urea) l-{3-[7-(l,2-dimercapto-1Η·imidazole W·yl)-imidazole [l,2-a]acridine- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l-{3-[7-(l,2-Dimethyl-lH-imida zol-4-yl) )-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -3-(2,232-trifluoro-eth yl)-urea) % S工z&gt;=〇Ll_ z 丫Z, t-H &lt; N m 322 m 200836725 [Μ+Η] + 415 [M+H] + 459 1HNMR (400 MHz, DMSO-d6): 7.87 (1H, d), 7.06 (1H, s), 7.03-7.02 (1H, m ), 6.98 (2H, d), 6.77 (1H, d), 6.69 (1H, t), 6.64-6.49 (2H, m), 6.37 (1H, dd), 5.78 (1H, d), 3.22 (3H, s), 3.15(2H, q). 1HNMR (400 MHz, Me-d3-OD): 8·69 (1H, d), 8.13 (1H, s), 7.85 (2H, s), 7 · 64 (1H, dd), 7.51 (lH, t), 7.44 (lH, d), 7.34 (1H, d), 3.96 (2H, q), 2.62-2.53 (lH?m), 1.42-1.31 (2H ,m),1.26-1.17 (2H,m). l ^ v ^ ^ v ^ Private tO recording ^ f ^22 l- {3-[7-(2-methyl-2H-pyrazol-3-yl)-imidazole [l,2-a]acridin-3-yl]•phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1 - { 3 - [7-(2-Methy l-2H-pyrazol-3 -yl)-imidazo[l52-a]pyridin-3-yl]-p henyl} -3 -(2,2?2-trifluoro-ethy l)-ur ea) l-{3-[7-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-imidazole [ 1,2-a] acridine-3-yl]-phenyl}-3-(2,2,2-tris-ethyl)-urea (1 - {3 -[7-(5-Cyclopropy 1- [ 1,3,4]th iadiazol-2-yl)-imidazo[ 1,2-a]pyrid m-3-yl]-phenyl}-3-(2?2,2-trifluoro -ethyl)-urea) ί / 乙z J % o 324 ro 200836725 [M+H] + 432 [M+H] + 445 [M+H] + 429 lHNMR (400MHz, Me-d3-OD): 8.66 (1H,d),7.95 (1H, s), 7.85 (1H, s), 7.80 (1H, s), 7.62 (lH, s), 7.50 (lH, t), 7.41 (1H, d), 7.37-7.27 (2H, m), 3.96 (2H,q),2.55 (3H,s). 1HNMR (400 MHz, Me-d3-OD): 8·73 (1H,d), 8.26 (1H,s),7·89 (1H,s) ,7·85 (1H, s) , 7.64 - 7.54 (2H, m), 7.51 (1H, t) , 7.44 (1H, d), 7.33 (1H, d), 3.96 (2H, q), 3.44-3.35 (1H, m), 1.50 (63⁄4 d). 1HNMR (400 MHz, Me-d3-0D): 8.64 (1H,d), 8.21 (1H,s),7·88 (1H , s), 7.79 (1H, s), 7.56 (lH, s), 7.49 (lH, t), 7.40 (lH, d), 7.32 (lH, d), 7.15 (1H, d), 3·95 ( 2H,q),2.39 (6H, s). 轵tO gallium φ ^ k &lt;4' heart roll I base®~ ^ ^ — 5^315^1 ^ iS Es: tO 萆, 丨11 w ^ Os ® Wei 5 K刼餐趑〇m? i · γλ' Le 1 1-{3-[7-(3·methyl-iso thiadiazole-5·yl)-imidazole [l,2-a]acridine-3 -yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3-[7-(3-Methyl-isothiazol-5-yl)-imidazo[ 1, 2-a]pyridin-3 -yl]-phe nyl} -3 -(2?2?2-trifluoro-ethyl)-urea ) ^{347-(5-isopropyl-[1,3,4] evil Diazol-2-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-tris-ethyl)-urea (l-{3 -[7-(5-Isopropyl-[l,3,4]oxad iazol-2-yl)-imidazo[ 152-a]pyridin-3-yl]-phenyl}-3-(2?2?2-trifluoro -et hyl)-urea) l-{3-[7-(3,5-Dimethyl-1H-pyrazol-4-yl)-imidazole [l,2-a]acridin-3-yl]benzene }}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7·(3,5 di D imethy 1-1 H-py raz ol-4-yl)- Imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-eth yl)-urea) iz^. &quot;V工z&gt;=〇°X =:&gt;=〇Xb^i 326 327 〇〇m 200836725 Example 329 Μ3-Γ7-Γ5-甲某-Γ1.3.41oxadiazol-2-ylimidazolium -3-yl 1_ loading a 丨-3彳2.2,2-trifluoro-acetamidine Π]3-Γ7-Γ5-Methyl-"1 •3»41oxadiazol-2-vl&gt;)-imidazof1 kiss 5 vridin- 3-vll-phenyl} - 3-(2,2,2-trifluoro-ethvlVurea) Step (a): Methylimidazolium "l,2-alpyridine-7-carboxylate imidazofl .2-a~1pvridine- 7-carboxvlate)

10 Add NaHC03 (11.1 g, 132 mmol, 2.0 equiv) to methyl 2-aminopyridine-4-carboxylate 5 10.0 g, 66 mmol 5 l. 〇equiv dissolved in EtOH In a solution of (150 ml), chloroacetaldehyde (13.0 ml, 99 mmol, 1 ·5 equiv) was then added. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the crude mixture was partitioned with water and EtOAc. The obtained precipitate was washed with Et 2 hydrazine and recrystallized from MeOH/EtOAc to afford 8.4 g of product. 1H NMR (400 MHz, DMSO-d6): 8·66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7·33 (1H, d), 3·90 (3H, s MS: [M+H]+ 177· 20 Step (b) Mercapto 3-iodo-imidazolium H,2_alpyridine-7-carboxylate (Methyl 3_iodo-imidazo "L2-alPvridine_7-carboxvlate"

460 200836725 Add N-iodosuccinimide (5.8 g, 26 mmol, 1.2 equiv) to 曱基口米嗤 and [l,2-a]^t σ定·7-Rebel The ester (Methyl imidazo[l,2-a]pyridine-7-carboxylate, 3.8 g, 21.6 5 mmol, 1.0 equiv) was dissolved in DMF (20 ml) and the mixture was stirred at room temperature for 2 hr. The resulting brown slurry was then diluted with water, 10% w/v sodium thiosulfate, and sodium carbonate (1M), and the obtained white solid was filtered, washed with diethyl ether and dried to yield 4.7 g of product. MS: [M+H]+ 303; 1H NMR (400 MHz,Me-d3-OD): 10 8·44 (1H,d),8·25 (1H,s),7_88 (1H,s),7 ·61 (1H,dd),3·95 (3H,s). Step (c) 3_Iodine·Imidazolium H,2-alpyridine-7-carboxylic acid hydrazine-Iodo-imidazo"1 J-alOvridine -T-carboxvnc acid 15 hvdrazide)

Add hydrazine hydrate (0·25 ml, 5.28 mmol) to methyl-3·iron-imidol[l,2-a]pyridin-7-carboxylate (Methyl-3-Iodo-imidazo[l,2 -a]pyridine-7-carboxylate, 0.420 g, 1·32 mmol) dissolved in MeOH (6 ml), the mixture was refluxed for 4 hrs, then hydrazine hydrate (0.25 ml, 5.28 mmol) The mixture was heated to o/n, cooled, and the solid was filtered and washed with MeOH. MS: [M+H]+ 3〇3· 461 200836725 Step (d) 3-iodo-7彳5-mercapto-[1,3,41oxadiazol-2-yl)-imidazolium "1, 2-&amp;1 Pilot (3-Iodo-7-(5-methvl-"l JJloxadiazoU-vn-imidazon,2-al 5 pyridine)

3-Iodo-imidazo[15 2-ajpyridine-7-carboxylic acid hydrazide (0.18 g, 0.59 mmol) as orthoacetic acid Triethyl ester (3 ml) and concentrated H2S04 (1 drop) treatment. The mixture was heated to 80 ° C / n. After cooling, the solid was filtered and washed with EtOH, and dried to give 0.165 g of product. MS: [M+H]+ 327 15 Step (e) W3-"7-(5-Methyl-"1,3,41oxadiazol-2-yl)-imidazolium "1,2-&amp;1 0 比口定-3-基1- 笨基卜 3-(2,2,2- 二气-乙)-脉Π - n-"7-(5-Methvl-Γ1,3,41oxadiazol-2- vlVimidaz〇ri ,2-a&quot;lp vridin-3-γΐΐ-phenyl I - 3-(2,2,2-trifluoro-ethvn-urea) 462 200836725

1-(3-(4,4,5,5-tetradecyl-[1,3,2]-diaoxaborolan-2-yl)-phenyl]-3-(2,2, 2·三败-ethyl)-pulse (16) (l_[3-(4,4,5,5-Tetramethyl-[l,3,2]-dioxaborolan-2-yl)_phen 5 yl]-3- (2,252-trifluoro-ethyl)-urea (I6), 0.226 g, 0.65 mmol) and 2M Na2C03 (3.4 ml) added to 3·iodo-7-(5-methyl-[1,3,4] Diazol-2-yl)-imidazo[l,2-a]pyridine (3-Iodo-7-(5-methyl-[l,3,4]oxadiazol-2_yl)_imidazo[l,2-a] pyridine, 0.165 g, 0·5 mmol) was dissolved in a solution of DME (10 ml) [10 for the reaction to remove the bubbles by nitrogen] followed by tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol). The mixture was heated to 80 ° C overnight, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated. The residue was triturated with EtOAc (EtOAc)EtOAc. MS: [M+H]+ 417 1H NMR (400 MHz,Me_d3-OD): 8·74 (1H,d),8·27 (1H,s),7·87 (2H,d),7·62 (1H,d),7·52 (1H,t),7·48_7·39 (1H,m),7.39-7.31 (1H,m),3·96 (2H,q),2.69 (3H,s) · 20 Example 330 1-Γ3_(7-Γ1.3,4Ίoxadiazole-2-m-imidazo-fl.2-alpyrid-3-yl-mosa 463 200836725 1-3-(2,2,2 -Trifluoro-ethylurea Π_"3-(7-"1,3,4~IOxadiazol-2-vl-imidazo"l,2-a~|pvridin-3-vn-phenvlI-S-^^^- trifluoro-ethvD-urea)

5 In the same manner as in Example 329, 1-[3-(7-[1,3,4]oxadiazol-2-yl-imidazo[1,2-] was prepared in the step d using triethyl orthoformate. a]pyridine•3-yl)-phenyl]-3_(2,2,2-trifluoroethyl)-urea (1-[3_(7-[1,3,4]Oxadiazol_2-yMmidazo[l,2 -a]pyridin_3-yl) phenyl]-3-(2,2,2-trifluoro-ethyl)-urea) 〇10 MS: [M+H]+ 403 1H NMR (400 MHz,Me-d3-OD): 9.11 (1H, s), 8.76 (1H, d), 8.34 (1H, s), 7.89 (2H, d), 7.67 (1H, dd), 7·52 (1H, t), 7· 45 (1H,d),7·36 (1H,d),3·96 (2H,q)· 15 Example 331 l-{3-"7_(5_ethyl_Π,3,41 oxadiazole -2-yl-V imidazo[1,2-al-pyridin-3-yl 1-methyl-purin-3-(2 on 2-trifluoro-ethylurea (lnnb-Ethvl-rU/loxadiazoU-vlVimidazorHalpvr idin-3- Yll-phenvll - 3-(2,2,2-trifluoro-ethyl)-urea) 464 200836725

In the same manner as in Example 329, 1-{3_[7-(5-ethyl-[1,3,4]oxadiazol-2-yl) was prepared using triethylorthopropionate in step d. -Imidazo[l,2-a]pyridin-3-yl]-phenyl}-3_(2,2,2-tris-5-fluoro-ethyl)-urea (1 - {3-[7-(5- Ethyl-[l 53 54]oxadiazol-2-yl)-imidazo[l52-a]pyr idin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea) 〇MS: [M+H]+ 431 1H NMR (400 MHz, DMSO-d6): 8·98 (1H, s) 5 8·72 (1H, 10 d), 8·21 (1H, s), 7·95 ( 1H, s), 7·77 (1H, s), 7.57-7.43 (3H, m), 7.30 (1H, d), 6·86 (1H, t), 4·03-3·88 (2H, m ), 2.99 (2H, q), 1.37 (3H, t). Example 332 15 1-{3-"7-(4-Methyl-5-thio- 4,5-dihydro-111-"1 , 2,4~|triazol-3-yl]()- 咪口坐 and "1,2-3&gt;10 than mouth -3- base 1-stupid 3-(2,2,2-two Gas-ethyl oxime · n-"7_(4-Methvl-5-thioxo-4,5-dihvdro-lH-Γ1,2,4&quot;ltriazol -3-vl)-imidaz〇ri,2-a1pyridin-3 -vl1-phenvn -3-(2,2,2-ΐΓΐί1πο ro-ethvD-urea) 465 20 200836725

Prepared as described in B3a. Step (b) M3-"7_(4-methyl-5-thioxo-4,5-dihydro-111-[~1,2,41 triazole 10 - 3 -yl)-mouth mouth and sit" 1,2 - a 1 mouth ratio -3 -yl 1 -styl}-3-(2,2,2-disorder -ethyl)-pulse nnnr^-MethvUthioxo-^^-dihvdro-lH-fUJltriazol -3_vlVimidazo"l,2-alpvridin-3-vll_phenvl}-3-(2,2,2-trifluo ro-ethvD-urea) 466 200836725

F F

H ^ will be 1-[3-(7-cultivated chloro-based-salt and [l,2-a]n ratio. -3 -yl)-phenyl]-3-(2,2,2-trifluoro -ethyl)-urea 5 (1 - [3-(7-hydrazinocarbonyl_imidazo[l,2-a]pyridin-3-yl)-ph enyl]-3-(2,2,2-trifluoro-ethyl)-urea , 90 mg, 0·23 mmol) and methyl isothiocyanate (17 mg, 0.23 mmol) dissolved in EtOH (3 ml) and heated to 70 ° C for 18 h. After cooling the reaction mixture, the precipitate was separated by filtration to give the product (34 mg). MS: 10 [M+H]+ 447 1H NMR (400 MHz, DMSO-d6): 14·04 (1H, s), 9.00 (1H, s), 8.68 (1H, d), 8.14 (1H ,s),7·92 (1H,s),7.78 (1H,s), 7.56-7.40 (2H,m),7.36-7.24 (2H,m),6·88 (1H,t), 4.02-3.88 (2H,m), 3.70 (3H,s). 15 467 200836725

.荽^〇〇寸^ΓηΓηε苳marriage ikwi筚鹓- 丧拎w fF叫书妩〇〇寸(四) εεΓηι¥^« MS Data [M+H] + 365 ί 1 [M+H] + 375 NMR·data 1HNMR (400 MHz, Me-d3-OD): 8.74 (1H, d)3 8.11(13⁄4 s)5 8.00 (1H, s), 7.95(lH,s), 7.56(lH,t), 7.49-7.40 (2H , m), 7.36 (1H, d), 3.95 (2H, q), 3.68 (2H, s). 1HNMR (400 MHz, Me-d3-OD): 8.50 (1H,d), 1 8.28 (1H,s ), 7·83 (1H, s), 7.74 (13⁄4 s), 7.54-7.32 (3H, m), 7.28 (1H, d), 6.88 (1H, d), 3.94 (2H, q), 3.38-3.26 (6H,m), 2.18-2.06 (1H,m), 1.25-1.11 (23⁄4 m), 0.98-0.86 (2H? m). Preparation steps ^ ^ 3 ^ ^ ^卜鍪"1 gallium 111 ^ pAU residual - Q人机械Φν ^ v ο Step SGH Chemical name l-[3-(7-Hydroxymethyl-imidazo[l,2-a]acridin-3-yl)-phenyl]-3-(2,2, 2-Trifluoro-ethyl)-urea hydrochloride (1 -[3 -(7-Hydroxymethyl-imid azo[ 1,2-a]pyridin-3 -yl)-pheny l]-3-(2,2,2 -trifluoro-ethyl)-ure a Hydrochloride) li, la 111 嗲A ® &amp; f:Special ϋϊΐ ΐ _! Compound sv Example No. mm cn 334 009 Inch 200836725

[M+H] + 428 1 [M+H] + 365 ^ S s ffi .K ffi ffi ^ J w C,w 1&gt; 〇〇ό K ... 2 S ^ c? £ ffi 1 2 ss 5 ^ ss 5g Www . 〇si 2 ? ^ ^ -. 1HNMR (400 MHz, Me-d3-0D): 8.43 (1H, d), 8.39 (lH, s), 7.79 (lH, s), 7·63 (1H, s ), 7.45 (1H, t), 7.38 (lH, d), 7.24 (lH, d), 7.03 (1H, d), 6·83 (1H, dd), 4.03-3.87 (5H, m). Step SGB Every 1 1 ^ ΐϋώ ^ ^ $ 卜 g ”1 J ά S d: ^ 〇J r^l ^ ^ ^ ^ έ ^ K 硇 n3 N-(3-{3-[3-(2,2,2 -trifluoro-ethyl)-urea]-phenyl}-imidazole [1,2-a] «比唆-6-yl)-methanoferrin (N-(3-{3-[3-( 2,2,2-Trifluoro-e thyl)-ureido]-phenyl} -imidazo [1,2-a]pyridin-6_yl)-methanes ulfonamide) s1 g ?? a 3 ft ί δ 1 &gt;&gt; 1 » 1 ^ A s α 〇AA砩匕:g | Dad θ ώ || Round 亢f锸d 7 3 £ Q. Public zx °t° %. / m cn mv〇m cn 69 inch 200836725

[M+H] + 379 [M+H]+ 389 1HNMR (400 MHz, DMSO-d6): 8.92 (1H, s), 8.39 (1H,d),7·67 (1H,s), 7.55 (1H , s), 7.45-7.37 (2H, m), 7.22-7.15 (13⁄4 m), 6.99 (1H, d), 6.83 (lH, t), 6.68 (lH, dd), 4.13 (2H, q), 3.98 -3.88 (2H, m), 1.38 (3H, t). 1HNMR (400 MHz, Me-d3-OD): 8.24 (1H, s), 7.86 (lH, s), 7.66 (lH, s), 7.47 ( 2H,d),7.35 (1H,d), 7.33-7.22 (2H, m)5 4.02-3.87 (2H,m), 1.99-1.90(13⁄4 m)5 1.05-0.96 (2H,m), 0.75-0.66 (2H,m). 趑,. SB 1 ^ ά S e - 5 -1 S ? ^ s J Let the two series κ v ^ Step SGC 11 ^ ^ ^ ή I . ? ^ ·| f 画奋 X错 I i ό S1 ; 111 , x 1 ά ·| I 1 :r 士5d Jin SI l-[3-(6-cyclopropyl-7-methyl-imidazo[l,2-a]acridin-3-yl )-Phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1 -[3 -(6-Cyclopropyl-7-methy 1-imidazo [ 1,2-a]pyridin-3 -y 1)-pheny 1] -3 -(2,2,2-trifluoro-eth yl)-urea) %〇337 〇〇m cn 0b inch 200836725

[M+H] + 431 [M+H] + 359 [M+H] + 360 1HNMR (400 MHz, Me-d3-OD): 8.52 (1H, d), 7.79 (lH, s), 7.77 (lH) ,s), 7.70 (lH,s), 7.48 (lH,t), 7·42 (1H,d),7·29 (1H,d), 6·98 (1H,d),3·95 (2H , q), 0.28 (9H, s). 1HNMR (400 MHz, Me-d3-OD): 8.53 (1H, d), 7.79 (1H, s), 7.77 (1H, s), 7.74 (1H, s) ,7·48 (1H,t), 7.41 (lH,d), 7.29 (lH,d), 7.01 (1H,dd),3.95 (2H,q), 3.83(13⁄4 s). 1HNMR (400 MHz, Me -d3-0D): 8.70 (1H,d), 8.18(lH,s), 7.96(lH,s), 7.84 (1H,t),7.5l(lH,t), 7.47-7.38 (lH, m), 7.37-7.28 (lH,m), 7.19 (1H,dd),3·95 (2H,q). $ ϊ 8 2 co SE ^ Q ^ 1 $卜 8 2 〇〇W. IS 〇Step SGE ^ ? V 1 ^ X ^ A 圣文 V ^ ^ A 4 ^ ^ ^ ^ 5 i ^ i 11 11 ^ 2 ^ d -s I ? Γ-, 'Ί ^ ? (N ^ V ί ^ til „If 1 Λ ^ 53⁄4 jS m 〇W ^ A w έ S Φ § 5 si I ϊ I ^ s 1 s I 1- [3-(7-Cyano-imidazo[l,2-a]acridin-3-yl) -phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1 -[3 -(7-Cyano-imidazo[ 1 ?2-a ]pyridin-3 -yl)-pheny 1 ] -3 -(2,2, 2- trifluoro-et Hyl)-urea) ί Os m cn om τ—H 200836725 [M+H] + 433 [M+H] + 393 1HNMR (400 MHz, Me-d3-OD): 8.57 (1H, d)5 7.86 -7.71 (4H,m), 7.49 (lH,t), 7.42 (lH,d), 7.37-7.27 (2H,m),6.67 (1H, d), 4.29 (2H, q), 3.95 (2H,q ), 1.36 (33⁄4 t). 1HNMR (400 MHz, Me-d3-OD): 8.57 (1H, d), 8·22 (1H, s), 7.85 (1H, s), 7.77 (2H, d), 7.49 (1H,t), 7·39 (1H,d), 7.30 (1H,d), 7.25 (1H,dd),3·95 (2H,q), 1.61(63⁄4 s). Step SGQ Step G1 and G2 step SGF (E)-3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea]-phenyl}-imidazole [l,2-a] bite- 7-yl)-acrylic acid ethyl S ((E)-3-(3-{3-[3-(2,2,2-Trifluor o-ethyl)-ureido]-phenyl}-imid azo[ 1,2-a]pyridin-7-yl)-acryli c acid ethyl ester) 1-{3_[7-(1·hydroxy-1-methyl-ethyl)-imidazole [l,2-a]acridine -3-yl]-phenyl}-3-(2,2,2·trifluoro-ethyl)-ureacarboxylate (1 - {3-[7-( 1 -Hydroxy-1 -methy ! l- Ethyl)-imidazo[ 1,2-a]pyridin -3-yl]-phenyl}-3-(2,252-trifluo ro-ethyl)-urea Formate) Completion iz&gt;=〇&quot;b-ci X 342 &lt; N Bu inch 200836725

[Μ+Η]+418 1 [M+HJ + 432 1HNMR (400 MHz, Me-d3-OD): 8.55 (1H, d), 7.82 (1H, s), 7.79-7.75 (1H, m), 7.73 (1H, s), 7.58 (1H, d), 7.48 (1H, t), 7.40 (1H, d), 7.30 (1H, d), 7.24 (1H, d), 6.71 (1H, d), 3.95 ( 2H, q), 2.89 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.55 (1H, d), 7.83 (1H, s), 7.81-7.76 (1H, m), 7.75 (1H , s), 7.61 (1H, d), 7.48 (1H, t), 7.45-7.35 (2H, m), 7.32-7.21 (2H, m), 3.95 (2H, q), 3.28 (3H, s), 3.09 (3H, s). Step SGQ Step SGG4 uses mercaptoamine 〇 gallium o ^ gallium M Φν K (E)-N-methyl-3-(3-{3-[3-(2,2,2- Tris-ethyl&gt;urea]-phenylimidazole[1,2-a]»pyridin-7-yl)-propenylamine ((E)-N-Methyl-3-(3-{3- [3-(2, 2,2-trifluoro-ethyl)-ureido] -ph enyl} -imidazo[ 152-a]pyridin-7 -yl)-acrylamide) (E)-N,N-dimethyl-3 -(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea]-phenyl} •imidazole [1,2-a]acridin-7-yl)-propenylamine ((E)-N,N-Dimethyl-3-(3-{3-[3 -(2,2,2-trifluoro-ethyl)-ureido] -phenyl} -imidazo[ 1,2-a]pyridi n -7-yl)-acrylamide) t 1 UL / ,〆;Λ〇^ΛΙ 344 345 £卜寸200836725 [M+ H] + 383 [M+H] + 363 1HNMR (400 MHz, Me-d3-OD): 8.59 (1H, s), 7·74 (1H, s), 7·66 (1H, s), 7.55 ( 1H, s)5 7.52-7.43 (23⁄4 m), 7.36 (1H, s), 7.28 (1H, d), 4.02-3.87 (2H, m), 2.50 (3H, s). 1HNMR (400 MHz, DMS0- D6): 9.43 (1H, s), 8.69 (1H, d), 8.33 (1H, s), 7.87 (lH, s), 7.81 (lH, s), 7.59-7.47 (2H, m), 7.43 (1H , dd), 7.33-7.24 (1H, m), 7.12 (lH, t), 4.02-3.87 (2H, m), 2·88 (2H, q), 1.29 (3H, t). 趑., A ^ ^ &lt; % u\ 踣A &lt; | gmg V ^ ^ ^ come to \ y γ to tO ^ , 丨 0 &lt; iB- i 'Ί ^ ^ 0 | ^ K ί V (〇〇J r^l ^ ^ ^ i4 余—3 people 硪淑阳γ硪ο l-[3-(6-gas-7-mercapto-imidazole [l,2-a]n pyridine-3-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea (l-[3-(6-Chloro-7-methyl-imi dazo[ 1 ?2-a]pyridin-3-yl)-phen yl]- 3-(2,2,2-trifluoro-ethyl)-ur ea) 1-[3-(7-ethyl-imidazo[l,2-a]acridin-3-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea hydrochloride (1 -[3 -(7-Ethyl-imidazo[ 1,2-a] pyridin-3 -yl)-phenyl] -3 -(2, 2,2 -trifluoro-ethyl)-urea Hydrochloride) ll 346 m Inch 200836725 [M+H] + 432 1 j [M+H] + 417 1HNMR (400 MHz, Me-d3-OD): 8_60 (1H,d), 8.20 (1H,s), 7.90 (1H,s) , 7.82 (1H, s), 7.73 (1H, s), 7.60-7.45 (2H, m), 7.42 (1H, d), 7.32 (lH, d), 3.95 (2H, q), 2.80 (3H, s 1 1HNMR (400 MHz, DMSO-d6): 9·48 (1H, s), 9.10 (lH, s), 9.01 (lH, s), 8.87 (1H, s), 8.75 (1H, s), 8.62 (1H, s), 8.52 (1H, s), 8.38 (lH, s), 8.12 (lH, s), 6.94 (1H, s), 3.93 (5H, s). Z κ ^ "I 3 卜 &lt; .O ^ &lt;NW ^ ^ &lt; Jrf vf 4 1 also Μ Μ Μ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -thiadiazol-4-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (l- {3-[7-(2-Methyl-thiazol-4-yl)-imidazo[ 1,2-a]pyridin-3 -yl]·phenyl} -3 -(2,2,2-trifluoro-ethy l) -urea) 1 1-{5-[6-(1-Mercapto-1H-pyrazol-4-yl)-»by-azolo[l,5-a]pyrimidin-3-yl]-0-唆- 3-yl}-3-(2,2,2-diox-ethyl)-pulsation (1 - {5-[6-( 1 -Methyl-1 H-pyrazo l-4-yl)-pyrazolo[ 155 -a]pyrimid in-3 -yl] -pyridin-3 -y 1} -3 -(2,2,2 -triflu Oro-ethyl)-urea) t V55, (/&gt; m On cn ς卜寸 200836725

[M+H] + 457 [M+H]+470 1HNMR (400 MHz, Me-d3-OD): 9.02 (1H,d), 8.44 (lH,s), 8.35 (lH,s), 8.11 (lH , s), 7.97 (lH, d), 7.64-7.56 (13⁄4 m), 7.48-7.38 (2H, m), 4.85-4.83 (2H, m), 4.76-4.71 (2H, m), 3.96 (2H, q), 3.87 (2H, t). 1HNMR (400 MHz, DMSO-d6): 9.03-8.94 (2H, m), 8_65 (1H, d), 8.25 (13⁄4 dd) 5 8.10 (13⁄4 s), 7.86- 7.74 (3H,m), 7.50-7.39 (3H,m), 7.33-7.24(13⁄4 m), 6.86 (13⁄4 1), 5.29 (13⁄4 s), 4.03-3.89 (2H,m), 1.50 (6H? s ). ^ 3 机械 S盖,一穿余Λ A 5 ^ νά ^ Φν i ^ ^ ^ ^ ^ ^ ^ 轵5 0铋&quot;ι1 $ Α訾毽-^ ^ f CN ^ ul ^ Aluminium S-mine (II) 1 Step AQ 1-{3-[7-(5,6,7,8-tetrahydro-[1,2,4]triazole [4,3^]° than indol-3-yl)-imidazole [l ,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (l-{3-[7-(5,6,7) , 8-Tetrahydro-[ l,2,4]triazolo[4,3-a]pyrazin-3-yl)-imidazo[ 1 ?2-a]pyridin-3 -yl ]-phenyl}-3-(25252- Trifluoro-et hyl)-urea hydrochloride) l-(3-{7-[6-(l-hydroxy-1-indolyl-ethyl)_0 than bite-3-yl]] - mouth rice mouth [1, 2-a] 比 ··3_ kibphenyl)-3-(2,2,2- Fluoro-ethyl)-pulse (1-(3-(7-[6-(1 -Hydroxy-1 -met hy 1-ethy l)-pyridin_3 -y 1] -imida zo[ 1,2-a]pyridin -3 -yl} -phenyl) -3 -(2,2,2-trifluoro-ethy l)-urea) /3 V % W- s 350 tH m 200836725 ίιν [M+H]+430 [M+H ] + 435 夺古^夺技* ® s ® 5令 K www ^ Ο: hh SK g S 芩 s | ^ . ^ 〇ffi ffi ffi ffi ^ si |^c,ooc,Sc^ · · · · T&quot ;&quot;^ · —(«卜卜s^ CO 1HNMR (400 MHz, DMSO-d6): 9.04 (1H, s), 8.62 (1H, d), 7.82 (2H, s), 7.70 (1H, s) , 7.55 (1H, d), 7.52-7.42 (1H, m), 7.42-7.34 (1H, m), 7.27 (1H, d), 6.93 (lH,t), 4.02-3.88 (2H, m). S s s s &lt; ^ λ ^ V ^ 7 g: ^ 5 ^ ^ ^ ^ ί ^ I ^ ^ s &lt; competition 2 ^ 3 S shout ^ &lt;! itf v ^ rA driving gallium S耱l Σλ Λ ^ U ^ fj Example 332, Step A, Step AL 〇1- {3-[7_(3_Amino-1-methyl-1H-11 than 〇4_基)_σ米嗤[1,2-a] ^Bist-3-yl]-phenyl}-3·(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(3 -Amino-1 -methyl-1 H) -pyrazol-4-yl)-imidazo[ 1,2-a ]pyridin-3-yl]-phenyl} -3-(2,2, 2- trifluoro-ethyl)-urea) l-{3-[7- (5-thio-4,5- Nitrogen-[1,3,4]oxadiazol-2-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-tris- Ethyl)-pulse (1 - {3 -[7-(5 -Thioxo-4,5 -dihydr 〇-[ 1,3,4]oxadiazol-2-yl)-imida zo[l,2-a]pyridin -3-yl]-phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) {y => 〇CM工CO Λ % m cn &gt;r\ cn LL&lt;r 200836725 t/ c

[M+H] + 449 [M+H] + 430 1HNMR (400 MHz, DMSO-d6): 8.98 (1H, s), 8.71 (lH,d), 8.24 (lH,s), 7.99-7.93 (1H , m), 7.78 (1H, s), 7.56-7.43 (3H, m), 7.30 (1H, d), 6.86 (lH,t), 4.01-3.89 (2H,m), 2.82 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.53 (1H,d), 7.83 (1H, s), 7.67 (1H, s), 7.64 (1H, s), 7.63 (1H, s), 7.48 (lH , t), 7.38 (lH, d), 7.30 (1H, d), 7.24 (1H, dd), 3.95 (2H, q), 3.71 (3H, s). Example 332, Step A, Step AM II S ^ ^ s ^ V 2 ^ 〇K &lt;N &lt; ^ ^ T Λ ^ ϊ ί 3 if 1 5 5 b S ' ^ 1 W &lt; Inch: SV ' ro \ ^ Σλ Λ ^ ^ f ^ 5ΪΙ 硪*t硪滔·目二1食 Sd目·τ Λ A 4 a ^ 11 ^ ^ ^ ^ S ^ ϊ 1 ά § $ 办 | 3 ; r者爱 | 工;:£砩i &gt; 3 1- {3-[ 7-(5-Amino-1-methyl-1H-σ is more than 4-*4-yl)-imiphate [1,2-a]n is more than -3-yl]-phenyl}-3-(2, 2,2-tri-milk-ethyl)-urea (1 - { 3 -[7-(5 -Amino-1 -methyl-1 H-pyrazol-4-yl)-imidazo[ 1,2-a ]pyridin- 3-yl]-phenyl} -3-(2,2, 2- trifluoro-ethyl)-urea) 2&gt;=〇Tb-€^o&gt;^z (7)〇CO X工\工?: m CO oo Inch 200836725

[M+H]+429 i [M+H]+462 1HNMR (400 MHz, DMSO-d6): 8.99 (1H, s), 8.60 (lH,d), 7.81 (1H, s), 7.78 (1H, s), 7.65 (2H, s), 7.50-7.41 (2H, m), 7.31-7.23 (ΙΗ,τη), 7.04 (1H, dd), 6.86 (1H, t), 4.01-3.89 (2H,m) , 3.64 (3H, s), 2.20 (3H, s). lHNMR (400MHz, DMSO-d6): 9.06 (1H, s), 8.69 (lH,d), 8.19 (1H, s), 8.05 (1H, s ), 7.89 (1H, s), 7.78 (1H, s), 7.54-7.42 (2H, m), 7.37 (1H, dd), 7.29 (lH,d), 6.95 (lH,t), 4.02-3.88 ( 2H, m), 3.74 (3H, s), 2.69 (3H, s). • ft . ^ ® ^ r; ^ ί ^ ^ SIS 1 t 5 0 I U.' ^ ^ ^ 1 β ^ ^ ^ ^ ^ l Saba, 丨硪 carboxy 澎 S | Step AE lP-[7-(3,5-Dimethyl-3H·imidazole 1_4_yl)-imidazole [1,2-a]pyridin-3-yl]- Phenyl}-3-(2,2,2-triethyl)-urea (l-{3-[7-(3,5-Dimethyl-3H-im idazol-4-yl)-imidazo[ 1,2 -a]pyr idin-3-yl]-phenyl} -3-(2,2,2-trif luoro-ethyl)-urea) l-{3-[7-(4-methyl-5-methyl 4H-[1,2,4]triazol-3-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea phthalate (1 - {3-[7-(4-Methyl-5-methyls ulfanyl-4H-[l,2,4]triazol-3-yl) -imidazo [ 1,2-a ]pyridi N-3 -yl] -p henyl} -3 -(2,2,2-trifluoro-ethyl )-urea formate) X2 &gt;=〇 Into z CO A〇 CO VO 200836725

[M+H]+402 1 [M+H]+417 1HNMR (400 MHz, Me-d3-OD): 8.66 (1H, d), 8.43-8.32 (1H, m), 8.12 (1H, s), 7.83 (1H, s), 7.76 (1H, s), 7.57 (1H, d), 7.50 (1H, t), 7·43 (1H, d), 7, 33 (1H, d), 3.96 (2H, q). 1HNMR (400 MHz, DMSO-d6): 8.98 (1H, s), 8.73 (1H, d), 8.27 (1H, s), 7.89 (1H, s), 7.76 (1H, s), 7.58 ( 1H, dd), 7.55-7.42 (2H, m), 7.30 (1H, d), 6.86 (1H, t), 4.48 (3H, s), 4.02-3.89 (2H, m). Step AF ! Step AI lP -[7-(3H-[l,2,3]triazol-4-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2 -Trifluoro-ethyl)-pulse (l-{3-[7-(3H-[l,2,3]Triazol-4-yl)-imidazo[ 1,2-a]pyridin-3 -yl ]- Phenyl}-3-(2,2,2-trifluoro-et hyl)-urea) l-{3_[7_(2-indolyl 2Η-tetrazol-5-yl)-imidazole [l,2-a] Acridine-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3-[7-(2-Methyl-2H-tetrazo 1-5 - Yl)-imidazo [ 1,2-a]pyridin-3-yl] -phenyl} -3 -(2,2,2-trifluor o-ethyl)-urea) % Completion z 2&gt;=〇% 〇〇 In cn On CO 000 inch 200836725 [M+H] + 432 1 1 [M+H]+446 1HNMR (400 MHz, Me-d3-OD): 8.63 (1H,d), 8.09 (1H, s), 7.88-7.80 (1H, m), 7.79 (1H, s), 7.67-7.59 (1H, m), 7.55 (lH, dd), 7.49 (lH, t), 7.45-7.38 (lH , m), 7.37-7.28 (1H, m), 3.96 (2H, q), 2·58 (3H, s). lHNMR (400MHz, Me-d3-OD): 8.63 (1H, d), 8.21 (2H , s), 7.85 (1H, s), 7.78 (1H, s), 7.69 (1H, s), 7.49 (1H, t), 7.40 (1H, d), 7.32 (lH,d), 7.14 (lH, d), 3.95 (2H, q), 2.72 (3H, s), 2.55 (3H, s). &quot; FT i 茨 ^ ^ S Ί 1 5 B | 'M ^ &lt; SA 惠 s $ ^ ^ V | Aluminium gallium s耩2K 1 Lamb 丨 1砩 蟛• , an ^ f 5 si 'M ^ ^ ^ -I ? rf £ 4 l Φ\ d M ^ ^ ^ ¥ l_{3-[7-(5- Mercapto-indenyl-2-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-difluoro-ethyl)-pulse (1 - {3 -[7-(5 -Methyl-thiazol-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3-(2,2,2-trifluoro-ethy l )-urea) l-{3-[7-(2,4-Dimercapto-thiadiazol-5-yl)-imidazole [1,2-a]»pyridin-3-yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (1 - {3 -[7 -(2,4-Dimethyl-thiazol -5 -yl)-imidazo[ 1,2- a]pyridin-3 -yl]-phenyl} -3-(2,2,2-trifluoro -ethyl)-urea formate) worker z&gt;〇xb^i °co Workers&gt;=〇CO, CO work sm tH v〇m 200836725 /k [M+H]+427 [M+H] + 417 1HNMR (400 MHz, Me-d3-OD): 8.70 (1H, d) , 8.23 (1H, s), 8.05-7.96 (2H, m), 7.92-7.86 (1H, m), 7.82 (1H, s), 7.51 (1H, t), 7.43-7.30 (3H, m), 7.11 (1H, dd), 7.08 (1H, s), 3.96 (2H, q). 1HNMR (400 MHz, Me-d3-OD): 8.79 (1H, d), 8.19 (1H, s), 7.95-7.85 ( 2H, m), 7.58-7.46 (2H, m), 7.43 (1H, d), 7.40-7.32 (1H, m), 4.35 (3H, s), 4.00-3.90 (2H, m)_ 2 s ' s ^ - S ^ t ^ 5 S s ^ &lt; 汔 2 3 tw &lt; inch: off s 5 $ section. ^ ^ A . #回呤 gallium d訾 f S π 5 ?. 7 P訾 domain t is + band &lt; 4二1·{3-[7-(2-amino-acridinyl)-imidazole [l,2-a]acridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-cyclinate (l-{3-[7-(2-Amino-pyridin-4-yl)-imidazo[ 1,2-a]pyridin -3 -yl ]-phenyl} -3-(2,2,2-trifluoro-et hyl)-urea formate) 1-{3-[7-(1-mercapto-1H-tetrazol-5-yl) -Imidazole [1,2-a]»pyridin-3-yl]-phenyl}-3-(2,2,2-tris-ethyl)-pulse (1-{3-[7-(1) -Methyl-1 H-tetrazo 1-5 -yl)-imidazo[ 1,2-a]pyridin-3 -yl] -phenyl} -3 -(2,2,2-trifluor o-ethyl)-urea) xz工z&gt;=〇V Π:/0 xz^a 〇· z CO S m 2 m 300 inch 200836725 ί.

[Μ+Η]+416 [M+H] + 418 吞 吞 ~ extract $ .id ai inch · ' ^ O CJ, ^ ^ ^ S $ S κ κ 〇 od i&gt; w CS s combined with c S裘^ oa ^ ^ -i . ffi ώ o ^ ffi ffi ffi 2 S 〇〇Ci O 1HNMR (400 MHz, Me-d3-0D): 8.68 (1H, d), 8.22 (1H, s), 7·97 ( 1H, d), 7.87-7.83 (1H, m), 7.82 (1H, s), 7.73 (1H, d), 7.64 (lH, dd), 7.51 (lH, t), 7.44 (1H, d), 7.35 (1H, d), 3.96 (2H, q). Step AG - FT , 茨 ^ ί ¥ ^ g &lt; VO 5 ^ 5 ^ ^ ^ 5 ^ 1 -- s I Aluminum gallium s 2 r κ 1 Φ\ a Ί ^ ^ ^ l-{3-[7-(5-Mercapto-isoxazol-3-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3- (2,2,2-digas-ethyl)-pulse (1 - {3 -[7-(5 -Methyl-isoxazol-3 -yl)-imidazo[ 1,2-a]pyridin-3-yl] -phenyl} -3-(2,2,2-trifluoro-et hyl)-urea) l-[3-(7-thiadiazole-2-yl-imidazole [l,2-a]n ratio bite-3 -yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-gland-1 -[3-(7-Thiazol-2-yl-imidazo[ 1.2- a]pyridin-3 -yl )-phenyl] -3 -( 2.2.2- trifluoro-ethyl)-urea work z &gt;=〇„ V sm 52 cn eoo inch 200836725 \ \1/

[M+H]+429 [M+H] + 429 1HNMR (400 MHz, Me-d3-OD): 8.55 (1H, d), 8.23 (1H, s), 8.01 (1H, s), 7.81 (1H , s), 7.76 (13⁄4 s), 7.66 (1H, s), 7.48 (1H, t), 7.39 (1H, d), 7.35-7.23 (2H, m), 4.27 (2H, q), 3.95 (2H , q), 1.53 (3H, t). lHNMR (400MHz, Me-d3-OD): 8.57 (1H, d), 7.96 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 7.63 (1H, s), 7.48 (1H, t), 7.39 (1H, d), 7.31 (lH,d), 7.16 (1H, dd), 4.02-3.86 (5H, m), 2.49 (3H, s) I1 is 1 ^ § ά IB 5 ά I Aluminum gallium S玑孓 difficult to 訾1舡巴,1硪鋈4丨1 f ^ ^ ^ ^ i 5 vs Ο KB ^ ! 5 v馨m面穿^ ^ ^ ^ ^ ^ ^ 1 electric d丨丨硪矾"1彳硪1_{3-[7-(1-ethyl-1H-pyrazol-4-yl)-imidazole [1,2-a]. -yl]-phenyl}-3-(2,2,2-difluoro-ethyl)-nuclear (1-{3-[7-(1 -Ethyl-1 H-pyrazol-4-yl)-imidazo [ 1,2-a]pyridin-3-yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea) 1-{3-[7-(1,3-dimethyl- 1H-pyrazole 4-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3 -[7-(1,3 -Dimethyl-1 H-py razol-4-yl)-imidazo[ 1,2-a]pyri din-3-yl]-phenyl} -3-(2,2,2- Trifl uoro-ethy l)-urea) CO CO 00 inch 200836725 cc [M+H]+429 | [M+H] + 429 1HNMR (400 MHz, Me-d3-OD): 8.59 (1H,d), 7.86-7.79 (1H, m), 7.75 (1H, s), 7.69 (1H, s), 7.59 (1H, s), 7.48 (1H, t), 7.39 (1H, d), 7.32 (lH, d), 7.15 ( lH, dd), 4.02-3.86 (5H, m), 2.54 (3H, s). 1HNMR (400 MHz, Me-d3-OD): 8.64 (1H, d), 7.85 (1H, s), 7.75 (1H , s), 7.67 (1H, s), 7.50 (lH, t), 7.40 (1H, d), 7.33 (lH,d), 7.18-7.10 (2H,m), 3.95 (2H, q), 3.74 ( 3H, s), 2.49 (3H, s). 5 3 , on i ^ It% a ^ m 1轵巴》1砩溪丨1 v砩- Ϊ7 . ^ ffi ^ ^ nf ^ t ^ ^ ci ^ ^ ^ 5 S s « 1 Zhu sd M 带 with l-{3-[7-(l,5-dimethyl-1H-pyrazole-4-yl)-imidazole [l,2-ap-pyridin-3 -yl]-phenyl}-3·(2,2,2-trifluoro-ethyl)-gland (l-{3-[7-(l,5-Dimethyl-lH-py razol-4-yl) -imidazo[ 1,2-a]pyri din-3-yl]-phenyl}-3-(2,2,2-trifl uoro-ethyl)-urea) 1-{3-[7-(2,3- Dimethyl-3Η-imidazole 1~4_ base 》)-Minami Jun [1,2-a]σ than bite-3-yl]-phenyl}-3-(2,2,2-trifluoro-B -) gland (l-{3-[7-(2,3-Dimethyl-3H-im idazol-4-yl)-imidazo[ 1,2-a]pyr idin-3-yl ]-phenyl} -3-(2,2,2-trif luoro-ethyl)-urea) :% =>=〇工% X m $ m S inch 200836725 [M+H] + 491 [M+H] + 493 1HNMR (400 MHz, DMSO-d6): 9.08 (1H, s), 8.62 (1H, d), 8.05 (1H, s), 7.99 (1H, d)5 7.86-7.78 (2H, m), 7.73 (1H, dd), 7.54 (1H, d), 7.45 (2H, d), 7.39 (lH, dd), 7.31-7.23 (1H, m), 6.98 (1H, s), 4.01-3.88 (2H, m 1HNMR (400 MHz, DMSO-d6): 9.12 (1H, s), 8.67 (lH, d), 8.18-8.05 (5H, m), 7.84 (1H, s), 7.81 (1H, s), 7.51 -7.42 (3H, m), 7.32-7.25 (1H, m), 7.02 (1H, s), 4.01-3.90 (2H, m), 2.62 (3H, s). 阳,, K &lt;J ^ CN 1 s 1 a 111 ^ a 2, A ^ ^ 1 S v硪〇ri糠赛4 1 吞, l &lt; B- ξ &lt; Ψ t ά ί ¥ t ? 1 ί 5 ^ 1 f ί 5 ί ά ^ α ^ ά ^ 1 S ν ^ Ό 4 ^ 1- {3-[7-(2,2-Difluoro-benzo[1,3]dioxol-5-yl]imidazole [l,2 -a]Acridine-3-yl]-phenyl}-3-(2,2,2-tri-1ethyl)-urea (1-{3-[7-(2,2-Difluoro-benzo[ 1 ,3]dioxol-5-yl)-imidazo[ 1,2-a ]pyridin-3-yl]-phenyl} -3-(2,2, 2- trifluoro-ethyl)-urea) 1-(3-{ 7-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-imidazole [l,2-a] Pyridin-3-ylphenyl) 3-(2,2,2-trifluoro-ethyl)-pulse (l-(3-{7-[4-(5-Methyl-[l,3,4 ]o xadiazol-2-yl)-phenyl]-imidaz 〇[ 1,2-a]pyridin-3-yl} -phenyl)-3-(2,2,2-trifluoro-ethyl)-urea) °5 % 〇ί χ_&gt;=〇XtHX V CO 〇m P: 900 inch 200836725

[M+H]. 429 [M+H] + 443 1HNMR (400MHz, DMSO-^): 9.01 (1H, s), 8.61 (lH,d), 8.16 (2H, s), 7.83 (1H, s) , 7.81 (1H, s), 7.78 (1H, s), 7.50-7.42 (2H, m), 7.31-7.23 (1H, m), 7.14 (1H, dd), 6.90 (1H, t), 6.38 (1H , s), 4.02-3.92 (2H, m), 3.90 (3H, s), 2.20 (3H, s). 'HNMRC^OMHz, Me-rfj-OD): 8.57 (1H, d), 8.30 (1H, s), 8.26 (1H, s), 8.03 (1H, s), 7.84 (1H, s), 7.81 (1H, s), 7.72 (1H, s), 7.49 (1H, t), 7.44-7.33 (2H ,m), 7.31 (lH,d), 4.61 (1H, septet), 3.95 (2H, dd), 1.57 (6H, d). f 3 Ώ t ' ^ ^ S ^ ^ £ ^ i ^ ^ 荽5 S耩2 · «Λ f S i4 4 4 1 S | ^ i ^ ^ t ^ ^ ^ ? f iik l-{3-[7-(2,5-dimercapto-2H-pyrazole-3·yl) -Imidazole [l,2-a] acridine-3-yl]-phenyl}-3_(2,2,2-trifluoro-ethyl)-carboxylate (l-{3-[7-( 2,5-Dimethyl-2H-py razol-3 -yl)-imidazo[ 1,2-a]pyri din-3-yl]-phenyl} -3-(2,2,2-trifl uoro-ethyl)- Urea formate) 1-{3-[7·(1-isopropyl-1H-pyrazol-4-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3·( 2,2,2-tris-ethyl)-ureacarboxylate (1 - {3 -[7-(1 -Isopropyl-1 H-pyra zol-4-yl)-imidazo[ 1,2-a] Pyridi n-3 -yl] -p Henyl} -3 -(2,2,2-triflu oro-ethyl)-urea formate) LL * ryg 工工2&gt;=〇 χζ^α z o CO X 1 372 cn oo inch 200836725

[M+H]+429 1 1 [M+HJ+415 1HNMR (400 MHz, DMSO-d6): 8.97 (1H, s), 8.57 (1H, d), 7.77-7.71 (4H, m), 7.47- 7.42 (3H, m), 7.26 (1H, dt), 6.85 (lH, t), 4.01-3.89 (2H, m), 3.63 (3H, s), 2.48 (3H, s). 1HNMR (400 MHz, Me -d3-OD): 8.56 (1H, d), 7.96 (1H, s), 7.80 (1H, s), 7·75 (1H, s), 7.70 (1H, s), 7.68 (1H, s), 7.49 (1H, t), 7.45-7.36 (2H, m), 7.31 (1H, d), 3.95 (2H, q), 3.83 (3H, s) · Step AK 2 ^ 2 ^ id J 〇余ώ &lt; ^ λ ^ V ^ v 余一五 4 ^ A碥^ ^ 5 ^ S f ^ vf 4 Aluminum gallium s several l Φ\ a Ί ^ ^ ^ l-{3-[7-(l,5-dimethyl keto-1H-imidazole 1-4-mimito[1,2-a]11 than acetyl-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea L-{3-[7-(l55-Dimethyl-lH-im idazol-4-yl)-imidazo[ 1,2-a]pyr idin-3 -yl] -phenyl} -3 -(2,2,2 -trif luoro-ethyl)-urea) l-{3_[7-(l-methyl-1H·imidazole 14-yl)-imidazole [l,2-ahb-pyridine-3-yl]-phenyl}-3- (2,2,2-trifluoro-ethyl)-gland (l-{3-[7-(l-Methyl-lH-imidaz ol-4-yl)-imidazo[ 1,2-a]pyridin -3 -yl] -phenyl} -3 -(2,2,2-trifluo ro-ethyl)-urea) H&gt; 374 m 800 inch 200836725

[M+H] + 435 [M+H] + 419 1HNMR (400 MHz, Me-d3-OD): 8.77 (1H, d), 8.36 (1H, s), 7.92 (1H, s), 7·87 (1H, s), 7.67 (1H, d), 7.52 (1H, t), 7.49-7.47 (1H, m), 7·45 (1H, d), 7.37 (lH, t), 4.00-3.89 (4H , m). lHNMR (400MHz, DMSO-d6): 12.80-12.73 (lH,m), 8.97 (1H, s), 8.66 (1H, d), 7.98 (1H, s), 7.92 (1H, s), 7.75 (1H, s), 7.54-7.44 (2H, m), 7.32 (1H, dd), 7.28 (1H, d), 6.85 (lH, t), 4.01-3.89 (2H, m). Step AO Step AP L-{3-[7-(5-fluoromethyl-[1,3,4]oxan-2-yl)-imidazole [l,2-a]° ratio -3-yl]-benzene }}-3-(2,2,2-trifluoro-ethyl)-gland (1 - {3 -[7-(5 -Fluoromethyl-[ 1,3» 4]oxadiazol-2-yl)-ixnidazo [ 1,2-a]pyridin-3 -yl] -phenyl} -3 -(2, 2,2-trifluoro-ethyl)-urea) l-{3-[7-(5-oxy-4,5- Dihydro-[1,3,4]oxadiazol-2-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea (l-{3-[7-(5-Oxo-4,5-dihydro-[ 1,3,4]oxadiazol-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl] -phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) 工z工z&gt;=〇% Completion 4% workzf U_v〇377 68 inch 200836725 [M+H] + 430 1 1 [M+H] + 430 1HNMR (400 MHz, DMSO-d6): 9.03 (1H, s), 8.64 (1H, d), 8.17 (1H, s), 7.84 (1H ,s),7·78 (1H,s), 7.76 (1H, s), 7.53-7.40 (3H,m), 7.31-7.23 (1H, m), 6.93 (1H, t), 4.03 (3H, s ), 4.00-3.90 (2H, m), 2.57 (3H, s). lHNMR (400MHz, Me-d3-OD): 8.73 (1H, d), 8.03 (1H, s), 7.90-7.82 (2H, m ), 7.51 (lH,t), 7.46-7.39 (1H, m), 7.39-7.30 (2H, m), 4.06 (3H, s), 3.95 (2H, q), 2.41 (3H, s). $ 5 Mourning 'recording ί. ^ ^ ? iss ^u' ά 1 ^ ? 5 ^ f &lt; ^ ^ fd: l ^ a Ί ^ ^ κ -r Step AJ_ 1- {3-|;7-(l,5-dimercapto-1H -[1,2,3]triazole "4-yl)-imidazole [l,2-a] «pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-B -urea phthalate (l-{3-[7-(l,5-Dimethyl-lH-[l, 2,3]triazol-4-yl)-imidazo[ 1,2-a ]pyridin-3 -yl]-phenyl} -3-(2,2, 2-trifluoro-ethyl)-urea formate) 1- {3-[7-(2,5-dimercapto•2H-[1,2,4] Triazol-3-yl)-imidazo[l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-pulse (l-{3 -[7-(2,5-Dimethyl-2H-[l, 2,4]triazol-3-yl)-imidazo[l ,2-a ]pyridin-3-yl]-phenyl} -3-(2, 2, 2- trifluoro-ethyl)-urea) 'Ζ·° ί COz CO X 378 Os m 06 inch 200836725 c [M+H] + 443 [M+H] + 470 1HNMR(400 MHz, Me-d3- OD): 8.65 (1H, d), 7.86 (1H, s), 7.77 (1H, s), 7.66 (1H, s), 7.50 (1H, t), 7.40 (1H, d), 7.36-7.29 (1H , m), 7.17-7.08 (2H, m), 4.19 (2H, q), 3.95 (2H, q), 2.52 (3H, s), 1.33 (3H, t). 1HNMR (400 MHz, DMSO-d6) : 9.02 (1H, s), 8.69 (1H, d), 8.60 (1H, d), 8.18 (lH,d), 8.08 (lH,d), 7.87 (1H, s), 7.81 (1H, s), 7. 74(lH,dd), 7.51-7.40 (3H, m), 7.34-7.25 (1H, m), 6.90 (1H, t), 5.33 (1H, s), 4.02-3.89 (2H, m), 1.51 ( 6H, s). ^ ^ ^ 1 ί I ® ^ ^ &lt; ^ -i ^ ^ ^ &lt;1 &lt; ^ v § Aluminium S nickel work 1轵au硪矾趑f ^ 3 Rugged record 2 S Ο ^ ^ j ? 11 4 s ^ | &lt;汔^ ^ 9 gallium κ ^ flocium S 2 2 · 分 哼 i轵巴 "砩矾S q l-{3-[7-(3-ethyl- 2-Methyl-3H-Minute 1&quot;4-base)-°m°[l,2-a]°bit -3-yl]-phenyl}-3·(2,2,2- Trifluoro-ethyl)-urea (1 - {3 -[7-(3 -Ethyl-2-methyl-3 H-imidazol-4-yl)-imidazo[ 1,2-a]pyridin-3-yl] -phenyl} -3-(2,2,2-trifluoro-ethyl)-urea) 1 -(3- {7-[2-( 1 -hydroxy-1-methyl-ethyl)-nbb -4- Base]-flavored β-[1,2-a]β-pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3- { 7-[2-( 1 -Hydroxy-1 -met hyl-ethyl)-pyridin-4-yl]-imida zo[l ,2-a]pyridin-3-yl} -phenyl) -3 -(2,2 ,2-trifluoro-ethyl)-urea) A work CO work CO work Z work z>=〇CO TH 00 cn 16 inch 200836725

MS: [M+H]+ 432 MS: [MH] + 432 1HNMR (400 MHz, Me-d3-OD): 8.75 (1H, d), 8.62 (1H, d), 8.53 (1H, d), 8.41 (lH,t), 8.31 (lH,s), 8.01 (1H,s),7·67 (1H,dd), 3.97 (2H, q), 3.06 (2H, q), 1.48 (3H,t). 1HNMR (400 MHz, Me-d3-OD): 8.66 (1H, d), 8.18 (lH, s), 7.83 (lH, t), 7.81 (1H, s), 7.60 (1H, dd), 7.51 (lH , t), 7.47-7.41 (1H, m), 7.34 (1H, d), 7.27 (1H, s), 3.96 (2H, q), 2.53 (3H, s). ά $I*ίS J ^ ^ ώ Λ ^ m ^ ^ ^ ^ &lt;N 忑 忑 〇〇 乂 乂 驷 长 长 长 4 4 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ r r r r r r r r r r r r r r r r r r r r Bark 1硪辕趑^{547-(5-ethyl-[1,3,4]oxadiazol-2-yl)-imidazole [l,2-a]pyridin-3-yl]-° ratio -3-yl}-3-(2,2,2-tris-ethyl) vein (l-{5-[7-(5-Ethyl-[l,3,4]oxadi azol-2-yl) -imidazo[ 1,2-a]pyrid in-3 -yl] -pyridin-3 -yl} -3 -(2,2,2 -trifluoro-ethyl)-urea) l-{3_[7-(4_ A -thiadiazole-2-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-nuclear (1 - {3-[7-(4-Methyl-thiazol-2-yl)-imidazo [ 1,2-a]pyridin-3 -yl]-phenyl} -3 -(2,2,2-trifluoro-ethy l) -urea) {V =>=〇χί&gt;α工2&gt;=〇Χ^Λ T \ zf 382 S3 200836725

MS: [M+H]+ 419 MS: [M+H1+ 403 lHNMR (400 MHz, DMSO-d6): 9.70 (1H, s), 8.98 (1H, s), 8.70 (1H, d), 8.35 (1H, s), 7.93 (1H, s), 7.78 (1H, s), 7.66 (1H, dd), 7.54-7.45 (2H, m), 7.33-7.28 (1H, m), 6.86 (1H, t), 4.00 -3.91 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9.19 (1H, s), 8.99 (1H, s), 8.76 (1H, dd), 8.46 (1H, dd), 8.03 (1H, s), 7.79 (1H, t), 7.58 (1H, dd), 7.55-7.46 (2H, m), 7.31 (1H, dt), 6.87 (1H, t), 4.02-3.89 (2H, m). cT • another, 1 ^ 哼 哼 S缈f 5V I ^ Φ ^ &lt; SJ f B driving gallium S # 2 t C la '1 ^ ^ Step AA step ab. Step AR〇1-[3-(7-[1,3,4]thiadiazole-2-yl-imidazo[l,2-a]acridin-3-yl)-phenyl]-3-(2 , 2,2-tris-ethyl)-gland (l-[3-(7-[l,3,4]Thiadiazol-2-yl-imidazo[ 1,2-a]pyridin-3 -yl)- p henyl]-3-(2,2,2-trifluoro-ethyl) -urea) 1-[3-(7-[1,2,4]oxadiazol-5-yl-imidazole [l,2-a Acridine-3-yl)-phenyl]-3-(2,2,2-disorder-ethyl)-pulse (l-[3-(7-[l,2,4]Oxadiazol-5- Yl-imidazo[ 1,2-a]pyridin-3 -yl)-p henyl]-3-(2,2,2-trifluoro-ethyl) -urea) V 〇fy % into s cn S3 cn Γη6 inch 200836725

MS: [M+H]+ 463 MS: [M+H] + 446 lHNMR (400 MHz, Me-d3-OD): 8.72 (1H, d), 8.24 (1H, s), 7.87 (2H, d), 7.73-7.64 (1H, m), 7.57-7.41 (2H, m), 7.36 (1H, d), 4.95 (2H, s), 3.96 (2H, q), 3.55 (3H, s). lHNMR (400MHz, Me-d3-OD): 8.63 (1H, d), 8.08 (1H, s), 7.82 (1H, s), 7.78 (1H, s), 7.58-7.51 (13⁄4 m), 7.49 (1H, d), 7.43 (1H, d), 7.33 (1H, d), 3.95 (2H, q), 2.48 (3H, s), 2.42 (3H, s). - f? , ^ ^ ί哼朵£, ^ ^ ^ £ S 5: 蕻录 S#工Tev 1 免巴丨1 Phosphorus per building ^ i 1 ^ 1 ί V ^ O 4v »1 g ϊ £ 1 ^ 5 ? C ^ ^ 5 (NW &lt;N ^ ^ Fsf 锘酴S玑&gt;1 1 du硪龛趑咿1-{3-[7-(5-decyloxymethyl-[1,3,4]thiadiazol-2-yl)-imidazole [l ,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {3 -[7-(5 -Methoxymethyl-[ 1 ,3,4] thiadiazol-2-yl)-imidazo [ 1,2-a]pyridin-3 -yl] -phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea) l-{3 -[7-(4,5-dimethyl-thiadiazol-2-yl)-imidazole [l,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1 - {3-[7-(4,5-Dimethyl-thiazol -2-yl)-imidazo[ 1,2-a]pyridin-3 -yl]- Phenyl} -3-(2,2,2-trifluoro -ethyl)-urea) Completion s =&gt;=. xb-a cn SS inch 6 inch 200836725

MS: [M+H]+ 445 MS: [M+H]+ 431 ^ ^ ^ ^ SSS ^ ? « 甶W w W rp Λ w 2 5n SS ζί &lt;n S 〇cx; r&gt; ^ ^ rn S Ii C? 3 S ^ O ffi κ K .Λ 1 s 1 2 ^ ^ ? S 1H NMR (400 MHz, DMSO-d6): 9.35 (1H, s), 8.90 (1H, d), 8.53 (1H, s), 8.41 (1H, s), 7.95 (1H, dd), 7.88 (1H, s), 7.61-7.52 (2H, m), 7.33 (lH, dt), 7.07 (1H, t), 4.86 (2H , q), 4.00-3.90 (2H, m), 1.63 (3H, t). 5 ^ $4 S ^ f &quot;fd: A t? ^ W &lt; s ^ ^ J 5 S 5 b 1 'Μ ί « Γ &lt; ^ λ igs it Al-Gallium - 1 to \巴 "砩矾蟛 余 φ ^ ^. J. 2 ^ — & 00 inch Hj ^ ,, A 2 3 έ § · 6» - § Zhu N CO driving Q l-{3-[7-(3-methyl-1-mercapto-1 Η-β ratio 0 sitting ~ 4-base ^-口米崎_[ 1,2-a]0 唆 - 3-yl]•phenyl}-3_(2,2,2-tris-ethyl)-pulse (1 - {3 -[7-(3 -Hydroxymethyl-1 -methyl-1 H-pyrazol-4- Yl)-imid azo[ 1,2-a]pyridin-3-yl]-phenyl } -3-(2,2,2-trifluoro-ethyl)-urea ) 1·{3_[7·(2-ethyl -2H-tetrazol-5-yl)-imidazole [1,2-a].pyridin-3-yl]-phenyl} -3 -(2,2,2-trifluoro-ethyl)-gland ( 1 - {3 -[7-(2-Ethyl-2H-tetrazol-5-yl)-imidazo[l , 2 -a]pyridin-3- 1 yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea ) {Y工兹卜0 Χ^ϊ g IZ H, OO oo cn ON OO m 200836725 MS: [M+H]+ 445 MS: [M+H]+ 449 1HNMR (400 MHz, DMSO-d6): 9.37 (1H, s), 8.96 (1H, br s), 8.47 (lH,br s) , 7.94 (1H, d), 7.89 (1H, s), 7.62-7.51 (2H, m), 7.34 (lH,d), 7.07 (lH,t), 5.33-5.22 (1H, m), 4.00-3.90 (2H, m), 1.67 (6H, d). 1HNMR (400 MHz, Me-d3-OD): 8.95 (1H, d), 8.61 (1H, s), 8.32 (1H, s), 8.21-8.11 ( lH,m), 8.02 (1H, s), 7.60 (1H, t), 7.54 (1H, d), 7.42 (1H, d), 5.09 (2H, s), 3.96 (2H, q). 1 fg. Sg CS 13⁄4- ^ Gallium® 私 Private f Ώ . --j CS ^ $ 3 inch cn ^ Φν ^ B ^ ^ SSJ II VS tO ^ ^ ^ &lt; 汔余又试Y电 P 1 私巴, 丨硪鋈 every l-{3-[7-(2- Isopropyl·2Η-tetrazol-5-yl)-imidazole [l,2-a]acridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)- Urea (1 - {3 -[7-(2-Isopropyl-2H-tetra zol-5-yl)-imidazo[l ,2-a]pyridi n-3-yl]-phenyl} -3-(2,2 ,2-triflu oro-ethyl)-urea) ^{347-(5-Hydroxymethyl-[1,3,4]thiaphenan-2-yl)-flavored saliva [1,2-a] ° ratio Benzo-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (l-{3-[7-(5-Hydroxymethyl-[l,3,4]] Thiadiazol-2-yl)-imidazo[ 1,2-a]pyridin-3 -yl] -phenyl} -3 -(2,2,2-trifluoro-ethyl)-urea hydrochloride) L m rH ON m 96 inch 200836725

MS: [M+H]+ 468 MS: [M+H] + 418 1HNMR (400 MHz, DMSO-d6): 9.06 (1H, s), 8.88 (2H, s), 8.60 (1H, d), 8.17 (2H, s), 8.00 (1H, s), 7.80 (1H, s), 7.77 (1H, s), 7.43 (2H, d), 7.37 (1H, dd), 7.26 (1H, d), 6.96 ( 1H, t), 4.12 (4H, t), 4.02-3.88 (2H, m)5 2.42-2.30 (2H, m). 1HNMR (400 MHz, DMSO-d6): 9.19 (1H, s), 8.76 (1H , d), 8.69 (1H, s), 8.52 (1H, s), 8.29 (1H, s), 8.21 (1H, s), 8.00 (1H, s), 7.60 (1H, d), 7.09 (1H, s), 4.48 (3H, s), 4.05-3.89 (2H, m). 3 31 沦1 ^ &lt; it t &lt; 汔3 3 s - 2 1 bar “蚴龛蚴龛々录ΛΛ ^ · 0 again Sister 1 ^ 00 q ^ qg $硪$ gallium Ϊ 12 4 ws 纳纳溪 1-{3-[7-(2-azetidin-1-yl-pyridin-5-yl)-imidazole [ 1,2-a] ° than benzyl-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea phthalate (1 - {3 -[7-(2) -Azetidin-1 -yl-pyri midin-5 -yl)-imidazo[ 1,2-a]pyr idin-3 -yl] -phenyl} -3 -(2,2,2-trif luoro-ethyl)-urea Formate) l-{547-(2-methyl-2H-four-position-5-yl)-imidazo[1,2-a]pyridin-3-yl]-pyridine-3-yl}-3-(2 , 2,2-tris-ethyl)-pulse (l-{5-[7-(2-Methyl-2H-tetrazo l-5-yl)-imidazo[ 1 ,2-a]pyridin-3 -yl] -pyridin-3 -yl} -3 -(2,2,2-tri fluoro-ethyl)-urea) \ ,工l \ cn

I 200836725 MS: [M+H]+ 416 1 MS: [M+H]+ 416 1HNMR (400 MHz, Me-d3-OD): 8.66 (1H, d), 7.90-7.81 (2H, m), 7.74 (1H, s), 7.50 (1H, t), 7.46-7.36 (2H, m), 7.34 (1H, d), 3.96 (2H, q). 1HNMR (400 MHz, DMSO-d6): 8·99 ( 1H, s), 8·35 (1H, d), 7.94 (1H, s), 7.73 (1H, s), 7.59-7.42 (3H, m), 7.24 (1H, d), 6.87 (1H, t) , 4.01-3.89 (2H,m), 2.15 (3H, s). &lt; 2 - •汔B ΐ ^ ^ 1 ή π ^ ^ ^ ^ ^ S ^ Λ 0 1 1_[3_(7-phenyl-d5 -imidazole [l,2-a] acridine-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-nuclear (1 -[3 -(7-Phenyl-d5) -imidazo[ 1, 2-a]pyridin-3-yl)-phenyl]-3-(2, 2,2-trifluoro-ethyl)-urea) 1-{3-[7-(5·methyl-iso Oxazole "4-yl)-imidazole [1,2-a]&quot;bipyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-gland (1 - {3 -[7-(5 -Methyl-isoxazol-4 -yl)-imidazo[ 1,2-a]pyridin-3 -yl]-phenyl} -3-(2,2,2-trifluoro-et hyl) -urea) 12 Industrial know-how: Q {y &gt;=〇xz 394 cn 200836725

MS: [M+H]+ 373 MS: [M+H] + 402 1HNMR (400 MHz, DMSO-d6): 8.94 (1H, s), 8.49 (1H, d), 7.80 (1H, s), 7.70 (2H,d), 7.52-7.39 (2H, m), 7.24 (lH,d), 6.91 (1H, dd), 6.84 (lH,t), 4.01-3.88 (2H,m),2.11(3H,s 1HNMR (400 MHz, DMSO-d6): 9.51 (1H, s), 8.97 (1H, s), 8.73 (1H, d), 8.33 (1H, s), 8.21 (1H, d), 7.84 (1H , s), 7.77 (1H, s), 7.60 (1H, dd), 7.53-7.42 (2H, m), 7.32-7.24 (1H, m), 6.86 (lH,t), 4.02-3.88 (2H, m ). 1 8 s Office CO Mill, 艮. s co S ; ψ U ^ 屯 2 VC driving Q II CT i SK ^ ! Step AS 1-[3_(7 small propynyl-imidazo[l,2-a]pyridin-3-yl)-phenyl]- 3-(2,2,2-tris-ethyl)-pulse (1 -[3 -(7-Prop-1 -ynyl-imidazo[ 1.2- a]pyridin-3 -yl)-phenyl] -3 - ( 2.2.2- trifluoro-ethyl)-urea) l-[3-(7-[l,2,4]triazol-1-yl-imidazo[l,2-a]pyridin-3-yl)-benzene 3-(2,2,2-trifluoro-ethyl)-urea (1 -[3 -(7-[ 1,2,4]Triazol-1 -yl-im idazo[ 1,2-a ]pyridin-3 -yl)-phen yl] -3 -(2,2,2-trifluoro-ethyl)-ur ea) Completion h into cn ON 66 inch 200836725

/M MS: [M+H]+ 450 MS: [M+H]+ 433 1HNMR (400 MHz, DMSO-d6): 9.25 (1H, s), 8.74 (1H, dd), 8.69 (1H, d), 8.52 (1H, d), 8.30-8.24 (1H, m), 8.22 (1H, t), 8.06 (1H, s), 7.51 (lH, dd), 7.14 (1H, t), 4.03-3.90 (2H, m), 2.82 (3H, s). 1HNMR (400 MHz, DMSO-d6): 9.06 (1H, s), 8.69 (1H, dd), 8.40 (1H, dd), 7.96 (1H, s) , 7.80-7.78 (1H, m), 7.58-7.43 (3H, m), 7.30 (1H, dt), 6.95 (1H, t), 4.02-3.88 (2H, m), 2.69 (3H, s). 5 ^ ^ ^ J ^ ^ ^ ^ s ξ v ^ ^ ^ ^ ^ ^ ^ 4: 19 碧Ξ3人成^ av ^ 'Ί ί s Ϊ ^ 5 a ^ ^ S | rii ^ cA ^ ^ ^ S ^ Aluminium Gallium S耩1 ZL Λ ^ ^ ^ Ψ 1- {5_[7-(5-Indolylsulfonyl-[1,3,4]oxadiazol-2-yl)-imidazole [1,2-a] σ than bite-3 -yl]-0 σ -3 -3·* yl}-3-(2,2,2-trifluoro-ethyl)-urea (1 - {5 -[7-(5 -Methylsulfanyl) -[ 1, 3,4]oxadiazol-2-yl)-imidazo[ 1, 2- a]pyridin-3 -yl] -pyridin-3 -yl} -3 -(2,2,2-trifluoro-ethyl) -urea) 1-{3-[7·(3-indolyl-[1,2,4]thiadispin-5-yl)-flavored 0 sitting [1,2-a]11 than lake-3 ]]-Phenyl 3-(2,2,2-trifluoroethyl)-urea (1 {3-[7-(3-Methyl-) [ 1,2,4]thia diazol-5-yl)-imidazo[ 1,2-a]pyr idin-3-yl]-phenyl} -3-(2,2,2-trif luoro-ethyl)-urea )工z &gt;=〇〇乂Z1 00 On cn 200836725 , /L· s inch +H+W _

0&gt;κζ) 96.ΓΠ ^ffiz) 98.S ΧΡffilir inch·b effil) 6 inch·//(51) 09·b Λ51) 90ooepffioCNroo •(saI)CNeooxsffiI) inch ooXPKI) 00·6 :(αο_ερύ2 NHWOOspiHMHI

If the rest of the electricity. S-inch gallium ^. Qrn gallium. Z-ϊ ΝΙ Φ ΝΙ 镓 镓 (&lt;L&gt;sJO2ooJpxq SJn-^sqd- {^^.spud Β-&lt;Ν^ΓοΖΒΡμυ·τ[&gt;,-ς-ozcd broom-ffi &lt;Ν-ί3 ·§η1π3_(Ν)_ 卜丫evs^lJPH-CNnCNH) 綮-(^i4-{^rA-^-i24?r I 】o , ym to-ί 丨rCNd: 丨一low

HN

LLLL 00 inch 200836725 Paste Examples 401-418 Examples 401-418 can be prepared using the methods described below: Example 401 1-(3-{7_-|~1-(2-Ph-ethyl-ethyl)-11 ^-咐14_4_一一_殊11 sits and "1,2_31 mouth pyridine_3_yl 1-phenyl)-3-(2,2,2_three free two Π some Π -(3:-{ ·2·-ϋ -(2-Hydroxy-ethvl) clock 1 H-pyra zol-4-vll -imidazol&quot; 1, 2&quot;a1p_yridin-3-yl} -pheny 1)-3-(2,2 Ί triflnoro- e thylVure a)

The compound as indicated in the heading can be passed through the same procedure as in General Procedure A, Steps A1-A3, and in step A3b, 16 [3-(4,4,5,5-tetramethyl-[1,3,2]- Oxypentan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (16 [3-(4,4,5,5-tetramethyl-[l, 3,2]dioxaborolan_2-yl)-phenyl]-3 -(2,2,2_trifluoro-ethyl)_urea), step E2 and step E3 using 15 2-(4-bromo-1H- η than 嗤-1-yl ) Ethanol (2-(4-bromo_lH-pyrazol-l-yl)ethanol) was prepared. Example 402 • L-(3-Amino-ethyl)-1Η-ρ ratio 17 sitting-4-base m ton "1,2-alg ratio 502 200836725 -3--3-基卜笨基)-3 -(2,2,2-trifluoro-ethyl)-pulmonium _Π]7-Γl-(2-Amino-ethvl&gt;)-lH-pvrazol-4-vlΊ-imidazoΓ1.2-a&quot;lpvridin-3- Vlレτ)henvΠ-3-(2,2,2trifluoro-ethvlVιιrea)

The compound as indicated in the heading can be subjected to the same procedure as in General Procedure A, Steps A1 - A3, but in the step A3b, 16 [3-(4,4,5,5-tetramethyl-[1,3,2] Oxaloborane-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (16 [3-(4,4,5,5_tetramethyl-[l,3, 2] dioxaborolan-2_yl)-phenyl]-3 10 -(2,2,2-trifluoro-ethyl)-urea), step E2 and step E3 use 2·(4-米比嗤-1_基)_ B Prepared by 2-(4-bromo_pyrazol-l_yl)-etliyl amine. Example 403 15 1-{3-"7-(4,5-Dimethyl-411-"1,2,41 triazole-3-yl)-imidazolium 1~1,241 pyridine-3-yl 1 - stylyl Indole-3-(2,2.2-trifluoroethyl)-urea n-{3-r7-(4,5-Dimethvl-4H-ri.2*41triazol-3_vlVimidazo"l,2 -alpvridin-3-vll -phenyl I-3-(2,2,2-trifluoro-ethvlVurea) 503 200836725

The compound as indicated in the heading can be passed through the same procedure as in General Procedure A, Steps A1 - A3, and in Step A3b, 16 [3-(4,4,5,5-tetramethyl·Π,3,2] Dioxooxy Pentaborane-2-yl)-phenyl]·3-(2,2,2-trifluoro-ethyl)urea (16 Γ) 5 [3-(4,4,5,5_tetramethyl-[l,3 , 2] dioxaborolan-2-yl)-phenyl]-3 -(2,2,2-trifluoro-ethyl)-urea), step E2 and step 3-3 using 3-i-4,5-dimercapto- 4H_[1,2,4]triazole (3 _halo_4,5-dimethyl-4H-[l,2,4]triazole) was prepared. 10 using commercially available 3-chloro-5-methyl-4H-[1,2,4]triazole (3-chloro-5-methyl-4H-[l,2,4]triazole) 3_ Halogen-4,5-dimercapto-4Η·[1,2,4]triazole (3-Halo-4,5•dimethylWH-[ 1,2,4]triazole) 〇 In addition, as the title shows The compound can pass through 1-{3-[7-(5-methyl15-[1,3,4]11oxadi-2-yl)-indomethacin and [1,2-a]^ σ定-3-yl]phenyl}·3-(2,2,2-trifluoro-ethyl)-urea (1 - {3-[7-(5-methyl· [ 1,3,4] oxadiazol -2-yl)-imidazo [ 1,2_a]py ridin-3-yl]-phenyl}-3-(2,2,2_trifluoro-ethyl)_urea) is obtained by reaction with methylamine. · 504 20 200836725 Example 404 1-{3-Γ7-(5-Mercapto-oxazol-2-yl)-imidazolium "l,2-alpyridine-3-yl-1-stupyl 3-(2 , 2,2-digas-ethyl vein 5 (1 -{3-"7-(5_Methvl-oxazol-2-vl)-imidaz〇ri .2-alr&gt;vridin-3-vl]-phenvl)-3 -r2.2,2-trifluoro-ethvl&gt;-urea&gt;)

10 Ο 15 The compound as indicated in the heading can be passed through the same general procedure as in steps A1-A3, but 16 [3-(4,4,5,5-tetradecyl-[1,3,2] is used in step A3b. Dioxaborolan-2-yl)-phenyl]_3-(2,2,2·trifluoroethyl)-urea (16 [3_(4,4,5,5_tetramethyl_[l,3, 2] dioxaborolan-2-yl)-phenyl] face 3 - (2,2,2-trifluoro-ethyl)_urea), step E2 and step E3 using 2-gas-5-methyl-mouth sputum (2 -chloro_5-methyl-oxazole) to prepare. Example 405 1-{3-"7-(4-Mercapto-oxazol-5-yl)-imidazolium "1,241 pyridin-3-yl 1-molyl V-3-(2,2,2 ·Tris-ethyl)-n-i3-r7-(4-Methyl-oxazol-5-YlVimidaz〇n, 2-alpvridin-3-vl 1-phenyl)-3-(2,2,2-trifluoro -ethvn-urea) 505 200836725

The compound as indicated in the heading can be prepared by the same method as AB, but the TosMIC must be replaced by Me-TosMIC (as described in Bioorg·Mc. Chem. Lett. 5 12 2002 1323). Example 406 M3-"4-(4-Methyl-oxazol-2-ylimidazolyl,H,2-alpyridine-3_1)Phenyl-3-(2,2,2-digas-B Base vein 10 Π· {3-r7-(4-Methvl-oxazol-2-vl)-imidaz〇ri ,2-alpvridin-3-y1 1-phenvU-3-r2,2,2-trifluor〇&quot;ethvlVurea&gt ;)

As the compound shown in the heading, imidazo[l,2-a]pyridine-7-carboxylic acid amide can be used as in the method of step Aca. Prepared by reaction with aerogel _ 506 200836725 (as described in J. Med. Chem. 1990, 33, 492). Subsequent to the general formula B, steps B2 and B3, the desired compound is obtained, as shown in the reaction scheme below.

Further, the compound as indicated in the heading can be obtained by a Stille Type coupling reaction as described in Synthesis 1987, 5, 693. Example 407 10 1-{5-"7-(5-Methyl-"1,3,41oxadiazol-2-yl)-imidazolium "1,2-31pyridine-3-yl-1-p ratio口定-3 基卜3-(2,2,2-二气-乙脉m-rT-O-Methvl-rU/loxadiazol-S-vlVimidazorU-alpv ridin&quot;3-yl1-pyridin-3-yn - 3-(2,2,2-trifluoro-ethyl)-urea) 507 200836725

F

The compound as indicated in the title can be subjected to the method described in Example 329, in step e, as 128 1-[5-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-ylpyridin-3-yl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[5-(4,4,5,5-) The completion of tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridi n-3-yl]-3-(2,2,2-trifluoro-etliyl)-urea). Example 408 1_"3 -(7-cyclopropylacetylene)-imidazolium "1.24~|pyridin-3-yl 1-methyl-3-(2,2,2-10 di-ethyl)-pulse (1 -r3&quot;(7 -Cyclopropvlethynyl)-imidaz〇r 1,2-a1pvridin-3-yl1-p henYl-3-(2,2,2-trifluoro-ethvn-urea&gt;)

The compound as indicated by the heading can be prepared by the method of the general formula SGD, using commercially available cyclopropylacetylene in 508 200836725, step SGD4a. Example 409 M3-"7-(4,5-Dimethyl-isoxazole-3-yl)-imidazolyl,2-alpyridine-3-5 base 1-stupyl 3-(2,2, 2-tris-ethyl) Π-{3-r7-(4,5-Dimethvl-isoxazol-3-vlVimidazo"l,2_alpvridi n-3-yl1-phenvU-3-(2,2,2-trifluoro -ethvl&gt;)-urea&gt;)

The 10 methyl ketone can be obtained by a Stille coupling reaction. Further, it can be reacted with a base and 3-bromo-2-butanone, and as described in J. Med. Chem., 2004, 792, a 1,3-diyl group is relatively produced. As described in Tetrahedron, 2006, 4430, reaction with hydroxylamine produces an oxazole which can be iodized and reacted under Suzuki coupling conditions as shown in General Formula B, Steps 2 and 3. . 509 200836725 Example 410

1-{3-"7-(2,4-dimethyl-isoxazol-5-yl)-imidazolium "1,241 pyridin-3-yl V-phenylindole-3-(2,2,2-tri) Fluoro-ethylurea 5 Π - {3-r7-(2,4-Dimethvl-isoxazol-5-vl&gt;-imidazof 1,2-alpvridi nB-yll-phenvn-B-^^.Z-trifluoro-ethvlVurea) F

An acid prepared by the step AB, as described in WBioorg. Med. Chem. Lett., 2003, 73, 2059, can be treated with 2-acetamidoacrylic acid to produce a dimercaptosine σ. Dimethyloxadiazole 〇Example 411 1-{3-"7-(2. Mercapto-isoxazol-5-ylimidazolium fl, 2-alpyridine-3-yl-1-phenyl 15) -(2,2,2 - two chaos - ethyl vein (1 - {3-r7-(2-Methvl&quot;isoxazol-5-yl&gt;)-imidaz〇ri, 2-a1pyridin-3-vll-phenvl) - 3-Γ2,2,2-trifluoro-ethyl)-urea) 510 200836725

An aldehyde obtained by the step AB can be used in an alkaline environment (as described in J. Het. Chem., 1981, 1133) as N-(toluene·4_sulfonate 5 fluorenyl)-acetamidine N-(toluene -4-sulfonylmethyl)-acetimidic acid methyl ester is treated (eg J. Het Chem., 1981, 1127) to produce the corresponding evil

10 In addition, the above methyl ketones are under photochemical conditions (WJ.Org·

Chem., 2005, 70(7), 2720), was brominated. Its bromo group can be substituted in the environment of basic 511 200836725 to produce the corresponding acetamide compound. This reaction can be reacted with a Burgess reagent under microwave conditions to form oxazole, as described in Synlett, 1999, 1642. The compound can be iodinated by 5 and subjected to a Suzuki coupling reaction as described in General Formula B, Steps 2 and 3. Example 412 1-(2,2,2-trifluoro-ethyl)_3_{3-|~7-(1,2,5-trimethyl-111-imidazol-4-yl) <RTIgt; Fh2,alpyridin-3-ylindole-jasperyl-urea 10 Π - (2,2,2-Trifluoro-ethvl)-3- Π-Γ7-Π ,2,5-trimethvl-lH-imid azol-4 -ylVimidaz〇ri, 2, a1pvridine-3&quot;vn-phenyl 1-urea)

4- 4-Bromo-1,2,5-trimethyl-1H-imidazole 15 (4_Bromo-l,2,5-trimethyl-lH-imidazole) via 2,4-dibromo-1,5-diindole The base-1H-imidazole (2,4-dibromo-l, 5-dimethyl-lH-imidazole) is obtained by treatment with n-butyllithium and strontium oxide, as in J. Org. Chem., 1994, 59, 5524. The method described. According to the step E3, the compound can be combined with l-[3-(7-boronic acid- 512 200836725 odor 0 and [l,2-a&gt;bidinyl_3_yl)-phenyl]_3_(2,2,2_ Trifluoro-ethyl)-urea (1 -[3-(7-bor〇nic acid-imidazofl 52-a]pyridin_3-yl)-phenyl]-3-(2 52,2-trifluoro -ethyl)-urea) Coupling. Example 413 A-gas-based-4 5-diindole-n 3 41 oxadiazole-2-yl)-mimoyl^3_(2 on 2_three gas_ethylurea (1 - {3-[7 -(4-Methyl-^-πχ〇-.4,5-dihydro-Γ1.3,41oxadiazol-2-y 10 l)iimidazo"l,2,alpyrirHrL-3_vll-phenvl}-3-r2,2,2 -trifluoro-et hvD-urea)

Its oxadiazolone can be obtained by the method described in Step AP (Example 377) and can be thiolized under Mitsunobu conditions. Using the general formula B, the methods of steps 2 and 3 for moth and Suzuki coupling reactions can produce the desired product. Example 414 · ί·-丄3_"7_(3,5-dimethyl-Γ1,2,41三峻-1-yl) tastes "1,2-alp ratio ° 2〇-3-yl 1-styl}-3_(2,2,2-trifluoroethyl 513 200836725 (1-Ι3-Γ7-Γ3.5-Dime thvl-Γ 1.2,41 triazol-l-vlVimidazor 1,2-alp Vridin-3-vl1-phenyn-3-(2&lt;t2,2-trifluoro-ethvlVurea&gt;)

F

5 7-Bromo-imidazo[l,2-a]pyridine and 3,5-dimethyl-[1,2,4 can be catalyzed by copper. ]_Triazole (3,5_ to 11^{1^1-[1,2,4]彳1^2〇4) coupling (\¥0 02085838). The product can then be iodinated and coupled in Suzuki reaction conditions as shown in General Formula B, Steps 2 and 3. 10 Example 415 1_{3-"7_(3_methyl-"1.2,41 triazol-1-yl]-imidazolium "1,24~1 pyridin-3-yl 1-molyl oxime-3 -(2,2,2-trifluoro-ethylurea Π · n-"7-(3-Methvl_ri , 2,41 triazol-1 -vlVimidazofl ,2-alp vrid 15 in-3-yll-phenvll - 3- F2,2,2-trifluor〇&quot;ethyl&gt;)-urea&gt;) 514 200836725

Under the catalysis of copper, 7-bromo-flavor σ can sit and [l,2-a]^b bite with 3-methyl-[1,2,4]-three-jun (3-methyl-[l,2 , 4]-triazole) coupling (WO 5 02085838). The product can then be serviced and coupled in Suzuki reaction conditions as shown in General Formula B, Steps 2 and 3. The isomers can be separated by column chromatography. Example 416 10 1-{3-"7-(4-methyl-imidazol-1-yl)-imidazolium "1,2-&amp;1pyridine-3-one 1-molyl-3-(2, 2,2-tris-ethyl)-pulse n-{3_r7_r4-Methvl-imidazol_l-vn_imidazo"l J-alpvridind-vll-phenvll-B-^^^-trifluoro-ethylVurea)

515 15 200836725 Under the catalysis of copper, the coupling of 7-moly- glutinous rice and [1,2 - a] 0 to sigma can be coupled with 4-methyl-lH-imidazole ( WO 02085838). The product can then be iodinated and coupled in Suzuki reaction conditions as shown in General Formula B, Steps 2 and 3. The isomers can be separated by column chromatography. Example 417_

1-(3-Γ7-(3,5-dimethylin-1-yl-imidazo"1,2-al0-bite-3·篡]^ 策基卜3-(2,2,2- Ercha-Ethyl vein (1-i3-"7-n,5-Dimethvlpvrazol-l-vlVimidazo"l,2-alpvridin-^-vl]-phenvl I-3-(2,2,2-trifluoro-ethvlVurea&quot ;)

U

Under the catalysis of copper, 7-bromo-imidazo[l,2-a]pyridine and 3,5-dimethyl-15-[1,2,4]-triterpene (3,5-〇^1116{ 1171-[1,2,4]-11^2〇16) Coupling (\¥0 02085838). The product can then be iodinated and coupled in Suzuki reaction conditions as shown in General Formula B, Steps 2 and 3. f Example 418 1-(3_"7-(5-methylpyrazole-1·yl V imidazolium "l,2-a>pyridin-3-ylindole-stupid 516 200836725 kib 3-(2, 2,2-three gas-ethyl serving (l-{3-"7-(5-Methvl-Pvrazol-l-vn-imidaz〇ri, 2-alpvridin-3-v ll-phenvU-3-(2, 2,2-trifluoro-ethvlVurea)

Under the catalysis of copper, 7-bromo-imidazole [l,2-a]pyridine and 3-methyl-[1,2,4]·Sanjun(3-methyl-1;l,2,4]- Triazole) coupling (WO 02085838). The product can then be iodinated and coupled in Suzuki reaction conditions as shown in General Formula B, Steps 2 and 3. The isomers can be separated by column chromatography. Biological Assays In vitro testing of the physical properties of FGFR3 and PDGFR kinase activity 15 Enzymes (purchased from Upstate) were formulated in a lx enzyme assay buffer to a final concentration of 2x ( As described below). The enzyme was mixed with the test compound, the substance-labeled Flt3 receptor (biotin-DNEYFYV) (Cell Signalling Technology Inc.), and ATP. At room temperature, shaking at 900 rpm for 3 hours (FGFR3) or 2.5 hours 20 (PDGFR-beta) followed by 20 μl, 35 mM EDTA, pH 8 (FGFR3) 517 200836725 or 55 mM EDTA, pH 8 (PDGFR-beta) terminates the reaction. Add 20 μΐ of the 5 χ test mixture (50 mM HEPES pH 7.5, 0.1% BSA, 2 nM Eu_anti_pY (PY20) (PerkinElmer) 15 nM SA-XL665 (Cisbio) used in FGFR3, and 50 5 used by PDGFR-beta. mM HEPES, pH 7.5, 0·5 M KF, 0.1% BSA, 11.34 nM Eu-anti-pY (PT66) (PerkinElmer), 94 nM SA-XL665 (Cisbio)) to each test unit, sealed at room temperature The shake was shaken at 900 rpm for 1 hour. The shaker was then placed in a Packard Fusion instrument and read in TRF mode. 10 Enzyme 1 X buffer solution Concentration of Flt3 ATP concentration FGFR3 A 0.125 μΜ 8 μΜ PDGFR-beta B 0.15 μΜ 30 μΜ Enzyme buffer solution:

A: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.1% TritonX-100 i 15 B: 20 mM MOPS pH 7.0, 10 mM MnCl2, 0.01%

Triton X-100, 1 mM DTT, 0.1 mM [正] Sodium orthovanadate The compounds of the invention (except for Examples 75 and 192) have IC50 values of less than 10 μΜ or at concentrations of 10 μΜ. It has at least 20% inhibition of FGFR3 activity. In the FGFR3 test, the compounds of the invention preferably have an IC50 value of less than 1 μΜ. 518 200836725 In vitro assay for inhibition of VEGFR2 kinase activity in 50 mM HEPES, pH 7.5, 6 mM MnC12, 1 mM DTT, 0.01% Triton X-100, 5 μΜ ATP (2.8 Ci/mmol) buffer solution, In the presence of the compound, a ratio of 4:1 VEGFR2 enzyme (purchased from 5 Upstate) and 250 μL Poly(Glu, Tyr) (CisBio) were prepared for testing. After the reaction was carried out for 15 minutes, the reaction was stopped by adding an excess of acid. The reaction mixture is then transferred to a microporous MAPH filter which collects the peptide and allows the useless ATP to be washed away. After rinsing, scintillant was added and the number of activated scintillators was calculated using a Packard Topcount scintillation counter. Inhibitory in vitro assays for FGFR1, FGFR2, FGFR4·VEGFR1 and VEGFR3 kinases The inhibition of FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3 15 activity can be measured by Upstate Discovery Ltd. The enzyme is in an enzyme buffer solution (20 mM MOPS, pH 7.0, 1 mM EDTA, 0.1% B_mercaptoethanol, 〇·〇1% Brij-35, 5% C} glycerol, 1 mg/ml BSA) Formulated to a final concentration of lOx. The enzyme is then mixed with various receptors and 33P-ATP (~500 cpm/pmol) 20 in a buffer solution as shown in the table below. The reaction was started by adding Mg/ATP. The reaction was then allowed to proceed for 40 minutes at room temperature, and the reaction was stopped with a 5 μΐ, 3% phosphoric acid solution. The reaction mixture was taken 10 μl and placed in a filter A (filter mat A) or P30 filter, and washed 3 times with 75 mM phosphoric acid, once with methanol, and then dried for 25 to perform a scintillation counter calculation. 519 200836725 The concentrations of the recorded compounds tested and the relative control group inhibited the activity of all kinases. And determine the level of its inhibition and its ic5 〇 value. Enzyme buffered ATP concentration solution (μΜ) FGFR1 A 250 μΜ KKKSPGEYVNIEFG 200μΜ FGFR2 B 0.1 mg/ml poly(Glu, Tyr) 4:1 90μΜ FGFR4 C 0.1 mg/ml poly(Glu, Tyr) 4:1 155μΜ VEGFR1 A 250 μΜ KKKSPGEYVNIEFG 200μΜ VEGFR3 A 500μΜ GGEEEEYFELVKKKK 200μΜ Enzyme buffer solution A: 8 mM MOPS, pH 7.0, 0.2 mM 5 EDTA, 10 mM magnesium acetate buffer solution B: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnC12 , 10 mM magnesium acetate buffer solution C: 8 mM Mops, Η 7.0, 0.2 mM EDTA, 10 mM MnC12, 10 mM acid analyzer j 10

Cell-based pERK ELISA Method Multiple doses of LP-1 or JIM-1 multiple myeloma cells were seeded in serum-free medium at a dose of lulO6 cells/ml per well of 200 ul. HUVEC cells were seeded at 2·5 χ 105 cells/ml and recovered for 24 hours before being placed in serum-free medium. The cells were allowed to stand at 37 ° C for 16 hours, and a test compound was added 30 minutes after the start of the placement. The test compound was administered at a final concentration of 0.1% 520 200836725 DMSO. After 30 minutes of this, a mixture of FGF-1/Heparin (FGF-1 100 ng/ml final concentration of FGF_1 and 10 〇Ug/ml Heparin) or VEGF165 (100 ug/ml) was added to each well and repositioned. Put it for 5 minutes. The medium was removed and 50 ul of 5 ERK ELISA lysis buffer (R for pERK and D Systems DuoSet ELISA and Total ERK #DYC-1940E, DYC-1018E) was added. The ELISA medium and the standard were calculated according to the DuoSet protocols standard, and the amount of pERK relative to the total ERK was calculated from the standard curve. In particular, the ability of the compounds of the invention to combat the LP-1 cell line (DSMZno:: ACC41) of human multiple myeloma cells can be tested. In this test, many of the compounds of the invention have IC50 values of less than 20 μΜ, and certain compounds (such as Examples 2, 5, 6, 7, 8, 9, 10, 15, 16, 28, 29, 35, 36 , 39, 43, 45, 49, 51,56, 57, 58, 59, 62, 64, 65, 66, 67, 78, 79, 80, 81,82, 83, 94, 103, 104, 107, 108 , 109, 111, 113, 15 114, 115, and 123) have an IC50 value of less than 1 μΜ. HUVEC cell selectivity test HU HUVEC cells were assayed in 6 media and resuscitated for 24 hours at 1 〇 6 cells per medium. The assay was again placed in serum-free medium for 20 16 hours, followed by treatment with the test compound for 30 minutes in a final concentration of 0.1% DMSO. This was followed by mixing with FGF-1 (100 ng/ml) and adding Heparin (100 ug/ml) or VEGF165 (100 ng/ml) for 5 minutes. After the medium was removed, it was washed with ice-cold PBS and added to 100 ul of TG lysis buffer (20 mM Tris, 130 nM NaCl, 1% Triton-X-100, 10% 25 Glycerol, protease and phosphatase inhibitors, pH 7.5). 521 200836725 bacteriostatic. Samples containing equal amounts of protein were prepared along with LDS sample buffer and run on SDS PAGE followed by Western blotting to detect downstream VEGFR and FGFR pathway targets, including phosphorylation-FGFR3, phosphorylation- VEGFR2 and phosphorylated 5-ERK1/2. In vivo blood pressure test Take a number of animal samples and measure the effects of small molecule inhibitors on their blood pressure. It can be divided into two types: indirect and direct. The most common direct method is the cuff technique. The advantages of this method are non-invasive and can be applied to a larger number of experimental animals. However, this method can only measure blood pressure intermittently, and the animal to be tested must be limited in some way. live. Addition to animal restrictions may stress the animal, and the effect of the drug on blood pressure is not easy to see. Direct methods include the use of radio telemetry techniques or methods of connecting to an external debt tester using an indwelling catheter. This method requires a higher level of skill in the specialized field for the initial implantation procedure and is quite expensive. However, a key advantage of this method 20 is that blood pressure can be observed continuously without the need to limit the animal in some way. This method is referred to from Kurz (2005), Hypertension 45, 299-310. The above-described embodiments are merely examples for the convenience of the description, and the scope of the claims is intended to be limited to the above embodiments. 522 200836725 [Simple description of the diagram] None 5 [Description of main component symbols]

Claims (2)

200836725 X. Patent application scope: L—a compound of the formula (I): .R1 Xl, X2 and X3 are each independently selected from carbon or nitrogen, and at least one of X1 to X3 is nitrogen; X4 is CR3 or nitrogen; X5 is CR6, nitrogen or C=0; 10 Χι No more than three nitrogen atoms in X5; - a single bond or a double bond, at least one of the five-membered rings is bonded to a double bond; R3 is hydrogen, halogen, Ci-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, hydrazine: 3-6 cycloalkyl, C3-6 cycloalkenyl, cyano, _ (6-6 alkyl, 15 Ck alkoxy Or = 〇; A is an aromatic or non-aromatic carbocyclic or heterocyclic group, and the ring- and heterocyclic groups are optionally one or more (eg, 1, 2 or 3) Ra groups. Replace; R1 is - NHCONR4R5, -NHCOOR4, 20 -NH-CO-(CH2)n-NR4R5, -NH^(CH2)n-CONR4R5 524 200836725 5 10 15 Ο 20 -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n -CSOR4, nhso2r4, NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -N HCSSR4, -NHC(=NR4)NR5, NHC(=NR4)R5, -NH_C(=NH2)-NH-CO-R4, -NHCSOR4 Or -NHCOSR4; R4 and R5 are each independently hydrogen, Cw alkyl, C2_6 alkenyl, C2-6 fast radical, C3_8 alkyl, Cw lozenge, C burnt, ® C ι·6 alkyl, - ( CH2)n-NRxRy, -(CH2)s-COORz, -(CH2)n-0-(CH2)m-0H, -(CH2)n-aryl, -(CH2)n-0_ aryl, _( CH2)n-heterocyclyl or (CH2)n-0-heterocyclyl, wherein the Cl-6 alkyl group, c2_6 alkenyl group, C2_6 alkynyl group, Cl8 cycloalkyl group, C3·8 cycloalkenyl group, aryl group and hetero The cyclic group may be optionally substituted by one or more (eg, 1, 2 or 3) Ra groups; the Rx, Ry and Rz systems are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, c2.6 Alkynyl, Cl-6 alkanol, -C00Ci 6 alkyl, hydroxyoxy, Ci 6 alkoxy, dentate cK6 alkyl, _C0-(CH2)n_Ci 6 alkoxy, Ci 6 alkylamino, C3-8 cycloalkyl Or c3-8 cycloalkenyl; R and R6 are each independently halogen, hydrogen, Ci6 alkyl, ei-6 alkane Oxy, c2-6, c2 6 alkynyl, _CsN, cycloalkyl, cycloalkenyl, -nhs〇2R'_CH, 〇RW, aryl or heterocyclic, wherein the Ci 6 alkyl^2· The 6 alkenyl group, the Cw alkynyl group, the aryl group and the heterocyclic group may be optionally substituted by one or more Rwb groups, and R 2 and R 6 are not hydrogen at the same time; R is hydrogen or a c1-6 substituent; _ R is Halogen, Cl-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3-8 % alkyl, C3 8 cycloalkenyl, 〇RX, ((3)2)n_〇_Ci 6 alkyl, 525 200836725 - 0_(CH2)n-0Rx, halogen Ci-6 alkyl, halogen Ci-6 alkoxy, Ci-6 ani alcohol, =0, =S, nitro, Si(Rx)4, -(CH2)s- CN, -S-Rx, -SO-Rx, -S02-Rx, _CORx, _(CRxRy)s_COORz, -(CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, (CH2)s-NRxS02-Ry, 5 -(CH2)s-NH-S02-NRxRy, _OCONRxRy, -(CH2)s-NRxC02Ry, -〇-(CH2)s-CRxRy-(CH2)t-ORz or- (CH2)s-S02NRxRy; Rb is an Ra or a 1-Y-carbocyclyl or a -Z-heterocyclyl group, wherein the carbocyclic group and the heterocyclic group are optionally one or more (eg, 1) , 2 or 3) Ra (') base substitution; 10 Y and Z systems are each independently a bond, -C0-(CH2)s-, -coo-, -(CH2)n-, -NRx-(CH2)n-, -(CH2)n-NRx-, -CONR,, -NRxC0-, -S02NRx·, -NRxS02_, -NRxCONRy-, -NRxCSNRy--〇-(CH2)s_, -( CH2)s-〇-, _S0_ or -(CH2)sS〇2_; m and n are each independently an integer from 1 to 4; 15 s and t are each independently an integer from 0 to 4; or a pharmacy An acceptable salt thereof, a solvate thereof or a derivative thereof, but the compound of the formula (I) is not: { } 3-(3-acetamidophenyl)-6-(4-mercaptobenzene) 3-(3-acetamidophenyl)-6-(4-methylphenyl) 20 pyrazolo(l,5a)pyrimidine); 3-(3-acetamidophenyl)-6-( 4-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo(l,5a) pyrimidine); N-(4-{6-[ 3-(4-Fluorophenyl)-lH-4-nbazolyl]imidazo[l,2_a]-吼25 pyridine-3-yl}phenyl)decylsulfonamide 526 200836725 (N-(4- {6-[3-(4-fluorophenyl)-lH-4-pyrazolyl]imidazo[l ,2-a] -pyridin-3-yl}phenyl)methane sulfonamide); N-(4-{6-[3- (4-fluorophenyl)-1-trityl-1H_4-oxazolyl]-imidazo[l,2-a]-acridin-3-yl}phenyl)methylsulfonate Amine 5 (N-(4-{6-[3_(4-fluorophenyl)-l-trityl-lH_4-pyrazolyl]_imida zo[l,2-a]pyridin-3-yl}phenyl)methane sulfonamide); N- Cyclohexyl-N'-{2-fluoro-4-[6-(l-triphenylmethyl-1H-4-oxazolyl)imidazo[l,2-a]pyridin-3-yl]phenyl}urea N-cyclohexyl-N5- {2-fluoro-4-[6-(l-trityl-lH-4-pyrazolyl)i I ) · 10 midazo[l,2-a]pyridin-3-yl] phenyl} urea) ; N-{2-fluoro-4-[6-(l-trityl-1H-4-pyrazolyl)imidazo[l,2-a] acridine-3-yl]phenyl}·Ν '_Isopropylurea (Ν-{2-fluoro-4-[6-(l-trityl-lH-4-pyrazolyl)imidazo[l,2-a]py ridine-3-yl] phenyl}-N5- Isopropyl urea); 15 N_cyclohexyl-N'-{2-fluoro-4-[6_(lH_4•pyrazolyl)imidazo[l,2-a] 0 than sigma-3-yl]phenyl} (N-cyclohexyl-N'-{2-fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l (,2-a]pyridin-3-yl] phenyl} urea); N-12-fluorine -4·[6·(1Η·4·oxazolyl)imidazo[l,2-a;hb pyridine-3-yl] 20 phenylindole--isopropylurea (N-12-fluoro-4 -[6-(lH-4-pyrazolyl)imidazo[l,2-a]pyridin-3-yl] phenyl)-N5-isopropylurea); or Nl-{2-fluoro-4-[6_(1Η-4- Pyrazolyl)imidazole And [l,2-a]pyridine-3-yl]phenyl phenyl 4-fluorobenzamide 25 (Nl-{2-fluoro-4-[6-(lH-4-pyrazolyl)imidazo[l52-a ]pyridin-3 527 200836725 -yl]phenyl}-4_fiu〇r〇benzamide) 〇2· The compound of claim 1, wherein χι, X2 and X3 are each independently selected from carbon or Nitrogen, at least one of Χι to X3 is nitrogen; 5 f) 10 15 u 20 X4 is CR3 or nitrogen; X5 is CH, nitrogen or C=〇; Xi to xs is nitrogen no more than three ; is a single bond or a double bond; R3 is hydrogen or = 〇; , -NHCOOR4 • NH-CO-(CH2)n-COOR4 A is an aromatic or non-aromatic carbocyclic or heterocyclic group , the carbocyclic and heterocyclic groups may be optionally substituted by one or more (eg, fluorene, 2 or 3) groups; R is -nhconW -NH-CO_(CH2)n-NR4R5, -NHS02R4, or An NHCSNR4R5; R4 and R5 are each independently hydrogen, Ci 6 alkyl, &amp; alkanol, -(CH2)n_NRxRy, -(CH2)n-aryl or _6 alkyl; ...Rx, RyA Rz are each independently Is gas, ^6 alkyl, alkane, decyloxy, CV6 silk, _ Ci ritual or | (ch^-Ci-6 gas-burning base; R is sulfhydryl or The hetero group or the heterocyclic group may be optionally substituted by one or more Rb groups; the Ra system is a functional group, a Cl-6 alkyl group, a ~alkenyl group, a C2-6 alkynyl group. 3-8 cycloalkyl, c3_8 ring dilute, zan, _〇_(CH2)n 〇RX, from Ci 6 alkyl, functional Cl6 alkoxy, Cl_6 alcohol, =〇, =s, bowl base, _ (CH2)S_CN, 528 200836725 -S-Rx, -SO_Rx, -S02_Rx, -CORx, _(CRxRy)s-COORz, -(CH2)s-CONRxRy, _(CH2)s-NRxRy, -(CH2)s -NRxCORy, -(CH2)s-NRxS02-Ry, -〇c〇NRxRy, -(CH2)s-NRxC02Ry, -0-(CH2)s-CRxRy-(CH2)t_〇Rz or .(CH2)s -S02NRxRy; 5 R is a mono-Y-aryl or -Z-heterocyclyl wherein the aryl and heterocyclyl are optionally substituted by one or more (eg, 1, 2 or 3) Ra groups However, when the R2 is a non-hydrogen functional group, χ5 is CH or C=0; Y and Z are each independently a bond, c〇, -(CH2)n-, f, _NRX-(CH2) N_, -〇_ or _〇_(ch2)s-; 10 melon and n series are each an integer from i to 4; s and t are each independently an integer from one to four; aryl is a carbon Ring; and hetero-»» is a '-heterocycle. 3. The compound of claim 1 or 2, wherein 15 A is a phenyl or pyridyl group which may be optionally substituted by one or more Ra groups. 4. A compound as claimed in any one of the preceding claims, wherein hydrazine is a phenyl or pyridine substituted at the 5-position with an R1 group and optionally substituted at the 3-position with a Ra group. base. 2. The compound of claim 4, wherein A is a non-substituted phenyl group. 6. A compound as claimed in any one of the preceding claims, wherein R1 is -NHCONR4R5 or -NHCSNR4R5. 7 · A compound as described in claim 6, wherein R1 529 200836725 is -NHCONR4R5 〇 5 10 15 20 8. The compound of claim 7, wherein Ri is -NHC〇NHCH2CF3 or -NHCONHCH2CH3. 9 · The compound described in claim 8 of the patent scope, wherein ri is _nhconhch2cf3. A compound according to any one of the preceding claims, wherein R2 is an aryl or heterocyclic group which may be optionally substituted by one or more groups. A compound according to any one of the preceding claims, wherein R2 is an aryl group which may be optionally substituted by a halogen, _z•heterocyclyl or —(CRRy)s-C00RZ Wherein the heterocyclic group is optionally substituted by a Cb6 alkyl group or _(CRxRy)s_c〇〇RZ. 12. The compound of claim 5, wherein R2 is a phenyl group optionally substituted with an Rb group. 13. The compound of claim 12, wherein R2 is a phenyl group which is optionally substituted by a fluorine atom. 14. The compound of claim 13, wherein r2 is 4-carbon benzene. The reticulated substance of any one of clauses 1 to 1 wherein R is a heterocyclic group which is optionally substituted by a _z-heterocyclic group or —(CH2) Substituting the VNRXRy group. I6. The compound of any one of clauses (7), wherein R is a heterocyclic group, and the heterocyclic group is optionally substituted by a 530 200836725. The compound of claim 16, wherein R 2 is a heterocyclic group, which may be optionally substituted by a =0, = s, halogen, Cu, halogen, Cu, or c3. 8 cycloalkyl, mono(CH2)s-NRxRy, -〇Rx, (CK^VO-Cu alkyl, -CORx, -(CRxRy)s-COORz, -S-Rx, 5 -S02-Rx, -( CH2) s-NRxRy, _(CH2)s-S02NRxRy or a Cu-alcoholyl group. 18. The compound of claim 17, wherein R2 is a 5-membered heterocyclic group. The compound of claim 18, wherein the R2 10 system is oxazole, oxadiazole, triazole, tetrazole, thiadiazole or °恶σ塞二口坐(oxathiadiaz Ole) 〇20. The compound of claim 19, wherein R2 is a 15 oxazole optionally substituted by one or more methyl, ethyl or -S-methyl groups. ), oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole 〇21. For example, the scope of patent application is 20 A compound according to the invention, wherein R2 is an oxadiazole, tetrazole*α stoppered dioxime (optionally substituted by monomethyl, ethyl or -S-methyl) The compound of any one of claims 1 to 10, wherein R 2 is a pyridyl 〇 23 selectively substituted by an NH 2 group. Compounds of any of the ranges, 531 200836725 wherein y and the oxime are each independently a bond, CO, -CH2_, -(CH2)2, -(CH2)3 or -0_. The compound according to Item 23, wherein the Z system is a bond or -CH2-. 5 25 · Any of the above patent applications The compound of item, wherein Xi to X5 are shown below the ring system having the structure: The compound of claim 25, wherein Xi to X5 have the ring structure shown below: 27. The compound of claim 26, wherein Xi to X5 have the ring structure shown below: 28. A compound as claimed in any one of the preceding claims, wherein the compound is selected from the group consisting of: Examples 2-17, 19, 24, 26-62, 64-67, 1075, 77-97, 100-109 , 111-115, 117, 119-131, 133-156, 158-166, and 168-418. 29. The compound of claim 28, wherein the compound of formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2 -a] -3--3-yl]-phenyl}-3-(2,2,2-dioxaethyl)-gland 15 (1- {3-[7_(4-fluoro-phenyl)-imidazo[l , 2-a]pyridin-3-yl]-phen 533 200836725 yl}-3-(2,2,2_trifluoro-ethyl)-urea) or a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof . 30. The compound of claim 29, wherein the compound of formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[5,2 -a]Acridine-3-yl]phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (l-{3-[7-(4-fluoro-phenyl)-imidazo [l52-a]pyridin-3-yl]-phen yl}-3-(2,2,2_trifluoro-ethyl)-urea hydrochloride) 〇31. A compound of the formula (Id): 10 wherein Ra, R2, R5 and q are as defined in claim 1 of the patent application, and the J and L systems are each independently selected from the group consisting of carbon or nitrogen. A compound as claimed in any one of the preceding claims, or a salt thereof, a tautomer, an N-oxide or a solvate. A compound or a salt or solvate thereof as described in any one of claims 1 to 31. 34. A method of preparing a compound as shown in formula (I) in any one of the above claims, comprising the steps of: (i) in a carbonyl diimidazole (CDI), a 20 A compound of the formula (XX) or (XXI): 534 200836725 Or a protected form thereof is reacted with an appropriately substituted isocyanate or an appropriately substituted amine; or (ii) a compound of the formula (XX) or (XXI) : Or a protected form thereof is reacted with an appropriately substituted acetic acid or a ketone; or (iii) a compound of the formula (XX) or (XXI) is H〇N-A 【2 \ (XXI), X4n (protected form), reacting with an appropriately substituted formic acid or a reactive derivative; or (iv) reacting a compound of the formula (V) with a compound of the formula (VI): 535 200836725 R1 (V) and (VI) and removing any protecting groups present after the reaction; and selectively converting a compound of the formula (I) to another compound represented by the formula (I). 35. A pharmaceutical composition comprising a compound of formula (I) as in any one of claims 1 to 33 of the patent application. 36. Use of a compound of formula (II) for the manufacture of a medicament for the treatment of fibroblast growth factor 10 receptors (FGFR) enzymes: (Π) wherein Xi-X5 and A are as defined in the compound of formula (I): 15 u is an integer from 0 to 2; Rla is -NHCONR4R5, -NHC00R4, 536 200836725 -NH-CO- (CH2)n-NR4R5, -NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -nhso2r4, -NHS02SR4, -NHS02NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -N 5 HCSSR4, -NR4R5, -C(=NR4)NR5, halogen, Cu alkyl, aryl, -CO-aryl, heterocyclic, -CO-heterocyclyl And — — — — — — — — — — — — — — — — — — — — Ra-substituent, which is as defined in the compound of formula (I); 10 R4 and R5 are as defined in the compound of formula (I), but when one of R4 and R5 is hydrogen The other is not a functional group of an -aryl or -heterocyclic group; R2 is as defined in the compound of the formula (I). 37. The use of claim 36, wherein the Rule 1 &amp; 15 is: a heterocyclic group optionally substituted with one or more Ra selected from the group consisting of: =S; -COOR4; -CO-heterocyclic group; -(CH2)S-CN; -(CH2)n_NR4COR5, a CONR4R5 or -NR4R5. 38. The use of claim 36 or 37, wherein u is 0 or 1. The use of any one of claims 36 to 38, wherein A is a phenyl group optionally substituted with one or more Ra selected from a Cle6 alkyl group. 40. The use of any one of claims 36 to 39, wherein A is pyridyl 537 200836725 (pyddyl), pyrazolyl, optionally substituted with one or more Ra Or an indazolyl or indazolyl, the Ra system is selected from the group consisting of: the use of any one of claims 36 to 40, wherein the use of any one of claims 36 to 40, wherein The compound represented by the formula (II) is a compound selected from the group consisting of: Examples 1, 18, 20-23, 25, 63, 68-69, 70-74, 76, 98·99, 110, 116, 118, 132, 157, 167, and 235. A compound according to any one of claims 3 to 33 for use in the treatment of a disease. A compound according to any one of claims 3 to 33 for use in the prevention or treatment of a disease or infection caused by a fibroblast growth factor receptor enzyme. 44. A compound according to any one of claims 1 to 33, which is for use in the production of a medicament for preventing or treating a disease or infection caused by a fibroblast growth factor receptor enzyme. . A compound according to any one of claims 1 to 33 for use in the manufacture of a medicament for the prevention or treatment of a disease or infection.斤4。 46. The use of any of the s systems of any one of claims 1 to 33 for the production of a medicament for the prevention or treatment of cancer. And a method for treating or preventing a disease or infection associated with fibroblast growth factor, the method comprising administering a receptor--such as: : in the range of the third item, as shown in the chemical formula (1) :: a method of treating or preventing a disease according to the method of treatment or prevention of 538 200836725, which comprises administering a receptor as in the chemical formula of any one of claims 1 to 33 ( The compound shown in I). A method for treating or preventing cancer, which comprises administering a compound as shown in the chemical formula (I) 5 in any one of claims 1 to 33 of the patent application. η 0&gt; 539 200836725 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Among them, A, &amp;, R2, XN5 are as defined in the specification 5