TWI415609B - 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

New compound

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 the treatment of a disease (e.g., cancer).

In various patents: U.S. Patent No. 7,074,801 (Eisai), U.S. Patent No. 2002/0041880 (Merck), WO Patent No. 98/54093 (Merck), 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 (Chugai), WO Patent No. 2006/094235 (Sirtris Pharmaceuticals), WO Patent No. 2006/034402 (Synta Pharmaceuticals), WO Patent No. 01/18000 (Merck), US Patent No. 5,990,146 (Warner Lambert) and WO Patent No. 00/12089 (Merck) disclose a series of heterocyclic derivatives.

A first aspect of the invention provides a compound of formula (I):

Wherein X ₁ , X ₂ and X ₃ are each independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ being nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is CR ⁶ , nitrogen Or C=O; no more than three are provided as nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond, at least one of the five-membered rings is bonded to a double bond; R ³ is hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, cyano, halo C _1-6 alkyl, halo C _1-6 alkoxy or =O A is an aromatic or non-aromatic carbocyclic or heterocyclic group, and the carbocyclic and heterocyclic groups are optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO-( CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , - NHCSSR ⁴ , -NHC(=NR ⁴ )NR ⁵ , NHC(=NR ⁴ )R ⁵ , -NH-C(=NH ₂ )-NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ; R ⁴ and R ⁵ is each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkane Alcohol, halogen C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _s -COOR ^z , -(CH ₂ ) _n -O-(CH ₂ ) _m -OH, - (CH _{2) n} - aryl, - (CH _{2) n} -O- aryl, - (CH _{2) n} - miscellaneous Or a group - (CH _{2) n} -O- heterocyclyl group, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 The cycloalkenyl, aryl and heterocyclic groups may be optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; the R ^x , R ^y and R ^z systems are each independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, -COOC _1-6 alkyl, hydroxyoxy, C _1-6 alkoxy, halogen C _1-6 Alkyl, -CO-(CH ₂ ) _n -C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or C _3-8 cycloalkenyl; each of R ² and R ⁶ Independently halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _3-8 cycloalkyl, C _{3 -8} cycloalkenyl, -NHSO ₂ R ^w , -CH=N-OR ^w , aryl or heterocyclic group, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, The aryl and heterocyclic groups may be optionally substituted by one or more R ^b groups, and R ² and R ^{6 are} not simultaneously hydrogen; R ^w is hydrogen or C _1-6 alkyl; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -(CH ₂ ) _n -OC _{1- 6} alkyl, -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro, Si(R ^x ) ₄ , -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , - COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO _{2 ^{R y, -O- (CH 2)}} s -CR x R y - (CH 2) t -OR z , or _{- (CH 2) s -SO 2} NR x R y; R b or R ^a is a line a - Y-carbocyclyl or -Z-heterocyclyl, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; each of the Y and Z systems Independently a bond, -CO-(CH ₂ ) _s -, -COO-, -(CH ₂ ) _n -, -NR ^x -(CH ₂ ) _n -, -(CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y --O-(CH ₂ ) _s -, -( CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; m and n are each independently an integer from 1 to 4; s and t are each independently a 0 to An integer of 4; or a pharmaceutically acceptable salt, solvate or derivative thereof, but the compound of formula (I) is not: 3-(3- 3-(3-acetamidophenyl)-6-(4-methylphenyl)pyrazolo(1,5a)pyrimidine); -(3-acetamidobenzene)-6-(4-methoxyphenyl)pyrazole (1,5a)pyrimidine (3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo (1, 5a) pyrimidine); N-(4-{6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl}phenyl Methanesulfonamide (N-(4-{6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl}phenyl)methane sulfonamide) ; N-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-imidazo[1,2-a]-pyridine-3- N-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-imidazo[1,2-a]pyridin-3 -yl}phenyl)methane sulfon amide); N-cyclohexyl-N'-{2-fluoro-4-[6-(1-tritylmethyl-1H-4-pyrazolyl)imidazo[1,2 -a]pyridin-3-yl]phenyl}urea (N-cyclohexyl-N'-{2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo[1,2-a] Pyridin-3-yl]phenyl}urea); N-{2-fluoro-4-[6-(1-tritylmethyl-1H-4-pyrazolyl)imidazo[1,2-a]pyridine- 3-yl]phenyl}-N'-isopropylurea (N-{2-fluoro-4-[6-(1-trityl-1H-4-pyrazol) Yl)imidazo[1,2-a]pyridine-3-yl]phenyl}-N'-isopropyl urea); N-cyclohexyl-N'-{2-fluoro-4-[6-(1H-4-pyridyl) N-cyclohexyl-N'-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1] ,2-a]pyridin-3-yl]phenyl}urea);N-12-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl Phenyl}-N'-isopropylurea (N-12-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl)-N'-isopropylurea); or N1-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}-4-fluorobenzoate Indoleamine (N1-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}-4-fluorobenzamide).

Detailed invention

A first aspect of the invention provides a compound of formula (I):

Wherein X ₁ , X ₂ and X ₃ are each independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ being nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is CR ⁶ , Nitrogen or C=O; no more than three of the nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond, at least one of the five-membered rings is bonded to a double bond; R ³ is hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, cyano, halo C _1-6 alkyl, halo C _1-6 alkoxy or =O A is an aromatic or non-aromatic carbocyclic or heterocyclic group, and the carbocyclic and heterocyclic groups are optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO-( CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , - NHCSSR ⁴ , -NHC(=NR ⁴ )NR ⁵ , NHC(=NR ⁴ )R ⁵ , -NH-C(=NH ₂ )-NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ; R ⁴ and R ⁵ is each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkane Alcohol, halogen C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _s -COOR ^z , -(CH ₂ ) _n -O-(CH ₂ ) _m -OH, - (CH _{2) n} - aryl, - (CH _{2) n} -O- aryl, - (CH _{2) n} - miscellaneous Or a group - (CH _{2) n} -O- heterocyclyl group, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 The cycloalkenyl, aryl and heterocyclic groups may be optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; the R ^x , R ^y and R ^z systems are each independently hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, -COOC _1-6 alkyl, hydroxyoxy, C _1-6 alkoxy, halogen C _1-6 Alkyl, -CO-(CH ₂ ) _n -C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or C _3-8 cycloalkenyl; each of R ² and R ⁶ Independently halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _3-8 cycloalkyl, C _{3 -8} cycloalkenyl, -NHSO ₂ R ^w , -CH=N-OR ^w , aryl or heterocyclic group, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, The aryl and heterocyclic groups may be optionally substituted by one or more R ^b groups, and R ² and R ^{6 are} not simultaneously hydrogen; R ^w is hydrogen or C _1-6 alkyl; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-s cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -(CH ₂ ) _n -OC _{1- 6} alkyl, -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro, Si(R ^x ) ₄ , -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , - COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO _{2 ^{R y, -O- (CH 2)}} s -CR x R y - (CH 2) t -OR z , or _{- (CH 2) s -SO 2} NR x R y; R b or R ^a is a line a - Y-carbocyclyl or -Z-heterocyclyl, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; each of the Y and Z systems Independently a bond, -CO-(CH ₂ ) _s -, -COO-, -(CH ₂ ) _n -, -NR ^x -(CH ₂ ) _n -, -(CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y --O-(CH ₂ ) _s -, -( CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; m and n are each independently an integer from 1 to 4; s and t are each independently a 0 to An integer of 4; or a pharmaceutically acceptable salt, solvate or derivative thereof, but the compound of formula (I) is not: 3-(3- Nonylphenyl)-6-(4-methylphenyl)pyrazole (1,5a)pyrimidine; 3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazole ( 1,5a)pyrimidine; N-(4-{6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl} Phenyl)methylsulfonamide; N-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-imidazo[1,2 -a]-pyridin-3-yl}phenyl)methylsulfonamide; N-cyclohexyl-N'-{2-fluoro-4-[6-(1-tritylmethyl-1H-4-pyridyl) Azyl)imidazo[1,2-a]pyridin-3-yl]phenyl}urea; N-{2-fluoro-4-[6-(1-tritylmethyl-1H-4-pyrazolyl) Imidazo[1,2-a]pyridin-3-yl]phenyl}-N'-isopropylurea;N-cyclohexyl-N'-{2-fluoro-4-[6-(1H-4)-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}urea; N-12-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1, 2-a]pyridin-3-yl]phenyl}-N'-isopropylurea; or N1-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2 -a]pyridin-3-yl]phenyl}-4-fluorobenzamide.

In one embodiment, a compound of formula (I) is provided:

Wherein X ₁ , X ₂ and X ₃ are each independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ being nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is CR ⁶ , Nitrogen or C=O; no more than three of the nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond, such that when X ₅ is C=O, X ₄ and X ₅ are bonded via a single bond such that at least one of the five-membered rings is bonded to a double bond ; R ³ is hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 a cycloalkenyl group, a cyano group, a halogen C _1-6 alkyl group, a halogen C _1-6 alkoxy group or a =0; A is an aromatic or non-aromatic carbocyclic or heterocyclic group, the carbocyclic ring and hetero The ring group is optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , -NHCSSR ⁴ , -NHC(=NR ⁴ )NR ⁵ , NHC(=NR ⁴ )R ⁵ , -NH -C(=NH ₂ )-NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkanol, halogen C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -( CH ₂ ) _s -COOR ^z , -(CH ₂ ) _n -O-(CH _{2 m} -OH, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -O-aryl, -(CH ₂ ) _n -heterocyclyl or -(CH ₂ ) _n -O-heterocyclyl Wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, aryl group and heterocyclic group are optionally Substituted by one or more (eg, 1, 2 or 3) R ^a groups; R ^x , R ^y and R ^z are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _1-6 alkanol, -COOC _1-6 alkyl, hydroxyoxy, C _1-6 alkoxy, halo C _1-6 alkyl, -CO-(CH ₂ ) _n -C _{1 -6} alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or C _3-8 cycloalkenyl; R ² and R ⁶ are each independently halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -NHSO ₂ R ^w , -CH =N-OR ^w , aryl or heterocyclic group, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, aryl group and heterocyclic group are optionally one or more R ^b is substituted, and R ² and R ^{6 are} not hydrogen at the same time; R ^w is hydrogen or C _1-6 alkyl; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -(CH ₂ ) _n -OC _1-6 alkyl, -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro , Si(R ^x ) ₄ , -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^{_{y - (CH 2) t -OR}} z , or _{- (CH 2) s -SO 2} NR x R y; R b is a line or a R ^a -Y- carbocyclic group or a heterocyclic group -Z-, wherein the The carbocyclic group and the heterocyclic group may be optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; the Y and Z systems are each independently a bond, -CO-(CH ₂ ) _s - , -COO-, -(CH ₂ ) _n -, -NR ^x -(CH ₂ ) _n -, -(CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y --O-(CH ₂ ) _s -, -(CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; m and n are each independently an integer from 1 to 4; s and t are each independently an integer from 0 to 4; the aryl is a carbocyclic ring; base Is a heterocyclic ring; or a pharmaceutically acceptable salt, solvate or derivative thereof, but must have a condition that the compound of formula (I) is not: 3-(3-acetamidobenzene - 6-(4-methylphenyl)pyrazole (1,5a) and pyrimidine; 3-(3-acetamidophenyl)-6-(4-methoxyphenyl)pyrazole (1,5a) And pyrimidine; N-(4-{6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl}phenyl) Sulfonamide; N-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-imidazo[1,2-a]- Pyridin-3-yl}phenyl)methylsulfonamide; N-cyclohexyl-N'-{2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazole And [1,2-a]pyridin-3-yl]phenyl}urea; N-{2-fluoro-4-[6-(1-tritylmethyl-1H-4-pyrazolyl)imidazo[ 1,2-a]pyridin-3-yl]phenyl}-N'-isopropylurea;N-cyclohexyl-N'-{2-fluoro-4-[6-(1H-4-pyrazolyl)Imidazo[1,2-a]pyridin-3-yl]phenyl}urea; N-12-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a] Pyridin-3-yl]phenyl}-N'-isopropylurea; or N1-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridine -3-yl]phenyl}-4-fluorobenzamide.

In one embodiment, a compound of formula (I) is provided:

Wherein X ₁ , X ₂ and X ₃ are each independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ being nitrogen; X ₄ is CR ³ or nitrogen; and X ₅ is CR ⁶ , nitrogen or C=O; no more than three of the nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond; R ³ is hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{3 6} cycloalkyl, C _3-6 cycloalkenyl, cyano, halo C _1-6 alkyl, halo C _1-6 alkoxy or =0; A is an aromatic or non-aromatic carbocyclic ring or a heterocyclic group which is optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , - NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , -NHCSSR ⁴ , -NHC(=NR ⁴ )NR ⁵ , NHC(=NR ⁴ )R ⁵ , -NH-C(=NH ₂ ) -NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkanol, halogen C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _s - COOR ^z , -(CH ₂ ) _n -O-(CH ₂ ) _m -OH, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -O-aryl, -(CH ₂ ) _n - cycloalkyl group or a - (CH _{2) n} -O- heterocyclyl group, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Group, C _3-8 cycloalkyl, C _3-8 cycloalkenyl group, aryl group and heterocyclic group optionally substituted with one or more (e.g., 1, 2 or 3) R ^a substituents; R ^x, R ^y and R ^z are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, -COOC _1-6 alkyl, hydroxyl , C _1-6 alkoxy, halo C _1-6 alkyl, -CO-(CH ₂ ) _n -C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or C _{3-8cycloalkenyl} ; R ² and R ⁶ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _{3 - a} cycloalkenyl, aryl or heterocyclic group, wherein the aryl and heterocyclic groups are optionally substituted by one or more R ^b groups, and R ⁶ is a heterocyclic group and the heterocyclic group is not pyrazole Pyrazolyl; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O-(CH ₂ ) _n -OR ^x , halo C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro, -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^y -(CH ₂ ) _t - OR ^z or -(CH ₂ ) _s -SO ₂ NR ^x R ^y ; R ^b is a R ^a or a -Y-aryl or a -Z-heterocyclic group, wherein the aryl group and the heterocyclic group are selectively The ground is substituted with one or more (eg, 1, 2 or 3) R ^a groups; but when the R ² is a non-hydrogen functional group, X ₅ is CH or C=O, and when R ² is hydrogen When R ⁶ is a non-hydrogen functional group; Y and Z are each independently a bond, -CO-(CH ₂ ) _s -, -COO-, -(CH ₂ ) _n -, -NR ^x -( CH ₂ ) _n -, -(CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, - NR ^x CSNR ^y --O-(CH ₂ ) _s -, -(CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; m and n are each independently An integer from 1 to 4; s and t are each independently an integer from 0 to 4; the aryl is a carbocyclic ring; and the heterocyclic group is a heterocyclic ring; or a pharmaceutically acceptable salt, solvent a compound or a derivative thereof, but the compound of the formula (I) is not 3-(3-acetamidophenyl)-6-(4-methylphenyl)pyrazole (1,5A) and pyrimidine or 3-( 3-ethylaminophenyl)-6-(4-methoxy Benzene pyrazole (1,5A) and pyrimidine.

In one embodiment, a compound of formula (I) is provided, wherein: X ₁ , X ₂ and X ₃ are each independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ Is nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is CH, nitrogen or C=O; and no more than three are nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond; R ³ is hydrogen or =0; A is an aromatic or non-aromatic carbocyclic or heterocyclic group, and the carbocyclic and heterocyclic groups are optionally Or more (eg, 1, 2 or 3) R ^a group substitutions; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH- CO-(CH ₂ ) _n -COOR ⁴ , -NHSO ₂ R ⁴ , or -NHCSNR ⁴ R ⁵ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkanol, - (CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _n -aryl or halogen C _1-6 alkyl; R ^x , R ^y and R ^z are each independently hydrogen, C _1-6 alkyl, C _1-6 alkanol, hydroxyl, C _1-6 alkoxy, halo C _1-6 alkyl or -CO-(CH ₂ ) _n -C _1-6 alkoxy; R ² is a aryl Or a heterocyclic group, the aryl or heterocyclic group may be optionally substituted by one or more R ^b groups; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2− 6} alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkane Oxy, C _1-6 alkanol, =O, =S, nitro, -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^y -(CH ₂ ) _t -OR ^z or -(CH ₂ ) _s -SO ₂ NR ^x R ^y ; R ^b is one a -Y-aryl or -Z-heterocyclic group, wherein the aryl and heterocyclic group are optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; but when the R ² is When it is a functional group other than hydrogen, X ₅ is CH or C=O; Y and Z are each independently a bond, CO, -(CH ₂ ) _n -, -NR ^x -(CH ₂ ) _n -, - O- or -O-(CH ₂ ) _s -; m and n are each independently an integer from 1 to 4; s and t are each independently an integer from 0 to 4; the aryl is a carbocyclic ring; The heterocyclic group is a heterocyclic ring.

Herein, the term "C _1-6 alkyl" as a part of a functional group or a functional group means a saturated linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.

Here, the term "C _1-6 alkoxy" means an -OC _1-6 alkyl group, wherein the C _1-6 alkyl group is as defined above. Examples of the "C _1-6 alkoxy group" include methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy and the like.

Herein, the term "C _1-6 alkanol" means that a C _1-6 alkyl group is substituted by one or more hydroxyl groups, and related examples include: hydroxymethyl, hydroxyethyl, hydroxypropyl and Similar.

Here, the term "C _3-8 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.

Here, the term "C _3-6 cycloalkyl" means a saturated monocyclic compound having 3 to 6 carbon atoms. Related examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Here, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

Here, the term "halogen C _1-6 alkyl" means a C _1-6 alkyl group as described above wherein at least one hydrogen atom is replaced by a halogen. Related examples include: fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

Herein, "halo C _1-6 alkoxy" shall mean as the above-described C _1-6 alkoxy group wherein at least one hydrogen atom is substituted with a halogen. Related examples include: difluoromethoxy or trifluoromethoxy and the like.

Unless otherwise specified, the above-mentioned "carbocyclic" and "heterocyclic" groups contain both aromatic and non-aromatic rings. Thus, for example, "carbocyclic and heterocyclic groups" are meant to include aromatic, non-aromatic, unsaturated, partially saturated, and saturated carbocyclic and heterocyclic ring systems. In general, such groups may be monocyclic or bicyclic or include, 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, generally a group containing 3 to 7 rings, and preferably a group containing 5 or 6 rings. Examples of bicyclic groups include groups containing 8, 9, 10, 11 and 12 rings, typically groups containing from 9 to 10 rings. Unless otherwise specified, the carbocyclic ring and the heterocyclic group referred to herein may have neither a carbocyclic ring nor a heterocyclic ring substituted or one or more, such as a molecular fragment, a molecular scaffold, or The above functional groups are substituted. Preferably, the "carbocyclic" and "heterocyclic" groups include carbocycles which are optionally substituted by one or more (eg, 1, 2 or 3) groups of R ^a or R ^b 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, "fang The term "base" refers to a carbocyclic ring having aromatic character. Further, the terms "aryl" and "heteroaryl" include a ring system of a polycyclic ring (e.g., a bicyclic ring) in which one or more rings are non-aromatic rings and at least one ring is an aromatic ring. In such a polycyclic ring system, the group is attached to an aromatic ring or a non-aromatic ring.

Here, the term "non-aromatic group" includes an unsaturated ring system having no aromatic character, a partially saturated, and a saturated carbocyclic ring and a heterocyclic ring system. Herein, the terms "unsaturated" and "partially saturated" mean that a certain atom in a ring structure shares more than one covalent bond with other atoms, that is, contains at least one multiple bond (eg, a C=C, Ring of C≡C or N=C bond). The term "saturated" means that there are no multiple bonds between atoms in a ring structure. Saturated carbocyclic groups include cycloalkyl groups, which are defined below. Partially saturated carbocyclic groups include cycloalkenyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, which are as defined below. Saturated heterocyclic groups include: piperidine, morpholine, thiomorpholine. Partially saturated heterocyclic groups include: pyrazoline, for example: 2-pyrazoline and 3-pyrazoline.

Examples of heteroaryl groups include monocyclic or bicyclic groups having five to twelve rings, more preferably five to ten members. For example, the heteroaryl group may be a 5- or 6-membered monocyclic ring, or a bicyclic ring in which each 5- and 6-membered ring is fused, a bicyclic ring in which two 6-membered rings are fused, or two The double ring of the fused ring. And each ring may include four or less heteroatoms 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 one embodiment, the heteroaryl ring includes A ring of nitrogen atoms. The nitrogen atom in the heteroaryl ring may be basic, such as imidazole or pyridine, or may be substantially non-basic, such as indole or pyrrole. Nitrogen atom. In general, the number of nitrogen atoms in the heteroaryl group (including any amine group substituted on the ring) is not more than five.

Examples of five-membered ring heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole (oxadiazole), oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and (tetrazole) groups. In addition, examples of five-membered ring heteroaryl groups include thiadiazole.

Examples of 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; b) a pyridine ring having a 5- or 6-membered ring containing 1, 2 or 3 ring hetero atoms fused to each other; c) fused to a 5- or 6-membered ring containing 1 or 2 ring hetero atoms a pyrimidine ring; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) and a 5- or 6-membered ring containing 1 or 2 ring heteroatoms An imidazole ring fused to each other; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring hetero atoms; h) and 1 or 2 ring hetero atoms a isoxazole ring in which 5- or 6-membered rings are fused to each other; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring hetero atoms; j) and 1 Or an isothiazole ring in which 5- or 6-membered rings of two ring heteroatoms are fused to each other; k) fused to a 5- or 6-membered ring containing 1, 2 or 3 ring hetero atoms a thiophene ring; l) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) and 5- or 1 ring hetero atom containing 5 or a oxazole ring in which 6-membered rings are fused to each other; n) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring hetero atoms; o) and a containing 1, 2 Or a cyclohexyl ring in which a 5- or 6-membered ring of three ring hetero atoms is fused to each other; and p) is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring hetero atoms. Cycloheptyl ring.

Specific examples of bicyclic heteroaryl groups having two five-membered rings fused to each other include, but are not limited to, imidazole thiazole (e.g., imidazo[2,1-b]thiazole) and imidazole imidazole (e.g., imidazole [1, 2-a]imidazole).

Specific examples of bicyclic heteroaryl groups comprising 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, anthraquinone Indole, isoindole, indolizine, indoline, isoindoline, anthraquinone (eg, adenine, guanine), indazole Pyrazolopyrimidine (eg, pyrazole [1,5-a] pyrimidine), triazolopyrimidine (eg, [1,2,4]triazolo[1,5-a]pyrimidine), Benzodioxole and pyrazolopyridine (eg, pyrazole [1,5-a]pyridine) group. Another bicyclic heterocyclic ring containing a six-membered ring and a five-membered ring fused to each other. Examples of aryl groups include imidazopyridine.

Specific examples of bicyclic heteroaryl groups having two six-membered rings fused to each other include, but are not limited to, quinoline, isoquinoline, chroma, thiochroman , chromene, isochromene, chroma, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazepine Benzodiazine, pyridopyridine, quinoxaline (quinoxaline), quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

Examples of polycyclic aryl groups and heteroaryl groups having an aromatic ring and a non-aromatic ring include: tetrahydronaphthalene), tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzoyl Dihydrobenzthiene, dihydrobenzfuran, 2,3-dihydrobenzene [1,4]dioxin (2,3-dihydro-benzo[1,4]dioxine), benzene [1,3] Dioxo (benzo[1,3]dioxole), 4,5,6,7-tetrahydrobenzofuran, indoline, and indane group. 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] triazole [4,3-a]pyrazine).

A nitrogen-containing heteroaryl ring must have at least one cyclic nitrogen atom. In addition, each ring may contain up to four heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. Generally, a heteroaryl ring system contains up to 3 heteroatoms, for example 1, 2 or 3 heteroatoms, more typically up to 2 nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, such as imidazole or pyridine, or may be substantially non-basic, such as indole or pyrrole. Nitrogen atom. In general, the number of nitrogen atoms in the heteroaryl group (including any amine group substituted on the ring) is not more than five.

Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiazolyl. (thiadiazolyl), oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl ( Pyrazinyl), pyrimidinyl, pyridazinyl, triazinyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazole) , tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole Benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl ), isoindolinyl, purinyl (eg, adenine [6-aminopurine]), (guanine [2-amino-6-hydroxyindole])), carbazolyl (indazolyl), quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl 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, tetrahydroquinolyl (tetrahydroquinolinyl), and indolinyl.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups are those having a 3 to 12 membered ring, more often a 5 to 10 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: cyclic ethers (eg, in tetrahydrofuran and dioxane), cyclic sulfides (eg, in tetrahydrothiophene and dithiane). Medium), cyclic amines (eg, in pyrrolidine), cyclic amides (eg, in pyrrolidine), cyclic thioamides, cyclic thioesters (cyclic thioesters), cyclic ureas (eg, in imidazolin-2-one), cyclic esters (eg, in butyrolactone), cyclic oximes (eg, in guanidine and cyclopentane) Among the olefins, cyclic sulphoxide, cyclic sulphonamide, and combinations thereof (eg, thiomorpholine).

Specific examples include: morpholine, piperidine (eg, 1-piperidine, 2-piperidine, 3-piperidine, and 4-piperidine), piperidone, pyrrolidine (eg, 1) - pyrrolidine, 2-pyrrolidine, and 3-pyrrolidine), pyrrolidone, azetidine, pyran (pyran, such as 2H-pyran or 4H-pyran), dihydrogen Dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (tetrahydropyran, such as 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline (2-pyrazoline), pyrazole Pyrazolidine, piperazone, piperazine, and N-alkyl piperazine (such as N-methylpiperazine). In general, non-aromatic heterocyclic groups are preferred, including: saturated groups such as piperididine, pyrrolidine, azetidine, morpholine, piperazine Piperazine and N-alkyl piperazine.

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, pyrrolidine, piperidone, or internal) Caprolactam, cyclic sulfonamide (eg, thiazolidine 1,1-dioxide, [1,2]thiazinane 1,1-dioxo ([1,2] Thiazinane 1,1-dioxide) or [1,2]thiazepane 1,1-dioxy (1,2)thiazepane 1,1-dioxide) and combinations thereof. Examples of specific nitrogen-containing non-aromatic heterocyclic groups include: aziridine, morpholine, thiomorpholine, piperidine (eg, 1-piperidine, 2-piperidin) Pyridine, 3-piperidine and 4-piperidine), pyrrolidine (eg 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole, Imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1,2,5-thiadiazine (6H-1,2,5-thiadiazine), 2 -pyrazoline, 3-pyrazoline, pyrazolidine (pyrazolidine), piperazine, and N-alkyl piperazine (eg, N-methylpiperazine).

The heterocyclic group may be a polycyclic fused ring system or a bridged ring system such as a bicycloalkane, a tricycloalkane, and an oxa and aza compound thereof. (eg, adamantane and oxa-adamantane). For more details on condensing and bridged ring systems, see Jerry March, Advanced Organic Chemistry , 4th edition, Wiley Interscience, pp. 131-133, 1992.

Non-aromatic carbocyclic groups include: cycloalkyl groups (such as cyclohexyl and cyclopentyl), cycloalkenyl groups (such as cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl), and Cyclohexadienyl, cyclooctyltetraenyl, tetrahydronaphthenyl, and decalinyl.

Each of its heterocyclic groups may be unsubstituted or substituted with one or more substituents. For example, a heterocyclic group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents. Wherein the heterocyclic group is monocyclic or bicyclic, and generally has no substituent or has 1, 2 or 3 substituents.

Among the above, Represents a single button or a double button. Those skilled in the art will recognize that when X ₅ is C=O or when R ³ is =0, X ₄ and X ₅ are linked via a single bond.

Special embodiment of the invention

The chemical formula (I) a-(I) t of the ring system defined by X ₁ -X ₅ is as follows:

The other chemical formula (I)u-(I)v of the ring system defined by X ₁ -X ₅ is as follows:

In one embodiment, the two bonds in the 5-membered ring are double bonds.

In one embodiment, X ₁ represents C.

In one embodiment, X ₁ , X ₃ and X ₅ represent C, and X ₂ and X ₄ represent nitrogen (ie, a ring system as shown in formula (I) a).

In another embodiment, X ₁ , X ₃ , X ₄ and X ₅ represent C, and X ₂ represents nitrogen (ie, a ring system as shown in formula (I)e).

In another embodiment, X ₁ , X ₃ and X ₄ represent C, and X ₂ and X ₅ represent nitrogen (ie, a ring system as shown in formula (I) f).

In another embodiment, X ₁ and X ₂ represent C, X ₃ represents nitrogen, X ₄ represents CR ³ (eg, CH), and X ₅ represents CR ⁶ (eg, C-Me) (ie, as in the chemical formula (I) h ring system shown).

In another embodiment, X ₁ , X ₂ , X ₄ and X ₅ represent C, and X ₃ represents nitrogen (ie, a ring system as shown in formula (I) j).

In another embodiment, X ₁ , X ₂ and X ₄ represent C, and X ₃ and X ₅ represent nitrogen (ie, a ring system as shown in formula (I) k). In another embodiment, X ₂ , X ₃ , X ₄ , and X ₅ represent C, and X ₁ represents nitrogen (ie, a ring system as shown in formula (I)q).

In another embodiment, X ₂ , X ₃ and X ₅ represent C, and X ₁ and X ₄ represent nitrogen (ie, a ring system as shown in formula (I) r).

In one embodiment, X ₁ -X ₅ represents a chemical formula (I) a, (I) e, (I) f, (I) j, (I) k, (I) q or (I) r The ring system shown. In yet another embodiment, X ₁ -X ₅ represents a ring system as shown in formula (I) a or (I) j. In yet another embodiment, X ₁ -X ₅ represents a ring system as shown in formula (I) j.

In one embodiment, when X ₁ , X ₃ and X ₅ represent C, and X ₂ and X ₄ represent nitrogen, R ¹ represents a group other than -NHCOR ⁴ .

In one embodiment, when X ₁ , X ₂ , X ₄ and X ₅ represent C, and X ₃ represents nitrogen, R ¹ represents a non-NHCO(CH ₂ ) _n NR ⁴ R ⁵ or —NHCONR ⁴ R ⁵ Group.

In one embodiment, when X ₃ represents nitrogen and A represents a phenyl group, R ¹ represents a group other than -NHCOR ⁴ .

In one embodiment, when X ₁ , X ₃ and X ₅ represent C, and X ₂ and X ₄ represent nitrogen, R ^a represents a group other than O.

In one embodiment, when X ₂ , X ₃ , X ₄ and X ₅ represent C, and X ₁ represents nitrogen, R ¹ represents a group other than -NHCOR ⁴ or -NHSO ₂ R ⁴ .

In one embodiment, when X ₅ represents CR ⁶ and R ⁶ represents a heterocyclic group, the heterocyclic group is a non-pyrazole group (eg, a pyrazolyl group which is optionally substituted).

In one embodiment, when X ₂ , X ₃ and X ₅ represent C, X ₁ and X ₄ represent nitrogen, and R ¹ represents —NHCONR ⁴ R ⁵ , and A represents a non-phenyl group.

The chemical formula (I) A-(I)O of the ring system defined by A is as follows:

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 (I) O.

In one embodiment, A is a non-pyrazolyl group.

In one embodiment, the A is selected from the group consisting of: (I) B, (I) N, and (I) O.

In one embodiment, A is an (I)A group, the (I)A group being optionally substituted with one or more (eg, 1, 2 or 3) R ^a groups.

Preferably, in one embodiment, wherein X ₁ represents nitrogen, ring A is added to the above X ₁ group by a carbon atom.

In one embodiment, A represents a monocyclic aromatic carbocyclic ring or a heterocyclic ring system having a ring of 5, 6 or 7 members. In yet another embodiment, A represents a 6-membered carbocyclic ring. In still another embodiment, A represents a phenyl group (ie, a ring system as shown in formula (I)A) is selectively substituted by one or more (eg, 1, 2 or 3) R ^a groups. Replaced by the regiment. In one embodiment, A represents unsubstituted phenyl or one via -(CH ₂ ) _s -CONR ^x R ^y (eg, -CONH ₂ ), -(CH ₂ ) _s -CN (eg, -CN a phenyl group substituted with a C _1-6 alkyl group (e.g., methyl group) or a group of -OR ^x (e.g., methoxy group).

In one embodiment, A represents a monocyclic aromatic carbocyclic ring or a heterocyclic ring system having a ring of 5, 6 or 7 members. In yet another embodiment, A represents a 6-membered carbocyclic ring. In still another embodiment, A represents a phenyl group (ie, a ring system as shown in formula (I)A) or a pyridyl group (ie, a ring group as shown in formula (IB) or (IC) System) and optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups.

In one embodiment, A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (e.g. phenyl or pyridyl), and which is substituted in the 3-position or 5-position R ^1. When A represents a phenyl group, in one embodiment, R ¹ is located at the 3-position of the phenyl group relative to the position to which X _{1 is} added.

In one embodiment, A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (eg, phenyl or pyridyl), and is substituted at the 5-position by R ¹ , and more selectively Substituted at the 3-position by a single R ^a group.

In one embodiment, A represents unsubstituted phenyl or is mono-(CH ₂ ) _s -CONR ^x R ^y (eg, -CONH ₂ ), -(CH ₂ ) _s -CN (eg, -CN) , halogen (eg, fluorine), C _1-6 alkyl (eg, methyl), C _1-6 alkanol (eg, -CH ₂ OH) or -OR ^x (eg, methoxy or -OCH (eg, methoxy or -OCH (eg, methoxy) Me) ₂ ) A phenyl group substituted by a group.

In yet another embodiment, A represents an unsubstituted phenyl group.

In one embodiment, R ¹ represents -NHCONR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO- (CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴

, -NHCSSR ⁴ , -NHC(=NR ⁴ )NR ⁵ , NHC(=NR ⁴ )R ⁵ , -NH-C(=NH ₂ )-NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ;

In one embodiment, R ¹ represents -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ ,- NHSO ₂ R ⁴ , or -NHCSNR ⁴ R ⁵ .

In one embodiment, R ¹ represents -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CH ₂ -aryl, - NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NHSO ₂ R ⁴ , or -NHCSNR ⁴ R ⁵ .

In one embodiment, R ¹ represents -NHCONR ⁴ R ⁵ . In still another embodiment, R ⁴ represents halogen or C _1-6 alkyl (eg, methyl), and R ⁵ represents hydrogen, C _1-6 alkyl (eg, methyl, ethyl or butyl), -(CH ₂ ) _n -NR ^x R ^y (eg, -(CH ₂ ) ₂ NH ₂ or -(CH ₂ ) ₃ NH ₂ ), -(CH ₂ ) _n -aryl (eg, selectively A halogen atom such as a fluorine atom, a substituted phenyl group, or a halogen C _1-6 alkyl group (e.g., -CH ₂ -CF ₃ ).

In one embodiment, R ¹ represents -NHCONR ⁴ R ⁵ . In still another embodiment, R ⁴ represents hydrogen or C _1-6 alkyl (eg, methyl), and R ⁵ represents hydrogen, C _1-6 alkyl (eg, methyl, ethyl, butyl, - CH(Me) ₂ , -CH ₂ CH(Me) ₂ or -C(Me) ₃ ), by one or more R ^a groups (eg, -CH ₂ -C(Me) ₂ -CH ₂ -NH ₂ a C _1-6 alkyl group, a C _1-6 alkanol group (eg, -CH ₂ ) substituted with -CH ₂ -CH(Me)-OMe or -CH ₂ -C(F) ₂ -CH ₂ NH ₂ ) -CH(OH)-CH ₂ OH), -(CH ₂ ) _n -NR ^x R ^y (eg, -(CH ₂ ) ₂ NHCOOt-Bu, -(CH ₂ ) ₂ NH ₂ or -(CH ₂ ) ₃ NH ₂ ), -(CH ₂ ) _n -aryl (eg, phenyl optionally substituted by a halogen atom such as a fluorine atom), -(CH ₂ ) _n -heterocyclic group (eg, -CH) _2- dioxaolanyl (optionally substituted by one or more C _1-6 alkyl (eg, methyl), -CH ₂ -tetrahydrofuran or -CH ₂ -piperidinyl)), or halogen C _1-6 alkane A group (e.g., -(CH ₂ ) ₂ -F, -CH ₂ -CH-F ₂ -CH(Me)-CF ₃ or -CH ₂ -CF ₃ ).

In one embodiment, when A represents phenyl and R ¹ represents -NHCONR ⁴ R ⁵ , R ⁴ and R ⁵ represent a non-phenyl group.

In one embodiment, R ¹ represents -NHCOOR ⁴ . In still another embodiment, R ⁴ represents C _1-6 alkyl (eg, methyl) or halo C _1-6 alkyl. In still another embodiment, R ⁴ represents C _1-6 alkyl (eg, methyl) or halo C _1-6 alkyl (eg, -CH ₂ -CF ₃ ). In still another embodiment, R ⁴ represents a C _1-6 alkyl group (eg, methyl).

In one embodiment, R ¹ represents -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ . In yet another embodiment, n represents 1 and both R ⁴ and R ⁵ represent hydrogen.

In one embodiment, R ¹ represents -NH-CO-(CH ₂ ) _n -COOR ⁴ . In yet another embodiment, n represents 2 and R ⁴ represents hydrogen.

In one embodiment, R ¹ represents -NHSO ₂ R ⁴ . In still another embodiment, R ⁴ represents C _1-6 alkyl (eg, methyl) or —(CH ₂ ) _n —NR ^x R ^y (eg, NH ₂ or NMe ₂ ).

In one embodiment, R ¹ represents -NHCSNR ⁴ R ⁵ . In yet another embodiment, one of R ⁴ and R ⁵ represents hydrogen and the other represents C _1-6 alkyl (eg, ethyl).

In one embodiment, R ¹ represents -NHCOR ⁴ . In still another embodiment, R ⁴ represents C _1-6 alkyl (eg, methyl, ethyl or propyl) or C _1-6 alkanol (eg, -CH ₂ OH).

In yet another embodiment, R ¹ represents -NHCONR ⁴ R ⁵ (eg, -NHCONHEt or -NHCONHCH ₂ CF ₃ ), or -NHCSNR ⁴ R ⁵ (eg, -NHCSNHEt). In still another embodiment, R ¹ represents -NHCONR ⁴ R ⁵ (eg, -NHCONHEt or -NHCONHCH ₂ CF ₃ ). In still another embodiment, R ¹ represents -NHCONHCH ₂ CF ₃ .

In one embodiment, R ¹ represents NHSO ₂ NR ⁴ R ⁵ . In yet another embodiment, R ⁴ represents hydrogen and R ⁵ represents halo C _1-6 alkyl (eg, —CH ₂ —CF ₃ ).

In one embodiment, R ¹ represents -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ . In still another embodiment, n represents 1, R ⁴ represents hydrogen, and R ⁵ represents hydrogen or a C _1-6 alkyl group (eg, methyl).

When R ² or R ⁶ represents a heterocyclic group, in one embodiment, the heterocyclic group is a non-pyrazolyl group (e.g., a group optionally substituted with a pyrazolyl group).

In one embodiment, when R ² represents hydrogen, X ₅ represents CR ⁶ , wherein R ⁶ represents a non-hydrogen group.

In one embodiment, when X ₅ represents CH or nitrogen, R ² represents a non-hydrogen group.

In one embodiment, when R ² represents a non-hydrogen group, X ₅ represents CH, nitrogen or C=O.

In one embodiment, when X ₅ represents CR ⁶ and wherein R ⁶ represents a non-hydrogen group, R ² represents hydrogen.

In one embodiment, R ² represents an aryl or heteroaryl group optionally substituted with one or more R ^a groups.

In one embodiment, R ² represents an aryl or heteroaryl group optionally substituted with one or more R ^b groups.

In one embodiment, R ² represents a phenyl group optionally substituted with an R ^b group.

In one embodiment, R ² represents an aryl group (eg, phenyl) optionally substituted with one or more (eg, 1, 2, or 3) R ^b groups, the R ^b group of which is selected from: Halogen (eg, fluorine), halogen C _1-6 alkoxy (eg, -OCF ₃ ), -OR ^x (eg, methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkanol (eg, , -CH ₂ OH), -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe, -C(Me) ₂ -COOH, -CH ₂ -COOH or -C(Me) ₂ -COOMe ), -(CH ₂ ) _s -CN (eg, -CH ₂ CN), -(CH ₂ ) _s -NR ^x R ^y (eg, -NMe _2, -(CH ₂ ) ₂ -NH ₂ , -(CH ₂ ) ₂ -NMe ₂ or -NH-CO-CH ₂ -methoxy), or -O-(CH ₂ ) _n -OR ^x (eg, -O-(CH ₂ ) ₂ -ethoxy) Group of.

In one embodiment, R ² represents an aryl group (eg, phenyl) optionally substituted with one or more (eg, 1, 2, or 3) R ^b groups, the R ^b group of which is selected from: Halogen (eg, fluorine or chlorine), hydrazine (eg, D ₅ ), halogen C _1-6 alkyl (eg, -CF ₃ ), halogen C _1-6 alkoxy (eg, -OCF ₃ ), -OR ^x (eg, methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkyl (eg, i-Pr), C _1-6 alkanol (eg, -CH ₂ OH), -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe, -C(Me) ₂ -COOH, -CH ₂ -COOH or -C(Me) ₂ -COOMe), -(CH ₂ ) _s -CN (eg , -CN or -CH ₂ CN), -(CH ₂ ) _s -NR ^x R ^y (eg, -NMe _2, -(CH ₂ ) ₂ -NH ₂ , -(CH ₂ ) ₂ -NMe ₂ or -NH -CO-CH ₂ -methoxy), -O-(CH ₂ ) _n -OR ^x (eg, -O-(CH ₂ ) ₂ -ethoxy), -(CH ₂ ) _s -CONR ^x R ^y (eg, -CONH ₂ , -CONHMe, -CONHEt, -CONH-iPr, -CH ₂ -CONHMe, -CONH-(CH ₂ ) ₂ -OMe or -CONH-(CH ₂ ) ₂ -NH ₂ ), -SO ₂ -R ^x (eg, -SO ₂ Me), -(CH ₂ ) _s -SO ₂ NR ^x R ^y (eg, -SO ₂ NH ₂ ), -(CH ₂ ) _s -NR ^x -SO ₂ -R ^y (eg, -NHSO ₂ Me or -CH ₂ -NHSO ₂ Me), -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y (eg, -NH-SO ₂ -NMe ₂ ).

In still another embodiment, R ² represents a selectively halogenated (eg, fluoro), -Z-heterocyclic group (eg, -CH ₂ -morpholinyl, -CH ₂ -piperazinyl, - CH ₂ - piperidinyl, -CH ₂ - ^{azetidinyl), - (CR x R y} ) s -COOR z ( eg, -COOH or -C (Me) ₂ -COOH) of the substituted aryl group (e.g., phenyl), wherein the above heterocyclic group is optionally substituted by a C _1-6 alkyl group (e.g., methyl), or -(CR ^x R ^y ) _s -COOR ^z (e.g., -COOH ) replaced by a group.

In one embodiment, R ² represents an aryl group which is optionally substituted with a mono-Y-aryl (eg, -Y-phenyl) group.

In one embodiment, Y represents -O-(CH ₂ ) _s - (eg, -O-CH ₂ -).

In one embodiment, R ² represents a mono-Z-heterocyclic group (eg, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, - An aryl group substituted with Z-triazolyl, -Z-piperidinyl, -Z-piperazinyl, wherein the above heterocyclic group may be optionally one or more (eg, 1, 2 or 3) ) R ^a substituted group, wherein the R ^a group selected from the group consisting of: C _1-6 alkyl (e.g., methyl) or _{^{- (CR x R y) s}} -COOR z ( eg, -COOH, -COOMe, or - COOtBu).

In one embodiment, R ² represents a mono-Z-heterocyclic group (eg, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, - Z-pyrazolyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl, -Z-diazepanyl or -Z-tetrahydropyridyl thiopyran-yl) substituted with the aryl group, the above-mentioned heterocyclic group which may optionally be substituted with one or more (e.g., 1, 2 or. 3) R ^a groups, wherein the R ^a group selected from the group consisting of: C _1-6 alkyl (eg, methyl or ethyl), =O, -COR ^x (eg, -COMe) or -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe or -COOtBu) ) group.

In still another embodiment, R ² represents a selectively halogenated (eg, fluoro), -Z-heterocyclic group (eg, -CH ₂ -morpholinyl, -CH ₂ -piperazinyl, - CH ₂ - piperidinyl, -CH ₂ - ^{azetidinyl), - (CR x R y} ) s -COOR z ( eg, -COOH or -C (Me) ₂ -COOH) of the substituted aryl group The above heterocyclic group may be optionally substituted by a C _1-6 alkyl group (e.g., methyl group) or -(CR ^x R ^y ) _s -COOR ^z (e.g., -COOH).

In still another embodiment, R ² represents a group optionally substituted by a halogen (eg, fluoro) or an aZ-heterocyclic group (eg, -CH ₂ -morpholinyl or -CH ₂ -piperazinyl). A substituted aryl group (e.g., phenyl) wherein the above heterocyclic group is optionally substituted with a C _1-6 alkyl group (e.g., methyl group).

In still another embodiment, R ² represents an aryl group (e.g., phenyl) that is optionally substituted with a halogen (e.g., fluorine) atom. In still another embodiment, R ² represents 4-fluoro-phenyl.

In one embodiment, R ² represents a 5-membered heterocyclic group optionally substituted with one or more R ^a groups.

In one embodiment, R ² represents a 5-membered heteroaryl group optionally substituted with one or more R ^a groups.

In one embodiment, R ² represents a heterocyclic group optionally substituted with an R ^b group.

In one embodiment, R ² represents a heterocyclic group optionally substituted with a -Z-heterocyclyl or -(CH ₂ ) _s -NR ^x R ^y group.

In one embodiment, R ² represents a heterocyclic group (eg, morpholinyl, piperazinyl, pyridine) which is optionally substituted with one or more (eg, 1, 2 or 3) R ^b groups. a base, thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl, the R ^b group of which is selected from: =O (eg, pyridone) (pyridinone)), C _1-6 alkyl (eg, methyl), -(CH ₂ ) _s -NR ^x R ^y (eg, -NH ₂ ), -OR ^x (eg, methoxy), -COR ^x (eg, -COMe) or a C _1-6 alkanol (e.g., -CH ₂ OH) groups.

In one embodiment, R ² represents a heterocyclic group (eg, morpholinyl, piperazinyl, pyridine) optionally substituted with one or more (eg, 1, 2, or 3) R ^b groups. Base, thienyl, pyrazinyl, phenylthienyl, furan, imidazolyl, pyrazolyl, benzodioxolyl, pyrrolidinyl, nitrogen Heterocyclobutane, piperidinyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, An oxadiazolyl, isoxazolyl, benzodioxolyl, tetrahydrotriazopyrazine or pyrimidinyl group, the R ^b group of which is selected from the group consisting of: =O (eg, pyridone or 5-oxo-4,5-dihydro-[1,3,4]oxadiazolyl), =S (eg, thio-4,5-dihydro-[1 , 3,4]oxadiazole), halogen (such as fluorine), C _1-6 alkyl (eg, methyl, ethyl, propyl, i-Pr or t-Bu), halogen C _1-6 Alkyl (eg, -CH ₂ -F, -CF ₃ or -CH ₂ CF ₃ ), C _3-8 cycloalkyl (eg, cyclopropyl), -(CH ₂ ) _s -NR ^x R ^y (eg ^{_{, -NH 2), - OR x}} ( e.g., hydroxyethyl , Methoxy or -Oi-Pr), - (CH 2) n -OC 1-6 alkyl _{(e.g., -CH 2 -O-Me),} - COR x ( eg, -COMe), - (CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOEt or -COOt-Bu), -SR ^x (eg, -S-Me), -SO ₂ -R ^x (eg, -SO ₂ -Et), -(CH ₂ ) _s -NR ^x R ^y (eg, -NH ₂ ), -(CH ₂ ) _s -SO ₂ NR ^x R ^y (eg, -SO ₂ -NMe ₂ ) or C _1-6 alkanol ( For example, a -C(OH)(Me) ₂ or -CH ₂ OH) group.

In one embodiment, R ² represents a heterocyclic group (eg, morpholinyl, piperazinyl, pyridine) which is optionally substituted with one or more (eg, 1, 2 or 3) R ^b groups. Base, thienyl, pyrazinyl, benzothienyl, furan, imidazolyl, pyrazolyl, benzodioxolyl, pyrrolidinyl, nitrogen heterocycle Butanyl, piperidinyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, dioxin An oxadiazolyl, isoxazolyl, benzodioxolyl, tetrahydrotriazopyrazine or pyrimidinyl group, the R ^b group of which is selected from the group consisting of: =O (eg, pyridone or 5-oxo-4,5-dihydro-[1,3,4]oxadiazolyl), =S (eg, thio-4,5-dihydro- [1,3,4]oxadiazole), halogen (such as fluorine), C _1-6 alkyl (eg, methyl, ethyl, propyl, i-Pr or t-Bu), halogen C _{1 -6} alkyl (eg, -CH ₂ -F or -CF ₃ ), C _3-8 cycloalkyl (eg, cyclopropyl), -(CH ₂ ) _s -NR ^x R ^y (eg, -NH _{2 )} ), - OR ^x (e.g., a hydroxyl group, A Group or ^{-Oi-Pr), - COR x} ( ^{eg, -COMe), - (CR x} R y) s -COOR z ( eg, -COOH, -COOEt or ^{-COOt-Bu), - SR x} ( e.g., -S-Me), -SO ₂ -R ^x (eg, -SO ₂ -Et), -(CH ₂ ) _s -NR ^x R ^y (eg, -NH ₂ ), -(CH ₂ ) _s -SO ₂ NR ^x R ^y (eg, -SO ₂ -NMe ₂ ) or a C _1-6 alkanol (eg, -C(OH)(Me) ₂ or -CH ₂ OH) group.

In yet another embodiment, R ² represents an oxazole, oxadiazole, triazole, tetrazole, pyrazole, which is optionally substituted with one or more R ^a groups. (pyrazole), thiadiazole, thiazole, imidazole or oxathiadiazole.

In yet another embodiment, R ² represents an oxazole, oxadiazole, triazole, tetrazole, thiazide optionally substituted with one or more R ^a groups. Thiadiazole or oxathiadiazole.

In yet another embodiment, R ² represents a thiadiazole, thiazole, or imidazole that is optionally substituted with one or more R ^a groups.

In yet another embodiment, R ² represents a 5 member optionally substituted with a C _1-6 alkyl (eg, methyl or ethyl) or —SR ^x (eg, —S-Me) group. a heterocyclic group (eg, oxazole, oxadiazole, triazole (eg, 1,2,3-triazole or 1,2,4-triazole), Tetrazole, thiadiazole or oxathiadiazole.

In still another embodiment, R ² represents an oxadiazole optionally substituted with a C _1-6 alkyl group (eg, methyl or ethyl) or —SR ^x (eg, —S—Me). For example, 1,3,4-oxadiazole), tetrazole or thiadiazole (such as 1,3,4-thiadiazole).

In still another embodiment, R ² represents a group optionally substituted with one or more R ^a (eg, one or two substituted C _1-4 alkyl groups (eg, CH ₃ , CH ₂ OH, ( CH ₂ ) ₂ OH or (CH ₂ ) ₂ NH ₂ )) substituted pyrazole.

In yet another embodiment, R ² represents a pyrazole optionally substituted with one or more R ^a groups (eg, one or two C _1-4 alkyl groups (eg, methyl)). .

In yet another embodiment, R ² represents an oxazole substituted with one or two optionally substituted C _1-4 alkyl (eg, CH ₃ , CH ₂ OH) or =0 groups. ), oxadiazole, triazole, tetrazole, imidazole, thiadiazole or oxathiadiazole.

In still another embodiment, R ² represents an oxazole, oxadiazole substituted with one or two optionally substituted C _1-4 alkyl groups (eg, CH ₃ , CH ₂ OH). , triazole, tetrazole, thiadiazole or oxathiadiazole.

In still another embodiment, R ² represents an aryl group (e.g., phenyl) optionally substituted with a halogen (e.g., fluoro), or R ² represents an optionally C _1-6 alkyl group. (eg, methyl or ethyl) or -SR ^x (eg, -S-Me) substituted with a 5-membered heterocyclic group (eg, oxadiazole, tetrazole, or thiadiazole) ).

In yet another embodiment, R ² represents an optionally mono-Z-heterocyclic group (eg, -Z-azetidinyl, -Z-piperazinyl, -Z-morpholinyl or a heterocyclic group (e.g., pyridyl or pyrimidinyl) substituted with -Z-piperidinyl).

In yet another embodiment, R ² represents a group optionally substituted with a mono-Z-heterocyclic group (eg, -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl). Heterocyclic group (e.g., pyridyl).

In still another embodiment, R ² represents a mono-Z-heterocyclic group (eg, -Z-piperazinyl, -Z-morpholinyl, Z-tetrahydropyranyl or -Z). a heterocyclic group (e.g., pyridyl) substituted with -piperidinyl).

In still another embodiment, R ² represents a heterocyclic group (e.g., pyridyl) optionally substituted with a -(CH ₂ ) _s -NR ^x R ^y (e.g., -NH ₂ ) group.

In one embodiment, R ² represents halogen (eg, fluoro or chloro).

In one embodiment, R ² represents a C _1- group optionally substituted with one or more R ^b groups (eg, —CH ₂ OH, —C(OH)(Me) ₂ or —CF ₃ ). ₆ alkyl (eg, methyl or ethyl).

In one embodiment, R ² represents a C _3-8 cycloalkyl group (eg, cyclopropyl).

In one embodiment, R ² represents -CH=N-OR ^w (eg, -CH=N-OH or -CH=N-OMe).

In one embodiment, R ² represents -NHSO ₂ R ^w (eg, -NHSO ₂ Me).

In one embodiment, R ² represents a C _1-6 alkoxy group (eg, methoxy or ethoxy).

In one embodiment, R ² represents a C _2-6 alkynyl group (eg, acetylene or propyne) optionally substituted with an R ^b group (eg, —C≡C—Si(Me) ₄ ). . In still another embodiment, R ² represents a C _2-6 alkynyl group (eg, acetylene) optionally substituted with an R ^b group (eg, —C≡C—Si(Me) ₄ ). In yet another embodiment, R ² represents a C _2-6 alkynyl group (eg, acetylene) optionally substituted with an R ^b group (eg, cyclopropyl).

In one embodiment, R ² represents -C≡N.

In one embodiment, R ² represents a C _2-6 alkenyl group (eg, —CH=CH-COOEt or —CH=CHCONHMe) that is optionally substituted with an R ^b group.

In one embodiment, R ⁶ represents halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _{3- 8} -cycloalkyl, C _3-8 cycloalkenyl, -NHSO ₂ R ^w , -CH=N-OR ^w , or a 3-6 membered monocyclic heterocyclic group, wherein the C _1-6 alkyl group, C _{The 2-6} alkenyl group, the C _2-6 alkynyl group, and the heterocyclic group may be optionally substituted with one or more R ^a groups.

In one embodiment, R ² and R ^{6 are} optionally substituted with an R ^b group. In still another embodiment, R ^b includes a R ^a group or a -Y-aryl group or a -Z-heterocyclic group.

In one embodiment, Y and Z each independently represent lines _{-CO -, - O- (CH 2} ) s - or -NH- (CH _{2) n} -.

In one embodiment, the Y and Z series each independently represent a bond, CO, -CH ₂ -, -(CH ₂ ) ₂ , -(CH ₂ ) ₃ or -O-.

In one embodiment, Z represents a bond, CO, -(CH ₂ ) _n - (eg, -CH ₂ -, -(CH ₂ ) ₂ or -(CH ₂ ) ₃ ) or -O-. In yet another embodiment, Z represents -(CH ₂ ) _n - (eg, -CH ₂ -).

In one embodiment, Z represents a bond, CO, -(CH ₂ ) _n - (eg, -CH ₂ -, -(CH ₂ ) ₂ or -(CH ₂ ) ₃ ), -NH-(CH ₂ ) _n - (eg, -NH-) or -O-. In yet another embodiment, Z represents -(CH ₂ ) _n - (eg, -CH ₂ -).

In one embodiment, Z represents a bond, CO, -(CH ₂ ) _n - (eg, -CH ₂ -, -(CH ₂ ) ₂ or -(CH ₂ ) ₃ ) or -O-.

In one embodiment, Z represents a bond or -CH ₂ -.

In one embodiment, R ^b represents a R ^a group or a -Y-aryl or -Z-heterocyclic group, wherein the aryl group and the heterocyclic group are optionally one or more (eg, , 1, 2 or 3) substituted by the R ^a group.

In one embodiment, the compound of formula (I) is as shown in formula (Ia) or (Ib): (Ia) (Ib)

Wherein A represents an aromatic carbocyclic or heterocyclic group which may be optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups; R ¹ represents -NHCONR ⁴ R ⁵ ,- NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , —NHSO ₂ NR ⁴ R ⁵ , —NHCOR ⁴ ; R ⁴ and R ⁵ each independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -8} cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkanol, halo C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _s -COOR ^z , -(CH ₂ ) _n -O-(CH ₂ ) _m -OH, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -O-aryl, -(CH ₂ ) _n -heterocycle Or -(CH ₂ ) _n -O-heterocyclyl, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 The cycloalkenyl, aryl and heterocyclic groups may be optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups; R ^x , R ^y and R ^z each independently represent hydrogen , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halo C _1-6 alkyl, -CO - (CH _{2) n} -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkyl Group; R ² each independently represent a hydrogen based, an aryl group or a heterocyclyl group, wherein the aryl group and heterocyclic group optionally substituted with one or more R ^b group; R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -(CH ₂ ) _n -OC _{1 -6} alkyl, -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro, -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^y -(CH ₂ ) _t -OR ^z or -(CH ₂ ) _s -SO ₂ NR ^x R ^y R ^b represents a R ^a group or an aY-aryl or -Z-heterocyclyl group, wherein the aryl group and the heterocyclic group are optionally one or more (eg, 1, 2) Or 3) R ^a groups are substituted; Y and Z systems each independently represent a bond, -CO-(CH ₂ ) _s -, -COO-, -(CH ₂ ) _n -, -NR ^x -( CH ₂ ) _n -, -(CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y --O-(CH ₂ ) _s -, -(CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; m and n each independently represent an integer from 1 to 4; s and t each independently represent an integer from 0 to 4; aryl Represents 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, R ¹ and R ² groups in the above chemical formulas (Ia) and (Ib) are those referred to in the above formula (I).

In one embodiment, the compound represented by the formula (I) is a compound defined by the above formula (Ia).

In one embodiment, the compound of formula (I) is a sub-formula of formula (Ia) and is a compound defined by formula (Ic):

Wherein R ^a , R ² , R ⁴ and R ⁵ are as defined above, and q represents an integer from 0 to 3.

Particularly preferred examples of the variables R ^a , R ² , R ⁴ and R ⁵ are as defined above.

In one embodiment, the compound of formula (I) is a sub-formula of formula (Ia) and is a compound defined by formula (Id):

Wherein R ^a , R ² , R ⁵ and q are as defined above, and J and L are each independently selected from carbon or nitrogen.

^A series of particularly preferred examples of the variables R ^a , R ² and R ⁵ are set forth herein.

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, R ⁵ is an alkyl group which is optionally substituted by a R ^a group. In particular, R ^{5 is} an optionally substituted ethyl group. Preferably, R ⁵ is a trifluoroethyl group.

In particular, R ² is a selectively substituted phenyl or a 5-6 membered monocyclic heterocyclic ring. A series of special preferred examples of R ² are set forth herein.

In one embodiment, the compound of formula (I) is a sub-formula of formula (Ia) and is a compound defined by formula (Ie):

Wherein R ^a , q and R ² and preferred examples thereof are listed herein.

In one embodiment, R ² is a phenyl group optionally substituted with R ^b . In another embodiment, R ² is a phenyl group optionally substituted with ^Ra . In one embodiment, the R ^a or R ^b group is at the 3- or 4-position of the phenyl ring. In one embodiment, when the phenyl ring is substituted by R ^a, R ^a group of the system located in the 4-position of the phenyl ring. In one embodiment, when the phenyl ring is substituted by R ^b and the R ^b group is a -Y-carbocyclic (eg, Y-aryl) group or a -Z-heterocyclyl group, the R ^{The b} group is located at the 3-position in the benzene ring.

In one embodiment, the R ^b group is selected from the group consisting of halogen (eg, fluorine or chlorine), hydrazine (eg, D ₅ ), halogen C _1-6 alkyl (eg, -CF ₃ ), halogen C _{1 -6} alkoxy (eg, -OCF ₃ ), -OR ^x (eg, methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkyl (eg, i-Pr), C _1-6 alkane Alcohol (eg, -CH ₂ OH), -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe, -C(Me) ₂ -COOH, -CH ₂ -COOH or -C(Me) ₂ -COOMe), -(CH ₂ ) _s -CN (eg, -CN or -CH ₂ CN), -(CH ₂ ) _s -NR ^x R ^y (eg, -NMe _2, -(CH ₂ ) ₂ - NH ₂ , -(CH ₂ ) ₂ -NMe ₂ or -NH-CO-CH ₂ -methoxy), -O-(CH ₂ ) _n -OR ^x (eg, -O-(CH ₂ ) ₂ - B Oxy), -(CH ₂ ) _s -CONR ^x R ^y (eg, -CONH ₂ , -CONHMe, -CONHEt, -CONH-iPr, -CH ₂ -CONHMe, -CONH-(CH ₂ ) ₂ -OMe or -CONH-(CH ₂ ) ₂ -NH ₂ ), -SO ₂ -R ^x (eg, -SO ₂ Me), -(CH ₂ ) _s -SO ₂ NR ^x R ^y (eg, -SO ₂ NH ₂ ) , -(CH ₂ ) _s -NR ^x -SO ₂ -R ^y (eg, -NHSO ₂ Me or -CH ₂ -NHSO ₂ Me), -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y ( For example, -NH-SO ₂ -NMe ₂ ).

In one embodiment, the R ^b group is selected from the group consisting of halogen (eg, fluorine), halogen C _1-6 alkoxy (eg, -OCF ₃ ), -OR ^x (eg, methoxy or -OCH) ₂ OHCH ₂ OH), C _1-6 alkanol (eg, -CH ₂ OH), -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe, -C(Me) ₂ -COOH, -CH ₂ -COOH or -C(Me) ₂ -COOMe), -(CH ₂ ) _s -CN(eg-CH ₂ CN), -(CH ₂ ) _s -NR ^x R ^y (eg, -NMe ₂ -(CH ₂ ) ₂ -NH ₂ , -(CH ₂ ) ₂ -NMe ₂ or -NH-CO-CH ₂ -methoxy) or -O-(CH ₂ ) _n -OR ^x (eg, -O- (CH ₂ ) ₂ -ethoxy).

In one embodiment, the R ^b group is selected from the group consisting of: halogen (eg, fluoro), -Y-aryl (eg, -Y-phenyl) group or -Z-heterocyclic group (( For example, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl) Wherein the heterocyclyl group is optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups, and the R ^a group thereof is selected from: C _1-6 alkyl (eg, methyl) or -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe or -COOtBu) groups, and wherein Z is CO, CH ₂ or a bond.

In one embodiment, the R ^b group is selected from the group consisting of: -Z-heterocyclic groups (eg, -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, - Z-pyrazolyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl, -Z-diazepanyl, or -Z a tetrahydropyranyl group, wherein the heterocyclyl group is optionally substituted by one or more (eg, 1, 2 or 3) R ^a groups, and the R ^a group thereof is selected from: C _1-6 alkyl (eg, methyl or ethyl), =O, -COR ^x (eg, -COMe) or -(CR ^x R ^y ) _s -COOR ^z (eg, -COOH, -COOMe or - a COOtBu) group, and wherein Z is CH ₂ or a bond.

In still another embodiment, R ² represents an aryl (e.g., phenyl) group optionally substituted with a halogen (e.g., fluorine) atom. In still another embodiment, R ² represents 4-fluoro-phenyl.

In one embodiment, the compound of formula (I) is a sub-formula of formula (Ia) and is a compound defined by formula (If):

Wherein R ^a , q and R ⁵ are as defined above and: J and L are each independently selected from: carbon or nitrogen; Q is carbon or nitrogen; and P, R, S, T may be carbon, nitrogen, oxygen or Sulfur, but the ring contains no more than 4 heteroatoms; R ¹² is selected from the group consisting of hydrogen, halogen, amine, hydroxy, C _1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl and t-butyl), substituted by the hydroxyl group, C _1-3 alkoxy or halo C _1-3 alkyl (e.g., hydroxymethyl, trifluoromethyl, mono-fluoroethyl, trifluoroacetate , methoxymethyl), C _1-3 alkylsulfonyl (eg, methylsulfonyl), C _2-4 cycloalkyl (eg, cyclopropyl), and C _1-3 alkoxy (eg, methoxy); and r is 0, 1, 2 or 3.

In particular, one of J or L is carbon and the other is nitrogen. In one embodiment, J and L are carbon.

In particular, R ⁵ is an alkyl group which is optionally substituted by a R ^a group. In particular, R ⁵ is an ethyl group which is optionally substituted. Preferably, R ⁵ is a trifluoroethyl group.

In one embodiment, Q is nitrogen and P, R, S, and T are all carbon.

Preferably, P, Q, R, S and T form an aromatic ring.

Preferably, Q is carbon.

In one embodiment, if P is a carbon substituted by any substance other than hydrogen, R is preferably N, O, or S.

Preferably, both of P, R, S, T are nitrogen and the balance is carbon, oxygen or sulfur.

Preferably, r is 0 or 1.

In one embodiment, R ¹² is selected from the group consisting of hydrogen, amine, SO ₂ NMe ₂ , C _1-3 alkyl (eg, methyl, ethyl, n-propyl, isopropyl), hydroxy, C C _1-3 alkyl substituted with _1-3 alkoxy or halogen (eg, hydroxymethyl, trifluoromethyl, monofluoroethyl, trifluoroethyl, methoxymethyl), and C _{1- 3} alkoxy (eg, methoxy).

Preferably, R ¹² is selected from the group consisting of: hydrogen, or a C _1-3 alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl).

Preferably, R ¹² is a methyl group.

In one embodiment, the compound of formula (I) is a sub-formula of formula (Ia) and is a compound defined by formula (Ig):

Wherein R ^a , q , R ⁵ , P, Q, R, S and T are as defined above, and R ^12r , R ^12p , R ^12s and R ^12t may be R ¹² as recited above.

In one embodiment, Q is nitrogen. In another embodiment, Q is nitrogen and one or both of P, R, S, T are also nitrogen.

In one embodiment, R ^12r and R ^12p are each independently selected from the group consisting of hydrogen, amine, methyl, trifluoromethyl, and methoxy.

In one embodiment, when one of R ^12r or R ^12p is a non-hydrogen group, the other is hydrogen.

In an embodiment, PR ^12p is CH.

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- Compounds shown in 115, 117, 119-131, 133-156, 158-166, 168-234, and 236-418.

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- Compounds shown in 115, 117, 119-131, 133-156, 158-166, 168-234, and 236-400.

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- Compounds shown in 115, 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, The compounds shown in 100-109, 111-115, 117 and 119-126.

In one embodiment, the compound of formula (I) is a non-N-{4-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl] -phenyl}acetamidamine (N-{4-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-acetamide, E75) and {3- [7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}carbamic acid 2,2,2-trifluoro-ethyl ester ({3-[ A compound of 7-(4-fluoro-phenyl)-imidazo[1,2-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 not shown in Examples 401-418.

In still another embodiment, the compound of formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]- Phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3- Yr]-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[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)- Urea hydrochloride.

In a second aspect of the invention, a compound of formula (II) is used in the manufacture of a medicament for the treatment of a fibroblast growth factor receptor (FGFR) enzyme-related disease:

Wherein X ₁ -X ₅ and the like based on the definition of A of compounds of formula (I), as represented by the: u represents an integer of 10 to 2; R ^1a Representative ^{-NHCONR 4 R 5, -NHCOOR 4,} -NH- CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , -NHSO ₂ SR ⁴ , -NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , -NHCSSR ⁴ , -NR ⁴ R ⁵ , - C(=NR ⁴ )NR ⁵ , halogen, C _1-6 alkyl, aryl, —CO—aryl, heterocyclyl, —CO—heterocyclyl, —CONR ⁴ R ⁵ , —(CH ₂ ) _n —NR ⁴ COR ⁵ , —(CH ₂ ) _s —CN, —OR ⁴ or —COOR ⁴ , wherein the aryl group and the heterocyclyl group are optionally one or more (eg, 1, 2 or 3) Substituting ^a R ^a group, and the R ^a group is as defined in the compound represented by the formula (I); R ⁴ and R ^{5 are} as defined in the compound represented by the formula (I), and must have a condition That is, when one of R ⁴ and R ⁵ represents hydrogen, the other represents a group of a non-aryl or -heterocyclic group; and R ² is as defined in the compound of the formula (I).

In one embodiment, a compound of the formula (II) is provided and the drug for the treatment of a disease associated with the fibroblast growth factor receptor (FGFR) enzyme is produced:

Wherein X ₁ -X ₅ and A are as defined in the compound of formula (I): u represents an integer from 0 to 2; R ^1a represents -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH- CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NH-CO-(CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , -NHSO ₂ SR ⁴ , -NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , -NHCSSR ⁴ , -NR ⁴ R ⁵ , -C(=NR ⁴ )NR ⁵ , C _1-6 alkane , aryl, -CO-aryl, heterocyclyl, -CO-heterocyclyl, -CONR ⁴ R ⁵ , -(CH ₂ ) _n -NR ⁴ COR ⁵ , -(CH ₂ ) _s -CN, -OR ⁴ or -COOR ⁴ , wherein the aryl group and the heterocyclyl group are optionally substituted by one or more (e.g., 1, 2 or 3) R ^a groups, and the R ^a group is as It is defined in the compound represented by the formula (I); R ⁴ and R ^{5 are} as defined in the compound represented by the formula (I); R ² is as defined in the compound represented by the formula (I), but is not affected by it. With the condition of (without the privoso).

In one embodiment, R ^1a represents a heterocyclic group, and the heterocyclic group is optionally selected from one or more R ^a groups: =S; -COOR ⁴ ; -CO-heterocyclyl; (CH ₂ ) _s -CN; -(CH ₂ ) _n -NR ⁴ COR ⁵ , -CONR ⁴ R ⁵ or -NR ⁴ R ⁵ is substituted.

In one embodiment, R ^1a represents a heterocyclic group (eg, pyridyl, pyrazolyl, indazolyl, indolyl or triazolyl), and the heterocyclic group optionally substituted with one or more R ^a groups, R ^a group which is selected from: halo (e.g., chloro) or = S (e.g., dihydro-triazole (triazole) thione ).

In one embodiment, R ^1a represents a heterocyclic group (eg, pyrazolyl or triazolyl), and the heterocyclic group is optionally substituted with one or more R ^a groups. , and the R ^a group selected from: = S (e.g., dihydro-triazole (triazole) thione).

In one embodiment, R ^1a represents -COOR ⁴ (eg, -COOMe).

In one embodiment, R ^1a represents a -CO-heterocyclyl (eg, -CO-morpholinyl).

In one embodiment, R ^1a represents -(CH ₂ ) _s -CN (eg, -CH ₂ -CN).

In one embodiment, R ^1a represents -(CH ₂ ) _n -NR ⁴ COR ⁵ (eg, -CH ₂ -NHCOMe).

In one embodiment, R ^1a represents -NR ⁴ R ⁵ . In still another embodiment, R ⁴ and R ^{5 each} represent hydrogen, or one of R ⁴ and R ⁵ represents hydrogen and the other represents C _1-6 alkyl (eg, ethyl).

In one embodiment, R ^1a represents -CONR ⁴ R ⁵ (eg, -CONHMe).

In one embodiment, u represents 0 or 1.

In one embodiment, A represents an aromatic carbocyclic group (eg, phenyl), and the aromatic carbocyclic group is optionally substituted with one or more R ^a groups, and R ^a The group is selected from a C _1-6 alkyl group (e.g., methyl).

In one embodiment, A represents an aromatic heterocyclic group (eg, pyridyl, pyrazolyl, indolyl or indazolyl), and an aromatic heterocyclic group thereof The group may be optionally substituted with one or more R ^a groups, and the R ^a group thereof is selected from a halogen (e.g., chlorine).

In one embodiment, when A represents an unsubstituted phenyl group, an unsubstituted thienyl group or a phenyl group substituted with a -OH, -OMe or -NH ₂ group, R ² represents a selectivity. An aryl or heterocyclic group substituted with a ground.

In one embodiment, when A represents unsubstituted phenyl, unsubstituted thiazolyl, phenyl substituted via a CN group, unsubstituted pyridinyl or unsubstituted In the case of a thienyl group, R ² represents a non-4-methoxyphenyl group or an aryl or heterocyclic ring substituted with -(CH ₂ ) _s -NR ^x R ^y , -Y-aryl or -Z-heterocyclyl. Base group.

Preferably, the specific example shown by the above formula (II) is the one referred to in the above formula (I).

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, 118 , 132, 157, 167, and 235.

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 associated disease is a non-tumor related disease (eg, any of the diseases discussed herein other than cancer). In one embodiment, the fibroblast growth factor receptor (FGFR) enzyme-associated disease refers herein to the state of a disease. In one embodiment, the fibroblast growth factor receptor (FGFR) enzyme associated disease is referred to herein as a bone health condition. Special variants of human bone growth include: abnormal cranial osteogenesis (craniosynostosis), apex (Apert (AP) syndrome), Crouzon syndrome, Jackson-Weiss syndrome , Beare-Stevenson cutis gyrate syndrome, Pfeiffer's syndrome, achondroplasia, and thanatophoric dwarfism (thanatophoric dysplasia).

In particular, unless otherwise specified, the relevant examples of the chemical formula (I) include sub-formulas such as (Ia), (Ib), (Ic), (Id), (Ie), (If) , (Ig) and chemical formula (II), and chemical formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) subgroups (sub-group) ), examples or embodiments.

Thus, for example, an example of a therapeutic use, a pharmaceutical formulation that is poly-related to formula (I), and a compound preparation step, also represent chemical formulas (I), (Ia), (Ib), (Ic), (Id) , (Ie), (If), (Ig), (II), and chemical formula Subgroups, examples or examples of (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (II).

Similarly, preferred embodiments, examples or examples of the compounds of the formula (I) can also be applied to the chemical formulas (I), (Ia), (Ib), (Ic), (except where specifically stated otherwise). Id), (Ie), (If), (Ig), (II), and Chemical Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), Ig) and subgroups, examples or examples of (II).

Preparation of a compound as shown in formula (I)

In this unit, as with other units, unless otherwise indicated, each reference meaning in the formula (I) is the same as that in the formula (II), and the other subgroups and the representative meanings of the examples are as follows.

The compound of the formula (I) can be prepared by a technique known to those skilled in the art. In particular, the compound of formula (I) may be via an aromatic chloride, bromide, iodide or pseudo-halogen such as trifluoromethanesulphonate, triflate or p-toluene. Tosylate, prepared by coupling with an aromatic boronic acid or a stannane derivative under the catalysis of palladium. In particular, Suzuki coupling reactions are widely used to synthesize such compounds. Suzuki coupling reaction may be under normal conditions, a palladium catalyst (e.g., bis (tri -t- butylphosphine) palladium (bis (tri- t -butylphosphine) palladium ), tetrakis (triphenylphosphine) palladium (tetrakis (triphenyl -phosphine) -palladium)) a base or a palladium catalyst (palladacycle catalyst, such as: in Bedford, RBand Cazin, CSJ (2001 ) Chem.Commun, 1540-1541 described herein of an alkali palladium catalyst), with a base (e.g. It is prepared in the presence of a carbonate similar to potassium carbonate. 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 heating. To a temperature of 80 ° C or higher (eg, over 100 ° C).

As shown in Reaction Scheme 1, the imidazo[1,2-a]pyridine core can be obtained from commercially available starting materials using Formula A (to obtain 3,7 pairs). Synthesized by substituting a ring or formula C (to give a 3,6 disubstituted ring).

Dissolving 4-chloro-pyridin-2-ylamine or 4-bromo-pyridin-2-ylamine in a suitable solvent And refluxing with chloroacetaldehyde to obtain the imidazole pyridine ring. The 7-chloro-imidazo[1,2-a]pyridine dissolved in a suitable solvent can be subsequently iodinated, for example: N at room temperature - N-iodosuccinimide is iodinated.

For example, a metal catalyzed reaction can be used to allow the appropriate functional groups to be added to the halogen. In particular, a suitably functionalized boric acid or a boronic ester thereof can be reacted with a haloaryl group. Such a transformation reaction, generally referred to as the Suzuki reaction, can be referred to in the text of Rossi et al (2004) Synthesis, 15 , 2419.

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-dioxane, 1,2-dimethoxyethane, acetonitrile, N-methylpyrrolidone, ethanol, methanol, and Dimethylformamide. The reaction mixture is then heated to, for example, a temperature in excess of 100 °C. The reaction is carried out under an alkaline environment. Suitable bases include: sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate. Examples of suitable catalysts include: bis(tri-t-butylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bistriphenylphosphinepalladium dichloride, palladium acetate (II) , tetrakis(triphenylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, dichloro Bis(trimethoxyphosphoryl)palladium(II), 2'-(dimethylamine)-2-biphenylphosphonium palladium(II) bis-dihydrocycloheptene phosphine complex and 2-(dimethylamine a ferrocene-1-yl-palladium(II) chloride 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-butylphosphine, 2,2-bis(diphenylphosphino)-1,1-binaphthalene, triphenylphosphine, 1,2-bis(diphenylphosphine) Ethane, 1,1'-bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, 9,9-dimethyl-4,5-bis(diphenylphosphino)oxaxene, 1,3 - bis(diphenylphosphino)propane, 2-(di-t-butylphosphino)diphenyl, 2-dicyclohexylphosphino-2'-(n,n-dimethylamine)diphenyl, three O-tolylphosphine, 2-(dicyclohexylphosphine)biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tris(2-furyl)phosphine, 2- Dicyclohexylphosphine-2',6'-dimethyl Oxybiphenyl and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl.

Other examples of functionalization of the halogen 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' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of Organo Palladium Chemistry for Organic Synthesis [Volume 1, Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

In particular, one can be used to convert the arylamine to a Buchwald-Hartwig type reaction via palladium catalysis (see Review: Hartwig, JF (1998) Angew. Chem. Int. Ed. 37, 2046-2067). To an aryl halide or pseudo halide (e.g., trifluoromethanesulfonate (triflate as a)) as a starting material, the reaction system in which a strong base, such as sodium tert-butoxide (sodium tert -butoxide) and a palladium catalyst (such as: Tris-(dibenzylideneacetone)-di-palladium, Pd ₂ (dba) ₃ ) or 2,2'-bisdiphenylphosphine-1,1'-binaphthyl (2,2) The reaction was carried out in the presence of '-bis(diphenylphosphino)-1'1-binaphthyl, BINAP).

Specifically, as the compound of the formula (II), the aryl halide can be obtained by using a metal catalyst (for example, bistriphenylphosphorium dichloride palladium) and 3-aminobenzeneboronic acid. The reaction forms an amine precursor prior to the formation of urea, amide, and secondary amine bonds.

The reaction sequence in Reaction Scheme A can be substituted in the order of Reaction Scheme B. As shown in the reaction scheme 2, the halogen group at the 7th position of imidazo[1,2-a]pyridine can be replaced with a boronic acid group or an ester group for other use. This can then be used directly in any of the metal catalyzed reactions described herein. For example, when a halogen is to be converted to a boronic acid group, the halogen is suitably boron-doped with a palladium catalyst and a phosphine coordination based on a suitable alkali-containing (eg, KOAc) solvent (eg, dioxane). Substituted by the compound.

General formula E

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 (for example, using Raney nickel catalyst), hydrolysis, deprotection, and oxidation.

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.

An amide bond can be obtained by a carboxylic acid or a reactive derivative thereof Prepared 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 generally used to form a peptide linkage. Examples of such agents include: dicyclohexyl carbodiimide (1,3-dicyclohexylcarbodiimide, DCC, refer to Sheehan et al (1955) J.Amer.Chem Soc 77, 1067.), 1- ethyl-3- (3'-dimethylaminopropyl)-carbodiimide, EDC, see Sheehan et al (1961) J. Org. Chem., 26 , 2525 ), an uronium-based coupling agent, such as 7- O- (7-azobenzotriazol-1-yl) -N,N,N',N' -tetramethylurea Fluorophosphate ( O- (7-azabenzotriazol-1-yl) -N,N,N',N'- tetramethyluronium hexafluorophosphate,HATU,refer to Carpino, LA (1993) J.Amer.Chem.Soc., 115 , 4397), and a phosphonium-based coupling agent, such as 1-benzo-triazolyloxytris (pyrrolidino) phosphoonium Hexafluorophosphate, PyBOP, can be found in Castro et al (1990) Tetrahedron Letters , 31 , 205). The carbodiimide-based coupling agent can be further combined with 1-hydroxyazabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt). Used together (in combination) (refer to Konig et al , Chem. Ber. , 103, 708, 2024-2034). Preferred coupling reagents include EDC and DCC in combination with HOAt or HOBt.

Generally, the coupling reaction is carried out in a non-aqueous, aprotic solvent (eg acetonitrile, dioxane, dimethylsulphoxide, dichloromethane, dimethylformamidine). The amine, or N-methylpyrrolidone, is carried out or optionally in an aqueous solvent with the addition of one or more miscible co-solvents. The reaction can be carried out at room temperature or when the reactivity of the reactants is poor (for example, an electron-withdrawing aniline which is similar to the electron-deficient group of sulphon amide). The reaction can also be carried out in a non-interfering base, for example, in a tertiary amine such as triethylamine or N,N -diisopropylethylamine.

Further, a reactive derivative of a monocarboxylic acid (e.g., an anhydrous compound or an acid chloride) can be used. The reaction with a reactive derivative (e.g., an anhydride) is generally carried out by stirring an amine and an anhydrate at room temperature in an environment of a base such as pyridine.

An amine can be obtained by reducing a nitrogen compound in a standard state. For example, the reaction may be subject to catalytic hydrolysis at room temperature in a polar solvent (eg, ethanol or dimethylformamide) and in the presence of a catalyst (eg, palladium on carbon). affected.

Urea is also prepared using standard methods. For example, such compounds can be prepared 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 (I) can be obtained by reacting an amine with an appropriately substituted amine in a carbonyl diimidazole (CDI). The reaction is generally dissolved in a polar solution The agent (e.g., THF) is heated (e.g., using a microwave heater) to about 150 °C. Coupling of two amines forming urea in a solvent (eg, dichloromethane) at room temperature or lower, in the presence of a non-interfering base such as triethylamine Triphosgene (bis(trichloromethyl)carbonate) is more effective than CDI. Another alternative to CDI is phosgene, not triphosgene.

A compound containing a carbamate as shown in the formula (I) can be obtained by a person having ordinary knowledge by using a standard synthetic amine formate, for example, an amine-based compound and a chemical formula R ¹ -OC ( O)-Cl chloroformate derivative is reacted and obtained in a conventional state.

A compound containing a sulfonamide as shown in the formula (I) can be produced by a standard method of synthesizing sulphonamide. For example, a monoamine compound can be reacted with a sulphonyl chloride group of the formula R ¹ SO ₂ Cl or an anhydride of a formula (R ¹ SO ₂ ) ₂ O. The reaction is generally carried out in a non-interfering base (eg, a tertiary amine (eg, triethylamine, or diisopropylamine, or pyridine)) in an aprotic solvent (eg, acetonitrile, or It is carried out in a monochlorinated hydrocarbon (e.g., dichloromethane). 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 R _1a is a primary amine, the compound of the formula (I) can be obtained by a series of methods using an amine compound. In an environment having a variety of reducing agents may be made with an appropriately substituted aldehydes or ketones of reductive amination (reductive amination) reaction (refer to Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, 1992 , pp898-900). For example, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride in an aprotic solvent (e.g., dichloromethane) at ambient temperature. It can also be obtained by performing a nucleophilic displacement reaction with an amine-based compound and a reactant having a leaving group such as 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-[1,3 , 2] dioxaborolan-2-yl)-phenyl]-urea) or 3-Methoxy-5-nitro-phenyl boronic acid pinacol ester. Such synthetic methods are illustrated herein.

Alternatively, the secondary amine can form a ring with a suitable reactive group via a cyclization reaction, as shown in Reaction Scheme 4.

The reaction is carried out in an anhydrous solvent (e.g., toluene), the amine compound and 1,1'-thiocarbonyldi-2(1H)-pyridone (1,1'-thiocarbonyldi-2(1H)- 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 cyclization product, so a separate separation step may be required.

When R ¹ is another example (eg, thiourea, thioamide, thiocarbamate (eg, O-substituted thiocarbamates or S-substituted thiocarbamates), dithiocarbamate, amidine, and guanidine time), are compounds of formula (I), it may be via the amine intermediate using a range of conventional art of a functional group interchange (interconversion) method obtained (refer to Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons , 1992).

Such reaction is used as the appropriate starting materials and the reactants are all commercially available, or widely known or by the step of synthesized standard synthetic (as seen Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, 1992, and Organic Syntheses , Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995, or reference to the methods described in the Examples below). 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 standard synthetic procedures well known, for example from Miyaura, N. and Suzuki, A. (1995) Chem. Rev. , 95 , 2457. The method shown is made. In this manner, after reacting the corresponding boron compound with monoalkyllithium (e.g., butyllithium) and then reacting with a boronic acid ester (e.g., ( ⁱ PrO) ₃ B), a boronic acid group can be obtained. The reaction is carried out in a dry polar solvent such as tetrahydrofuran and in a low temperature environment (e.g., -78 ° C). Borate (e.g., pinacol boronate (pinacolatoboronate) frequency) may also consist of a boron compound with a two boronic ester (e.g., (pinacolato boronate (bis (pinacolato) diboron)) double frequency at phosphine (eg, tricyclohexyl-phosphine), and the presence of a palladium (0) reagent (eg, tris (dibenzylideneacetone)-dipalladium (0)) The reaction is carried out in the following manner. The reaction of the borate formation is generally carried out in a dry polar aprotic solvent (e.g., dioxane or DMSO), heated to about 100 ° C, or, for example, 80 ° C. It is desirable that the borate derivative obtained can be hydrolyzed to give the corresponding boric acid or converted to 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.

Pyrazole [1,5-a]pyrimidine (Pyrazolo[1,5-a]pyrimidine)

Its pyrazolo[1,5-a]pyrimidine can be suitably substituted with aminopyrazole (VI) and fragment (VII) (fragment (VII) Syntheticly obtained as shown in Reaction Scheme 5A, and wherein R _a can be hydrogen or R ₁ . This reaction can be carried out in a single step or in two steps, wherein X ₁ and X ₂ are electrophilic carbons (ie, carbonyl, masked carbonyl (ie, acetal), enamine, conjugated olefin Or alkyne) (Perkin I, JCS (1979), 3085-3094). X ₃ is a suitable substituent which is R ₂ or a group such as a halogen or a pseudohalogen which can introduce R ₂ into the reaction. A substituted pyrazole [1,5-a]pyrimidine can be prepared by cyclization of pyrazole (VI) with a suitably 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 an additive (for example, piperidine, sodium ethoxide, HCl, AcOH, pTsOH, or ZnCl ₂ ) is among them (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).

A special synthetic reaction scheme for the preparation of 3,7-disubstituted pyrazole [1,5-a]pyrimidine (Pyrazolo [1,5-a] pyrimidine) is shown in Reaction Scheme 5B. 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)-malonaldehyde) or by a latent functionality (e.g., as desired). Substituted by a halogen in 2-bromo-malonaldehyde, and further derivatized at the position of the substitution, as shown in the reaction scheme shown below.

In a cyclization reaction, a malonaldehyde dissolved in a solvent is added to the 3-aminopyrazole followed by an acid (e.g., glacial acetic acid). The reactants are then subjected to a cyclization reaction by heating under reflux. Thereby, the compound represented by the formula (I) can be synthesized via a halogenation reaction and a metal catalytic reaction described herein.

The compounds of the formulae (VI) and (VII) are generally known compounds which can be synthesized by well-known techniques. Many of the pyrazoles of formula (VI) are commercially available. Alternatively, it may be synthesized starting from a ketone by a known technique (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 the pyrazole in the formula (VI) or the compound represented by the formula (I) by a standard method. It is prepared by conversion to an R ¹ functional group, wherein R _a is hydrogen, halogen, nitrogen, ester, or amide. For example, when R ¹ is a halogen, a coupling reaction with tin or palladium can be performed.

Pyrazole [1,5-a]pyrazine (Pyrazolo[1,5-a]pyrazine)

Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions, a suitable solvent and a base (eg, DMF/Et ₃ N), with ethynyl-trimethyl-silane, using a palladium catalyst (eg, Pd(PPh ₃ ) ₄ ), at room temperature to give 2-bromo- 5-Bromo-5-trimethylsilanylethynyl-pyrazine. This material can be purified without further reaction and can then be reacted with O-(mesitylenesulfonyl)hydroxylamine to form an N-amino adduct (ie, 6-bromo- 2-bromo-2-trimethylsilanyl-pyrazolo [1,5-a]pyrazine). And cyclization with a base (eg, K ₂ CO ₃ ) to form a pyrazolopyrazine core, as shown in Reaction Scheme 6.

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.

Pyrazolo[1,5-a]pyridine

3-Bromopyridine is reacted with an appropriately substituted boric acid in a solvent (eg, DME containing a base (Na ₂ CO ₃ ) under inert conditions) and a palladium catalyst to form a 3-substituted pyridine (eg, a reaction scheme) Figure 7). Next, under inert conditions, O-(Mesitylenesulfonyl)hydroxylamine is reacted with 3-substituted pyridine to form N-aminopyridine, which is an N-amine. The pyridine can be used directly without further purification. N-adduct is used in an inert environment using a base (K ₂ CO ₃ ) and 2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester Cyclization is carried out to give 3-carboxylate pyrazole [1,5-a]pyridine. The carboxylic acid ester can be removed by, for example, a saponification reaction using 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 the catalytic reaction of a metal catalyst to reverse the halogen aryl group with N-iodosuccinimide. Should be completed.

Imidazo[4,5-b]pyridine

The imidazo[4,5-b]pyridine ring system can be derived from aniline and 2-chloro-3-amino pyridine using, for example, J. Heterocyclic Chemistry (1983), 20 (5 ). ) , the method described in 1339 is obtained by reaction (as shown in Reaction Scheme 8).

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

The above-mentioned similar haloaryl group can be subjected to a series of metal catalyzed reactions to form a desired compound of the formula (I).

Imidazo[4,5-c]pyridine

The 3-aryl-3H-imidazo[4,5-c]pyridine ring system can be obtained from a 3H-imidazo[4,5-c]pyridine and an aryl iodide using, for example, Biorg. Med. Chem. Lett. (2004 ), the method described in 14 , 5263 is obtained by reaction (as shown in Reaction Scheme 10).

It is known that 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).

N-oxide can be prepared by reaction with an oxidizing agent such as 3-chloroperbenzoic acid, and the N-oxide can be rearranged with each reactant (eg, POCl ₃ , SOCl ₂ ) A disubstituted 3H-imidazo[4,5-c]pyridine is formed. 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.

Another example is shown in Reaction Scheme 12. The synthesis of 6-chloro-3H-imidazo[4,5-c]pyridine is described in J. Heterocyclic Chem (1965), 2(2) , 196-201 in the text. In the presence of a metal catalyst (e.g., palladium), the chloro group can be substituted with a nucleophilic group to provide an aryl and amine substituted product. In this process, a protecting group (e.g., a carbamate or a phenyl group) can be used. The N-aryl compound can then be further processed via the process as shown in Reaction Scheme 10.

1,5-Diaryl-1H-benzoimidazole

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

The fluorine is replaced by 4-bromo-1-fluoro-2-nitrobenzene-benzene into an aniline, followed by reduction and cyclization with triethyl orthoformate to obtain a substituted bromo-benzene. And bromo-benzoimidazole.

The product can be further reacted with bromine under metal catalysis to form 1,5-disubstituted benzimidazole.

Imidazo[1,2-c]pyrimidine (imidazo[1,2-c]pyrimidine)

The disubstituted imidazo[1,2-c]pyrimidine can be prepared via the preparation procedure as in Reaction Scheme 14.

This reaction is initiated by 7-chloro-imidazo[1,2-c]pyrimidine, the synthesis of which is described in Yanai et al, Heterocyclic compounds. XVIII Synthesis of imidazo [1,2-c]-and pyrimido [1,2-c]pyrimidine derivatives, Yakugaku Zasshi (1974), 94(12) , 1503-14. This material can be further processed using any of the above reactions.

Alternatively, when the first position is a nitrogen attached 7 saturated heterocyclic group, for example: morpholine (morpholine), it may be a S _N Ar reaction (e.g., in "Advanced Organic Chemistry" by Jerry March , 4 th edition, The S _N Ar reaction described in pages 641-644) is, for example, the embodiment described in U.S. Patent 4,503,050, as shown in Reaction Scheme 15.

When the 7th position is an aryl or heteroaryl group, the S _N Ar group can be replaced by a similar compound using a standard cross-coupling reaction (as shown in Reaction Scheme 16). ).

Imidazo[1,2-c]pyrimidin-5-one

3,7 disubstituted imidazo[1,2-c]pyrimidin-5-one may be 7-chloro-6H-imidazo[1,2-c]pyrimidin-5-one (7-Chloro-6H-imidazo[1,2 -c]pyrimidin-5-one, CAS number 56817-09-5) is prepared as a starting material, such as Maggiali et al (1982) Acta Naturalia de l'Ateneo Parmense, 18(3) , 93- 101 and Bartholomew et al (1975) Journal of Organic Chemistry, 40 (25) , 3708-13.

7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one (7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one) can be substituted by nucleophilic substitution (eg, S _N Ar reaction) is induced or added using a Suzuki reaction based on the 7th position (eg, Reaction Scheme 17). This compound can be iodinated as described above prior to further functionalization using the Suzuki reaction.

Alternatively, 7-chloro-6H-imidazo[1,2-c]pyrimidin-5-one (7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one) can be directly iodinated The following intermediates are used in the reactions described herein (eg, Reaction Scheme 18)

Further, other oxygen-containing heterocycles can be synthesized by appropriately hydrolyzing a chlorine derivative. The protecting compound is subjected to alkaline hydrolysis to afford the pyridone. And the reaction can be used in H ₂ O / MeOH or H ₂ O / dioxane solution of NaOH (or NaOH / H ₂ O ₂ ), using literature (eg, Australian J. Chem. (1984), 37 ( 12) , chloropyridine hydrolysis as described in 2469-2477).

Imidazo[1,2-b]pyridazine

The synthesis of the compound imidazo[1,2-b]pyridazine nucleus can be carried out using a pyridazin-3-yl amine derivative in the reaction scheme. For the synthesis of the method described in 19, reference is made to J. Heterocyclic Chem. (2002), 39(4) , p737-742. For the substitution method at the third position, reference may be made to the examples in J. Med. Chem (2006), 49(4) , p1235-1238 to obtain a compound substituted at the 3,7 position.

The synthesis of other heterocycles can be carried out using conventional techniques such as Comprehensive Heterocyclic Chemistry I (Edited by ARKatritzky, CWRees, Elsevier, 1982) and Comprehensive Heterocyclic Chemistry II (Edited by ARKatritzky, CWRees, EFVScriven, Elsevier , 1996, ISBN 0-08-042072-9).

In many of the above reactions, it may be necessary to protect one or more substituent position groups to prevent substitution of the substituents to undesired positions while the reaction is proceeding. Examples of protecting groups, as well as methods for protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example, the monohydroxy group may be protected as an ether (-OR) or a monoester (-OC(=O)R), for example: t-butyl ether; monophenyl, diphenylmethane (benzhydryl, diphenylmethyl), or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyldimethylsilyl ether; or acetate (-OC ( =O)CH ₃ , -OAc)). For example, the monoaldehyde or ketone may each be protected in the form of an acetal (R-CH(OR) ₂ ) or a ketal (R ₂ C(OR) ₂ ), wherein the acetal and the acetal The carbonyl group (>C=O) in the ketone is converted to a diether by, for example, a reaction 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 may be protected by the form of amide (-NRCO-R) or urethane (-NRCO-OR), for example: monomethyl decylamine (-NHCO-CH ₃ ); Benzyloxy amide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); t-butoxy amide (-NHCO-OC(CH ₃ ) ₃ , -NH -Boc); 2-biphenyl-2-propoxy amide, -NHCO-OC(CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ , -NH-Bpoc ), 9-fluorenylmethoxy amide (-NH-Fmoc), 6-nitroveratryloxy amide (-NH-Nvoc), 1-2-3 2-trimethylsilylethyloxy amide (-NH-Teoc), 2,2,2-trichloroethyloxy amide (-NH-Troc) , allyloxy amide (-NH-Alloc), or 2 (-phenylsulphonyl) ethyloxy amide (-NH-Psec). Other protecting groups for protecting amines (eg, cyclic amines and heterocyclic NH groups) include: toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups, and a phenyl group (eg, a para -methoxybenzyl (PMB) group. The monocarboxylic acid group may be protected as a monoester, for example, a C _1-7 alkyl ester (eg, a monomethyl ester; a tert-butyl ester); a C _1-7 haloalkyl ester (eg, a C _1-7 trialkyl ester); a tri C _1-7 alkyl decyl-C _1-7 alkyl ester; or a C _5-20 aryl-C _1-7 alkyl ester (eg, monophenyl ester; monophenyl phenyl ester); alternatively, amide is protected via methyl amide. For example, a thiol group is protected by a thiol ether (-SR), for example, benzyl thioether; acetamidomethyl ether (-S-CH ₂ NHC) (=O)CH ₃ ).

The key intermediate in the preparation of the compound of formula (I) is a compound of formula (XX). A novel chemical intermediate as shown in formula (XX) is another aspect of the invention.

Another aspect of the present invention is the preparation of a compound of the formula (I), which comprises: (i) a compound of the formula (XX) or (XXI) or a protective form thereof, as appropriate Substituted isocyanate or an appropriately substituted amine in the presence of carbonyl diimidazole (CDI); or

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

(iii) a compound of the formula (XX) or (XXI) wherein X _1-5 , A, and R ₂ are as defined herein, or a protected form thereof and an appropriately substituted carboxylic acid or active Derivative reaction

Next and remove any protective groups that appear; And then one of the compounds of formula (I) is selectively converted to another compound of formula (I).

In one embodiment, the step of preparing a compound of formula (I) further comprises: (iv) reacting a compound as shown in formulas (V) and (VI), In which R ¹ and R ² on the same line of formula (I) R in the compounds represented by the defined ¹ and R ^2.

In one embodiment, R ¹ represents -NHCON(H)(C _1-6 alkyl) or -NHCON(H)(CH ₂ CF ₃ ), and R ² represents 4-fluorophenyl.

In another aspect of the invention, a novel intermediate product is provided. In one embodiment, the novel intermediate product is selected from the group consisting of: 1-(3-bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-) Phenyl)-3-(2,2,2-trifluoro-ethyl)-urea); 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine); and 7-(4-fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine (7- (4-Fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine).

a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative 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. Preferred examples and embodiments thereof are described herein.

Unless otherwise specified, the reference meaning of a particular compound in the text may also refer to its ionic form, its salts, its solvates (solvates), its isomers, its tautomerism. Tautomer, its N-oxide, its ester compound, its prodrug, its isotope, and its protective form, for example, as described below; preferably its ionic form Or a salt thereof or a tautomer thereof or an isomer thereof or an N-oxide thereof or a solvate thereof; and more preferably, an ionic form thereof, or a salt thereof or a tautomer thereof or a solvent thereof Compound or its protective form. Many of the compounds of formula (I) may exist in the form of their salts, for example, acid addition salts or, under special conditions, organic and inorganic base salts (eg, carboxylic acids, sulfonic acids, and phosphates). . All of the above salts are included in the scope of the present invention, and the reference meaning of the compound represented by the formula (I) is the salt type of the compound.

The salt in the present invention may be a parent compound containing a base or an acid moiety, for example, Pharmaceutical Salts: Properties, Selection, and Use , P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3 Synthesized by the method described in -90639-026-8, Hardcover, 388 pages, August 2002. In general, the salt can be formed by reacting a free acid or base formed from such a compound with a suitable base or acid in water or an organic solvent, or a mixed solution thereof; and, usually, a non-aqueous phase is used ( For example, 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 (both inorganic and organic). Related acid addition salts include a salt formed from an acid selected from the group consisting of: acetic acid, 2,2-dichloroacetic acid, adipic, alginate, ascorbic, for example, L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+ ) camphoric acid ((+)camphoric), camphor-sulphonic, (+)-(1 S )-camphor-10-sulfonic acid ((+)-(1 S )-camphor-10-sulphonic) , capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, Ethyl-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, Galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (eg, D-glucuronic acid) Glutamate (eg, L-glutamic acid), --ketoglutaric, glycolic acid, hippuric, hydrobromic, hydrochloric, hydriodic, hydroxyethyl sulfonate Acidic acid, lactic acid (such as (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic, (-) -L-malic acid ((-)-L-malic), malonic acid, (±)-DL-malonic acid ((±)-DL-mandelic), methanesulphonic, naphthalene Sulfonic acid (naphthalenesulphonic, such as naphthalene-2-sulphonic), naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic acid ( 1-hydroxy-2-naphthoic), nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamomic, Phosphoric acid, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic ), stearic, succinic, sulphuric, tannic, (+)-L-tartaric acid ((+)-L-tartar IC), thiocyanate (thiocyanic), toluenesulfonic acid (toluenesulphonic (e.g., p-toluenesulfonic acid (p -toluenesulphonic)), undecylenic acid (undecylenic) and pentanoic acid (valeric acid), such as the acylated amine Acid (acylated amino acid) and cation exchange resin.

A special group of salts comprises one selected from the group consisting of: acetic acid, hydrochloric, hydriodic, phosphoric acid, nitric, lactic acid, succinic, horse. Maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic Sulfonic acid (methanesulphonic; mesylate), ethanesulphonic, naphthalenesulphonic, valeric acetic acid, propionic acid, butyric acid, malonic acid, malonic acid a salt formed from glucuronic and lactobionic.

Another group of acid addition salts comprises one selected from the group consisting of: acetic acid, adipic, ascorbic, aspartic, citric, DL-lactic. , fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, 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.

Assuming it is an anionic compound, or with a functional group of an anionic (e.g., -COOH may be -COO ^-), then it may be formed of a suitable salt with a cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (eg, Na ⁺ and K ⁺ ), alkaline earth metal ions (eg, Ca ²⁺ and Mg ²⁺ ), and other cations (eg, Al ³⁺ ). . Examples of suitable organic cations include, but are not limited to, ammonium ions (NH ₄ ⁺ ) and substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ).

An example of a suitable ammonium ion is via: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, Diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amine groups An ammonium ion derived from an acid (eg, lysine and arginine). One example of a quaternary ammonium is N(CH ₃ ) ₄ ⁺ .

The compound containing an amine functional group as shown in the formula (I) may be obtained by a reaction of a quaternary ammonium salt, for example, a person having ordinary knowledge and an alkylating group reagent by conventional techniques (alkylating Agent) obtained by reaction. Such quaternary ammonium is also included in the range of the chemical formula (I).

The salts of the compounds of the present invention are conventional pharmaceutically acceptable salts, and related examples of pharmaceutically acceptable salts are described in Berge et al . (1977) "Pharmaceutically Acceptable Salts," J. Pharm. Sci. , Vol.66, pp.1-19 is discussed in the article. However, the non-pharmaceutically acceptable salt can also be an intermediate 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.

A compound having an amine functional group as shown in the formula (I) may also form an N-oxide. An N-oxide is also included in the examples of the compound having an amine functional group represented by the formula (I).

A compound having a plurality of amine functional groups, wherein one or more nitrogen atoms can 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.

N- oxides may be by the corresponding amine with an oxidizing agent (e.g., hydrogen peroxide or a peracid (e.g., peracetic acid)) to give the reaction, see Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, an example in pages. Furthermore, N- oxides may LWDeady (Syn.Comm. (1977), 7, 509-514) the preparation of step, and wherein the amine compound is m-chloroperbenzoic acid (m -chloroperoxybenzoic acid, MCPBA), For example, the reaction is carried out in an inert solvent such as dichloromethane. Specific examples of N-oxides include: morpholine N-oxides and pyridine N-oxides.

The compound represented by the formula (I) may have various stereoisomers and tautomerics, and the compound represented by 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 scope of the chemical formula (I).

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, thioketone ) / enethiol, and nitro / aci-nitro.

Unless specifically claimed in the context, a compound of formula (I) comprises one or more chiral centres and may exist in two or more optical isomers as shown in formula (I) Examples of compounds include all optical isomers (eg, enantiomers, epimers, and diastereoisomers), and individual optical isomers (individuals) Optical isomer), or a mixture (eg, a racemic mixture) or two or more optical isomers.

This optical isomer can be distinguished by its optical activity (ie, + and - isomers, or d and l isomers), or by the "R and S" nomenclature proposed by Cahn, Ingold, and Prelog. out, please refer to Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and Cahn, 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 conventional techniques.

Another method for separating optical isomers other than palm chromatography can be by palm acid (eg, (+)-tartaric acid, (-)-pyroglutamic acid ((-)-pyroglutamic acid), -)-(-)-di-toluoyl-L-tartaric acid, (+)-malonic acid ((+)-mandelic acid), (-)-malic acid (( -)-malic acid), and (-)-camphorsulfonic acid ((-)-camphorsulphonic) forms a salt of a diastereoisomer, separates the non-corresponding isomer by preferential crystallization, and then separates the salt to obtain a single species in a free base Mirroring isomers.

The compound represented by the formula (I) has two or more optical isomeric forms, and one of the pair of enantiomers may have better properties than the other, for example, biological activity. Thus, in some instances, only one of the mirror image isomers may be used for medical purposes or may comprise one of a plurality of non-reciprocal isomers. Accordingly, the compound of formula (I) as provided in the present invention has more than one chiral centre wherein at least 55% of the compound of formula (I) (eg, at least 60%) , 65%, 70%, 75%, 80%, 85%, 90%, or 95%) is a single optical isomer (eg, an enantiomer or a diastereoisomer) The form exists. In a typical embodiment, 99% or more (i.e., almost all) of the compound represented by the formula (I) may be a single optical isomer (i.e., mirror image isomer or non- The form of the corresponding isomer) exists.

The compounds of the present invention comprise a compound having one or more isotopic substitutions, and the reference meaning of a particular element also encompasses all isotopes of the element. For example, the reference meaning of hydrogen includes ¹ H, ² H(D), and ³ H(T). Similarly, the reference meanings of carbon and oxygen each include ¹² C, ¹³ C, and ¹⁴ C and ¹⁶ O, and ¹⁸ O.

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, A compound may contain one or more radioisotopes. Such 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). In one embodiment of the present invention, the range represented by the formula (I) also includes a compound represented by the formula (I) having a carboxylic acid group or a monohydroxy group. In another embodiment of the present invention, the range represented by the formula (I) does not include an ester of the compound of the formula (I) having a carboxylic acid group or a monohydroxy group. An example of a related ester is a compound containing a -C(=O)OR group, wherein R is a monoester substituent such as a C _1-7 alkyl group, a C _3-20 heterocyclic group, or a C _{5- 20} aryl, preferably a C _1-7 alkyl group. Examples of specific ester groups include, but are not limited to: -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -C(=O)OC(CH ₃ ) ₃ , and -C (=O) OPh. Specific examples of acyloxy groups include, but are not limited to: -OC(=O)CH ₃ (acetoxy), -OC(=O)CH ₂ CH ₃ , -OC(= O) C(CH ₃ ) ₃ , -OC(=O)Ph, and -OC(=O)CH ₂ Ph. In addition, included in the formula (I) also includes a plurality of forms of any compound, a solvent compound of the compound (such as a hydrate), a complex (for example, a package formed with a compound such as cyclodextrin). An inclusion complex or a clathrate, or a complex with a metal, and a prodrug. By "prodrug" is meant, for example, any compound that is biologically active as shown in formula (I) in vivo.

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(=O)OR) are cleaved to form an active drug. Such an esterification can be formed by esterification, for example, esterification of a carboxylic acid group (-C(=O)OH) 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(=O)OR wherein R is: _C1-7 alkyl (eg, -Me, -Et, -nPr, -iPr, -nBu) , -sBu, -iBu, -tBu); C 1-7 aminoalkyl (C _1-7 aminoalkyl) (e.g., aminoethyl; 2- (N, N- diethylamino) ethyl; 2- (4-morpholino) ethyl (2- (4-morpholino) ethyl )); and C _1-7 alkyl carboxylic acyl oxygen (acyloxy-C _1-7 alkyl) (e.g., methyl acyl oxymethyl; A Ethoxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl) 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl); 1-(benzoyloxy)ethyl; 1-isopropyloxy Isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonoxyl (1-cyclohexyloxy-carbonyloxyethyl); 4-(tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbenyloxy 1-(4-tetrahydropyranyloxy)carbonyloxyethyl); (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonium 1-(4-tetrahydropyranyl)carbonyloxyethyl)). In addition, some prodrugs are active compounds obtained by enzymatic activation, or active compounds obtained by chemical reaction (for example, antigen-directed enzyme pro-drug therapy (ADEPT), gene-specific Gene-directed enzyme pro-drug therapy (GDEPT), and ligand-directed enzyme pro-drug therapy (LIDEPT). For example, the prodrug can be a monosaccharide derivative or other glycoside conjugate, or can be an amino acid ester derivative.

References to the "derivative" include: ionic forms, salts, solvent compounds, isomers, tautomers, N-oxides, esters, prodrugs, isotopes, and Protective 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 present invention, a definition is provided as defined in the text. Compound or salt, solvent compound.

Compounds of the formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (II), (Ia), (Ib) And (Ic), (Id), (Ie), (If), (Ig), and (II), and the reference meanings of the subgroups thereof as defined herein, include salts of the compounds, or solvent compounds, Or tautomers, or N-oxides.

Tyrosine protein kinase (PTK)

The compounds described herein can inhibit or coordinate the activity of certain tyrosine kinases, and thus the compounds can be used in the treatment or prevention of diseases or conditions caused by tyrosine kinases, particularly FGFR.

FGFR

The fibroblast growth factor (FGF) family of tyrosine protein kinase (PTK) receptors regulates a range of physiological functions including: mitogenesis (mitogenesis) ), wound healing (wound healing), cell differentiation, and angiogenesis, and development. Cell growth phenomena of normal and abnormal (eg, proliferation) 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 steroid hormone dependent cancers are exacerbated by hormones (Powers, et al. (2000) Endocr. Relat. cancer, 7 , 165-197).

FGFs and their receptors are expressed in an increased degree in various tissues and cell lines, and their over-expression is thought to be due to the malignant phenotype. In addition, a number of oncogenes with homologues encode growth factor receptors, and there is a potential for abnormal activation of FGF-dependent signaling in human pancreatic cancer (see Ozawa, Et al . (2001), Teratog. Carcinog. Mutagen., 21 , 27-44).

The second prototypic member is acid fibroblast growth factor (FGF), aFGF or FGF1, and basic fibroblast growth factor (basic fibroblast growth factor). (fibroblast growth factor, FGF), bFGF or FGF2), and to date, at least twenty distinguishable FGF family members have been identified. The response of cells to FGFs via four high affinity transmembrane proteins tyrosine-kinase fibroblast growth factor receptor (fibroblast growth factor (FGF) receptor, FGFR ) Transfers 1 to 4 (FGFR1 to FGFR4). By the addition of a ligand, the receptor becomes a dimer and the specific cytoplasmic tyrosine residue is autophosphorylated or auto-or trans-phosphorylate. Signals act as regulatory nuclear transcription factors.

If the path of action of FGFR1 is interrupted, it may cause proliferation of tumor cells, which is caused by the activation of endothelial cells in the form of a tumor. FGFR1 in tumor-related vascular The overexpression and overactivation in (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 by fibroblast growth factor and keratinocyte growth factor ligands. influences. Fibroblast growth factor receptor 2 also has an effect on the osteogenic effects of FGFs during osteoblast growth and differentiation. Mutations in fibroblast growth factor receptor 2, which regulates the developmental sequence of complex functionalities, cause an abnormality in cranial sutures ossification, craniosynostosis, implying FGFR signaling. The effect of the rules on osteogenesis in the membrane. For example, in the case of the apex syndrome (AP, which is a cranial ossification immature phenomenon), most of the examples are related to the enhancement of fibroblast growth factor receptor 2 (gain- Point-of-function mutations (see from Lemonnier, et al . (2001), J. Bone Miner. Res., 16 , 832-845). In addition, from the screening of patients with primary spondylosis (syndromic craniosynostoses) and mutations, the recurrence of FGFR2 mutations is related to the severity of Pfeiffer's disease (cf. Lajeunie et al, European Journal of Human Genetics (2006) 14, 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 include: tower head and Apert, Crouchon's disease, Jackson-Weiss's disease, Beare-Stevenson cutis gyrata's disease, and Pfeiffer's disease, which are associated with fibroblast growth factor. Mutation of the body 2 gene is related. Most, but not all, Pfeiffer Syndrome (PS) is caused by a remutation of the fibroblast growth factor receptor 2 gene (see (1996) Am. J. Hum. Genet., 58 491-498; Plomp, et al . (1998) Am. J. Med. Genet., 75 , 245-251), and recent findings indicate that mutations in fibroblast growth factor receptor 2 disrupt the dominant ligand. One of the main rules of particularity. That is, the interface type of the two fibroblast growth factor receptor mutations, FGFR2c and FGFR2b, have developed the ability to be linked to and activated by atypical FGF ligand. Loss of ligand specificity can cause abnormal signaling, and it is known that the various phenotypes of these symptoms are due to the ectopic ligand of fibroblast growth factor receptor 2 (ectopic ligand). -activated by activation (cf. Yu, et al . (2000), Proc. Natl. Acad. Sci. USA, 97 , 14536-14541).

A genetic abnormality of the FGFR3 receptor tyrosine kinase (eg, chromosomal shift or point mutation) causes ectopic or de- deregulated activation of the FGFR3 receptor. These abnormalities are connected to a subset of multiple myeloma in the bladder, hepatocellular, oral squamous cell carcinoma , and cervical carcinoma ( Reference is from Powers, CJ (2000), et al ., Endocr. Rel. 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 in invasive bladder cancer. FGFR3 is frequently 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 overexpressed tumors do not detect mutations, including many myometrial invasion tumors (muscle-invasive) Tumors).

Thus, a compound which inhibits FGFR can achieve a method for preventing tumor growth or inducing apoptosis of tumor cells, particularly by inhibiting angiogenesis. Therefore, it is expected that this compound is proven to be effective for treating or preventing hyperplastic abnormalities such as cancer. In particular, tumors with activating mutations in receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to these inhibitors. Patients with any of the above-mentioned activating mutations of the specific RTKs isoforms may also find it very economical to treat with RTK inhibitors.

The overexpression of FGFR4 is also associated with prostate and thyroid cancer (see Ezzat, S., et al . (2002) The Journal of Clinical Investigation, 109 , 1; Wang et al . (2004) Clinical Cancer Research, 10 ) . In addition, germline polymorphism (Gly388Arg) is also associated with increased lung, breast, colon, and prostate cancer decline (see Wang et al . (2004) Clinical Cancer Research, 10 ). Furthermore, the truncated form of FGFR4 (region with kinase) was also found in 40% of pituitary tumors, but not in normal tissues.

Recent research indicates that the typical lobular carcinoma (Classic Lobular carcinoma, CLC) in, FGFR1 expression lines and tumor growth (tumorigenicity) related. 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 the case of approximately 50% of lobular carcinoma (CLC), amplification of the 8p12 to p11.2 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 the inhibition of the information transfer process by the amplified fixed reaction lines (see Reis-Filho et al . (2006)). Clin Cancer Res. 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 an over-expression phenomenon in the early stage of rhabdomyosarcoma tumor formation, and hypomethylation with the 5' CpG island (5' CpG island) and abnormal expression of AKT1, NOG, and BMP4 genes. Related (Reference to Genes, Chromosomes & Cancer (2007), 46(11) , 1028-1038).

Fibrosis caused by abnormal or excessive deposition of 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, but it has been attributed to various cytokines associated with increased fibroblasts and ectopic 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 beta (transforming growth factor) Factor beta, TGF- β ) caused by activities. 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 clinical pulmonary fibrosis samples (see Inoue, et al . (1997 &2002); Barrios, et Al . (1997)). It has been reported that TGFβ1 and PDGF are involved in the fibrotic 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 an increase in TGFβ1 (cf. Khalil, et al ., 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, et al ., 2005).

Idiopathic Pulmonary Fibrosis (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 an inability to respond to tissue loss (transfer of oxygen into the blood). Symptoms of this condition include: short-lived, chronic dry cough (chronic dry) Coughing), fatigue, chest pain, and loss of appetite, resulting in rapid weight loss. This condition is very serious and usually has a mortality rate of nearly 50% after more than 5 years.

Vascular endothelial growth factor Factor, VEGFR)

Chronic hyperplasia is usually accompanied by deep angiogenesis, which can cause or remain in an inflammatory and/or hyperplastic state, or cause tissue to be destroyed by invasive proliferation of blood vessels (see from Folkman ( 1997), 79 , 1-81; Folkman (1995), Nature Medicine , 1 , 27-31; Folkman and Shing (1992) J. Biol . Chem ., 267 , 10931).

Angiogenesis is often used to describe new or replaced blood vessels, or neovascularisation. In embryos, the establishment of vasculature is necessary and physiologically normal. But in most mature tissues, angiogenesis usually does not occur except for ovulation, menstruation, or wound healing. However, in many diseases, there is a steady, or cluttered, angiogenesis phenomenon. For example, in arthritic diseases, new microvasculature invades the joint and destroys the cartilage (cf. Colville-Nash and Scott (1992), Ann . Rhum . Dis ., 51 , 919). In the disease of diabetes (and in many different eye diseases), new blood vessels invade into the macula or other ocular structures and may cause blindness (cf. Brooks, et al . (994) Cell , 79 , 1157). ). The process of atherosclerosis is also associated with angiogenesis (cf. Kahlon, et al . (1992) Can. J. Cardiol. , 8 , 60). Tumor growth and metastasis have also been confirmed to be angiogenesis dependent (cf. Folkman (1992), Cancer Biol , 3 , 65; Denekamp, (1993) Br. J. Rad. , 66 , 181; Fidler and Ellis (1994). ), Cell , 79 , 185).

The process of how angiogenesis participates in various diseases is investigated by studies on the identification and inhibition of angiogenesis. Such inhibitors are generally distinguished as: secreted for reactions in the angiogenesis cascade reaction (eg, endothelial cells are activated by angiogenic signals); synthesis of degradative enzymes And release; endothelial cell migration; endothelial cell proliferation; and microvascular formation. Angiogenesis occurs in many stages, so many people try various methods to discover and develop compounds that are used to stop angiogenesis at various stages.

There are some reports that indicate that angiogenesis inhibitors can help with some diseases through separate mechanisms, such as cancer and metastasis (see O'Reilly, et al . (1994) Cell , 79 , 315; Ingber , et al . (1990) Nature , 348 , 555), eye related diseases (cf. from Friedlander, et al . (1995) Science , 270 , 1500), arthritis (cf. from Peacock, et al . (1992), J .Exp.Med. , 175 , 1135; Peacock et al . (1995), Cell. Immun. , 160 , 178), and hemangioma (cf. Taraboletti, et al . (1995) J. Natl. Cancer Inst ., 87 , 293).

Receptor tyrosine kinases (RTKs) play an important role in biochemical signaling between the cytoplasmic membranes of cells. These transmembrane molecules have a special extracellular ligand binding domain, and these extracellular ligand binding regions pass through a segment located between the plasma membrane of the cell and a tyrosine kinase region in the cell. (tyrosine kinase domain) linkage. Binding of the ligand to the receptor results in activation of the receptor-associated tyrosine kinase, which causes the receptor for the tyrosine fragment and other intracellular proteins to be simultaneously phosphorylated, further contributing to a cascade of cellular responses. To date, at least nineteen distinguishable RTK subfamilies have been identified via the similarity of amino acid sequences.

Vascular endothelial growth factor (VEGF), a polypeptide, has been shown to promote endothelial cell division in vitro, but stimulates angiogenesis in vivo. VEGF is also thought to be associated with abnormal angiogenesis (see Pinedo, HM, et al . (2000), The Oncologist , 5 (90001) , 1-2). VEGFR is a protein tyrosine kinases (PTKs). In cell function, PTK catalyzes phosphorylation of specific tyrosine fragments in proteins, thereby regulating cell growth, survival, and differentiation (see Wilks, AF (1990), Progress in Growth Factor 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), Curr. Opin. Immunol. , 8(3) , 394-401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1); VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and are involved in signal transduction (see, from Mustonen, T. (1995), et al. , J. Cell Biol. , 129 , 895-898).

Of particular interest is VEGFR-2, a transmembrane receptor PTK that is initially expressed in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the initial signaling process of tumor angiogenesis. The performance of VEGF may be a positive effect on tumor cells and, due to such stimulation, a response that is promoted. One of the above-mentioned stimuli is tissue hypoxia, which can improve the performance of VEGF in tumors and related host tissues. The VEGF ligand activates VEGFR-2 by binding to the extracellular VEGF binding site. This results in a double polymerization of the receptor for VEGFR and autophosphorylation of the intracellular kinase region of VEGFR-2 of the tyrosine fragment. Its kinase region transfers ATP from ATP to the tyrosine fragment, thereby providing a signalling protein of VEGFR-2 to the downstream binding site, and finally begins angiogenesis (cf. McMahon, G. (2000), The Oncologist , 5 (90001) , 3-10).

Inhibition of the kinase domain binding site of VEGFR-2 will stop the phosphorylation of the tyrosine fragment and interrupt the initial role of angiogenesis.

The angiogenesis is a physiologically occurring step of angiogenesis, which is regulated by various cytokines such as 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 recently researched. 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 angiogenesis in pathophysiologic are still to be studied comprehensively, experimental data show that many angiogenic factors play an important role in the development of the disease. New blood vessel Biologic markers can also be used as a distinguishing indicator 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. The tumor grabs 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 led to the concept of an "angiogenic switch", which stimulates angiogenesis in tumors. Factor 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 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 (eg, thrombospondin (Tsp-1), angiostatin, and endostatin) can be used as a negative regulation of angiogenesis.

In experimental mice, inhibition of VEGFR2 (rather than VEGFR1) is evident An angiogenic hub, the formation of new blood vessels, and initial 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-related proangiogenic factors, including the FGF family. These different pre-angiogenic signals imply the retreat of blood vessels and tumor regeneration, and the blockade of FGF is gradually slowed down by VEGF inhibition. In experimental mice, inhibition of VEGFR2 (but not VEGFR1) significantly affected angiogenesis hubs, 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-related proangiogenic factors, including the FGF family. These different pre-angiogenic signals imply the retreat of blood vessels and tumor regeneration, and the blockade of FGF is gradually slowed down by VEGF inhibition.

It has been reported that an FGF-trap adenovirus can bind to and block various ligands of the FGF family (FGF1, FGF3, FGF7, and FGF10), and can effectively inhibit in vitro collection. Angiogenesis in the body. In fact, the application of the FGF trap treatment method to the regenerative phase of experimental mice is effective in reducing tumor growth relative to the use of anti-VEGFR2 agent alone (anti-VEGFR2). This reduces the growth of tumors The image is accompanied by a decrease in angiogenesis (which is known from the phenomenon that the density of blood vessels in the tumor is reduced).

Batchelor et al. confirmed the use of a pan-VEGF receptor tyrosine protein kinase inhibitor (AZD2171) in the second phase of patients to normalize the blood vessels of the glioblastoma (normalization) The phenomenon (see from Batchelor et al ., 2007, cancer Cell , 11(1) , 83-95). In the case of living breast cancer, the reason for its treatment with AZD2171 is due to the effect of reducing the density of blood vessel distribution (refer to Miller et al ., 2006, Clin. Cancer Res . 12 , 281-288). Furthermore, it has been observed via an 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 content increases, resulting in an increase in interstitial pressure and an increase in tumor permeability. (Reference from Winkler et al ., 2004, Cancer Cell 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. And vascular permeability.

The authors point out that the increase in circulating progenitor cells (CPCs) and plasma FGF2 (plasma FGF2) levels after drug blockade confirms that the use of the AZD2171 treatment line is associated with increased CECs, SDF1, and FGF2. Observed by MRI measurements The plasma level of SDF1 and FGF2 is increased, indicating an increase in relative vessel density and size. Thus, the value of normalization of 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 fine balance between growth-promoting 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 a normal state and function. Malignant cells can escape this control; their natural equilibrium state is destroyed (caused by some mechanisms) and cannot be regulated, resulting in abnormal cell growth. 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 cells. The surface tyrosine kinase receptor (PDGFR) transmits information and stimulates various cellular functions (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)methyl]-N-[4-methyl-3- [[4-(3-Pyridyl)-2-ylpyridinyl]amino]-phenyl]benzoguanamine methanesulfonate (4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-ylpyridinyl]amino]-phenyl]benzamide methanesulfonate), hindered The activity of the Bcr-Abl oncoprotein and the cell surface tyrosine kinase receptor 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 inhibitor of PDGFR kinase and has recently been used to treat chronic myelomonocytic leukemia and based on the activation of PDGFR mutations in these diseases. Used in glioblastoma multiforme. In addition, an oral anticancer drug Sorafenib (BAY 43-9006), chemical name is 4-(4-(3-chloro-4-(trifluoromethyl)phenyl)ureido)phenoxy -N2-methylpyridine-2-carboxamide (4-(4-(3-(4-chloro))))))))) The Raf signaling pathway and the VEGFR/PDGFR signaling cascade are used to inhibit cell proliferation and tumor angiogenesis. Sorafenib is currently being developed for use as a treatment for a range of cancers including hepatitis and kidney cancer.

These symptoms are all diseases associated with PDGFR activation (eg, hypereosinophilic syndrome). Activation of PDGFR is also associated with other malignancy, including chronic myelomonocytic leukemia (CMML). In another malignant disease, dermatofibrosarcoma protuberan, a permeable skin tumor, colocalizes with PDGF-B The reciprocal translocation of the base encodes a constitutive secretion of the chimeric 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 target agents in the treatment of sub-group patients with diseases caused by FGFR regulatory disorders. Compounds with lower inhibitory activity on the activity of additional kinases (particularly VEGFR2 and PDGFR-beta) provide an opportunity to have differentiated side-effect or toxicity profile to make this possible These treatment instructions are more effective. Inhibitors of VEGFR2 and PDGFR-beta are associated with toxicity (eg, associated with hypertension or edema, respectively). When a VEGFR2 inhibitor is used, the condition of hypertension limits the amount of drug used, and thus may limit the use of certain patients and require clinical management.

Biological activity and use of treatment

The compounds of the present invention and subsets thereof inhibit or modulate the activity of fibroblast growth factor receptor (FGFR) and/or inhibit or modulate vascular endothelial growth factor receptor (VEGF) Factor receptor, VEGF), and/or inhibit or regulate platelet derived growth factor receptor, and can be used as The related diseases described herein are prevented or treated. Furthermore, the compounds of the invention, as well as subsets thereof, can be used as a prophylactic or therapeutic kinase related disease or condition. The meaning of preventing or treating a condition or condition (e.g., cancer) of a disease as described herein includes reducing or reducing the symptoms of the cancer.

Herein, the term "modulation" means the application to the activity of a kinase, 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 "inhibition." Regulation may be performed directly or indirectly, and may be regulated by any mechanism, as well as any physiological aspect, including, for example, at the level of gene expression (including, for example, transcription, translation, and/or post-translational modification). (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 a kinase, including gene amplification (ie, ploidy replication of a gene) and/or an increase or decrease in expression via a transcriptional effect, as Hyper- (or hypo-) activity and (de)activation of the kinase protein by mutation (deactivation). Here, "modulated", "modulating", and "modulate" all have the same meaning.

Here, the term "mediated", as described in connection with a kinase in a text (applies to various physiological processes, diseases, states, conditions, treatments (therapies) ), treatments, and interventions, which are applied to these various steps, diseases, conditions, conditions, treatments, and in a limited state. In the diagnosis and treatment, the kinase can play a biological role in it. 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 a kinase (and particularly abnormal kinase activity, such as overexpression of a kinase) need not be the greatest cause of a disease, condition, or condition; rather, after careful consideration, a kinase-related disease, condition, 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 for diagnosis, Prevent, or cure, its intervention. Thereby, the disease state or condition is associated with a kinase and includes resistance to any drug or course of treatment for cancer.

Thus, for example, the compounds of the invention are assumed to be useful for alleviating or alleviating the effects of cancer.

In particular, the compound represented by the formula (I) and a sub-group thereof are inhibitors of FGFR. For example, a compound of the invention has an inhibitory effect on the activity of FGFR1, FGFR2, FGFR3, and/or FGFR4, more particularly from FGFR1, FGFR2, and FGFR3.

Preferred compounds are those which inhibit one or more FGFRs selected from the group consisting of FGFR1, FGFR2, and FGFR3, and also FGFR4. Preferred compounds of the present invention based compound IC ₅₀ value of less than 0.1 μM Such has.

The compounds of the invention also have properties against VEGFR.

The compounds of the invention also have properties against PDGFR kinase. In particular, this compound is an inhibitor of PDGFR, for example, inhibiting PDGFR A and/or PDGFR B.

In addition, many of the compounds of the invention have selectivity for FGFR 1, 2, and/or 3 kinases, and/or FGFR4, relative to VEGFR (particularly VEGFR2) and/or PDGFR, and such compounds are inventive One of the preferred embodiments. In particular, this compound has selectivity for VEGFR2. For example, many of the compounds of the present invention is effective against FGFR1,2, and / or 3 and / or of the IC ₅₀ value against FGFR4 of VEGFR (in particular, of VEGFR2) times and / or values of IC PDGFR B ₅₀ to a hundred times. In particular, preferred compounds of the invention have a 10-fold or greater property against or inhibiting FGFR (particularly, FGFR1, FGFR2, FGFR3, and/or FGFR4) relative to the inhibition or inhibition of VEGFR2. More preferably, the compounds of the invention have a 100-fold or greater property against or inhibiting FGFR (particularly, FGFR1, FGFR2, FGFR3, and/or FGFR4) relative to the inhibition or inhibition of VEGFR2. This can be achieved by the methods described herein.

For the regulation or inhibition of the activity of FGFR, VEGFR and/or PDGFR, such compounds are useful for preventing the growth of cells or causing tumor-induced cell wilting, particularly inhibition of angiogenesis. Thus, it is expected that this compound can be used to treat or prevent abnormal proliferation, such as cancer. Furthermore, the compounds of the invention are useful in the treatment of diseases wherein the disease is abnormal hyperplasia, cell dying, or differentiation.

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 activating mutation of any one of the specific RTKs described herein may be treated with a compound of the invention. For example, VEGFR may have an overexpression phenomenon in acute leukemia cells, in which progenitor cells can express VEGFR in acute leukemia cells. In addition, a particular tumor (having an activated mutation, or an elevation of any FGFR isoform, or overexpression (eg, FGFR1, FGFR2, or FGFR3, or FGFR4)) may be particularly susceptible to the compounds of the invention, and thus have this Patients with specific tumors can be treated with the compounds of the invention. Preferably, the treatment is directed to or directed against a mutant of a receptor tyrosine kinases as described herein. Methods for detecting tumors having such mutations can be performed using methods of the prior art (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) Cancer, ovarian cancer, pancreatic cancer (eg, exocrine pancreatic carcinoma), gastric cancer, cervix cancer, endometrium cancer, thyroid cancer, prostate cancer Or skin cancer (eg, Squamous cell carcinoma; hematopoietic tumour of lymphoid lineage (eg, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B) - B-cell lymphoma, T-cell lymphoma, Hodgkin's Lymphoma, non-Hodgkin's Lymphoma, hairy cell lymph Hairy cell lymphoma, or Burkett's lymphoma; hematopoietic tumour of myeloid lineage (eg, leukemia, acute and chronic myeloid leukemias, bone marrow) Myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; mesenchymal origin Tumors of Mesenchymal Origin (eg, fibrosarcoma, or rhabdomyosarcoma (rha) Bdomyosarcoma)); central or peripheral nervous system tumors (eg, astrocytoma, neuroblastoma, glioma, or schwannoma; melanoma; Seminoma; terato carcinoma; osteosarcoma (Osteosarcoma); xeroderma pigmentosum; keratoctanthoma; thyroid follicular carcinoma; or Kaposi's sarcoma (Kaposi's sarcoma).

Certain cancers are resistant to specific drugs. It may be caused by the type of tumor itself or by the compound used in the treatment. Therefore, the reference meaning of multiple myeloma includes: proteasome inhibitor (bortezomib) sensitive multiple myeloma, or refractory multiple myeloma. Similarly, the reference significance of chronic myelogenous leukemias includes: chronic myelogenous leukemia sensitive to imitanib and refractory chronic myelogenous leukemia. Chronic myelogenous leukemias are also known as chronic myeloid leukemia, chronic granulocytic leukem, or CML. Also, acute myelogenous leukemia, also known as acute myeloblastic leukemia, acute granulocytic leukemia, acute nonlymphocytic leukaemia, or AML.

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 (MPD) are a group of diseases in which bones multiply with excess cells. It is associated with myelodysplastic syndrome and may gradually evolve into myeloproliferative syndrome. Myeloproliferative diseases include: Polycythemia vera (PV), essential thrombocytopenia (essential) Thrombocythemia), and primary myelofibrosis.

Furthermore, T-cell lymphoproliferative disease contains such diseases that have evolved from Natural Killer Cells. Here, the term "B-cell lymphoma" includes a diffuse large B-cell lymphoma.

Furthermore, the compounds of the invention may be used in gastrointestinal cancers (also known as gastric cancers) (e.g., gastrointestinal stromal tumours). Gastrointestinal cancer means the gastrointestinal tract in a malignant state, including: esophagus, stomach, liver, biliary system, pancreas, bowels, and anus (anus).

An example of a tumour of mesenchymal origin is Ewings Sarcoma.

Thus, among the pharmaceutical compositions, a disease or a symptom having abnormal cell growth is treated by the method of the present invention, and an example of the disease or symptom of the abnormal cell growth is cancer.

Specific subsets of cancer include: multiple myeloma, bladder cancer, cervical cancer, prostate, and thyroid cancer, lung cancer, breast cancer, and colon cancer. .

Another subset of cancers include: multiple myeloma, bladder cancer, and cervical cancer.

Furthermore, the compounds of the invention may have an inhibitory effect on FGFR (eg, FGFR1) The effect of activity, and in particular, can be used to treat or prevent breast cancer, particularly typical Lobular carcinoma.

The compounds of the invention have FGFR4 activity and are therefore useful in the treatment of prostate or pituitary cancer.

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, breast cancer, gastric cancer, colorectal cancer, and oral squamous cell carcinoma.

Furthermore, a subset of cancer also includes 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 cancer (hormone refractory prostrate carcinoma), endometrial cancer (in particular, endometrial tumor with activating mutation in FGFR2), and breast cancer (in particular, lobular in situ) Breast cancer).

In particular, compounds can treat lobular carcinoma in situ (eg, typical leaflet in situ) Classic Lobular carcinoma (CLC).

Compounds having a function against FGFR3 activity can be used as a treatment for multiple myeloma and bladder tumors.

In particular, its compounds are useful in the treatment of t(4;14) translocation of positive multiple myeloma.

Compounds having resistance to FGFR2 activity can be used to treat endometrial cancer, ovarian cancer, gastric cancer, and colorectal cancer. FGFR2 has also been shown to be a manifestation in epithelial ovarian cancer, and thus the compounds of the invention may be particularly useful for treating ovarian cancers (e.g., epithelial ovarian cancers).

The compounds of the invention may also be used as a pre-treated with a VEGFR2 inhibitor or a VEGFR2 antibody (e.g., Avastin) for the treatment of tumors.

In particular, the compounds of the invention may also be useful in the treatment of anti-VEGFR2 tumors (VEGFR2-resistant tumour). VEGFR2 inhibitors or antibodies can be used to treat thyroid cancer as well as renal cell carcinoma, and thus the compounds of the invention can be used to treat anti-VEGFR2 thyroid cancer as well as renal cell carcinoma.

Such cancers may be cancers that are susceptible to inhibition of any one or more FGFRs selected from the group consisting of: FGFR1, FGFR2, FGFR3, FGFR4 (eg, one or more FGFRs selected from: FGFR1, FGFR2, or FGFR3).

Regardless of whether a particular or non-specific cancer is sensitive to the will of FGFR, VEGFR or PDGFR signals, cell growth assays can be used, as described in Examples 79 and 80 below, or in "Diagnosis The method described in the section "Methods of Diagnosis" is identified.

Furthermore, the compounds of the present invention, particularly those having activity against FGFR, VEGFR, or PDGFR, are particularly effective for use in the treatment or prevention of elevated progressions via the appearance of FGFR, VEGFR, or PDGFR. Cancer, for example, is described in the context of this chapter.

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 supranuclear Palsy), Corticobasal degeneration, and Pick's disease (eg, autoimmune disease and neurodegenerative disease).

For sub-groups of its disease, the compounds of the invention are useful in the treatment of: inflammatory diseases, neovascular diseases, and wound healing.

FGFR, VEGFR, and PDGFR, as known, play an important role in apoptosis, angiogenesis, cell proliferation, cell differentiation, and cell metastasis, and thus the compounds of the present invention can also be used in Treatment of diseases other than cancer: chronic inflammatory diseases such as Systemic Lupus Erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, Inflammatory bowel disease, autoimmune diabetes, Eczema hypersensitivity reaction, asthma (asthma), COPD, rhinitis, and upper respiratory tract disease; Cardiovascular diseases such as cardiac hypertrophy, cardiovascular restenosis, atherosclerosis; neurodegenerative diseases such as Alzheimer's disease, AIDS- Related dementia, Parkinson's Disease , amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atophy, and cerebellar degeneration; glomerulonephritis ); myelodysplastic syndrome, ischemic injury-related myocardial infarction (myocardial infarction), stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcoholic liver disease, haematological disease, such as: Chronic anemia and Aplastic Anemia; degenerative diseases of the musculoskeletal system, such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, pouch Cystic fibrosis, multiple sclerosis, kidney disease, 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 (cranial sutures) Craniosynostosis), tower head refers to apert syndrome (AP), Crouchon's disease, Jackson-Weiss's disease, Beare-Stevenson 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. Specific skeletal muscle-related diseases are achondroplasia or thanatophoric dwarfism (also known as thanatophoric dysplasia).

The compounds of the present invention have the ability to inhibit the activity of FGFR (e.g., FGFR1, FGFR2 or FGFR3), and in particular can be used for the treatment or prevention of diseases of fibrotic symptoms. The compound of the present invention can treat the disease of fibrotic symptoms Includes diseases of abnormal or excessive fibrotic deposition in tissues such as liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid The natural process of rheumatoid arthritis and 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 direction 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 eyes), ischemic proliferative retinopathies (eg, Retinopathy of Prematurity (ROP) and 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 and leukemias, including: glioblastomas (eg, glioblastoma multiforme, prostate cancer) , gastrointestinal stromal tumour, liver cancer, kidney cancer, chronic myeloid leukemia, chronic monocytic leukemia (chronic myelomonocytic leukemia, CMML), and hypereosinophilic syndrome, rare proliferative blood disease, and dermatofibrosarcoma protuberan, infiltrative skin tumour.

The compounds of this invention FGFR1-4, VEGFR and / or PDGFR A / B of efficacy may be measured using the following experimental method, the measured and the inhibitory compounds may be obtained as IC ₅₀ values for inhibition expressed. Preferably, the compounds of the present invention have IC ₅₀ values of less than 1μM, more preferably less than 0.1 μM.

The compounds provided by the present invention have a function of inhibiting or regulating FGFR activity, and are expected to be useful 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 provides a disease or condition associated with the prevention or treatment of FGFR kinase.

Thus, for example, the compounds of the invention may be used to soothe or alleviate the symptoms of cancer.

Thus, in one aspect, the invention provides a compound for use in the manufacture of a medicament for the manufacture of a disease or condition associated with the prevention or treatment of FGFR kinase, the compound of which is as defined in formula (I).

In one embodiment, the invention provides a compound for use in the manufacture of a medicament for the manufacture of a medicament for the prevention or treatment of a disease or condition as described herein.

In yet another embodiment, the invention provides a compound for use in the manufacture of a medicament for the manufacture or prevention of cancer.

Furthermore, the invention provides other: A method of preventing or treating a disease or symptom associated with FGFR kinase, the method comprising administering to a patient a compound of the formula (I).

In one embodiment, a method of preventing or treating a disease or condition described herein is provided, the method comprising administering to a patient a compound of formula (I).

In yet another embodiment, a method of preventing or treating cancer is provided, the method comprising administering to a patient a compound of formula (I).

A method of soothing or ameliorating a disease or condition associated with FGFR kinase, the method comprising administering a compound as shown in formula (I).

A method of inhibiting FGFR kinase, the method comprising contacting the kinase with a compound of formula (I) having inhibitory kinase properties.

A method of using a compound of 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 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 of the formula (I) is used to produce an agent that modulates (e.g., inhibits) FGFR activity.

A compound represented by the formula (I) is used to produce an agent which modulates a cellular process such as cell division by inhibiting the activity of FGFR.

The use of a compound of formula (I) for the production of a FGFR kinase (eg, FGFR1, FGFR2, FGFR3, or FGFR4) is produced. An agent for a disease or condition caused by up-regulation.

A compound of 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).

A compound of the formula (I) is used to produce an agent for preventing or treating a cancer patient, the cancer of which is selected from the group consisting of a genetic aberration having a FGFR3 kinase.

A compound such as the formula (I) 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 method for preventing or treating a disease caused by an increase in a FGFR kinase (e.g., FGFR1, FGFR2, FGFR3, or FGFR4), the method comprising administering a compound of the formula (I).

A method of soothing or alleviating a disease or condition caused by an increase in FGFR kinase (e.g., FGFR1, FGFR2, FGFR3, or FGFR4), the method comprising administering a compound of the formula (I).

A method of preventing or treating (or soothing or alleviating) a patient suffering from cancer or being presumed to have a cancer, the method comprising (i) causing a patient to undergo a medical test to determine whether it has a FGFR3 genetic aberration. And (ii) the patient having the FGFR3 gene mutation is administered to a compound represented by the formula (I) (having an ability to inhibit FGFR3 kinase activity).

A disease caused by an increase in FGFR kinase (eg, FGFR1, FGFR2, FGFR3, or FGFR4) that is prevented or treated (or soothed or reduced) Or a method of symptom; comprising: (i) causing a patient to undergo a medical test to determine whether it has an elevated FGFR kinase (eg, FGFR1, FGFR2, FGFR3, or FGFR4), and (ii) then, the patient A patient having an increase in FGFR kinase is administered a compound represented by the formula (I) (having an ability to inhibit FGFR kinase activity).

Mutant kinase

Drug-resistant kinase mutations increase the number of patients treated with kinase inhibitors. At the time of treatment, this condition occurs, in part, on areas of the protein that bind or react with a particular inhibitor. Such mutations reduce or increase the occurrence of inhibition and binding of the inhibitor to the kinase. It can occur on any amino acid fragment that reacts with the inhibitor or that supports the binding of the inhibitor to the target. An inhibitor that does not require binding to a mutated amino acid fragment, which may be less susceptible to mutations while retaining the effective inhibitory properties of the enzyme during binding to the target kinase. (Reference from Carter et al (2005), PNAS, 102 (31) , 11011-110116).

These mutations have been found in PDGFR in patients receiving imatinib therapy, particularly the T674I mutation. The clinical importance of these mutations 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.

Therefore, the compounds of the present invention are particularly useful for expressing mutant molecular markers Target (eg, FGFR or PDGFR (comprising PDGFR-beta and PDGFR-alpha, particularly the T674I mutant of PDGFR)) cancer. Methods for diagnosing such tumors can be judged using techniques well known in the art (e.g., RTPCR and FISH).

It is known that mutations in the retained threonine residue of the ATP binding site in the 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 Abl (T315) and EGFR (T766), and the Abl (T315) and EGFR. (T766) is associated with resistance to selective inhibitors. Experimentally confirmed data indicate that the mutant of FGFR1 V561M has resistance to tyrosine kinase inhibitors relative to the wild type.

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, together with one or more pharmaceutically acceptable carriers ( Carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, 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 providing a preparation comprising mixing at least one of the above active compounds with one or more drugs Pharmaceutical compositions of acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other conventional materials.

As used herein, the term "pharmaceutically acceptable" relates to a compound, material, composition, and/or agent (inclusion) which, with sufficient medical judgment, can be associated with a receptor ( For example, humans are exposed to tissue without excessive toxicity, moodiness, depression, or other problems or complexity, and the ratio of benefits/harms is within reasonable limits. Each carrier, adjuvant, etc. must also be "pharmaceutically acceptable" to be capable of being produced together with other materials.

A pharmaceutical composition comprising a compound of the formula (I) can be exemplified by a conventional technique such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Further, in another aspect, the present invention provides a compound represented by the formula (I) and a sub-group thereof, and is presented in the form of a pharmaceutical composition.

The pharmaceutical composition can be administered orally, parenterally, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal. ) to administer drugs. These components, which are originally administered parenterally, can be administered intravenously, intramuscularly, intraperitoneally, or subcutaneous directly or by injection, infusion, or other means. . Its drug delivery method can be quickly injected via the use of a suitable infusion pump (Bolus Injection), short term infusion, or interm term infusion for transmission.

Pharmaceutically acceptable formulations for parenteral administration include water-soluble and water-insoluble sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats, Co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), microlipid composition Liposome components (to form a liposome), gelable polymers (to form a polymeric gel), lyophilisation protectants, and combinations of such agents, especially The active compositions are 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, which may contain suspension reagents and thickening agents (cf. from RG Strickly (2004), Solubilizing) Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) , p 201-230).

Liposomes are closed globular vesicles comprising an outer lipid bilayer membrane and an internal water soluble core layer with a total diameter of <100 μm. Depending on its hydrophobicity, a drug with moderate hydrophobicity can be coated or embedded in the liposome to be soluble 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 is dissolved in the lipid site of the lipid bilayer membrane.

The formulation can be packaged in single or multiple doses, such as sealed ampoules and vials, and can also be stored in a refrigerated (lyophilized) state, with sterility added prior to use. A liquid carrier such as water can be used for injection.

Pharmaceutically acceptable formulations can be obtained by lyophilising a compound of formula (I), 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, oil) Ethyl ethyl ester (ethyl oleate). Proper fluidity can be adjusted, for example, 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 agents). Agents), and dispersing agents). In order to prevent the growth of microorganisms, a series of antibacterial agents and antifungal agents can be used, for example, paraben, chlorobutanol, phenol sorbic acid, and Similar. It may also contain isotonic agents (eg, sugar, sodium chloride, and the like) as desired. To prolong the absorption time of the injectable drug, it is possible to pass an agent which will prolong absorption (for example, aluminum monostearate and gelatin).

In a preferred embodiment of the invention, the pharmaceutical composition is administered in a form suitable for administration, such as by 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 a suitable form.

Pharmaceutically acceptable agents for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules ( 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): / or non-saccharide derived diluent (eg, sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivatives (eg, methyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and starch (eg, corn starch)). Tablets may also contain standard components such as binding and granulating agents (eg, polyvinylpyrrolidone), disintegrants (eg, swellable crosslinked polymers (eg, croscarmellose) (carboxymethylcellulose)), lubricants (eg, stearates), preservatives (eg, paraben), antioxidants (eg, BHT), buffers (eg, phosphoric acid) Salt or citrate buffers, as well as blowing agents (e.g., citrate/bicarbonate mixtures). Such adjuvants are well known and need not be discussed further herein.

The administration form of the capsule may be a gelatin or a soft gel, and comprises an active compound in a solid, semi-solid, or liquid form. Gel capsules can be formed from animal gels, or synthetic, or plant derived equivalents.

The solid dosage form (eg, tablets, capsules, etc.) can be coated or uncoated, and typically coated, such as a protective coating (eg, wax or lacquer) or a controlled release coating. (release controlling coating). The coating (e.g., an Eudragit polymer) can be designed to have properties that release the active composition between the gastrointestinal tract. Thus, the coating is designed to lyse under the pH conditions of a certain gastrointestinal tract, and may selectively release the compound in the stomach, or in the ileum, or in the duodenum.

In addition to the coating, the agent can be presented in a solid matrix comprising a release agent (eg, a release delaying agent) to allow the compound to be in a different acidic or alkaline environment in the gastrointestinal tract. freed. In addition, the framework material or release-delay coating may be erodible polymers (eg, anhydrous male polymer), which is sustainable when the agent passes through the gastrointestinal tract. Ground corrosion. Alternatively, the active compound can be shipped in a system that controls the permeability of the compound. Formulations of the above-described permeability controlled release, and other delayed release, or sustained release can be prepared in accordance with methods known in the 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 agent (eg, Ampoules, vials, suppositories, tablets (drag) Es), pills, or capsules.

The oral pharmaceutical composition is obtained by combining the active composition with a solid carrier, and if necessary, granulating the obtained mixture, and adding appropriate excipients to the ingot, dragee core After the capsule, or after the capsule, the mixture is reprocessed as needed. It can also be incorporated into plastics carriers to allow the active composition to diffuse or be released at a measured level.

The compounds of the invention may also be formulated to be solid dispersion. The solid dispersion is a homogeneous finely dispersed phase having two or more solids therein. A solid solution (molecular dispersion system), a type of solid dispersion, is a widely used technique in medicine (see (Chiou and Riegelman (1971), J. Pharm. Sci., 60 , 1281-1300), which is for Those that are not readily soluble in water can effectively increase their rate of dissolution and increase their biological effectiveness.

The invention also provides a solid medicament comprising the above solid solution (solid dosage) form. Solid pharmaceutical agents include tablets, capsules, and chewable tablets. Commonly used adjuvants can be combined with the solid solution to provide the desired dosage form. For example, a capsule may comprise a solid solution with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant, and an interface activity. Surfactant. A tablet may comprise the solid solution with at least one 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 an artificial sweetener) as appropriate, and a suitable perfume.

The pharmaceutically acceptable formulation can be a "patient packs" containing all of the requirements for a single treatment, typically a blister pack. The advantage of the patient package over the traditional prescription is that the patient is allowed to take the contents of the patient because the patient package is separated from the large medical source and the patient needs to be separated. Identify the necessary uses in large medical sources. The contents of the patient's pack can help the patient follow the medical instructions.

Compositions for topical use include ointments, salves, sprays, patches, gels, droplets, and implants (eg, ophthalmic implants). Such compositions can be prepared by known related techniques.

Administration of the rectum as well as the internal vagina comprises pessaries and suppositories, for example, which can be made via preformed or waxy materials comprising one of the active compounds.

Inhalation administration can be achieved by inhalation powder composition or liquid or powder spray, or by standard type of powder inhalation device or aerosol dispensing devices. Inhalation administration, the powder generally comprises both the active compound and an inert solid powder diluent (eg, lactose).

A compound of formula (I) can be presented in 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 (eg, 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 from 10 mg to 1 g (eg, 50 mg to 500 mg)), or from 1 microgram to 20 mg (eg, 1) The active composition is micrograms to 10 mg (e.g., 0.1 mg to 2 mg).

For oral compositions, a single agent may contain from 1 mg to 2 grams, more typically from 10 mg to 1 gram, such as from 50 mg to 1 gram, (e.g., from 100 mg to 1 gram) of the active composition.

The active compound can be administered in a sufficient amount to the patient in need (e.g., in a human or animal condition) to achieve the desired medical effect.

Related examples of pharmacy composition (i) drug form

A tablet comprising a compound of formula (I) may be prepared by mixing 50 mg of the compound, 197 mg of lactose (BP) as a diluent, and 3 mg of stearic acid as a lubricant (lubricant). Magnesium is obtained by compressing it into a tablet by conventional techniques.

(ii) Capsule type

The capsules were prepared by mixing 100 mg of the compound of formula (I) with 100 mg of lactose and filling the mixture into a standard opaque hard gelatin capsules.

(iii) Injection type I

A parenteral injection method is a method in which a compound represented by the formula (I) (for example, a salt form) is dissolved in water containing 10% propylene glycol to obtain a solution of 1.5% by weight of the active compound. . The solution was filtered, filled into an ampoule and sealed.

(iv) Injection Type II

A parenteral injection method is a method in which a compound (for example, a salt form) (2 mg/ml) and a mannitol (50 mg/ml) represented by the formula (I) are dissolved in water, and the solution is dissolved. Sterile filtration and filling into a sealable 1 ml vial or ampoule.

(v) Injection type III

Formulations by injection or infusion (i.v. delivery) can be prepared by dissolving a compound (e.g., a salt form) as shown in the formula (I) in 20 mg/ml of water. The vial was sealed and sterilized by high pressure.

(vi) Injection type IV

The formulation of the injection (i.v. delivery) by injection or infusion may be dissolved in a compound (for example, a salt form) as shown in the formula (I) It is prepared by using a buffer (for example, 0.2 M acetic acid pH 4.6) in 20 mg/ml water. The vial was sealed and sterilized by high pressure.

(vii) subcutaneous injection pattern

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) Lyophilised type

A test solution of a compound of the formula (I) was placed in a 50 ml vial and lyophilized. During lyophilization, the composition was frozen using a one-step freezing method (at -45 ° C). The temperature was raised to -10 ° C, then lowered to -45 ° C, and the first drying was carried out at +25 ° C for 3400 minutes, followed by raising the temperature to 50 ° C at a progressive speed for secondary drying. The pressure between primary drying and secondary drying was set to 80 millitor.

treatment method

The above compounds represented by the formula (I) and subsets thereof can be used for the prevention or treatment of diseases or signs associated with FGFR. Examples of diseases and symptoms have been described in the previous section.

This compound is generally administered to a recipient that 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.

However, in certain situations (for example, when life-threatening diseases are involved) If the amount of the compound represented by the formula (I) may exceed the range of use and has toxic effects or side effects, it is necessary to consider the required amount and the corresponding toxic level when administering the drug.

This compound can be administered in a long period of time for treatment or only for a short period of time. Furthermore, it can be administered discontinuously or continuously.

Suitable daily doses of the compound of formula (I) are from 100 picograms to 100 mg, more preferably from 5 nanograms to 25 mg, and more preferably Preferably, the amount is from 10 ng to 15 mg per kilogram of body weight (e.g., 10 to 10 mg, more preferably 1 to 10 mg, for example, 1 to 10 mg) of the body weight of the kilogram, which may be increased or decreased as needed. The compound of formula (I) can be administered daily, or, for example, at intervals of 2, 3, or 4, or 5, or 6, or 7, or 10, or 14, or 21, or 28 days. Dosing.

The compounds of the invention may be orally administered in a range of doses, for example, from 1 to 1500 mg, from 2 to 800 mg, or from 5 to 500 mg (eg, from 2 to 200 mg or from 10 to 1000 mg), with a particular dosage example comprising 10. 20, 50, and 80 mg. This compound can be taken once or more than once a day. This compound can be taken continuously (ie, uninterrupted daily during the treatment period). In addition, the compound can be administered intermittently, that is, during the entire treatment period, for a period of time (eg, one week), then for a period of time (eg, one week), and then for another period (eg, one week). Take it. The time of administration can be a cyclical intermittent administration. For example, one cycle is: one week, one week, or two weeks, one week, or three weeks, one week, or two weeks, two weeks. Deactivated; or taken four weeks, deactivated for two weeks; or Take one week, discontinue for three weeks, and perform 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 infused with a compound of formula (I) for one hour for one hour and for up to ten days, in particular, up to five days a week, and the treatment is Repeat within the interval (eg, two to four weeks, in particular, every three weeks).

In addition, a patient may be infused for one hour per day for five consecutive days as shown in formula (I) and repeated every three weeks.

In another mode of administration, the patient is given a 30 minute to an 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 administered 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 can be administered alone or in combination with one or more other compounds to treat a particular condition, such as a neoplastic disease (e.g., cancer). Other drugs which can be administered together with a compound of the formula (I) (at the same time or at different times) include, but are not limited to: Topoisomerase I inhibitors

Antimetabolites

Tubulin targeting agents

DNA binder and Topoisomerase II inhibitors

Alkylating agents

Monoclonal Antibodies

Anti-Hormones

Signal Transduction Inhibitors

Proteasome Inhibitors

DNA methyl transferases

Cytokine and vitamin A derivatives (retinoids)

Chromatin targeted therapies

Radiotherapy, and, Other therapeutic or prophylactic agents; for example, agents that reduce or soothe side effects caused by chemotherapy. Specific examples of such agents include: anti-emetics, and prevention or alleviation of neutropenia associated with chemotherapy, and prevention of red blood cells or white blood cells (eg, erythropoietin (EPO), granulocytes) A complex disease caused by a decrease in granulocyte macrophage-colony stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Also included are agents that inhibit bone resorption, such as bisphosphonate agents (eg, zoledronate, pamidronate, and ibandronate). )), anti-inflammatory reagents (such as dexamethazone, prednisone, and prednisolone), and terminal hypertrophy patients used to reduce blood levels of growth hormone and IGF-I reagent (eg, brain hormone somatostatin) is a long-acting octapeptide type of acetic acid that mimics the natural hormone somatostatin and has a medical property. 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) An agent that causes side effects such as an event (eg, megestrol acetate).

Each of the compounds of the present invention can be administered individually in accordance with a schedule and in accordance with special rules.

The compound of the formula (I) can be administered in combination with one, two, three, four or more pharmaceutical agents, preferably one or two, more preferably one, which can be administered together at the same time. Or in order to administer drugs. When administered sequentially, it can be separated for a short period of time (eg, 5-10 minutes) or a longer 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 with non-chemotherapeutic (e.g., radiation therapy, photodynamic Therapy, gene therapy; surgery and diet control) treatments.

For use in combination with other chemotherapeutic agents, for example, a compound of formula (I) can be formed together with one, two, three, four, or more pharmaceutical agents (including two, three, four , or more pharmaceutical 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.

Methods of Diagnosis

Prior to administration of a compound of formula (I), the patient must be screened to determine if there is a degree of treatment with a compound that is required to receive anti-FGFR, VEGFR and/or PDGFR activity.

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 activity). Grade elevation, or particularly sensitive to normal FGFR, VEGFR and/or PDGFR activity, or an increase in growth factor ligand activity level, or an increase in biochemical activity downstream of FGFR, VEGFR and/or PDGFR activity).

Such abnormalities that are sensitive to FGFR, VEGFR and/or PDGFR activation include: inhibition or loss of apoptopaths, elevation of receptors or ligands, or various mutations in receptors or ligands. The occurrence (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 functionalized FGFR2 caused by point mutations can be judged by some symptoms (cf. from Lemonnier, et al . (2001), J. Bone Miner. Res., 16 , 832-845). In particular, activating mutations in FGFR2 have been diagnosed in 10% of endometrial tumors (cf. Pollock et al , Oncogene, 2007, 26 , 7158-7162).

In addition, genetic variants of the FGFR3 receptor tyrosine kinase (eg, chromosomal translocation or point mutation) cause abnormal or deregulated, and the sustained activation of the FGFR3 receptor is thought to be associated with multiple myeloma ( Multiple myeloma), bladder, and cervical cancer are associated (Reference from Powers, CJ, et al. (2000), Endocr. Rel. Cancer, 7, 165). A specific mutation of T674I in the PDGF receptor was found in patients treated with imatinib.

Furthermore, the gene amplification of 8p12-p11.2 was found in ~50% of typical cases of Classical Lobular carcinoma (CLC), and this was associated with an increase in FGFR1 expression. related. Initial studies of siRNA against FGFR1, or small molecule inhibitors of receptors, suggest that cell line masking of this broadening is particularly sensitive to inhibition of this signaling pathway (see Reis-Filho et al). (2006), Clin Cancer Res. 12(22) , 6652-6662).

Moreover, biological samples obtained from patients can be used to analyze whether the negative regulation or repression of FGFR, VEGFR, or PDGFR is lost. Here, the term "loss" includes: deletion of a control-regulated or repressible gene sequence, truncation of a gene (for example, by mutation), truncation of a gene transcript, or deactivation of a gene transcript. (eg, via a canonical mutation) or by another gene product.

The term "up-regulation" is an increase or an overperformance of expression, including: gene amplification (ie, multi-gene replication) and increased expression via transcription, as well as high activation and activation (including via mutation). The resulting activation). Therefore, patients may need to undergo a diagnosis to measure whether there is an elevated feature of FGFR, VEGFR and/or PDGFR. And "diagnosis The word "diagnosis" includes screening. The marker used comprises a genetic marker (including, for example, DNA heavy to confirm mutations in FGFR, VEGFR and/or PDGFR). Herein, the term "marker" includes the property of confirming the enhancement of FGFR, VEGFR and/or PDGFR (including; enzyme activity, enzyme grade, enzyme state (eg, whether it is phosphorylated), and the above proteins Marker of the mRNA grade).

Diagnostic tests and screening must generally be performed by tumor section samples, blood samples (isolated by tumor cells and contained in tumor cells), biopsy, salut, chromosomal analysis, pleural fluid ), peritoneal fluid, buccal spears, biopsy, or urine samples.

Confirmation and analysis of mutations and ascension of proteins can be measured by those skilled in the art. Screening methods include, but are not limited to, standard methods (eg, reverse-transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization techniques (eg, fluorescent in situ) Fluorescence in situ hybridization (FISH)

A patient identified with a FGFR, VEGFR and/or PDGFR mutation is particularly suitable for treatment with FGFR, VEGFR and/or PDGFR inhibitors. Prior to treatment, the tumor 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. Furthermore, the diagnosis of tumors with associated mutations can be performed using conventional general techniques (e.g., RT-PCR and FISH).

Furthermore, for example, mutations in FGFR or VEGFR2 can be confirmed by tumor biopsy using PCR and direct sequencing of the PCR sequence. 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 was estimated by replicating cDNA from mRNA, followed by amplification of the cDNA by PCR. In the method of PCR amplification, the selection of primers and conditions for amplification are described in the art of the prior art. Nucleic acid modification and PCR are carried out using conventional methods, see Ausubel, FM et al ., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al ., Eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego example. The reaction method and modifications of nucleic acids may also refer to Sambrook et al, (2001), 3 rd Ed, Molecular Cloning:. A Laboratory Manual, Cold Spring Harbor Laboratory Press describes in progress. In addition, a commercially available RT-PCR kit (e.g., Roche Molecular Biochemical), or the methods described in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 may also be used. An example of an in situ hybridization technique for assessing mRNA expression may be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152 : 649).

In general, in situ hybridization involves the following major steps: (1) immobilization of the tissue to be analyzed; (2) prehybridization of the sample to increase compatibility with the target nucleic acid. (3) hybridizing a hybrid of nucleic acids to a nucleic acid in a biological structure or tissue; (4) washing the nucleic acid fragments that have not been hybridized after washing; and (5) measuring the nucleic acid fragments of the hybridization. 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 from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides to achieve a particular hybridization requirement for an emergency with a target nucleic acid. Standard methods for using FISH can be found in Ausubel, FM et al ., eds. (2004) Current Protocols in 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.

A related method for gene expression is described in (DePrimo et al . (2003), BMC Cancer , 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 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, proteins expressed by the mRNAs can be examined by immunohistochemistry using tumor tissue using a microtitre plate. By solid phase immunoassay test, Western blotting, 2D SDS-polyacryl amide gel electrophoresis, ELISA, flow cytometry, and others A conventional test method is used to measure its specific protein. The use of site specific antibodies is included in the measurement method. Those of ordinary skill in the art will appreciate how the elevation of FGFR, VEGFR and/or PDGFR, or the variation or mutation of FGFR, VEGFR and/or PDGFR can be measured by conventional methods.

The degree of abnormality of a protein (e.g., FGFR or VEGFR) can be used, 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 tyrosine kinase using a method such as the method described in Chemicon International. The pre-known tyrosine kinase can be obtained by immunoprecipitation of a sample lysate and measuring its activity.

Other methods of measuring the overexpression or activation of FGFR or VEGFR (including its isoforms) include measuring its microvessel density. An example of this method can be found in the method described in Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). Markers are also used in such methods, for example, in VEGFR examples containing CD31, CD34, and CD105 (see from Mineo et al . (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. The G697C mutation in FGFR3 was observed in 62% of oral squamous cell carcinoma, and it caused activation of kinase activity. Activating mutations in FGFR3 have also been observed in cases of bladder cancer. These mutations contain six different and varying degrees of mutations: R248C, S249C, G372C, S373C, Y375C, K652Q. Furthermore, the polymorphism of Gly388Arg in FGFR4 was found to be associated with increased prostate and colon, lung, and breast cancer.

Accordingly, another aspect of the present invention comprises the use of a compound of the present invention to produce a medicament for treating or preventing a disease or condition, wherein a patient having the disease or condition is screened and suffering from a disease, and the disease is A compound that is resistant to FGFR activity can be treated.

Specific mutations to be performed in patients include G697C, R248C, S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and polymorphism of Gly388Arg in FGFR4.

Another aspect of the invention comprises a compound of the invention for use in the prevention or treatment of a cancer patient selected from the group consisting of: having a FGFR gene abnormality (e.g., a G697C mutation in FGFR3 and a Gly388Arg polymorphism in FGFR4) Subgroup

Use MRI to measure vascular normalization (eg, using MRI gradient echo, spin echo, and contrast to measure blood volume, relative vessel size, and vascular permeability) and with circulating organisms Circulating biomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2) For use, an anti-VEGFR2 tumor that can be treated with a compound of the invention can be identified.

experimental method LC-MS system analysis and its method (Analytical LC-MS system and method d Scription)

In the examples, the compounds were prepared using liquid chromatography and mass spectrometry, using a commercially available instrument (Waters Platform LC-MS system, Waters Fractionlynx LC-MS system), and using standard measurements with Commercially available columns (Phenomenex, Waters etc) are available, but those skilled in the art can make changes based on their judgment and needs. 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, 35Cl; 79Br, etc.).

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 have better separation of raw materials and increase the sensitivity of MS to sample testing. Optimizing 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 have been conventional techniques, and thus such methods can be used to purify compounds. These methods have been Described in 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 chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.

Two systems for purifying compounds using LC-MS are Waters Fractionlynx system or Agilent 1100 LC-MS, and those skilled in the art can rely on their needs and needs. In particular, HPLC analysis can be carried out here 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 compatible with positive ion electrospray mass spectrometry, reverse phase chromatography LC is used in most LC-MS systems. Volatile acid modifier. 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, then this method can be used as a more appropriate method. A series of chromatographic solutions (eg, forward or reverse phase chromatography LC; acid, base, polar, or lipophilic buffered mobile phase; alkaline modifier) can be used to purify the compound. Thus, a person skilled in the art can purify the compound via the LC-MS method described herein.

All compounds were dissolved in 100% MeOH or 100% DMSO.

General synthetic path General formula A

Step A1 - Formation of a general imidazole pyridine ring:

Add NaHCO ₃ (16.8 g, 200 mmol, 2.0 equiv) to 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, dissolved in EtOH (170 ml). In a 1.0 equiv) solution, chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv) was then added. The mixture was refluxed for 6 hours. The solvent was removed under reduced pressure and the crude mixture was partitioned with water and EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), filtered, and concentrated under reduced pressure. The product was purified by column chromatography (SiO _2, 50% EtOAC- in petroleum ether) to afford 13.2 g via product.

Step A2-General Iodination Reaction

N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) was added to 7-oxo-imidazo[1,2-a]pyridine (7- dissolved in DMF (280 ml). Chloro-imidazo[1,2-a]pyridine, 30.9 g, 186 mmol, 1.0 equiv), and the mixture was stirred at room temperature overnight. The thin brown mud was diluted with water (840 ml), brine (br. The aqueous layer was then extracted with EtOAc (3 x 280 mL). The organic layer and the adduct with water (2 x 280ml), 10% w / v sodium thiosulfate (280 ml), saturated brine (brine, 280ml), dried (MgSO _4), filtered and dried in vacuo To get a brown residue. The residue was triturated with EtOAc (EtOAc) (EtOAc)

Step A3 generally Suzuki reaction, in the third position Step A3a - Suzuki reaction

3-Aminobenzeneboronic acid (2.5 g, 10.57 mmol), 2M Na ₂ CO ₃ (21.6 ml) [with bubbles removed via nitrogen] was added to 7-chloro-3-iodo in acetonitrile (100 mL). -Imidazo[1,2-a]pyridine (7-Chloro-3-iodo-imidazo[1,2-a]pyridine, 2.8 g, 10 mmol) followed by bis(triphenylphosphine)palladium(II) chloride (bis(triphenyl 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 saturated aqueous sodium chloride (brine), dried (MgSO _4), filtered, and concentrated under reduced pressure, and then purified by column chromatography using a Biotage (SiO _2, eluting with 80% EtOAC- petroleum ether to 100% EtOAC ) to give 1.9 g of product. MS: [M+H] ⁺ 244

Step A3b - Suzuki reaction

3-Aminobenzeneboronic acid (0.69 g, 4.8 mmol) and 2 M Na ₂ CO ₃ (6.93 ml) [with air bubbles removed via nitrogen] were added to 3-iodo-7- dissolved in DME (20 mL). (3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridine (3-Iodo-7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2 -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 saturated aqueous sodium chloride (brine), dried (MgSO _4), filtered, and concentrated under reduced pressure, and then purified by column chromatography using a Biotage (SiO _2, in EtOAC-20% MeOH / EtOAC elution) to give 0.56 g of product. MS: [M+H] ⁺ 385

Step A4 is generally palladium-catalyzed addition reaction of the seventh position ring Step A4a - Suzuki reaction

4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-pyridine, 0.078g, 0.36mmol), K ₂ CO ₃ (0.25g, 1.8mmol), MeOH (0.5ml), EtOH (0.5ml), with H ₂ O (0.75 ml) [Breaking bubbles by nitrogen gas] N-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]B dissolved in toluene (0.5 ml) Indoleamine (N-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide, 0.090 g, 0.3 mmol), followed by the addition of bis(tri-t-butyl) Phenylphosphine) palladium (0) (0.003 g, 0.0058 mmol). The mixture was heated in a CEM Discover microwave synthesizer (50 W) using a microwave irradiation at 140 ° C until the reaction was completed. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride (brine), dried through (MgSO _4), filtered, and concentrated under reduced pressure, and purified by HPLC to give 0.007g of product. MS: [M+H] ⁺ 329

Step A4b - Suzuki reaction

Add 4-fluorophenylboronic acid (0.059 g, 4.2 mmol) and 2M Na ₂ CO ₃ (1.2 ml) [to remove bubbles via nitrogen gas] to N-[3-( dissolved in DME (4 ml) 7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]acetamidamine (N-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl) In the -phenyl]-acetamide, 0.1 g, 0.35 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol) was then added. The mixture was heated at 80 ° C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. MS: [M+H] ⁺ 346

Step A4c-Buchwald reaction

Morpholine (0.03 ml, 0.35 mmol), NaO ^t Bu (0.096 g, 0.96 mmol) [with bubbles removed via nitrogen gas] was added to 1-hydrogenated dioxane (4 ml) [3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl-urea (1-[3-(7-Chloro-imidazo [1,2] -a]pyridin-3-yl)-phenyl]-3-ethyl-urea, 0.1 g, 0.32 mmol), followed by BINAP (0.021 g, 0.033 mmol) and Pd ₂ (dba) ₃ (tris(dibenzylidene) Phenylacetone) palladium (0); tris-(dibenzylideneacetone) dipalladium (0), 0.016 g, 0.017 mmol). The mixture was heated overnight at 80 ° C, then diluted with EtOAc EtOAc EtOAc (EtOAc) 0.015 g of product. MS: [M+H] ⁺ 366

Step A4d - Suzuki reaction coupling

1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl-urea (1-[3-(7-chloro-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-3-ethyl urea, 200 mg, 0.636 mmol, 1 equivalent (prepared using the procedure of step Fla), 1-methylpyrazole-4-boronic acid 1-methylpyrazole-4-boronic acid pinacol ester (commercially available, 265 mg, 1.272 mmol, 2 equivalents), potassium carbonate (527 mg, 3.816 mmol, 6 equivalents), and bis(tri-tert-butylphosphine) Palladium (0) (16 mg, 0.032 mmol, 0.05 equivalent) was dissolved in a mixed solution of ethanol (10 ml), toluene (10 ml) and water (10 ml), and heated at 70 ° C for 24 hours. The mixture was separated from water by ethyl acetate. The organic layer was washed with brine (brine) solution was washed, dried (MgSO _4), filtered and the solvent was evaporated in vacuo method. The residue was purified by column chromatography (Biotage EtOAc, EtOAc (EtOAc: EtOAc) [7-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea (1-ethyl-3-{3- [7-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea). MS: [M+H] ⁺ 361.

Step A4e-using microwave conditions

K ₃ PO ₄ (636 mg, 3 mmol) dissolved in water (1 ml) was added to 1-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2 ,2-trifluoro-ethyl)-urea (370mg, 1.0mmol)) with I40,1-dimethylaminosulfonyl-1H-pyrazole-4-boronic acid (I40, 1-Dimethylsulfamoyl-1H-pyrazole-4-boronic) Acid (440 mg, 2.0 mmol). After adding S-Phos (41 mg, 0.1 mmol) and Pd ₂ (dba) ₃ (45 mg, 0.05 mmol), the mixed solution was deoxygenated, followed by microwave irradiation at 130 ° C. . the mixture of water minutes CH ₂ Cl ₂ and separated, followed by separation of the product obtained by filtration and dried in vacuo to give a gray solid which was finally (350mg) .MS: [M + H] + 508

General formula B

Step B1 - General Palladium Catalysis, Substitution Reaction at the 7th Position of the Ring Step B1a - Suzuki reaction of aromatic ring

Using the method as described in general procedure A, step 4a or 4b

Step B1b-Buchwald saturated ring reaction

Using the method as described in general procedure A, step 4c

Step B1c - Suzuki Reaction of Heterocyclic Coupling

7-Bromo-imidazo[1,2-a]pyridine (0.5 g, 2.54 mmol, 1 equivalent, using the procedure of Step A1 as 4-bromo-pyridin-2-ylamine instead of 4-chloro -4-Chloro-pyridin-2-yl amine)), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2 Dioxaborolan-2-yl)-1H-pyrazole (1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H -pyrazole, 1.1 g, 5.08 mmol, 2 eq.), bis(tri-tert-butylphosphine)palladium(0) (66 mg, 0.13 mmol, 0.05 eq.), and potassium carbonate (2.1 g, 15.24 mmol, 6 eq.). A mixed solution of ethanol (10 ml), toluene (10 ml) and water (10 ml) was heated at 75 ° C for 2 hours. The mixture was separated from water by ethyl acetate. The organic layer was then washed with saturated saline solution, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo to remove method. The residue was purified by column chromatography (EtOAc EtOAc (EtOAc) (EtOAc (EtOAc) Pyrazol-3-yl)-imidazo[1,2-a]pyridine (7-(2-methyl-2H-pyrazol-3-yl)-imidazo[1,2,a]pyridine, 350 mg, 70%) . MS: [M+H] ⁺ 199.

Step B1d 7-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-imidazo[1,2-a]pyridine (7-[3-(4-Methyl-piperazin-1-) Synthesis of ylmethyl)-phenyl]-imidazo[1,2-a]pyridine)

Prepared using the method described in General Procedure A, Step A4a, and 3-formylphenylboronic acid

N-methylpiperazine (1.1 ml, 10.2 mmol, 1.2 equiv) was added to 3-imidazo[1,2-a]pyridine in toluene (30 ml) and methanol (10 ml). 7-Bestbenzaldehyde 3-Imidazo[1,2-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 solvent was evaporated. The crude imine product was then dissolved in a solution of ethanol and methanol (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 2N aqueous NaOH (20 mL). Ethyl acetate was then added to separate the layers. The organic layer was washed with brine (MgSO ₄ ) The compound was purified by column chromatography (EtOAc EtOAc:EtOAc)

Step B2-Iodination

As described in the general formula A, step A2

Step B3a - General Suzuki reaction, in the third position

The method described in the general formula A, step A3a or A3b

Step B3b - General Suzuki reaction, in the third position

The method described in the general formula B step B1c

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

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

Add 3-bromoanisole (3-bromoanisole, 0.24 g, 1.3 mmol), 2M Na ₂ CO ₃ (1.5 ml) [to remove air bubbles via nitrogen gas] to dissolve in EtOH (2.7 ml), toluene (2.7 ml) Of imidazo[1,2-a]pyridin-6-ylboronic acid (imidazo[1,2-a]pyridin-6-ylboronic acid, 0.162 g, 1 mmol), followed by tetrakis(triphenylphosphine)palladium (0) (tetrakis (triphenylphosphine)) palladium (0), 0.059 g, 0.05 mmol). The mixture was heated at 70 ° C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine (MgSO ₄ ) The product was obtained after drying (0.3 g). MS: [M+H] ⁺ 225

Step C1(b) - Addition reaction of the 6th position ring catalyzed by general palladium

2-[3-Methoxyphenyl]-4,4,5,5,-tetramethyl-[1,3,2]-diadeoxyborane (2-[3-methoxyphenyl]-4, 4,5,5,-tetramethyl-[1,3,2]-dioxaborolane, 0.304g, 1.3mmol), 2M Na ₂ CO ₃ (1.5ml) [with air bubbles removed via nitrogen] added to EtOH (2.7ml) With 6-bromoimidazo[1,2a]pyridine, 0.197 g, 1 mmol of toluene (2.7 ml), followed by tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.05 mmol). 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 (br.), dried (MgSO? MS: [M+H] ⁺ 225

Step C2-Iodination

As described in the general formula A, step A2

Step C3-General General Suzuki reacts to the 3rd position

The method described in the general formula A, step 3b

General formula C4

As step A3a

(3-acetylaminophenyl) boronic acid (0.11 g, 0.71 mmol), K ₂ CO ₃ (0.59 g, 3.55 mmol), MeOH (1 ml), EtOH (1 ml), H ₂ O (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 ml). Bis(tri-t-butylphosphine)palladium(0) (0.006 g, 0.0116 mmol) was added. The mixture was heated at 100 ° C for 2 hours, then an excess of boric acid (0.06 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, dried (MgSO 4), filtered and evaporated. MS: [M+H] ⁺ 286

Add bis(tri-t-butylphosphine)palladium(0) (0.004 g, 0.0077 mmol) to 1-[3-(6-chloro-imidazo[1,2-a]pyridin-3-yl)- Phenyl]-ethanone (0.1 g, 0.35 mmol), phenylboronic acid (0.043 g, 0.35 mmol), K ₂ CO ₃ (0.29 g, 2.1 mmol), MeOH (0.5 ml), EtOH (0.5 ml), H ₂ O (0.8 ml) [in the solution of removing bubbles via nitrogen gas]. The mixture was heated in a CEM discovery 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 was washed with brine, dried (MgSO 4), filtered and evaporated. MS: [M+H] ⁺ 328

General modification D, in the 7th position

The latent functionality of the imidazo[1,2-a]pyridine at position 7 can be utilized for further synthetic use.

Step D1-Hydrogenation

Add Raney Ni to 1-{3-[7-(3-cyanomethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl dissolved in 2M methanolic ammonia (10 ml) ]-phenyl}-3-ethyl-urea (1-{3-[7-(3-Cyanomethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-ethyl -urea, 0.03 g, 0.76 mmol). The mixture was shaken in a hydrogen atmosphere at ambient temperature for 48 hours. The catalyst was filtered under reduced pressure on GF/A paper, followed by trituration with MeOH and drying of the solid to afford 12 mgs. MS: [M+H] ⁺ 400

Step D2-hydrolysis

2M NaOH (0.48 ml) was added to 1-(4-{3-[3-(3-ethyl-ureido)-phenyl]-imidazo[1,2-a] dissolved in EtOH (0.4 mL) Pyridine-7-yl}-benzyl)-3-methyl-piperidine-3-carboxylic acid ethyl ester (1-(4-{3-[3-(3-Ethyl-ureido)-phenyl]-imidazo [1,2-a]pyridin-7-yl}-benzyl)-3-methyl-piperidine-3-carboxylic acid ethyl ester, 0.020 g, 0.037 mmol). The reaction was heated to 50 ° C for 24 hours, then concentrated under reduced pressure and was crystallized by HPLC to give 0.07 g of product. MS: [M+H] ⁺ 512

Step D3-Boc Deprotection (Deprotection) Step D3a-Boc Deprotection (Deprotection)

4-(4-{3-[3-(3-Ethyl-ureido)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-phenyl)-piperazine-1 - tert-butyl carboxylate (4-(4-{3-[3-

(3-Ethyl-ureido)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 0.015 g, 0.027 mmol) in saturated EtOAc/ After HCl treatment, it was stirred at ambient temperature for 3 hr then concentrated under reduced pressure and dried to give product (0.010 g). MS: [M+H] ⁺ 441

D3b: 1-(2-Amino-ethyl)-3-{3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-phenyl}- Urea Preparation of (1-(2-Amino-ethyl)-3-{3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-phenyl}-urea)

A mixture of TFA (2ml) was slowly added to a stirred solution dissolved in CH ₂ Cl ₂ (4ml) of [2- (3- {3- [6- (4-fluoro - phenyl) - pyrazolo [1, 5-a]pyrimidin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester ([2-(3-{3-[6-(4-Fluoro-phenyl)-pyrazolo [1,5-a]pyrimidin-3-yl]-phenyl}-ureido)-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). To elute 2M NH _3- MeOH, vacuum compound (155 mg) as a yellow solid of the title is obtained after the solvent is volatilized.

Step D4-Pyridone formation

Step D4a

Add pyridine hydrochloride (0.59 g, 5.1 mmol) to 1-ethyl-3-{3-[7-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a] Pyridin-3-yl]-phenyl}-urea (1-ethyl-3-{3-[7-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl ]-phenyl}-urea, 0.1 g, 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 product ( 0.001 g). MS: [M+H] ⁺ 374

Step D4b

1-Ethyl-3-{3-[7-(2-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea ( 1-Ethyl-3-{3-[7-(2-methoxy-pyridin- 4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea, 0.03g, 0.077mmol) Treated with EtOAc / EtOAc (5 mL)EtOAcEtOAcEtOAc The reaction was concentrated under reduced pressure and then EtOAcEtOAcEtOAc MS: [M+H] ⁺ 374.

General modification of D5-pyridine N-oxidation

The mCPBA (29 mg, 0.17 mmol, 1.2 equiv.) Was dissolved was added to CH ₂ Cl ₂ (5 ml) of 1-ethyl-3- [3- (7-pyridin-3-yl - imidazo [1, 2-a]pyridin-3-yl)-phenyl]-urea (1-ethyl-3-[3-(7-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl)- Phenyl]-urea, 50 mg, 0.14 mmol, 1 equiv.), and 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 h. Then fared 2N NaOH was added to the reaction, CH ₂ Cl ₂ and to be separated from water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo. CH ₂ Cl ₂ as eluent to obtain N- oxide as a yellow solid (7 mg, 13%): isolated as an oil phase out of the 10% MeOH purified via column chromatography (SiO _2),.

General modification of D6-debenzylation (Debenzylation)

7-(3-Benzyloxypyrrolidin-1-yl)-imidazo[1,2-a]pyridine (7-(3-Benzyloxypyrrolidin-1-yl)-imidazo[1,2-a] pyridine, 68 mg, 0.23 mmol) was dissolved in CH ₂ Cl _2, and cooled to 0 ℃. Trimethylsilyl iodide (41 μL, 1.3 equiv) was added and the mixture was stirred for a further 30 minutes before the solution was warmed to room temperature. MeOH (4 mL, excess) was added and the mixture was concentrated. The product was purified by column chromatography _{(0-80% MeOH in Et 2 O} ) .MS: [M + H] + 204.

Step D7

Add 1 M HCl (2 ml) to N-[(E)-3-{7-[4-(2,2-dimethyl-[1,3]dioxolane-4 dissolved in MeOH (3 mL) -ylmethoxy)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-1-(E)-ethylene-but-2-enyl]-acetamide (N -[(E)-3-{7-[4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-imidazo[1,2-a]pyridin-3-yl} -1-eth-(E)-ylidene-but-2 -enyl]-acetamide (0.24 g, 0.52 mmol) was stirred at ambient temperature for 1 hour, then concentrated under reduced pressure and purified with EtOAc product. MS: [M+H] ⁺ 418

Step D8 - Demethylation

1M BBr ₃ dissolved in CH ₂ Cl ₂ (1.84 ml) was added to 1-{3-[7-(5-methoxymethyl-[] dissolved in CHCl ₃ (1 ml) at a temperature of -78 °C. 1,3,4]thiazol-2-yl)-imidazo[1,2-a]pyridin-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, 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 off and washed with ₂ Cl ₂ and EtOAc CH, followed by HPLC purification to afford compound (5mg). MS: [M+H] ⁺ 449.

General modification E, in the 7th position

Synthesis of Step E1-1-Bromo-3-(2-methoxy-ethoxy)-benzene (1-Bromo-3-(2-methoxy-ethoxy)-benzene)

The 2-bromoethyl methyl ether (0.56ml, 6mmol) was dissolved was added to MeOH (1.5ml) 3-bromo-phenol (0.865g, 5mmol), followed by addition of _{K 2 CO 3 (0.68g, 5mmol} ). The mixture was heated to 100 ° C using microwave irradiation in a CEM Discover microwave synthesizer (50 W) until the reaction was complete. The reaction was diluted with diethyl ether and the solid was filtered, and the solid was washed again with diethyl ether. Filtration and concentration under reduced pressure gave the product (0.8 g).

Step E2 - Conversion of a Halo Group to a Boric Acid Group

Tricyclohexyl phosphine (0.028 g, 0.098 mmol), KOAc (0.12 g, 1.23 mmol), bis(pinacolatoboron, 0.23 g, 0.9 mmol) Removal of air bubbles by nitrogen] was added to 1-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl dissolved in dioxane (5 ml) In the form of 1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl-urea, 0.258 g, 0.82 mmol), followed by the addition of Pd ₂ (dba) ₃ (0.038g). The mixture was heated at 80 deg.] C overnight, followed by GFA filter paper, washed in CH ₂ Cl _2, and concentrated under reduced pressure. The reaction mixture was used directly.

Step E3 - Conversion of borate groups to aryl groups using Suzuki reaction

Dicyclohexyl-(2',6'-dimethoxy-biphenyl-2-yl)-phosphane, [S -PHOS], 0.038 g, 0.0625 mmol), potassium phosphate (0.31 g, 1.6 mmol) [with air bubbles removed via nitrogen] was added to 1-ethyl ether dissolved in dioxane (5 ml) and water (2.5 ml) -3-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a] Pyridin-3-yl]-phenyl}-urea (1-Ethyl-3-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- In imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea (0.333 g, 0.82 mmol), palladium acetate II (0.008 g, 0.04 mmol) was then added. The reaction was continuously heated at 80 ° C. hours, then triturated in CH ₂ Cl _2, and then washed with CH ₂ Cl _2. after filtration, concentrated and purified by HPLC to give the impure product under reduced pressure. after the mixture by SCX column to obtain the product magazine (0.004 g ).MS:[M+H] ⁺ 431

Step E3b - Suzuki reaction

The conditions used in the general Suzuki reaction A4b were used.

Step E3c-{3-[7-(1-Methyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea ({3-[7-(1-Methyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea)

Step E3c uses the conditions used in the general Suzuki reaction A4e.

4-iodo-1-methyl-1H-imidazole (83 mg, 0.39 mmol), SPHOS (6.5 mg, 0.016 mmol) and Pd ₂ (dba) ₃ dissolved in dioxane (2 ml) in a MW tube. 7 mg, 0.0076 mmol) was added to 1-[3-(7-Boronic acid-imidazo[1,2-a]pyridn-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)- It was stirred under a urea (0.15 g, 0.39 mmol), and then K ₃ PO ₄ (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, followed by separation in EtOAc / H ₂ O, the organic layer was separated, dried (MgSO _4), filtered, and the solvent removed in vacuo method. The residue was purified using HPLC to give product (8 mg). MS: [M+H] ⁺ =415.

Step E3d-1-{3-[7-(2-Methyl-thiazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (1-{3-[7-(2-Methyl-thiazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea)

PdCl ₂ dppf (19 mg, 0.3 mmol) was added to 1-[3-(7-boronic acid-imidazo[1,2-a]pyridin-3-yl) dissolved in dioxane (4 ml) and water (1 ml) )-Phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Boronic acid-imidazo[1,2-a]pyridn-3-yl)- Phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 200 mg, 0.26 mmol), 4-bromo-2-methylthiazole (61 mg, 0.34 mmol), and K ₃ PO ₄ (168 mg, 0.79) Mmmol) [with air bubbles removed via nitrogen] and stirred. The reaction was heated to 80 ° C for 4 hours. The mixture was cooled, and separated in EtOAc / H ₂ O, the organic layer was separated, dried (MgSO _4), filtered, and the solvent removed in vacuo method. The residue was purified using HPLC to give the product (26mg). MS: [M+H] ⁺ =432.

Step E3e

Add cesium carbonate (228 mg, 0.7 mmol) to 1-{3-[7-(4,4,5,5) in a mixed solution of toluene (2 ml), n-butanol (2 ml), and water (0.5 ml). -tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea (1-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2 -a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, 107 mg, 0.23 mmol) and 2-bromo-[1,3,4]thiadiazole ( 96 mg, 0.58 mmol). The reaction mixture was deoxygenated and tetrakis(triphenylphosphine)palladium (0) (81 mg, 0.07 mmol) was added. The reaction mixture was again degassed and heated to 80 °C overnight. The mixture was then cooled, EtOAc and H ₂ O was separated out and the organic layer was separated, dried (MgSO _4), filtered, and the solution is removed in a vacuum process. This crude product was purified by HPLC to give 18 mg of product. MS: [M+H] ⁺ 419.

General modification F, in the third position

The latent functionality of the 3rd position of imidazo[1,2-a]pyridine can be utilized for subsequent synthesis

Step F1a - Formation of urea

Triethylamine (3.3 ml, 23.4 mmol) and ethyl isocyanate (0.93 ml, 11.7 mmol) were added dropwise to 3-(7-chloro-imidazo[1] dissolved in THF (30 ml). , 2-a]7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl amine) [Method as described in Step A3a ] (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 used for separation of water and EtOAc, and the organic layer was washed with water, then with saturated aqueous sodium chloride (brine) wash, dried (MgSO _4), filtered, and concentrated under reduced pressure. Biotage product was purified (SiO _2, to 50% EtOAC / petroleum ether, EtOAc, 10% MeOH / EtOAC elution) to give 1.1g of product.

Step F1b-2 step urea synthesis

3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-isopropoxy-phenylamine (3-[7-(4- Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-isopropoxy-phenyl amine) (90 mg, 0.25 mmol) and p-nitrophenyl chloroformic acid (50 mg, 0.25 mmol) 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 the crude residue was purified on 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 dimethylaminosulfonyl chloride (0.069 ml, 0.5 mmol, 1.5 equiv) were added dropwise to 3-[7-(s) dissolved in THF (3.3 ml). 4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin -3-yl]-phenyl amine, 100 mg, 0.33 mmol, 1.0 equiv). The mixture was stirred overnight at 60 ° C and the mixture was evaporated under reduced pressure. The crude mixture was used as water and EtOAc and separated organic layer was saturated brine (brine), dried (MgSO _4), and concentrated under reduced pressure. The product was purified using HPLC to give 40 mg of product.

Step F3a - Formation of amide

N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol, 1.1 equiv) And 1-hydroxybenzotriazole (49 mg, 0.36 mmol, 1.1 equiv) was added to 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a] dissolved in DMF (2 ml) 3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl amine, 100 mg, 0.33 mmol, 1.0 equiv ) and glycolic acid (34 μl, 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.

Step F3b - amide formation

Triethylamine (0.09 ml, 0.66 mol) was added to the amine 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl] dissolved in THF (3 mL) -Phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl amine, 0.1 g, 0.33 mmol), followed by dropwise addition of propionium Propionyl chloride (28 μl, 0.33 mmol). The reaction was stirred 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] ⁺ = 360.

Step F4-Formation of Carbamate

Triethylamine (0.138 ml, 0.99 mmol) was added to 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl] dissolved in THF (3.3 mL) -Phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl amine, 0.1 g, 0.33 mol), followed by dropwise addition of methyl Chloroformate (38 μl, 0.50 mmol). The reaction mixture was stirred overnight at 60 ° C, cooled and the solvent was removed in vacuo. The residue was isolated in EtOAc and H ₂ O, and the organic layer was separated, dried (MgSO _4), filtered, and the solvent removed in vacuo method. The crude material was purified using reverse phase HPLC to afford product (33mg). MS: [M+H] ⁺ =362.

Step F5-triazole-3-thione; synthesis of (triazole-3-thiones)

1,1'-thiocarbonyldi-2(1h)-pyridone (1,1'-thiocarbonyldi-2(1h)-pyridone, 0.51g, 0.65mmol) was added to dissolve in toluene (20ml). 3-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamine (3-[7-(3-Morpholin) -4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamine, 0.25 g, 0.65 mmol), stirred and heated to 110 ° C for 1 hour. The reaction was cooled to ambient temperature, diluted in CH _{2 2} Cl, water and saturated saline water (brine) wash, dried (Na ₂ SO _4), filtered, and concentrated under reduced pressure to obtain a brown oil. The residue was taken up in EtOAc (4 mL)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, 0.66 mmol) dissolved in DMF (5 ml). )in.

After 30 minutes, additional diethyl chlorophosphate was added. The reaction mixture was taken up in 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 amino-thiadiazoles.

Step F6 - Reductive Amination

Add acetaldehyde (17 μl, 0.40 mmol, 1.2 equiv) to 3-[7-(4-fluoro-phenyl)-imidazo[1,2- in toluene (30 ml) and methanol (10 ml) a]3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl amine, 100 mg, 0.33 mmol, 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 sodium borohydride (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 2N NaOH (20 ml). Ethyl acetate was then added to separate the layers. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and concentrated under reduced pressure. The compound was purified using HPLC to give the desired product.

Step F7-alkylation

2-Chloro-acetamide (30 mg, 0.33 mmol) and sodium acetate in water (54 mg, 0.66 mmol) were added to 3-[7-(4-fluoro-phenyl)-imidazole dissolved in EtOH (0.5 ml). And [1,2-a]pyridin-3-yl]-phenylamine (3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyla mine, 100 mg, 0.33 mmol) [as shown in step A3a]. The reaction was heated to 78 ° C for 18 hours. It was then triturated in MeOH and the obtained solid was filtered. The solid was then alcoholized by reverse phase HPLC to give the product (7 mg). MS: [M+H] ⁺ 361

General procedure H - Synthesis of a trisubstituted benzene at the 3rd position of imidazo[1,2-a]pyridine Step H1: 3-[7-(3-Morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-nitro-benzoguanamine (3-[7-(3-Morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-nitro-benzamide)

The 3-aminobenzene boronic acid was replaced with (3-aminocarbonyl-5-nitrophenyl)boronic acid using the procedure of General Procedure A, step A3b. MS: [M+H] ⁺ 458.

Step H2: 3-amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridine-3- Phenylamine (3-Amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzamide)

The _{Pd (OH) 2 (30mg)} , 3- [7- (3- morpholin-4-yl-methyl - phenyl) - imidazo [1,2-a] pyridin-3-yl] -5-nitro 3-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-nitro-benzamide) (135 mg), 2N HCl (0.15 ml), and HCO ₂ NH ₄ (150 mg, 2.4 mmol) were dissolved in EtOH/H ₂ O (4:1, 5 ml) and stirred at 90 ° C for 90 min. After cooling to room temperature, the mixture was diluted with MeOH and placed in EtOAc. Wash with MeOH, followed by 2M NH ₃ -MeOH washed, to give the compound shown in the title (90mg, gum). MS: [M+H] ⁺ 428

Step H3: 3-Acetylamino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzamide

3-Amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl] dissolved in dry DMF (2 mL) -Amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzamide, 90 mg), AcOH (29 μL, 0.5 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (N-(3-dimethylaminopropyl)-N'- The ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol) was stirred at room temperature under nitrogen for 24 hr. then the mixture was partitioned from CH ₂ Cl ₂ /H ₂ O. After layering, the aqueous layer was placed in EtOAc. , followed by 2M NH ₃ -MeOH for cleansing. NH which is part of ₃ -MeOH evaporate, and the residue is purified using HPLC to give the title product as shown ^{(40mg, solid). 1 H} NMR (400 MHz, DMSO- d 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).

Step H4: N-{3-Cyano-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} -Acetamine (N-{3-Cyano-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-acetamide)

Further, the preparation is carried out by the method described in the general procedure H, steps H1 and H3. In the step 1, 3-aminocarbonyl-5-nitrophenylboronic acid is substituted with 3-amino-5-cyanobenzeneboronic acid.

¹ H NMR (400 MHz, DMSO- d ₆ ): 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).

Step H5: N-{3-Methoxy-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzene }--acetamide (N-{3-Methoxy-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-acetamide)

Further, as in Example H, steps H1, H2 and H3 are used. In step 1, 3-aminocarbonyl is replaced by 3-methoxy-5-nitro-phenylboronic acid pinacol ester (I8). -5-nitrophenylboronic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ): 10.11 (1H, s), 8.64 (1H, 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).

Step I - Synthesis of boric acid and esters Boric acid I1 2-methoxy-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (2-Methoxy-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide)

Triethylamine (0.95 ml, 6.84 mmol) and methoxyethyl hydrazine chloride (0.417 ml, 4.56 mmol) were added dropwise to 4-(4,4,5,5-tetramethyl) dissolved in THF (20 ml). -[1,3,2]disoxaboropen-2-yl)-phenylamine (4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl In a -phenylamine, 1 g, 4.56 mmol) mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc, and washed with water, then with saturated aqueous sodium chloride (brine) wash, dried (Na ₂ SO _4), filtered and concentrated in vacuo to afford the product as an orange oil (1.2g). MS: M+H] ⁺ 292

Boric acid I2

2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (2-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester)

2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester, 0.5 g, 1.94 mmol, [ 1,1'-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'-eight in dioxane (4 ml) Methyl-2,2'-di-1,3,2-dioxaoxyborane (4,4,5,5,4',4',5',5'-Octamethyl-2,2'- Bi-1,3,2-dioxaborolane, 0.74 g, 2.91 mmol), and heated to 80 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and then with saturated aqueous sodium chloride (brine) wash, dried (Na ₂ SO _4), filtered, and concentrated in vacuo to give a brown oily product (0.7g). MS: [M+H] ⁺ 305.

Boric acid I3

1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (1-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one)

K ₂ CO ₃ (6.36, 45.7 mmol) and MeI (2.84 ml, 45.7 mmol) were added to 5-bromo-1H-pyridin-2-one (5-Bromo-1H-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 the solid was washed with DME. Filtered and concentrated by vacuum, and separated from the water using EtOAc to give an oil, the organic layer was washed with brine (brine) wash, dried (Na ₂ SO _4), filtered, and concentrated in vacuo to give an oily product crystallized and spare.

5-Bromo-1-methyl-1H-pyridin-2-one (0.5 g, 2.65 mmol) [reaction to remove bubbles via nitrogen gas], [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride ([1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), 59mgs, 0.080 mmol), dppf (88 mgs, 0.16 mmol) and potassium acetate (0.77 g, 7.84 mmol) were added to 4,4,5,5,4',4',5',5'-octamethyl-2,2'-di-1,3,2-dioxaoxylan dissolved in dioxane (40ml) Borane (0.88 g, 3.46 mmol) was heated to 80 ° C for one week. The reaction mixture was diluted with EtOAc, washed with water and then with saturated aqueous sodium chloride (brine) wash, dried (Na ₂ SO _4), filtered, and concentrated under reduced pressure to give a brown oily product, and not via the purification step or by using The Biotage was purified by column chromatography eluting with EtOAc (EtOAc). MS: [M+H] ⁺ 224

Boric acid I6

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2- Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea) Step 1: 1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-phenyl)-3-(2,2,2 -trifluoro-ethyl)-urea)

At 0 deg.] C, under ambient N ₂ gas, the 3-bromophenyl isocyanate (1.0ml, 8.1 mmol) was added slowly dissolved to THF (10ml) was stirred 2,2,2-trifluoroethylamine (3.2 mL , 40 mmol) in solution. After 1 hour, the reaction was allowed to warm to room temperature and maintained for 16 hours. The solvent was evaporated in vacuo to give the compound (2.5 g, solid). ¹ H NMR (400 MHz, DMSO-d6): 9.00 (1H, s), 7.86 (1H, t), 7.33 (1H, ddd), 7.26 (1H, t), 7.18 (1H, ddd), 6.89 (1H) , t), 4.03-3.92 (2H, m).

Step 2: 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2 , 2-trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

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) Mmmol) Evacuation deoxygenation/refill with N ₂ (x3). PdCl ₂ ddpf (512 mg, 0.7 mmol) was added, and the mixture was again deoxygenated (x 2), then stirred and heated at 100 ° C under N ₂ for 3 hours. The reaction was cooled to room temperature and allowed to stand at this temperature for 18 hours. In EtOAc / H ₂ O The mixture was separated by filtration using Celite ^®. After separation, the aqueous layer was extracted with EtOAc (EtOAc). The organic layer was extracted with water (X1), saturated brine (brine) (x1) washed, then dried (MgSO _4), filtered and the solvent evaporated. The residue was triturated in petroleum ether to give compound (2.6 g, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 7.65 (1H, s), 7.60 (1H, d), 7.49 (1H, d), 7.37 (1H, t), 6.64 (1H, brs), 5.20 (1H, Brs), 3.99-3.86 (2H, m), 1.35 (12H, s).

Boric acid I7 1-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (1-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea)

For example, 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, 2-Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2 Prepared by the same method as 2-trifluoro-ethyl)-urea, I6), but in step 1, 2,2,2-trifluoroethylamine was replaced with methylamine dissolved in THF (2M). ¹ H NMR (400 MHz, CDCl ₃ ): 7.59-7.53 (2H, m), 7.50 (1H, d), 7.34 (1H, t), 2.83 (3H, s), 1.33 (12H, s).

Boric acid I8 3-methoxy-5-nitro-phenylboronic acid pinacol ester (3-Methoxy-5-nitro-phenyl 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 degassed/refilled with N ₂ (x3). PdCl ₂ ddpf (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, EtOAc / H ₂ O The mixture was separated, Celite ^® filter. The layers were separated and the aqueous extracted with EtOAc (EtOAc). The organic layer was washed with brine (brine) (x1) washing, followed by drying (Na ₂ SO _4), filtered, and evaporated. The residue was purified using EtOAc (EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ): 8.23 (1H, d), 7.79 (1H, t), 7.62 (1H, d), 3.90 (3H, s), 1.36 (12H, s).

Boric acid I9 1-ethyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (1-Ethyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea)

Triethylamine (58 ml, 410 mmol, 3.0 equiv) and ethyl isocyanate (16.3 ml, 205 mmol, 1.5 equiv) were added to 3-(4,4,5,5-four in THF (300 ml) Methyl-1,3,2-dioxaborolan-2-yl)aniline (3-(4,4,5,5-tetramethyl-1,3,2-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 diethyl ether to give the desired product 34 g.

Boric acid I10-I13 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-amine (1-[4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-amine)

K ₂ CO ₃ (2 eq), amine (1.25 eq), and (4-bromomethylphenyl) boronic acid pinacol ester (1 eq) were dissolved in dry DMF ( 1 ml/mmol) and stirred at room temperature for 20 hours. The mixture was separated with Et ₂ O/H ₂ O. The organic layer was washed with water (x1), brine (x1), and then dried (Na) ₂ SO ₄ ), filtered and evaporated to give the title compound.

Boric acid I14 4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl-boronic acid (4-(2,2-Dimethyl-[1,3]dioxolan- 4-ylmethoxy)-phenyl-boronic acid)

Sodium hydride (200 mg, 5.0 mmol, 1.0 equiv) was added in portions to 4-bromophenol (865 mg, 5.0 mmol, 1.0 equiv) in DMF (10 mL). Then add 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, 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, then MeOH (10 mL) was evaporated and evaporated. The crude mixture was separated into water with ethyl acetate and layered. The organic layer was washed with water, dried (MgSO _4), and concentrated under reduced pressure. The crude mixture was purified by column chromatography eluting with EtOAc EtOAc EtOAc

n-BuLi (2.25 ml of a 1.6 M solution in hexanes, 3.6 mmol, 1.0 equiv) was added dropwise to the aryl bromide compound (1.0 ml) dissolved in THF (10 ml) under nitrogen atmosphere at -78 °C. g, 3.6 mmol, 1.0 equiv). After 15 minutes, a solution of trimethyl borate (1.3 ml, 12.3 mmol, 3.5 equiv) was added slowly (additional time must exceed 15 minutes). The reaction mixture was warmed to room temperature and placed overnight. The solvent was removed by vacuum. The mixture was separated with diethyl ether and Sorenson's buffer solution (pH 5.5-Na ₂ HPO ₄ in water and KH ₂ PO ₄ ). The aqueous layer (3 x) and extracted with diethyl ether, and the organic layer was with water, saturated aqueous sodium chloride solution (brine), dried (MgSO _4), filtered, and concentrated under reduced pressure to give the product as a colorless solid (852 mg, 94%) .

Boric acid I15 Step 1: 4-(4-Bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (4-(4-Bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester)

Add Na ₂ CO ₃ (1.6 g, 18.9 mmol) and (BOC) ₂ O (1.3 g, 5.9 mmol) to 4-(4-bromo-phenoxy)-piperidine dissolved in dioxane (20 ml) (4-(4-Bromo-phenoxy)-piperidine, 1 g, 3.9 mmol), followed by water (20 ml). After stirring at ambient temperature for 48 hours, the solvent was evaporated <RTI ID=0.0> The organic layer was washed with saturated aqueous sodium chloride (brine), dried (MgSO _4), concentrated under reduced pressure to afford the product (1.2g).

Step 2: 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidin-1- Tert-butyl carboxylate (4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester)

Bis pinacolto diboron (0.93 g, 36.5 mmol), KOAc (0.83 g, 84.5 mmol), PdCl ₂ ddpf (0.061 g, 0.84 mmol), and dppf (0.092 g, 0.16) Add to 4-(4-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (4-(4-Bromo-phenoxy)-piperidine-1- dissolved in dioxane (25 ml) In the carboxylic acid tert-butyl ester, 1 g, 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, EtOAc / H ₂ O The mixture was separated, the organic layer which was washed with saturated aqueous sodium chloride (brine), dried through (MgSO4), filtered, and concentrated under reduced pressure to afford the product (1.06g). MS: [M+H] ⁺ (no mass ion used crude)

Boric acid I18 N-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-acetamide (N-Methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-acetamide)

1-hydroxybenzotriazole (1-hydroxybenzotriazole 0.37 g, 2.73 mmol) and TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3- dissolved in DMF (15 ml) A solution of 2-(1H-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate, 0.88 g, 2.73 mmol) was added to DMF (15 ml). 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid ([3-(4,4,5,5) -Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid, 0.60 g, 2.28 mmol). Then triethylamine (0.95 ml) and methylamine (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 using reverse chromatography to give a mixture of boronic acid/acids which was used directly. MS: [MH ⁺ ] 276 (ester), [MH ⁺ ] 193 (acid).

Boric acid I19 (3-methylpiperazinone) phenyl boronic acid ((3-methylpiperazinone) phenyl boronic acid)

(3-Bromomethylphenylboronic acid, neopentyl glycol ester (0.45 g, 1.6 mmol), NaHCO ₃ (0.34 g, 4 mmol) and NaI (0.01 g, 0.74 mmol) were added to dry THF/DMSO ( 10 ml: 2.5 ml) of piperazine-2-one (0.2 g, 2 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. Direct access. MS: [MH ⁺ ]235

Borate ester I20 1-(3-Amino-2,2-difluoro-propyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane -2-yl)-phenyl]-urea (1-(3-Amino-2,2-difluoro-propyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- Urea)

step 1:

Under a nitrogen atmosphere, a 7N aqueous solution of ammonia dissolved in methanol (14.3 ml, 101.9 mmol, 4 equiv) was added to diethyl difluoromalonate (5 g, 25.5 mmol) dissolved in methanol (15 ml). , 1 equiv). After the reaction was completed, the mixture was concentrated under reduced pressure. The crude mixture was ground in petroleum ether to give a white solid of 2,2-difluoro-propanediamine. (2,2-difluoro-malon amide) (98%).

Step 2:

Add 2,2-difluoro-malonamide (1.34 g, 9.7 mmol) in THF (26 ml) to BH3.THF [1M in THF] (58ml, 58mmol) in. The reaction mixture was heated to 45 ° C and stirred overnight, then cooled with EtOAc EtOAc EtOAc EtOAc EtOAc After filtration and drying, 2,2-difluoro-propane-1,3-diamine (0.92 g) was obtained. MS: [M+H] ⁺ 111.

Step 3:

2,2-Difluoro-propane-1,3-diamine (0.4 g, 2.2 mmol) and triethylamine (1.5 ml, 11 mmol) were added to 2-(3-isocyanic acid) in THF (15 ml). Phenyl)-4,4,5,5-tetramethyl-[1,3,2]-diadeoxyborane, 2-(3-isocyanatophenyl)-4,4,5, 5-tetramethyl-[1,3,2]-dioxab orolane, pinacol ester, 0.135 g, 0.55 mmol) was stirred at ambient temperature until the reaction was complete. The solid was filtered, washed with THF, filtered and concentrated under reduced pressure. MS: [M+H] ⁺ 356

Boric acid I21 2-(tetrahydro-pyran-4-yloxy)-4-pyridylboronic acid (2-(tetrahydro-pyran-4-yloxy)-4-pyridinylboronic acid)

4-Hydroxytetrahydropyran (4-hydroxytetrahydropyran, 1.02 ml, 10 mmol) was added to NaH (0.4 g, 10 mmol) in THF (20 ml). The reaction mixture was warmed to room temperature and stirred for 30 minutes before dropwise addition of 4-bromo-2-chloropyridine (0.89 ml, 8.0 mmol). In EtOH (1 ml) before the reaction was stopped, the reaction mixture was stirred for 18 hours, to CH ₂ Cl ₂ and H ₂ O as separated and the CH ₂ Cl ₂ (x2) and extracted. The organic layer was collected, dried (MgSO ₄₎ and solvent was removed in vacuo method. Purification using column chromatography gave 4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine). MS: [MH] ⁺ 258,260

4,4,5,5,4',4',5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane (4,4,5 , 5,4',4',5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, 0.39g, 1.55mmol) and potassium acetate (0.27g, 2.31mmol) 4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.2 g, dissolved in DMSO (5 ml), 0.77 mmol) (by N ₂ to degas). Then PdCl ₂ ddpf (0.028 g, 0.04 mmol) was added, then the reaction mixture was again degassed and heated at 100 ° C for 5 hours. The compound is passed through a C18 reverse layer pipette to give the desired compound and can be used directly. MS: [MH] ⁺ 224.

Boric acid I22 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid Butyl ester (4-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester)

Cs ₂ CO ₃ (44.4 g), 136.3 mmol, 3.0 equiv) and 4-methanesulfonyloxy-piperidine-1-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]disoxaborane-dissolved in NMP (100 ml) 2-yl)-phenol (3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol, 10.0 g, 45.4 mmol, 1.0 equiv). The reaction mixture was heated to 80 ° C until the reaction was complete. The reaction mixture was then cooled to room temperature. Dilute with water and extract with EtOAc. The organic layer 2N KOH, water, saturated aqueous sodium chloride (brine) wash, dried (MgSO _4), filtered, and concentrated under reduced pressure. The target molecule was purified by column chromatography (SiO ₂₎ through to elute the 5 → 30% EtOAc- petroleum ether was obtained as a colorless liquid (9.5 g) and crystallized its standby. 1H NMR (400 MHz, CDCl3): 7.42 (1H, d), 7.37 (1H, d), 7.31 (1H, t), 7.03 (1H, 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 I24 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,-di Fluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,-difluoro-ethyl)-urea)

The preparation was carried out in the same manner as in the step I6 except that 2,2-difluoroethylamine was substituted with 2,2-difluoroethylamine. 1H NMR (400 MHz, CDCl ₃ ): 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).

Borate I25 1-(2-Fluoro-ethyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl Urea (1-(2-Fluoro-ethyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea)

The preparation was carried out in the same manner as in the step I6 except that 2,2,2-trifluoroethylamine was substituted with 2-fluoroethylamine. 1H NMR (400 MHz, CDCl ₃ ): 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).

Borate I26 (2-{3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-B Tert-butyl carbamate ((2-{3-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-ethyl)-carbamic acid tert-butyl ester )

Prepared in the same manner as in step I6, but substituting (2-amino-ethyl)-aminecarboxylic acid tert-butyl ester for 2,2,2-trifluoroethylamine. 1H NMR (400 MHz, DMSO-d ⁶ ): 8.59 (1H, s), 7.77 (1H, s), 7.47 (1H, dt), 7.26-7.17 (2H, m), 6.84 (1H, t), 6.16 (1H, t), 3.18-3.07 (2H, m), 3.07-2.95 (2H, m), 1.39 (9H, s), 1.29 (12H, s).

Borate I27 (3-{3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-prop Tert-butyl carbamate ((3-{3-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-propyl)-carbamic acid tert-butyl ester )

(3-Amino-propyl-carbamic acid tert-butyl ester, 0.79 ml, 4.5 mmol) was slowly added to the mixture under nitrogen at room temperature. 2-(3-Isocyanate-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2-() dissolved in dry THF (8 ml) 3-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, 1 g, 4.1 mmol). After 16 hours the solvent is evaporated in vacuo and the residue was isolated in EtOAc / H ₂ O. The organic layer was washed with saturated aqueous sodium chloride (brine) (x1), and dried (Na ₂ SO _4), filtered, and the volatiles to afford a colorless solid of the title compound as shown in (1.6g). </ RTI><RTIgt; 1H, t), 3.13-3.02 (2H, m), 3.02-2.89 (2H, m), 1.57-1.48 (2H, m), 1.39 (9H, s), 1.29 (12H, s).

Borate ester I28: 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-3 -(2,2,2-trifluoro-ethyl)-urea (I28: 1-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-3-(2,2,2-trifluoro -ethyl)-urea)

Add bis(pinacolato diboron, 0.88 g, 3.45 mmol) to 1-(5-bromo-pyridin-3-yl)-3- dissolved in dehydrated DMSO (3 mL) (2,2,2-trifluoro-ethyl)-urea (1-(5-bromo-pyridin-3-yl)-3-(2,2,2-trifluoro-ethyl)-urea, 0.51 g, 1.72 Mm). The vial of the reaction was filled with N ₂ and PdCl ₂ dppf (40 mg, 0.05 mmol). Next, N ₂ was again poured and heated to 100 ° C for 22 hours. After cooling to room temperature, was added H ₂ O (30 mL) and EtOAc (30 mL) and the two phases separated. The organic phase layer was washed with H2O ( ₂ ×35 mL). The organic layer was then dried MgSO _4, filtered and concentrated under reduced pressure, the product can be taken directly to use.

Borate ester I29- (tetrahydro-pyran-4-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] -amine ((Tetrahydro-pyran-4-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine) Step 1: (3-Bromo-phenyl)-(tetrahydro-pyran-4-yl)-amine ((3-Bromo-phenyl)-(tetrahydro-pyran-4-yl)-amine)

Sodium triacetoxyborohydride (1.48 g, 7 mmol) and acetic acid (0.3 g) were added to 3-bromo-phenylamine (0.54 ml, 5 mmol) and tetrahydro-4H-pyran dissolved in DCE (20 ml). 4-ketone (tetrahydro-4H-pyran-4-one, 0.5 g, 5 mmol). The mixture was stirred for 18 hours before stopping the reaction with 1 N NaOH (10 mL). The mixture was separated with Et ₂ O and H ₂ O. The aqueous layer was extracted with Et ₂ O. The organic layers were collected, dried (MgSO ₄ ), filtered, and solvent was removed in vacuo to give a colorless liquid. Things. Purification by column chromatography (0-80%EtOAcEtOAcEtOAc) MS: [M+H] ⁺ =256,258

Step 2: (tetrahydro-pyran-4-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dihydrogen Pentaborane-2-yl)-phenyl]-amine ((Tetrahydro-pyran-4-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine)

Add bis (pinacolato diboron, 0.4 g, 1.55 mmol) and potassium acetate (0.23 g, 2.31 mmol) to (3-bromo-phenyl) dissolved in DMSO (5 ml) -(3-Bromo-phenyl-(tetrahydro-pyran-4-yl)-amine, 0.2 g, 0.77 mmol). The reaction was deoxygenated, and PdCl ₂ ddpf (28 mg, 39 μmol) was added, and the mixture was again deoxygenated and stirred, and heated to 100 ° C for 18 hours under a nitrogen atmosphere. The reaction mixture was coarsely purified using reverse silica chromatography _{(0-100% MeCN in H 2 O} ), to afford the product as a beige gum (0.24g). MS: [M+H] ⁺ =304

Borate ester I30-N-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (N-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

EDAC (0.17 g, 0.88 mmol), HOAt (0.12 g, 0.88 mol), and triethylamine (0.1 ml, 0.8 mmol) were added to 3-(4,4,5,5- in THF (6 ml). Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic Acid, 0.2 g, 0.8 mmol). After adding ethylamine (0.4 g, 0.8 mmol), the reaction mixture was stirred at room temperature for 2 hr. Subsequently it is separated in CH ₂ Cl ₂ and 5% citric acid (citric acid), and the organic layer was separated, saturated di-saturated brine (brine) wash, dried (MgSO _4), filtered, and the solvent Remove by vacuum. This crude residue can be used directly in the next reaction. MS: [M+H] ⁺ =276

Borate ester I31 N-azetidin-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide-benzene Guanamine (N-azetidine-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

The same procedure as in step I30, but substituting ethylamine with azetidine. MS: [M+H] ⁺ =288

Borate ester I32-{2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylamino]- Ethyl}-carbamic acid tert-butyl ester ({2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo ylamino]-ethyl}-carbamic acid tert-butyl ester)

The same procedure as in step I30 was followed except that the ethylamine was replaced with tert-butyl N-(2-aminoethyl)carbamate. MS: [M+H] ⁺ =391

Borate ester I33-N-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (N-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)

The same procedure as in step I30 was followed except that the ethylamine was replaced with isopropylamine. MS: [M+H] ⁺ =290

Borate ester I34-(4-ethyl-piperazin-1-yl)-{3-(4,4,5,5-tetramethyl-[1,3,2]-diadooxaborane- 2-yl)-phenyl}-methanone ((4-ethyl-piperazin-1-yl)-{3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl}-methanone)

The same procedure as in step I30, but substituting ethylamine with 1-ethyl-piperazine. MS: [M+H] ⁺ =345

Borate ester I35-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-[1, 4] diazepine-1-carboxylic acid tert-butyl ester (4-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-[1,4]diazepane-1-carboxylic acid tert-butylester)

Substituting ethylamine.MS with [1,4] Diazepane-1-carboxylic acid tert-butyl ester, as in step I30, but with [1,4]diazepene-1-carboxylic acid tert-butyl ester. :[M+H] ⁺ =431

Borate ester I36-2-(3-isopropoxy-5-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]disoxaborane (2-(3-Isopropoxy-5-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 0

step 1

Isopropyl iodide (0.37 ml, 3.70 mmol) was added to 3-bromo-5-nitro-phenol (0.40 g, 1.83 mmol) dissolved in dry DMF (2 mL) and K ₂ CO ₃ (0.51) g, 3.67 mmol), and the mixture was stirred for 18 hours. The reaction mixture was separated with EtOAc / H ₂ O. The organic layer was with water (X1), saturated brine (brine) (x1) washed, dried (Na ₂ SO _4), filtered, and the solvent removed in vacuo method. The residue was purified with EtOAc EtOAc EtOAcEtOAc 1H NMR (400 MHz, CDCl3): 7.94 (1H, t), 7.67 (1H, t), 7.36 (1H, t), 4.71-4.57 (1H, m), 1.40 (6H, d).

Step 2

The same procedure as in step I8 was carried out without purification, and the crude product was used directly in the next step.

Borate ester I37-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl)-methanol)

step 1

Under nitrogen atmosphere, _{BH 3 .THF (1.0M in THF,} 100ml) was added dropwise with stirring sulfate was dissolved in THF (100ml) 3-bromo-5-nitro - benzoic acid (15.0g, 61mmol) was added. The reaction mixture was stirred overnight at room temperature before addition to saturated NaHCO3 _(aq) . Et ₂ O was then added to the reaction mixture and stirred for 20 minutes and then separated. The aqueous layer is extracted with Et ₂ O (x 2 ), and the organic layer is partially collected and extracted with 1N NaOH (x1), brine (x1), dried (Na ₂ SO ₄ ), filtered, and solvent Remove by vacuum. The residue was purified with EtOAc EtOAc EtOAcEtOAcEtOAc 1H NMR (400MHz, CDCl3): 8.31 (1H, s), 8.20 (1H, s), 7.89 (1H, s), 4.84 (2H, s).

Step 2

The same procedure as in step I8 was carried out without purification, and the crude product was used directly in the next step.

Borate ester I38-1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- 3-(2,2,2-trifluoro-ethyl)-urea (1-[4-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl )-urea)

step one

2-Chloro-1-fluoro-4-isocyanato-benzene (5.0 g, 29 mmol) was slowly added to dry THF at 0 ° C under nitrogen. (40 ml) of 2,2,2-trifluoroethylamine (12 ml, 150 mmol). After 1 hour, the reaction was warmed to room temperature and stirred for 18 hours. The solvent was removed in vacuo method, residue was triturated in Et ₂ O to give a colorless solid (6.2g). 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 I8 was followed, except that Pd ₂ dba ₃ and S-Phos were substituted for PdCl ₂ ddpf. After the completion of the aqueous solution, the product was isolated by trituration with petroleum ether (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 ester I39-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl amine)

The same procedure as in step I8 was carried out without purification, and the crude product was used directly in the next step.

Boric acid I40-1-dimethylaminosulfonyl-1H-pyrazole-4-boronic acid

Step--4-Bromo-pyrazole-1-sulfonic acid dimethyl decylamine

Dimethylaminosulfonium chloride (1.61 ml, 15 mmol) was added to 4-bromopyrazole (2.20 g, 15 mmol) and DABCO (1.85 g, 16.5 mmol). . The reaction mixture was stirred for 20 h and then EtOAc ₍ EtOAc ₎ The aqueous layer was EtOAc (x2) and extracted, the organic portion was collected, (brine) (x1) washed with saturated brine, dried (MgSO _4), filtered, and the solvent removed in vacuo to afford a colorless liquid product method ( 3.79g). 1H NMR (400 MHz, CDCl ₃ ): 8.00 (1H, s), 7.70 (1H, s), 2.99 (6H, s).

Step 2-1-Dimethylaminosulfonyl-1H-pyrazole-4-boronic acid

Methyl lithium (1.6 M in Et ₂ O, 12.2 ml, 19.5 mmol) was added to 4-bromo-pyrazole-1-sulfonic acid dimethyl amide (3.18) dissolved in dehydrated THF (40 ml). g, 14.9 mmol) and triethyl borate (3.80 ml, 22.3 mmol) were maintained at an internal temperature of <-60 °C. After 30 minutes, the reaction temperature was returned to room temperature and stirring was continued for 18 hours. The reaction was quenched with EtOAc (EtOAc) The organic extracts were collected, dried (Na ₂ SO _4), filtered, and the solvent removed in vacuo method. The material was purified by column chromatography to give a colorless gum (2.1 g). MS: [M+H] ⁺ =220

Borate ester I41-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-pyridine (4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-pyridine)

The same procedure as in step I8 was used, but purification was not carried out, and the crude product was used directly in the next step (1.25 g). 1H NMR (400 MHz, DMSO-d ⁶ ): 8.93 (1H, s), 8.29. (1H, d), 7.91 (1H, d), 1.34 (12H, s).

Borate ester I42-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methyl ester (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methyl ester)

The same procedure as in step I8 was carried out without purification, and the crude product was used directly in the next step (3.1 g). 1H NMR (400 MHz, DMSO- d 6): 8.88 (1H, dd), 8.21 (1H, dd), 8.06 (1H, dd), 3.90 (3H, s), 1.34 (12H, s).

Step J1-HCl salt formation 1-(3-{7-[3-(2-Amino-ethyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-ethyl- Urea dihydrochloride (1-(3-{7-[3-(2-Amino-ethyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-ethyl-urea dihydrochloride salt)

1-(3-{7-[3-(2-Amino-ethyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-benzene dissolved in EtOH (2 ml) 3-ethyl-urea (1-(3-{7-[3-(2-Amino-ethyl)-phenyl]-imidazo[1,2-a]pyridin- 3-yl}-phenyl)- 3-ethyl-urea, 0.01 g) was treated with saturated EtOAc / EtOAc. Stirred until completely dissolved, then concentrated under reduced pressure. MS: [M+H] ⁺ 400

Step J2 Step 1: [2-(3-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl ]-tert-butyl carbamate ([2-(3-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl Ester)

Imidazol-1-yl-(3H-pyrrol-3-yl)-methanone, 240 mg, 1.5 mmol, at 0 ° C under N ₂ Add to 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamine (3-[] in stirring in THF (10 mL) 7-(4-fluoro-phenyl)-imidazo[1,2-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, 2 mmol) deal with. The mixture was stirred at room temperature for 16 hours. Volatiles were removed in vacuo, the residue was purified by silica _{(2 → 4% 2M NH 3} -MeOH / CH 2 Cl 2) to give the compound shown in the title. (85mg, foam).MS: [M+H] ⁺ 490.

Step 2: 1-(2-Amino-ethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl }-urea (1-(2-Amino-ethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea)

Trifluoroacetic acid (1 ml) was added to [2-(3-{3-[7-(4-fluoro-phenyl)-imidazolyl] dissolved in CH ₂ Cl ₂ (2 ml) at a temperature of 0 ° C. 1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester ([2-(3-{3-[7-(4-fluoro-phenyl)) -imidazo[1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester, 85 mg, 0.17 mmol). After 1 h, the volatiles were removed in vacuo <RTI ID=0.0>

Reaction scheme for the synthesis of pyrazolo[1,5-a]pyrimidine

Preparation (or step) formation of K-general ring

3-aminopyrazole (6 g, 37 mmol) was added to 2-bromo-malonaldehyde (22.8 g, 80 mmol) dissolved in EtOH (150 ml), followed by addition Glacial acetic acid (10 ml). The mixture was refluxed for 4 hours. After cooling, the solid was filtered and evaporated. The residue was separated with 1M NaOH (50 mL) and EtOAc (200 mL). The organic layer was washed with saturated aqueous sodium chloride (brine), dried through (MgSO _4), filtered, and concentrated under reduced pressure. The solid was recrystallized from MeOH, filtered hot and washed with MeOH then dried. MS: [M+H] ⁺ 198

Preparation (or step) K1

Prepared as in the same procedure as in the preparation of K (above), but substituted 2-bromo-malonaldehyde with 2-(4-fluoro-phenyl)-malonaldehyde ( 2-bromo-malonaldehyde).

Preparation (or step) of L-Suzuki reaction

4-Fluorophenylboronic acid (0.46 g, 3.25 mmol) and 2M Na ₂ CO ₃ (10 ml) were added to 6-bromo-pyrazolo[1,5-a]pyrimidine (6-Bromo) dissolved in DME (10 ml) -pyrazolo[1,5-a]pyrimidine, 0.5 g, 2.5 mmol) [Break through a nitrogen purge] followed by tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 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 (MgSO4) The residue was triturated with EtOAc (EtOAc)EtOAc. The filtrate was then concentrated under reduced pressure. The product was purified by Biotage column chromatography (SiO _2, petroleum ether to 5% EtOAC- -50% EtOAC- petroleum ether) to afford the product 0.223g. MS: [M+H] ⁺ 214

Preparation (or step) M-iodination

As described in General Procedure A, Step 2 (A2)

Preparation (or step) of N-Suzuki reaction in the third position

As described in General Procedure A, Step 3b (A3b)

General procedure O benzimazole model Step O1: N-(4-bromo-2-nitro-phenyl)-benzene-1,3-diamine (N-(4-Bromo-2-nitro-phenyl)-benzene-1,3-diamine)

4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol) and benzene-1,3-diamine (1.96 g) dissolved in dry NMP (5 ml). , 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) mixed solution were vacuumed/N ₂ (x3) deoxygenated, then stirred and heated to 120 ° 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 O (x1), brine (x1), dried (MgSO ₄ ), filtered and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc) 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, 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 O2: N-(4-Fluoro-3-nitro-biphenyl-4-yl)-benzene-1,3-diamine (N-(4'-Fluoro-3-nitro-biphenyl-4-yl)-benzene-1,3-diamine)

2N Na ₂ CO ₃ (10 ml) was added to PdCl ₂ dppf (210 mg, 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-1,3-diamine, step O1, 1.8 g, 5.8 mmol) and 4-fluorophenylboronic acid (975 mg, 7.0 mmol). The reaction was vacuum / fill N ₂ (x3) deoxygenated and stirred under a nitrogen atmosphere heated to 90 deg.] C for 18 h. After cooling to room temperature, the mixture was separated with EtOAc /EtOAc. The organic layer was H ₂ O (x1), saturated brine (brine) (x1) washed, dried (MgSO _4), filtered and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc:EtOAc: 1H NMR (400 MHz, DMSO-d6): 9.30 (1H, s), 8.32 (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 O3: N ^* 4 ^* -(3-Amino-phenyl)-4'-fluoro-biphenyl-3,4-diamine (N ^* 4 ^* -(3-Amino-phenyl)-4'-fluoro-biphenyl-3,4-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 O2, 1.66 g, 5.1 mmol) was hydrogenated in EtOH/AcOH (3:1, 40 mL) over 10% Pd/C (300 mg). The atom is 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.

Step O4: 3-[5-(4-Fluoro-phenyl)-benzimidazol-1-yl]-phenylamine (3-[5-(4-Fluoro-phenyl)-benzoimidazol-1-yl]-phenylamine)

Under a N ₂ environment, the N ^{* 4 * -} (3- amino-phenyl) - 4'-fluoro - diphenyl-3,4-diamine ^{(N * 4 * - (3} -Amino-phenyl) -4'-fluoro-biphenyl-3,4-diamine, step O3, ~5.1 mmol) was dissolved in trimethylorthoformate (30 ml) and stirred and heated to 120 ° C for 10 hours. The volatiles were removed in vacuo and EtOAcqqqqqqqqqqq After cooling to room temperature, the mixture was concentrated to ~2 mL then diluted with water. NaHCO ₃ (sat) was added to achieve ~pH 7.5. The solid was taken up in CH ₂ Cl ₂ . The organic layer was dried and evaporated. The residue is purified using silica gel chromatography to give the product (0% → 1% → 2 %, 2M NH 3 -MeOH / CH 2 Cl 2). The object of such milling to give an off-white solid (890 mg of) the title compound in Et ₂ O as shown in.

Step O5: 1-{3-[5-(4-Fluoro-phenyl)-benzimidazol-1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[5-(4-Fluoro-phenyl)-benzoimidazol-1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea)

3-[5-(4-Fluoro-phenyl)-benzimidazol-1-yl]-phenylamine (3-[5-(4-fluoro-phenyl)-benzoimidazol-1-yl]-phenyl amine 150 mg, 0.5 mmol) and 4-nitrochlorochloroformic acid phenyl ester (105 mg, 0.52 mmol) were dissolved in dry THF (5 ml), stirred and warmed to 60 ° C under nitrogen for 3 h. 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 mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue was taken in CH ₂ Cl _2, to put on a SCX tray. The cartridge was eluted with MeOH to remove phenol, then eluting with 2M NH ₃ -MeOH to afford the product. After a small portion of the volatiles, to the residue was triturated in Et ₂ O, to give a colorless solid of the title compound as shown in (180mg).

Step O6: Salt formation; 1-{3-[5-(4-fluoro-phenyl)-benzimidazol-1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl )-urea hydrochloric acid (1-{3-[5-(4-Fluoro-phenyl)-benzoimidazol-1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea Hydrochloride)

1-{3-[5-(4-Fluoro-phenyl)-benzimidazol-1-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (step O5) was dissolved in MeOH and treated with EtOAc in hydrogen chloride. The solid was collected and dried under vacuum. General procedure P: azabenzamidazole model

Preparation of P1: N-(5-bromo-3-nitro-pyridin-2-yl)-benzene-1,3-diamine (N-(5-Bromo-3-nitro-pyridin-2-yl)-benzene-1,3-diamine)

5-Bromo-2-chloro-3-nitro-pyridine (5-bromo-2-chloro-3-nitro-pyridine, 2.4 g, 10.1 mmol), benzene-1,3-diamine (2.7 g, 25 Methyl) and DIPEA (5.3 ml, 30 mmol) were dissolved in dry NMP (20 ml) and heated to 120 ° C under nitrogen atmosphere for 2 h. After cooling to room temperature, EtOAc and H ₂ O the mixture was separated. The organic layer with saturated aqueous sodium chloride (brine) (x1), and dried (MgSO _4), filtered and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc) 1H NMR (400 MHz, DMSO-d6): 9.78 (1H, s), 8.66 (1H, d), 8.60 (1H, d), 7.00 (1H, t), 6.83-6.71 (2H, m), 6.39 ( 1H, d), 5.13 (2H, s).

Preparation of P2: N-[5-(4-fluoro-phenyl)-3-nitro-pyridin-2-yl]-benzene-1,3-diamine (N-[5-(4-Fluoro-phenyl)-3-nitro-pyridin-2-yl]-benzene-1,3-diamine)

PdCl ₂ dppf (300 mg, 0.4 mmol), N-(5-bromo-3-nitro-pyridin-2-yl)-benzene-1,3-diamine (N-(5-bromo-3-nitro-) Pyridin-2-yl)-benzene-1,3-diamine, preparation of P1, 2.5 g, 8.2 mmol) and 4-fluorophenylboronic acid (1.4 g, 10 mmol) dissolved in DME (16 ml) and 2N Na ₂ CO ₃ ( In 16 ml), after vacuum/filling with N ₂ (x3), the mixture was stirred under a nitrogen atmosphere and heated to 80 ° C for 4 hours. After cooling to room temperature, the mixture was separated with EtOAc /EtOAc. The organic layer with saturated aqueous sodium chloride (brine) (x1), then dried (MgSO _4), filtered and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc) 1H NMR (400 MHz, DMSO-d6): 9.85 (1H, s), 8.87 (1H, d), 8.78 (1H, d), 7.82 (2H, dd), 7.33 (2H, t), 7.02 (1H, t), 6.92-6.81 (2H, m), 6.40 (1H, d), 5.15 (2H, s).

Preparation of P3: 3-[6-(4-fluoro-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenylamine (3-[6-(4-Fluoro-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl amine)

Zinc powder (9.3 g, 142 mmol) was added to a stirred solution of N-[5-(4-fluoro-phenyl)-3-nitro-pyridine-2- in AcOH (35 ml). N-[5-(4-fluoro-phenyl)-3-nitro-pyridin-2-yl]-benzene-1,3-diamine) (2.3 g, 7.1 mmol) ) in solution. After the end of the exotherm, it 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 for 1 hour under nitrogen. 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 NaHCO _3. The aqueous mixture was extracted with CH ₂ Cl ₂ (x3). The collected extracts were dried (MgSO _4), filtered and evaporated. The residue was purified with EtOAc (EtOAc:EtOAcEtOAcEtOAc

General procedure R-urea formation Step R1 1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazo[1, 2-a]pyridin-3-yl]-phenyl}-urea (1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3- Yl]-phenyl}-urea)

The CDI (0.054g, 0.33mmol) was dissolved was added to CH ₂ Cl ₂ (7ml) 3- [7- (4-fluoro - phenyl) - imidazo [1,2-a] pyridin-3-yl] -Phenylamine (3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl amine, 0.1 g, 0.33 mmol), stirred at ambient temperature 5 hours. Add (2,2-dimethyl-[1,3]-dioxolan-4-yl)-methylamine (2,2-dimethyl-[1,3]-dioxolan-4-yl)-methyl Amine, 0.04 ml, 0.33 mmol) to form a precipitate, which was then warmed to 50 &lt;0&gt;C overnight. Washed with saturated sodium bicarbonate salt compound reactant, an organic layer was washed with saturated aqueous sodium chloride (brine), dried (MgSO _4), and concentrated under reduced pressure, then the residue was purified by HPLC to give the title as shown in the (8mg ). MS: [M+H] ⁺ 461 .

Step R2:

1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-{3-[7-(4-fluoro-phenyl)-imidazo[1] ,2-a]pyridin-3-yl]-phenyl}-urea (1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-{3-[7-(4- Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea, b 0.02 g) was treated with saturated EtOAc/EtOAc (3 mL) Over night, concentrate under reduced pressure to give compound (12 mg): MS: [M+H] ⁺ 421

Step S 1-(3-{7-[6-oxy-1-(3-piperidin-1-yl-propyl)-1,6-dihydro-pyridin-3-yl]-imidazo[1,2 -a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1-(3-{7-[6-Oxo-1-(3-piperidin-1-yl-propyl)-1,6-dihydro-pyridin-3-yl]-imidazo[1,2-a]pyridin -3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride)

General formula A, step A3b using 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3 -(2,2,2-trifluoro-ethyl)-urea), step A4b uses 2-methoxy-5-pyridine boronic acid.

PBr ₃ (0.174 ml) was added to 1-{3-[7-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridine-3 dissolved in DCE (10 mL). -yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(6-Methoxy-pyridin-3-yl)-imidazo[1, 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 with EtOAc and water. The insoluble material was filtered and dried to give 1-{3-[7-(6-oxy-1,6-dihydro- Pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3- [7-(6-Oxo-1,6-dihydro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea, 0.12g) MS: [M+H] ⁺ 428

N-(3-chloropropyl)piperidine hydrochloride (0.15 g, 0.63 mmol), Cs ₂ CO ₃ (0.32 g, 0.98 mmol) and NaI (0.095 g, 0.63 mmol) Add to 1-{3-[7-(6-oxy-1,6-dihydro-pyridin-3-yl)-imidazo[1,2-a]pyridine in DMF (1.5 ml) 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(6-Oxo-1,6-dihydro-pyridin-3- Yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, 0.12 g, 0.63 mmol). The reaction was heated to 80.degree. C. for 48 h then EtOAc (EtOAc m. The residue was purified by HPLC to to afford the title as shown in the compound (16mg) MS: [M + H] + 553

Step T 1-(3-{7-[3-(1-Ethyl-piperidin-4-yloxy)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl) -3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[3-(1-Acetyl-piperidin-4-yloxy)-phenyl]-imidazo[1,2-a]pyridine-3-yl}-phenyl)-3-(2, 2,2-trifluoro-ethyl)-urea)

Acetyl chloride (6.3 μl, 82 μmol) and Et ₃ N (14 μl) were added to 1-(3-{7-[3-(piperidin-4-yloxy)-phenyl) dissolved in DMF (10 ml) ]-Imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[3 -(Piperidin-4-yloxy)-phenyl]-imidazo[1,2-a]pyridine-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea, 50mg, 98μmol) in. At room temperature, the reaction was stirred for 3 hours, followed by EtOAc and H ₂ O which is isolated. The aqueous layer was re-extracted with EtOAc, the organic layer was concentrated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified by 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-yl)-3-ethyl-urea)

EtNCO (1.6 ml, 20 mmol) and 5-bromo-pyridin-3-ylamine (1.73 g, 10 mmol) were dissolved in DME (10 mL) under nitrogen. Stir and heat 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. Compound (2.2 g) The solid was collected by filtration and dried in vacuo to to give the title as shown as a colorless solid .1H NMR (400 MHz, DMSO- d 6): 8.85 (1H, s), 8.43 (1H, d ), 8.27 (1H, t), 8.21 (1H, d), 6.39 (1H, t), 3.19-3.05 (2H, m), 1.06 (3H, t).

Step U3: 1-(5-Bromo-pyridin-3-yl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(5-Bromo-pyridin-3-yl)-3-(2,2,2-trifluoro-ethyl)-urea)

5-Bromo-pyridin-3-ylamine (1.73 g, 10 mmol) and phenyl 4-nitrochloroformate (2.2 g, 11 mmol) were dissolved in dry THF (40 mL). 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 then the residue was crystallised eluted with EtOAc and 1 N EtOAc. The organic layer followed by H ₂ O (x1), and saturated aqueous sodium chloride solution (brine) (x1) washed, dried (MgSO _4), filtered and evaporated. The residue was triturated in CH ₂ Cl ₂ . After the solid was collected by filtration, washed Et ₂ O, and dried in vacuo to give a colorless solid as the title compound shown (1.7g). 1H NMR (400 MHz, DMSO-d ⁶ ): 9.18 (1H, s), 8.49 (1H, d), 8.28 (1H, d), 8.25 (1H, t), 7.06 (1H, t), 3.99-3.88 (2H,m).

Step U4: 1-(2-Chloro-pyridin-4-yl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(2-Chloro-pyridin-4-yl)-3-(2,2,2-trifluoro-ethyl)-urea)

Add 4-amino-2-chloropyridine (2.08 g, 16.2 mmol) to phenyl 4-nitrochloroformate (2.91 g, 14.5 mmol) in THF (35 mL). Stir 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 EtOAc EtOAc m. The organic phase was collected with brine (brine) (60 mL) washed, dried MgSO _4, filtered and concentrated in vacuo. The resulting yellow solid was suspended in CH ₂ Cl _2, filtered and washed CH ₂ Cl ₂ to give a pale yellow solid product (1.72 g).

Step U5: 1-(4-Chloro-pyridin-2-ylamine)-3-ethyl-urea (1-(4-Chloro-pyridin-2-yl)-3-ethyl-urea)

Ethyl isocyanate (0.69 ml, 8.69 mmol) was added to 2-amino-4-chloropyridine (1.02 g, 7.9 mmol) in THF (20 mL). 55 ° C, 18 hours. The reaction was concentrated in vacuo. The resulting white solid was suspended in EtOAc (EtOAc)

Step U6: 2-(4-Bromo-pyridin-2-yl)-propan-2-ol (2-(4-Bromo-pyridin-2-yl)-propan-2-ol)

A solution of 4-bromo-pyridine-2-carboxylic acid methyl ester (1.08 g, 5 mmol) in dry THF (10 ml) was slowly added to a dry THF (20 ml) MeMgBr (3M in Et ₂ O, 4.2 ml, 12.6 mmol) stirred solution. After 1 hour, the ice bath was removed and the mixture was stirred at room temperature for 2 hours. With saturated NaHCO ₃ solution to stop the reaction, followed by EtOAc / H ₂ O to separate. The aqueous layer was extracted with EtOAc (x2). The collected extract was washed with H ₂ O (x1), brine (x1), dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified with EtOAc EtOAc EtOAc:EtOAc ¹ H NMR (400 MHz, CDCl ₃ ): 8.36 (1H, d), 7.60 (1H, d), 7.39 (1H, dd), 4.52 (1H, s), 1.56 (6H, s).

Step U7-2-Bromo-[1,3,4]thiazole (2-Bromo-[1,3,4]thiadiazole)

Add 48% aqueous HBr (10 ml) and H ₂ O (10 ml) to [1,3,4]thiazol-2-ylamine ([1,3,4]thiadiazol-2-yl amine, 1 g, 9.89 mmol) 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 sodium nitrite (0.682 mg, 9.89 mmol) in H ₂ O (10 ml), and the mixture was stirred for 10 min. . The reaction mixture was gradually warmed 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. Aqueous layer EtOAc (x3), and the organic layer was concentrated, dried (MgSO _4), filtered and the solvent removed in vacuo. A gray-yellow solid (1 g) was obtained which was used directly in the next step. 1H NMR (400 MHz, DMSO- d 6): 9.63 (1H, s).

Step U8-2-Bromo-5-methoxymethyl-[1,3,4]thiazole (2-Bromo-5-methoxymethyl-[1,3,4]thiadiazole)

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-[1,3,4]thiadiazol-2-yl amine, 348 mg, 2.4 mmol) and sodium nitrite (0.759 g, 11 mmol) in portions over 30 minutes Time is added to it. The reaction mixture was stirred at -7 ° C for 1 hour and then at room temperature for a further 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 60 ° C for 30 min and neutralized. The reaction mixture was extracted with cyclohexane (X2), the organic layer was collected fractions were dried (MgSO _4), filtered and the solvent removed in vacuo to give the product (123mg). MS: [M+H] ⁺ 209,211.

Step U9-2-Bromo-4,5-dimethyl-thiazole (2-Bromo-4,5-dimethyl-thiazole)

At a temperature of 0 ℃, the bromine (bromine, 6.8ml, 0.132mol) was added dropwise to a solution CHCl ₃ (125ml) of 4,5-dimethyl - thiazole (5.00g, 44.3mmol) in. The reaction was warmed to room temperature and stirred for 5 hours before being treated with aqueous sodium thiosulfate solution. Which is layered, and the aqueous layer was extracted with CHCl _3. The organic portion was collected, to H ₂ O, followed by saturated aqueous sodium chloride (brine) wash, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography eluting with EtOAc EtOAc MS: [M+H] ⁺ 192,194.

General formula V

Step V1-Iodination

As described in General Procedure A, Step 2 (A2).

Step V2-6-(4-Fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole And [1,5-a]pyrimidine (V2-6-(4-Fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine) Formation

Add bis(pinacolato) diboron (1.03g, 4.07 mmol) and KOAc (0.63g, 6.38 mmol) to 6-(4-fluoro-phenyl)-3-iodo-pyrazole And [1,5-a]pyrimidine (6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidine, 0.69 g, 2.02 mmol) in water-depleted DMSO (4 mL) . The reaction flask was filled with nitrogen and PdCl ₂ dppf (82 mg, 0.11 mmol) 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 H ₂ O (30 mL), and the insolubles were filtered off. The filtrate is retained and the organic and aqueous layers are separated. The aqueous layer was then re-extracted with EtOAc (25 mL). And dry the organic layer was collected in a system MgSO _4, filtered, and concentrated in vacuo. The solid was triturated in Et ₂ O in order to give a brown solid of the title compound as shown in (0.35 g).

Step V3b - Suzuki reaction (1-Ethyl-3-{2-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-4-yl}-urea (1-Ethyl-3-{2-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-4-yl}-urea)

K ₃ PO ₄ (640 mg, 3 mmol) of H ₂ O (2 ml) was added to a stirred solution of 6-(4-fluoro-phenyl) in dioxane (8 ml) under nitrogen atmosphere. -3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine (6-( 4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine, 330 mg, 0.97 mmol) 1-(2-Chloro-pyridin-4-yl)-3-ethyl-urea (1-(2-chloro-pyridin-4-yl)-3-ethyl-urea, step U4, 420 mg, 2.1 mmol) Solution. The mixture was deoxygenated under vacuum/nitrogen (x2) and PdCl ₂ dppf (40 mg, 0.05 mmol) was added, 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 with CH ₂ Cl ₂ /H ₂ O. The aqueous layer was extracted with CH ₂ Cl ₂ (x1). The collected extract was dried and evaporated. The residue was purified with EtOAc (EtOAc)EtOAc

Step W: Heck reaction 5-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-pyridin-3-ylamine (5-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-pyridin -3-ylamine)

Add 0.5 MK ₂ CO ₃ (2.06 mL, 1.03 mmol) to 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (7-(4-Fluoro-phenyl)-imidazo[1, 2-a]pyridine) (0.1093 g, 0.52 mmol) and 3-amino-5-bromopyridine (3-amino-5-bromopyridine 0.181 g, 1.05 mmol) in DMF (2 mL). The reaction jar was filled with nitrogen and was added _{Pd (PPh 3) 4 (63} mg, 0.055 mmol). The reaction flask was then refilled with nitrogen and heated to 120 ° C for 30 minutes. Further, 3-amino-5-bromopyridine (0.13 g, 0.75 mmol) and Pd(PPh ₃ ) ₄ (43 mg, 0.037 mmol) were added, and the reaction was heated to 140 ° C for one hour. The solid was filtered and the filtrate was concentrated in vacuo. Followed by H ₂ O (20 ml) and EtOAc (2x20 mL) The residue was separated. The organic layer was collected to be dried over MgSO _4, filtered, concentrated in vacuo, and the resulting product is used directly.

Step XX (2,2,2-trifluoroethyl)amine sulfonyl)chloro ((2,2,2-Trifluoroethyl)sulfamoyl)chloride)

Sulfo acyl chloride (8ml) in CH ₃ CN (15ml) was added dropwise slowly added to 2,2,2-trifluoroethylamine (amine, 3.9ml, 4.9mmol) in. A solid precipitated from the reaction mixture. The reaction was stirred at 42 ° C overnight, and the solid was filtered, and the filtrate was concentrated under reduced pressure and then evaporated toluene, and used directly.

General procedure, synthesis of imidazole [1,2-c]pyrimidine model

Step X-General formula, preparation of imidazo[1,2c]pyrimidine Preparation of X1-Suzuki reaction

A solution of 4-fluorophenylboronic acid (0.7 g, 5.00 mmol) and K ₃ PO ₄ (2.87 g, 13.55 mmol) in H ₂ O was added to 6-chloro-pyrimidine-4 dissolved in dioxane (15 ml). - a base amine (0.5 g, 3.87 mmol). The reaction mixture was deoxygenated, bistriphenylphosphinepalladium dichloride (54 mg) was added, and the mixture was heated to 50 ° C for 4 hr. Followed by EtOAc, and H ₂ O and the reaction mixture was separated, the aqueous layer was washed with EtOAc, and the organic layer was concentrated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was triturated with EtOAc (EtOAc) MS: [M+H] ⁺ 190.

Step X2-ring formation

Prepared as in the same conditions as in Preparation A1

Step X3-Heterocyclic Cyclization

Sodium acetate (69 mg, 0.84 mmol) was added to 7-(4-fluoro-phenyl)-imidazo[1,2-c]pyrimidine (7-(4-Fluoro-phenyl)-imidazo[1,2-c] To a solution of pyrimidine (120 mg, 0.56 mmol) in EtOAc (2 mL). Followed by EtOAc and saturated bicarbonate, the reaction mixture was separated, the aqueous layer was washed with EtOAc, the organic layer was concentrated, dried (MgSO _4), and the solvent was removed in vacuo to afford the product (40mg). MS: [M+H] ⁺ 292,294.

Step X4-Suzuki Coupling Reaction

Follow the procedure of step A3b, but replace DME with THF.

Steps for preparing Y-general synthetic Imidazo [1,2-a]pyrazine model

Preparation of Y1-6-(4-fluoro-phenyl)-imidazole [1,2-a]pyrazine (6-(4-Fluoro-phenyl)-imidazo[1,2-a]pyrazine)

4-Fluorophenylboronic acid is used as described in General Procedure A, Step A4b.

Preparation of Y2-6-(4fluoro-phenyl)-3-iodo-imidazole [1,2-a]pyrazine (6-(4-Fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyrazine)

The method described in General Procedure A, Step 2.

Preparation of Y3-1-{3-[6-(4-fluoro-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-phenyl}-3-(2,2,2-tri Fluoro-ethyl)-urea (1-{3-[6-(4-Fluoro-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea )

As described in A4b, I6 1- [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2 -trifluoro-ethyl)-urea, and substituting K ₃ PO ₄ with Na ₂ CO ₃ .

Step Z-1,1,1-Trifluoro-2-isocyanate-ethane (1,1,1-Trifluoro-2-isocyanato-ethane)

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). 110 ° C for 2.5 hours. Triethylamine (0.24 ml, 1.72 mmol) was added and the mixture was heated to 70 ° C for 18 h. The reaction solution was used as it was. MS: [M+H] ⁺ 361.

Step AA-1-{3-[7-(4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4H-[1,2,4]Triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea)

a) 3-[3-[3-(2,2,2-Trifluoroethyl)ureido]-phenyl]imidazo[1,2-a]pyridine-7-carboxylic acid decylamine (3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl}imidazo[1,2-a]pyridine-7-carboxylic acid amide)

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2 -Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, 2-trifluoro-ethyl)-urea, 1.2 equivalents, 1 M Na ₂ CO ₃ (8 equivalents) added to 7-nonylamino-3-iodo-imidazo[1,2-a]pyridine (1) dissolved in DME Equivalent) (using steps 4 and A2, prepared with 4-nonylamino-pyridin-2-ylamine) [to remove bubbles via nitrogen gas], followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.05 equivalent). The mixture was heated overnight at 80 ° C, then diluted with water and extracted with EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and concentrated under reduced pressure. The purified product was milled or (0 → 50% MeOH / Et 2 O) via a column chromatography on silica in Et ₂ O.

b) 3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-II Methylamino-(E) methylene decylamine (3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1, 2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylidene amide)

Add Bredereck's reagent (25 μl, 0.12 mmol) to 3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl]imidazole dissolved in dry DMF (0.5 ml). 1,2-a]pyridine-7-carboxylic acid decylamine (3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl]imidazo[1,2-a]pyridine-7-carboxylic The reaction mixture was stirred for 1 hour in acid amide (20 mg, 0.053 mmol). Additional Et ₂ O was added and the precipitate was filtered off. The precipitate was redissolved in MeOH, taken to abr. MS: [M+H] ⁺ 433.

c) 1-{3-[7-(4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3- (2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4H-[1,2,4]Triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea)

Hydrazine hydrate (5 μl, 0.1 mmol) was added to 3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido]-phenyl}- dissolved in acetic acid (0.5 ml) Imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-(E) methylene decylamine (3-{3-[3-(2,2,2-Trifluoro-ethyl) )-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylidene amide, 17 mg, 0.04 mmol). The reaction mixture was heated to 90 ° C 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 Et ₂ O to give the product as a pink solid (12mg). MS: [M+H] ⁺ 402.

Step AB-1-[3-(7-oxazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro- Ethyl)-urea (1-[3-(7-Oxazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea) a) Imidazo[1,2-a]pyridin-7-yl-methanol (Imidazo[1,2-a]pyridin-7-yl-methanol)

Add NaHCO ₃ (0.56 g, 6.67 mmol) to (2-amino-pyridin-4-yl)-methanol (0.40 g, 3.3 mmol) eluted with EtOH, followed by chloroacetaldehyde (0.81 ml, 5.0 mmol) ). The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the crude mixture was separated from EtOAc using water. A water layer was extracted with EtOAc, the organic layer was concentrated, dried (MgSO _4), solvent was removed in vacuo. The residue was purified using silica column chromatography _{(0-50% MeOH / Et 2 O} ), to afford the product MS 0.40g ^{of: [M + H] + =} 149.

b) (3-iodo-imidazo[1,2-a]pyridin-7-yl)-methanol ((3-Iodo-imidazo[1,2-a]pyridin-7-yl)-methanol)

Use the method as described in step A2.

c) 1-[3-(7-Hydroxymethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)- Urea (1-[3-(7-Hydroxymethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

Use the method as described in A3b.

d) 1-[3-(7-Mercapto-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)- Urea (1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-Hydroxymethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl) at 0 ° C -1-[3-(7-Hydroxymethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 1.42 g, 3.90 mmol) and NMO (1.38, 11.7 mmol) were dissolved in CH ₂ Cl ₂ (30 mL) and EtOAc (3 g), and TPAP (0.14 g, 0.38 mmol). 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 H ₂ O (x2) washed, dried (MgSO _4), and the solvent removed in vacuo. The residue was purified by column chromatography in silica _{(0-60% MeOH in Et 2 O} ) to afford the product (0.2g). MS: [M+H] ⁺ =363

e) 1-[3-(7-oxazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-B Urea (1-[3-(7-Oxazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-Mercapto-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2,-trifluoro-ethyl)- A mixed solution of urea (15 mg, 0.04 mmol), potassium carbonate (11 mg, 0.08 mmol) and TosMic (9.7 mg, 0.05 mmol) was heated to 80 ° C for 3 hours in MeOH (2 mL). The reaction mixture was purified using EtOAc (EtOAc) eluting The solvent was removed in vacuo to give the title compound (6 mg). MS: [M+H] ⁺ =402

Step AC-1-{3-[7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2 -trifluoro-ethyl)-urea (1-{3-[7-(2H-Tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl) -urea)

a) Imidazo[1,2-a]pyridine-7-carboxylic acid decylamine (Imidazo[1,2-a]pyridine-7-carboxylic acid amide)

Prepared according to the method in Step A1 using 2-aminoisonicotin amide. MS: [M+H] ⁺ 162.

b) Imidazo[1,2-a]pyridine-7-cyano (Imidazo[1,2-a]pyridine-7-carbonitrile)

Trifluoroacetic anhydride (0.39, 2.83 mmol) was added dropwise to the imidazo[1,2-a]pyridine-7-carboxylic acid decylamine (Imidazo [in 1 ml] dissolved in CH ₂ Cl ₂ (5 ml). 1,2-a]pyridine-7-carboxylic acid amide, 38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol). As before SCX SPE cartridge crude mixture, the reaction mixture was stirred for 2 hours at room temperature, washed with MeOH, and eluted 2MNH ₃ / MeOH. The solvent was removed in vacuo to give the compound (32 mg). MS: [M+H] ⁺ 143.

c) 3-iodo-imidazo[1,2-a]pyridine-7-cyano (3-Iodo-imidazo[1,2-a]pyridine-7-carbonitrile)

As described in step A2, imidazo[1,2-a]pyridine-7-cyano is used. MS: [M+H] ⁺ 270.

d) 1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

As described in the step A3b, 3-iodo-imidazo [1,2-a]pyridine-7-carbonitrile was used. Purification by reverse phase HPLC gave the product as a white solid. MS: [M+H] ⁺ 360.

e) 1-{3-[7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1-{3-[7-(2H-Tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl) -urea)

1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea 1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 65 mg, 0.18 mmol), Sodium azide (14 mg, 0.19 mmol) and ammonium chloride (11 mg, 0.20 mmol) were dissolved in DMF (2 mL). After the reaction mixture was cooled, 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.

Step AE: S-alkylated triazole (Alkylated triazole) Step a) 1-{3-[7-(5-Hydroxythio-4-methyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridine -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl }-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-Mercaptocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 200mg, 0.51mmol) Methyl isothiocyanate (37 mg, 0.57 mmol) was dissolved in EtOH (6 mL). The reaction mixture was cooled and ice bathed until a precipitate formed. The solid was filtered off with EtOAc and Et ₂ O washed, and then dried to give the title compound, as shown. (72 mg). MS: [M+H] ⁺ = 448.

Step b) 1-{3-[7-(4-Methyl-5-methylsulfonyl-4H-[1,2,4]triazole-3- -Imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (1-{3-[7-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-imdazo[1,2-a]pyridin-3-yl]-phenyl }-3-(2,2,2-trifluoro-ethyl)-urea formate)

KOH (10 mg, 0.18 mmol) and methyl iodide (20 μl, 0.16 mmol) were added to 1-{3-[7-(5-hydroxythio-4-methyl-4H-[1] dissolved in EtOH (3 mL) ,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl The reaction mixture was stirred at room temperature overnight, under EtOAc (EtOAc: EtOAc). The reaction mixture was ice bathed 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 Step a) Imidazo[1,2-a]pyridin-7-yl-methanol (Imidazo[1,2-a]pyridin-7-yl-methanol)

Add NaHCO ₃ (0.56 g, 6.67 mmol) to (2-Amino-pyridin-4-yl)-methanol (0.40 g, 3.3 mmol) in EtOH, followed by chloroacetaldehyde (0.81 ml, 5.0 mmol) . The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the crude mixture was separated from EtOAc using water. The aqueous layer was re-extracted with EtOAc, the organic layer was concentrated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified using, silica column chromatography _{(0-50% MeOH / Et 2 O} ) to give 0.40g of product. MS: [M+H] ⁺ = 149.

Step b) (3-Iodo-imidazo[1,2-a]pyridin-7-yl)-methanol ((3-Iodo-imidazo[1,2-a]pyridin-7-yl)-methanol)

Use the method as described in step A2.

Step c) 3-iodo-imidazo[1,2-a]pyridine-7-formaldehyde (3-Iodo-imidazo[1,2-a]pyridine-7-carbaldehyde)

( 3-Iodo-imidazo[1,2-a]pyridin-7-yl )methanol (1.00 g, 3.65 mmol) and NMO (0.64 g, 5.47 mmol) in CH ₂ Cl ₂ (30 mL) With sieve (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 H ₂ O (x2) washed, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified in a silica column _{(0-60% MeOH in Et 2 O} ) The product (0.15 g of) to give the. MS: [M+H] ⁺ =273

Step d) 1-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-2-nitro-ethanol (1-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-2-nitro-ethanol)

Nitromethane (88 μl, 1.63 mmol), diethylamine (6 μl, 0.05 mmol) and sieve (300 mg) were added to 3-iodo-imidazo[1,2-a]pyridine-7 dissolved in THF (10 ml). - Formaldehyde (3-Iodo-imidazo [1,2-a]pyridine-7-carbaldehyde, 150 mg, 0.54 mmol). The reaction mixture was heated to 55 ° C for 2 hours before cooling. The sieve was removed by filtration, and the solution was extracted with EtOAc and H ₂ O which is isolated. The organic layer was separated, dried (MgSO _4), filtered and the solvent removed in vacuo to give the crude product can be used directly (116mg). MS: [M+H] ⁺ =334.

Step e) 3-iodo-7-((E)-2-nitro-vinyl)-imidazo[1,2-a]pyridine (3-Iodo-7-((E)-2-nitro-vinyl)-imidazo[1,2-a]pyridine)

Triethylamine (121 μl, 0.87 mmol) and methanesulfonium chloride (38 μl, 0.49 mmol) were added to 1-(3-iodo-imidazo[1,2-) in CH ₂ Cl ₂ (2 ml) at 0 ° C. a] Pyridin-7-yl)-2-nitro-ethanol (1-(3-Iodo-imidazo[1,2-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. CH ₂ Cl ₂ followed by H ₂ O and the mixture was separated, the organic layer was separated out, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography in silica (0-50% MeOH dissolved in Et ₂ O) to give the product (57mg). MS: [M+H] ⁺ = 316.

Step f) 3-iodo-7-(3H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridine (3-Iodo-7-(3H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridine)

3-iodo-7-((E)-2-nitro-vinyl)-imidazo[1,2-a]pyridine (3-Iodo-7-((E)-2-nitro-vinyl)- Imidazo [1,2-a]pyridine, 57 mg, 0.17 mmol) and trimethylsilylazide (33 μl, 0.24 mmol) were dissolved in DMF (3 mL) and the mixture was warmed to 50 ° C for 10 min. Next, a solution of tetrabutylammonium fluoride (0.18 ml, 1.0 M solution in THF, 0.18 mmol) was added, and the reaction mixture was heated to 50 ° C for an additional 10 minutes. The reaction mixture was cooled, followed by EtOAc and H ₂ O which is separated, the organic layer was separated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified in a silica column _{(0-20% MeOH in Et 2 O} ) to give the product (34mg). MS: [M+H] ⁺ = 312.

Step g) 1-{3-[7-(3H-[1,2,3]Triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(3H-[1,2,3]Triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 ,2-trifluoro-ethyl)-urea)

I6 (45 mg, 0.13 mmol) and Cs ₂ CO ₃ (107 mg) were added to 3-iodo-7-(3H-[1,2,3]triazol-4-yl)-imidazole dissolved in DME (10 ml) And [1,2-a]pyridine (3-Iodo-7-(3H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridine, 34 mg, 0.11 mmol) The bubbles were removed via nitrogen gas, followed by tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.01 mmol). The mixture was heated overnight at 80 ° C and directly charged to a pad of EtOAc, washed with MeOH and eluted with NH ₃ /MeOH. After the solvent was removed in vacuo, the residue was purified by HPLC to afford 1.6 mg of product. MS: [M+H] ⁺ 402.

Step AG: Oxazole Step a imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-decylamine (Imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-amide)

0 ℃, of 2M trimethylaluminum in hexane (3.8ml, 9.57mmol) was added to a solution of imidazole was dissolved in CH ₂ Cl ₂ (40ml) and [1,2-a] pyridine-7-carboxylic acid methyl ester (Imidazo [1,2-a]pyridine-7-carboxylic acid methyl ester, 0.67 g, 3.83 mmol) and dimethylhydroxylamine (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, followed by CH ₂ Cl ₂ / H ₂ O liquid phase separation. The organic layer was separated, dried (MgSO _4), filtered and the solvent removed in vacuo to give crude product. The residue was purified by column chromatography in silica (0-50% MeOH dissolved in Et ₂ O) to afford the product (187mg). MS: [M+H] ⁺ = 206.

Step b) 1-Imidazo[1,2-a]pyridin-7-yl-2-butyn-1-one (1-Imidazo[1,2-a]pyridin-7-yl-but-2-yn-1-one)

1-propynylmagnesium bromide (0.5 M in THF, 2.74 ml) was added to imidazo[1,2-a]pyridine-7-carboxylic acid in THF (10 ml) at -78 °C. Imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-amide, 187 mg, 0.91 mmol. Prior to M HCl (2ml) to stop the reaction, the reaction was warmed to room temperature and stirred for 1.5 hours and washed in CH ₂ Cl _2. A portion of the aqueous phase was basified with Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried (MgSO _4), filtered and the solvent removed in vacuo. The product was obtained (168 mg). MS: [M+H] ⁺ = 185.

Step c) 7-(5-Methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridine (7-(5-Methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridine)

Triethylamine (0.21 ml, 1.83 mmol) was added to 1-imidazo[1,2-a]pyridin-7-yl-2-butyn-1-one (1-Imidazo[d] dissolved in DMF (10 mL) 1,2-a]pyridin-7-yl-but-2-yn-1-one, 168 mg, 0.91 mmol) and hydroxylamine hydrochloride (94 mg, 1.37 mmol). The reaction mixture was heated to 80 _&lt;0&gt_; C for 18 h then separated with EtOAc &EtOAc. The organic layer was separated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified using silica column chromatography _{(0-50% MeOH in Et 2 O} ) to give the product (46mg). MS: [M+H] ⁺ = 200.

Step d) 3-iodo-7-(5-methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridine (3-Iodo-7-(5-methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridine)

The method as described in Step A2 (59 mg) was used. MS: [M+H] ⁺ = 326.

Step e) 1-{3-[7-(5-Methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 , 2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Methyl-isoxazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

The method (15 mg) as described in the step A3b was used. MS: [M+H] ⁺ =416.

Step AH: alkylated triazole Step a) 1-[3-(7-acetylene-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Ethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

Method step SGD4a as described herein.

Step b) 1-{3-[7-(1-Methyl-1H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]- Phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(1-Methyl-1H-[1,2,3]Triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3- (2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-acetylene-imidazo[1,2-a]pyridin-3-yl)-benzene 3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Ethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3 -(2,2,2-trifluoro-ethyl)-urea, 130 mg, 0.36 mmol) was dissolved in t-butyl alcohol (2 mL) and water (2 mL). Sodium azide (24 mg, 0.36 mmol) was added followed by iodomethane (0.18 mL of a 2M in THF, 0.36 mmol). The reaction was stirred at room temperature for 5 minutes before the addition of copper sulfate (0.02 mL of a 1M aqueous solution, 0.02 mmol) and sodium ascorbate (7 mg, 0.04 mmol). The reaction was stirred at room temperature for 2 hours.

The solution was then separated with water and dichloromethane, dried over a pad of phase and concentrated in vacuo. The residue was purified by HPLC to give white white solid (l.

Step AI: Methyl tetrazole Step 1: Imidazo[1,2-a]pyridine-7-cyano (Imidazo[1,2-a]pyridine-7-carbonitrile)

Chloroacetaldehyde (~50% in H ₂ O, 3.24 ml, 26 mmol) was added to stirred 2-amino-isonicotinonitrile (1.6 g, 3.4 mmol) and NaHCO at room temperature under nitrogen. ₃ (2.23 g, 26.5 mmol) was dissolved in a solution of ethanol (20 mL). The reaction was stirred and heated to 80 ° C for 18 hours. After cooling to room temperature, the volatiles were removed in vacuo, and the residue in EtOAc / H ₂ O to separate. 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 (Na ₂ SO ₄₎ and filtered. A MeOH lotion was added and the volatiles were removed in vacuo. The residue was purified by column chromatography: EtOAc: EtOAc:EtOAc: ¹ H 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).

Step 2: 7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (7-(2H-Tetrazol-5-yl)-imidazo[1,2-a]pyridine)

At room temperature, under nitrogen atmosphere, sodium azide (97mg, 1.45 mmol) was added to dissolved in dry DMF (5ml) was stirred in _{NH 4 Cl (82mg, 1.53 mmol} ) , and imidazo [1,2-a a solution of pyridine-7-cyano (imidazo[1,2-a]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 were performed simultaneously]. After cooling to room temperature, the reaction mixture was collected, and diluted with Et ₂ O. The solid was collected by filtration and dried to give a bright brown compound (860 mg). [may contain NaCl] ¹ H NMR (400 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-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine) and its isomeric form

Methyl iodide (530 μl, 8.4 mmol) was added to a stirred solution of 7-(2H-tetrazol-5-yl)-imidazole in dry DMF (4 ml) at room temperature [1, 2 -a] a mixed solution of pyridine (7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine, ~4.2 mmol) and K ₂ CO ₃ (1.16 g, 8.4 mmol). After 5 hours, in EtOAc / H ₂ O and the reaction was separated. The aqueous layer was extracted with EtOAc (x2). The collected EtOAc extracts were dried (Na ₂ SO ₄₎ and filtered, and evaporated. The residue was purified by column chromatography: 100% DCM→4% 2M NH ₃ -MeOH/DCM to give two regioisomers [regiochemistry based on the results of the nOe study]: 7 -(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2- a] pyridine) (less polar): ¹ H 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 (3H, s).

7-(1-Methyl-1H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (more polar): ¹ H NMR (400 MHz, DMSO-d6): 8.78 (1H, Dd), 8.18-8.15 (2H, m), 7.79 (1H, d), 7.35 (1H, dd), 4.28 (3H, s).

Step 4: 3-iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin Pyridine

(3-Iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine)

N-Iodo succinimide (300 mg, 1.3 mmol) was added to a stirred solution of 7-(2-methyl-2H- in dry DMF (2 mL) at room temperature under nitrogen. Tetraazol-5-yl)-imidazo[1,2-a]pyridine (7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine, 240 mg, 1.2 mmol) mixture. After 5 hours, the reaction aqueous sodium thiosulfate / saturated aqueous NaHCO ₃ (1: 1,2 ml) is stopped. Water (2 ml) was added and the mixture was stirred at room temperature for 15 min. The solid was filtered and dried in vacuo to give compound (360 mg). ^{1 H 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).

Step 5: 1-{3-[7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-( 2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea)

3-iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (3-iodo-7-(2-methyl-2H-tetrazol-5) -yl)-imidazo[1,2-a]pyridine, 170 mg, 0.52 mmol), 1-[3-(4,4,5,5-tetramethyl-[1,3,2]disazopentyl boron Alkan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3, 2] dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, I6, 225 mg, 0.65 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol) dissolved in dry DME (2.5 ml) and vacuum/nitrogenated (x2) deoxygenation. PdCl ₂ dppf (38 mg, 0.05 mmol) was added and the mixture was again deoxygenated (x3). The reaction was stirred and heated to 80 ° C for 16 hours. After cooling to room temperature, followed by EtOAc / H ₂ O The mixture was separated. The aqueous layer was extracted with EtOAc (x2). The collected EtOAc extracts were dried (Na ₂ SO _4), and filtered, and evaporated. The residue was purified with EtOAc (EtOAc)

In another process of step AI, step 3 can be performed as follows: Step 3b:

Step AI, Step 3b: 7-[2-(2,2,2-Trifluoro-ethyl)-2H-tetrazol-5-yl]-imidazo[1,2-a]pyridine (7-[2-(2,2,2-Trifluoro-ethyl)-2H-tetrazol-5-yl]-imidazo[1,2-a]pyridine)

Sodium hydride (60 mg, 1.5 mmol) was added to a stirred solution of 7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (7) in dry DMF (4 mL). -(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine, 250 mg, 1.3 mmol) mixed solution. 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 rt EtOAc (EtOAc) The collected organic extracts with saturated aqueous sodium chloride (brine) (x1) washed, dried (Na ₂ SO _4), filtered and the solvent was removed in vacuo. In silicon column chromatography _{(0-2% 2M NH 3 .MeOH /} CH 2 Cl 2) to give the product (138mg). MS: [M+H] ⁺ 269.

Step AJ Step 1: 5-Chloro-1,3-dimethyl-1H-[1,2,4]triazole (5-Chloro-1,3-dimethyl-1H-[1,2,4]triazole) and its isomers

5-Chloro-3-methyl-1H-[1,2,4]triazole (1.76 g, 15 mmol), K ₂ CO ₃ (4.2 g, 30 mmol) and methyl iodide (MeI, 1.4 ml, 22 Methyl) was dissolved in acetone (15 ml) and stirred at room temperature for 20 hours. After filtration, the solid was washed with EtOAc and then with CH ₂ Cl ₂ / H ₂ O to solids. The CH ₂ Cl ₂ layer was separated and added to the aforementioned filtrate. The collected organic extracts were evaporated, CH ₂ Cl ₂ and to the residue was taken. This was followed by one phase separation and volatilization to give isomeric mixed methylated triazoles (1.6 g, brown liquid). ¹ H NMR (400 MHz, CDCl ₃ ): 3.77 (3H, s), 2.43 (3H, s) [measurement signal for only major isomers]. This material is not purified and can be used directly.

Step 21-{3-[7-(2,5-Dimethyl-2H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl] -phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(2,5-Dimethyl-2H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea)

The same preparation method as described in step E3d, but must: replace 4-bromo-2 with 5-chloro-1,3-dimethyl-1H-[1,2,4]triazole (and its isomeric form) -methylthiazole. The request to separate the heterogeneous silicon out chromatography: 100% DCM → 6% 2M NH 3 -MeOH / DCM. Regiochemistry is based on the nOe research theory.

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

4-iodo-5-methyl-1H-imidazole (2.1 g, 10 mmol) and K ₂ CO ₃ (2.1 g, 15 mmol) were dissolved in dry DMF (5 ml) under a nitrogen atmosphere at room temperature and stirred. Treatment with methyl iodide (940 μl, 15 mmol). After 5 hours, the reaction was quenched with water and then with EtOAc / H ₂ O to separate. The aqueous layer was extracted with EtOAc (x2). The collected EtOAc extracts dried brittle (Na ₂ SO _4), filtered, and evaporated. The residue was purified by silica column _{chromatography: 60% EtOAc / CH 2 Cl} 2 → 80% EtOAc / CH 2 Cl 2 → 100% EtOAc, and the resulting bit anisotropy cart (regioisomer): [Chemical position (regiochemistry) system based on The theory of nOe research]

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 (3H, s).

5-iodo-1,4-dimethyl-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-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(1,5-Dimethyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin -3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea)

Prepared in the same manner as described in Step E3d, but 4-bromo-2-methylthiazole was replaced with 4-iodo-1,5-dimethyl-1H-imidazole.

Step AL 1-{3-[7-(5-Thio-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridine- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Thioxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl }-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-fluorenylcarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phe Nyl]-3-(2,2,2-trifluoro-ethyl)-urea) was prepared in the same manner as described in Example 332.

Carbon disulfide (22 μl, 0.36 mmol) was added to 1-[3-(7-fluorenylcarbonyl-imidazo[1,2-a]pyridin-3-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 off with EtOAc and Et ₂ O washed, then dried to give the title compound as indicated by (69 mg). MS: [M+H] ⁺ = 435.

Step AM 1-{3-[7-(5-Methylsulfonyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-benzene }}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Methylsulfanyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 ,2,2-trifluoro-ethyl)-urea)

1-[3-(7-fluorenylcarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), as in Example 332 Said phase The preparation was carried out in the same manner.

Carbon disulfide (22 μl, 0.36 mmol) was added to 1-[3-(7-fluorenylcarbonyl-imidazo[1,2-a]pyridin-3-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 for 3 hours. Methyl iodide (20 μl, excess) was then added and the reaction mixture was warmed to 65 ° C for 1 hour. The mixture was cooled as far as hell until the precipitate formed. The solid was filtered off with EtOAc and Et ₂ O washed, and dried to give the title compound as indicated by (89 mg). MS: [M+H] ⁺ = 449.

Step AN

3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide, 906 mg, 3 mmol) The procedure described in the preparation of step 2 of Example 329 was suspended in THF (10 mL). Triethylamine (0.42 mL, 3 mmol) was added followed by 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 the solid with EtOAc and Et ₂ O, and then dried to give 3-iodo-white solid - imidazo [1,2-a] pyridine-7-carboxylic acid N '- (2,2 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid N'-(2,2-dimethylpropionyl)hydrazide, 875 mg).

3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid N'-(2,2-dimethylpropanthene) oxime (3-Iodo-imidazo[1,2] under nitrogen atmosphere -a]pyridine-7-carboxylic acid N'-(2,2-dimethylpropionyl)hydrazide, 875 mg, 2.27 mmol) was suspended in anhydrous THF (15 mL). Pyridine (0.388 mL, 4.76 mmol) and tosyl chloride 518 mg (2.72 mmol) were added and the mixture was heated to 70 ° C overnight. After the reaction was cooled, it was separated with EtOAc and 1M EtOAc. The aqueous portion was basified with 2M sodium carbonate solution, and extracted with CH ₂ Cl _2. 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[1,2-a]pyridine (7-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-3-iodo-imidazo[1,2-a]pyridine, 70 Mg).

The Suzuki coupling reaction as described in Example 329 was used to synthesize the final product.

Step AO Formation of mono-fluorooxadiazole 2-imino-1-(1-iodo-vinyl)-1,2-dihydro-pyridine-4-carboxylic acid N'-(2-fluoro-acetyl)-hydrazine (2-Imino-1-(1-iodo-vinyl)-1,2-dihydro-pyridine-4-carboxylic acid N'-(2-fluoro-acetyl)-hydrazide)

The EDC (127mg, 0.66mmol) and DMAP (5mg, catalytic) was dissolved was added to CH ₂ Cl ₂ (5ml) of trifluoroacetic acid (52mg, 0.66mmol) solution, and the reaction mixture was stirred at room temperature for 15 minutes. Add 3-iodo-imidazo[1,2-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 Et ₂ O and dried to give crude product (101 mg), and the crude product was used directly in the next step. MS: [M+H] ⁺ = 363.

7-(5-fluoromethyl-[1,3,4]oxadiazol-2-yl)-3-iodo-imidazo[1,2-a]pyridine (7-(5-Fluoromethyl-[1,3,4]oxadiazol-2-yl)-3-iodo-imidazo[1,2-a]pyridine)

2-Imino-1-(1-iodo-vinyl)-1,2-dihydro-pyridine-4-carboxylic acid N'-(2-fluoro-acetamido)-indole (2-Imino- 1-(1-iodo-vinyl)-1,2-dihydro-pyridine-4-carboxylic acid N'-(2-fluoro-acetyl)-hydrazide, 89 mg, 0.25 mmol), DIPEA (0.24 ml, 1.48 mmol) 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

As in step e of Example 329, and using 7-(5-fluoromethyl-[1,3,4]oxadiazol-2-yl)-3-iodo-imidazo[1,2-a] Pyridine (7-(5-Fluoromethyl-[1,3,4]oxadiazol-2-yl)-3-iodo-imidazo[1,2-a]pyridine) is contained therein.

Step AP Ring formation method 5-(3-iodo-imidazo[1,2-a]pyridin-7-yl)-3H-[1,3,4]oxadiazol-2-one (5-(3-Iodo-imidazo[1] ,2-a]pyridin-7-yl)-3H-[1,3,4]oxadiazol- 2-one)

Carbonyldiimidazole (243 mg, 1.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) were added to 3-iodo-imidazo[1,2-a]pyridine-7-carboxylate in THF (10 ml). 3-(Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide, 196 mg, 0.5 mmol) (as described in Example 329, step ac), and the reaction mixture was stirred for 3 hr. The precipitate formed in the reaction was filtered and washed with Et ₂ O and dried to give the desired product (189 mg). MS: [M+H] ⁺ = 329.

The same procedure as in step e of Example 329, but using 5-(3-iodo-imidazo[1,2-a]pyridin-7-yl)-3H-[1,3,4]oxadiazole- 2-keto(5-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-3H-[1,3,4]oxadiazol-2-one) is contained therein.

Step AQ Step a) 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine (7-(4,4,5,5-Tetranethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine)

7-Chloro-imidazo[1,2-a]pyridine (7-Chloro-imidazo[1,2-a]pyridine, 2 g, 13.1 mmol), bis pinacolatoboron (4 g, 15.8 mmol) K ₂ CO ₃ (2.7 g, 19.5 mmol), Pd(OAc) ₂ (146 mg, 0.63 mmol), tricyclohexylphospine (360 mg, 1.3 mmol) dissolved in diglyme (20 ml) And water (27 μl) and stirred. The reaction mixture was heated to 100 ° C for 24 hours and then stirred at ambient temperature overnight. The solid was filtered off and washed with diglyme. The residue was suspended in water (25 ml), and stirred for 1 hour, filtered, and the solid was washed with water and dried to give the desired compound (1.48 g). MS: [{M-pinacol}+H] ⁺ =163

Step b) 5-Imidazo[1,2-a]pyridin-7-yl-pyridine-2-carboxylic acid methyl ester (5-Imidazo[1,2-a]pyridin-7-yl-pyridine-2-carboxylic acid methyl ester)

PdCl ₂ dppf (220 mg, 0.3 mmol) and H ₂ O (55 μl, 3 mmol) were added to 7-(4,4,5,5-tetramethyl-[1,3,2) dissolved in dry DME (15 ml) Dioxaborolan-2-yl)-imidazo[1,2-a]pyridine (7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -imidazo[1,2-a]pyridine, 732mg, 3mmol), 5-bromopyridine-2-carboxylic acid methyl ester (650mg, 3mmol) and cesium carbonate (2.0g) , 6 mmol) in a stirred solution. The reaction mixture was deoxygenated and heated to 80 ° C for 3 hours. The mixture was cooled, then separated with CH ₂ Cl ₂ /H ₂ O and stirred for 20 min. The solid portion was filtered and washed with MeOH (100 mL). The CH ₂ Cl ₂ layer was separated, collected along the lotion MeOH, and the solvent was removed in vacuo. The residue was purified by silica column chromatography _{(0-3% 2M NH 3 .MeOH /} CH 2 Cl 2) to give a dark yellow solid to, and directly use in the next step. (492 mg). MS: [M+H] ⁺ = 254. ¹ 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 (1H, s), 7.43 (1H, dd), 3.92 (3H, s).

Step c) 2-(5-Imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-ol (2-(5-Imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-ol)

Add methylmagnesium bromide (3M in Et ₂ O, 0.5 ml) to 5-imidazo[1,2-a]pyridin-7-yl-pyridine-2-carboxylate dissolved in dry THF (5 mL). A solution of 5-methylidazo [1,2-a]pyridin-7-yl-pyridine-2-carboxylic acid methyl ester, 135 mg, 0.53 mmol. After 1 h, then added another portion of methylmagnesium bromide (3M in Et2O, 0.5ml), and then the reaction mixture was stirred for 1 hour, and washed with saturated NH ₄ Cl _(aq) the reaction was stopped. The reaction mixture followed by EtOAc / H ₂ O which is separated, the aqueous layer was extracted with EtOAc (x2), the organic layer was concentrated, dried (MgSO _4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography _{(0-3% 2M NH 3 .MeOH /} CH 2 Cl 2) to to give a yellow gum, which was used in and directly in the next step. (44 mg). MS: [M+H] ⁺ = 254. ¹ H NMR (400 MHz, CDCl3): 8.84 (1H, d), 8.27 (1H, d), 7.99 (1H, dd), 7.90 (1H, s), 7.74 (1H, s), 7.67 (1H, s), 7.53 (1H, d), 7.11 (1H, dd), 1.62 (6H, s).

Step d) 2-[5-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-pyridin-2-yl]-propan-2-ol (2-[5-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-pyridin-2-yl]-propan-2-ol)

Use the method as described in step A2.

¹ H NMR (400 MHz, DMSO-d6): 8.97 (1H, d), 8.41 (1H, dd), 8.24 (1H, dd), 8.05 (1H, s), 7.80-7.76 (2H, m), 7.49 (1H, dd), 5.30 (1H, s), 1.49 (6H, s).

Step e) 1-(3-{7-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-imidazo[1,2-a]pyridin-3-yl} -phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3 -(2,2,2-trifluoro-ethyl)-urea)

The method as described in step B3a was used, but Pd tetrakis was replaced with PdCl ₂ dppf.

Step AR-1-[3-(7-[1,2,4]oxadiazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2 , 2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,2,4]Oxadiazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro -ethyl)-urea)

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]pyridine-7-carboxylic acid 1-dimethylamino-(E) methylene decylamine (3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido ]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylidene amide, 135 mg, 0.3 mmol) and 5N NaOH (75 μl, 0.38 mmol) of AcOH/H ₂ O (7:3, 1 ml) 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-[3-(7-[1,2,4]triazol-1-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2, 2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,2,4]Triazol-1-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro -ethyl)-urea) Step 1-7-[1,2,4]Triazol-1-yl-imidazo[1,2-a]pyridine (7-[1,2,4]Triazol-1-yl-imidazo[1,2 -a]pyridine)

Ethylacetate iron (0.94 g, 2.59 mmol), copper (II) oxide (86 mg, 0.86 mmol), 1H-[1,2,4]triazole (0.90 g, 12.9 mmol), cesium carbonate (5.65 g, 17.3 mmol) and 7-bromo-imidazo[1,2-a]pyridine (7-bromo-imidazo[1,2-a]pyridine, 1.7 g, 8.63 mmol) dissolved in anhydrous DMF (43 ml) Heat to 90 ° C for 30 hours under ambient conditions. The reaction mixture was cooled, diluted with CH _{2 2} Cl, filtered, and the organic portion in H ₂ O (x2) cleaning. The aqueous portion washed in CH ₂ Cl _2, and concentrate the organic portion, dried (MgSO ₄₎ and solvent was removed in vacuo. The residue was triturated with EtOAc (EtOAc) MS: [M+H] ⁺ 185.

Step 2-3-Iodo-7-[1,2,4]triazol-1-yl-imidazo[1,2-a]pyridine (3-Iodo-7-[1,2,4]triazol-1-yl-imidazo[1,2-a]pyridine)

The method described in the general formula B step B2.

Step 3-3-1-[3-(7-[1,2,4]Triazol-1-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2, 2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,2,4]Triazol-1-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro -ethyl)-urea)

As described in General Formula B, Step B3a, but using I6[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-( 2,2,2-trifluoro-ethyl)-urea acts as the other half of the coupling.

General SGA

Step SGA1-Imidazole Pyridine Ring Formation

NaHCO ₃ (2.0 eq.) was added to 4-substituted-pyridin-2-ylamine (1.0 eq.) dissolved 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 separated from EtOAc using water. The product is purified by column chromatography, titration, or recrystallization.

Step SGA2-Iodination

N-iodosuccinimide (1.2 equivalents) was added to 7-substituted imidazo[1,2-a]pyridine (1.0 eq.) dissolved in DMF, and the mixed solution was placed in the room. Stir for 2 hours at room temperature. The resulting thin brown slurry, 10% w / v of sodium thiosulfate and sodium carbonate (1M) was diluted with water, and is extracted with CH ₂ Cl _2. The aqueous layer was then extracted with CH ₂ Cl ₂ . The organic layer was collected with brine (brine) wash, dried (MgSO _4), and concentrated in vacuo to afford the product. If necessary, the product can be purified by grinding or column chromatography.

Step SGA3a- and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2, 2,2-trifluoro-ethyl)-urea

(1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny]-3-(2,2,2-trifluoro-ethyl)-urea) Suzuki reaction

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2 -Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, 2-trifluoro-ethyl)-urea, 1.2 equivalents, 1 M Na ₂ CO ₃ (8 equivalents) added to 7-substituted-3-iodo-imidazo[1,2-a]pyridine (7-substituted) dissolved in DME In -3-iodo-imidazo[1,2-a]pyridine, 1 equivalent) [to remove bubbles via nitrogen gas], then tetrakis(triphenylphosphine)palladium(0) (0.05 eq.) was added. The mixture was heated at 80 &lt;0&gt;C overnight, then diluted with water and extracted with EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and concentrated under reduced pressure. The product was used for grinding in Et ₂ O, and purified by silica column chromatography, or reverse HPLC. Suitably, the product can be dissolved in HCl/dioxane, the solvent removed, and the product recrystallized from MeOH to give hydrogen chloride.

Step SGB

Step SGB1-(5-Nitro-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester ((5-Nitro-pyridin-2-yl)-carbamic acid tert-butyl ester)

2-Amino-5-nitropyridine (0.70 g, 5 mmol) was added to a solution of sodium hydride (0.20 g, 5 <RTIgt; The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was evaporated to dryness <RTI ID=0.0></RTI> to <RTIgt;</RTI></RTI></RTI></RTI><RTIgt; The reaction mixture was stirred for 3 hours before the reaction was quenched with EtOH (1 mL) and was partitioned from CH ₂ Cl ₂ and H ₂ O. In which an aqueous layer was extracted with CH ₂ Cl _2, the organic layer was concentrated, dried (MgSO ₄₎ and the solvent removed in vacuo. The residue was triturated with EtOAc EtOAc (EtOAc) MS: [MH] ^- 238

Step SGB2-(5-Amino-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester ((5-Amino-pyridin-2-yl)-carbamic acid tert-butyl ester)

Add 10% Pd/C (0.08 g) to (5-Nitro-pyridin) (5-Nitro-pyridin-2-yl)-aminecarboxylic acid in THF: MeOH (1:1, 80 ml) -2-yl)-carbamic acid tert-butyl ester, 0.80 g, 3.4 mmol), and the reaction was placed in a hydrogen atmosphere for 3 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give a white solid compound (0.70 g). MS: [M+H] ⁺ 210

Step SGB3-(5-Methanesulfonylamino-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester ((5-Methanesulfonylamino-pyridin-2-yl)-carbamic acid tert-butyl ester)

Pyridine (0.44 ml, 5.68 mmol) was added to (5-Amino-pyridin-2-yl) (5-Amino-pyridin-2-yl)-aminecarboxylic acid in CH ₂ Cl ₂ (70 mL) )-carbamic acid tert-butyl ester, 0.70 g, 3.36 mmol). The reaction was cooled to 0.degree. C. and dichloromethane (0.42 mL, 5.. The reaction mixture was then warmed to room temperature and stirred for 18 h. The resulting crude material was silica column chromatography (using dissolved in Et 0-30% MeOH, gradient ₂ O) to afford the product as a white solid (0.43g). MS: [M+H] ⁺ 288

Step SGB4-N-(6-amino-pyridin-3-yl)-methanesulfonamide (N-(6-Amino-pyridin-3-yl)-methanesulfonamide)

4M HCl in dioxane (20 ml) was added to (5-Methanesulfonylamino) (5-Methanesulfonylamino) in dioxane (10 ml) (5-methanesulfonylamino-pyridin-2-yl)-aminecarboxylic acid. The reaction was heated to 55 ° C for 18 hours in -pyridin-2-yl)-carbamic acid tert-butyl ester (0.43 g, 1.48 mmol). Which solvent is removed in vacuo, and the crude material was purified by column chromatography using silica, 0-60% MeOH run Et ₂ O was dissolved in the gradient, to give the product as a white solid (0.28g). MS: [M+H] ⁺ 188

Step SGB5-N-imidazo[1,2-a]pyridin-6-yl-methylsulfonamide (N-Imidazo[1,2-a]pyridin-6-yl-methanesulfonamide)

Chloroacetaldehyde (0.3 ml, 2,25 mmol) and sodium hydrogencarbonate (0.25 g, 3 mmol) were added to N-(6-amino-pyridin-3-yl)-methylsulfonate dissolved in EtOH (30 ml). Amine (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. Then isolated in EtOAc and H ₂ O as the residue. Its aqueous layer was extracted with EtOAc, the organic layer was concentrated 'dried (MgSO _4), and the solvent removed in vacuo. The residue was purified by column chromatography using silica, 0-50% MeOH in Et ₂ O was dissolved run to give a white solid (0.15g). MS: [M+H] ⁺ 212

Step SGB6-N-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-methylsulfonamide (N-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-methanesulfonamide)

N-iodosuccinimide (70 mg, 0.31 mmol) was added to N-imidazo[1,2-a]pyridin-6-yl-methylsulfonate dissolved in DMF (3 ml) Indoleamine (N-Imidazo[1,2-a]pyridin-6-yl-methanesulfonamide, 61 mg, 0.29 mmol). The reaction was stirred at room temperature for 2 h and diluted with water, 10% w/v sodium thiosulfate, and sodium carbonate (1M) and extracted with EtOAc. The aqueous layer was then extracted with EtOAc. The organic phase was collected with brine (brine) (80 ml) washed, dried (MgSO _4), and concentrated in vacuo to give a gray-green residue. The residue was purified by silica column chromatography (0 → 30% MeOH / Et 2 O) to to give the crude product (72mg), and the crude product was used directly in the next step. MS: [M+H] ⁺ 338

Step SGB7-N-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenylamino}-imidazo[1,2-a]pyridine-6 -yl)-methylsulfonamide (N-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenylamino}-imidazo[1,2-a]pyridin-6-yl)-methanesulfonamide)

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2 -Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, 2-trifluoro-ethyl)-urea, 87 mg, 0.25 mmol), 1 M Na ₂ CO ₃ (2 ml) was added to N-(3-iodo-imidazo[1,2-a]pyridine in DME (5 mL). 6-yl)-methylsulfonamide (N-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-methanesulfonamide, 72 mg, 0.21 mmol) [with bubbles removed via nitrogen gas], followed by Tetrakis(triphenylphosphine)palladium(0) (12 mg) was added. The mixture was heated overnight at 80 ° C, then diluted with water and extracted with EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and the solvent was removed in vacuo. The product was purified using reverse EtOAc to afford white solid (yield: MS: [M+H] ⁺ 428

Step SGC

Step SGC1-6-iodo-7-methyl-imidazo[1,2-a]pyridine (6-Iodo-7-methyl-imidazo[1,2-a]pyridine)

As in the step of SGA1, but using 5-iodo-4-methyl-pyridin-2-ylamine

Step SGC2-6-cyclopropyl-7-methyl-imidazo[1,2-a]pyridine (6-Cyclopropyl-7-methyl-imidazo[1,2-a]pyridine)

1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2 -Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2, 2-trifluoro-ethyl)-urea, 33 mg, 0.39 mmol), 1 M Na ₂ CO ₃ (1.6 ml) was added to 6-Iodo-7-methyl-imidazo[1,2-a]pyridine dissolved in DME (5 ml) (50 mg, 019) [Break the bubbles via nitrogen gas], followed by the addition of tetrakis(triphenylphosphine)palladium(0) (11 mg). The mixture was heated to 120 ° C for 30 minutes using microwave irradiation, then diluted with water and extracted with CH ₂ Cl ₂ . The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and the solvent was removed 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 (34 mg). MS: [M+H] ⁺ 173

Step SGC3-6-cyclopropyl-3-iodo-7-methyl-imidazo[1,2-a]pyridine (6-Cyclopropyl-3-iodo-7-methyl-imidazo[1,2-a]pyridine)

As in the step in SGA2, but using 6-cyclopropyl-7-methyl-imidazo[1,2-a]pyridine, 165 mg) .MS:[M+H] ⁺ 299

Step SGC4-1-[3-(6-Cyclopropyl-7-methyl-imidazo[1,2-a]pyridin-3-ylamino)-phenyl]-3-(2,2,2 -trifluoro-ethyl)-urea (1-[3-(6-Cyclopropyl-7-methyl-imidazo[1,2-a]pyridin-3-ylamino)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

As in the step in SGA3a, but using 6-cyclopropyl-3-iodo-7-methyl-imidazo[1,2-a]pyridine (6-Cyclopropyl-3-iodo-7-methyl-imidazo[1, 2-a]pyridine, 7 mg). MS: [M+H] ⁺ 389

General procedure SGD

Step SGD1-General imidazole pyridine ring formation

Add NaHCO ₃ (16.8 g, 200 mmol, 2.0 eq.) to 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol) dissolved in EtOH (170 ml) In 1.0 equivalents, chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 eq.) was then added. The mixture was refluxed for 6 hours. The solvent was removed under reduced pressure and the crude mixture was partitioned with water and EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO ₄₎ and concentrated under reduced pressure. The product was purified by column chromatography (SiO _2, 50% EtOAC- in petroleum ether) to afford 13.2 g via product. MS: [M+H] ⁺ 153

Step SGD2-General Iodination

Step A2: N-iodosuccinimide (43.6 g, 194 mmol, 1.05 eq.) was added to 7-chloro-imidazo[1,2-a] dissolved in DMF (280 mL). Pyridine (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), brine (br. The aqueous phase was extracted with EtOAc (3× 280 mL). The organic phase was collected, to which water (2 x 280ml), 10% w / v of sodium thiosulfate (280 ml), saturated aqueous sodium chloride (brine) (280 ml) washed, dried (MgSO _4), and concentrated in vacuo To get a brown residue. The residue was triturated with diethyl ether (200 mL), filtered and evaporated. MS: [M+H] ⁺ 279

Step SGD3- with 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2, 2,2-trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea) Suzuki reaction

Step A3b: 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2, 2,2-Trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2 , 2,2-trifluoro-ethyl)-urea, 1.2 equivalents), 1 M Na ₂ CO ₃ (8 equivalents) added to 7-chloro-3-iodo-imidazo[1,2-a]pyridine dissolved in DME ( 7-chloro-3-iodo-imidazo[1,2-a]pyridine, 1 equivalent) [with bubbles removed via nitrogen gas] followed by tetrakis(triphenylphosphine)palladium(0) (0.05 eq.). The mixture was heated overnight at 80 ° C, then diluted with water and extracted with EtOAc. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), and concentrated under reduced pressure. The crude material was triturated in CH ₂ Cl ₂ to give a beige solid product. MS: [M+H] ⁺ 389

Step SGD4a-Sonagshira reaction

1-[3-(7-acetylene-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1- Preparation of [3-(7-Ethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1 -[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 0.59 g, 1.6 mmol), Trimethylsilylacetylene (0.92 ml, 6.4 mmol), potassium carbonate (0.44 g, 3,2 mmol), palladium acetate (0.07 g, 0.32 mmol) and 2,2'-Bis (diphenyl) Phosphine-1,1'-binaphthalene (0.4 g, 0.64 mmol) was dissolved in toluene (20 ml). The reaction mixture was microwaved (2 x 90 min) to 120 ° C and cooled then separated with CH ₂ Cl ₂ and H ₂ O. In aqueous layer was extracted with CH ₂ Cl _2, the organic layer was concentrated, dried (MgSO ₄₎ and solvent was removed in vacuo. The residue was purified in a silica column _{(0-60% MeOH in Et 2 O} ) to give a solid which was used directly in the next step.

At 0 ° C, 1 M solution of tetrabutylammonium fluoride (0.09 ml) was added to 1-(2,2,2-trifluoro-ethyl)-3-[3- dissolved in THF (5 ml). (7-trimethyldecylamine acetylene-imidazo[1,2-a]pyridin-3-yl)-phenyl]-urea (1-(2,2,2-Trifluoro-ethyl)-3-[3 -(7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-urea, 25 mg, 0.06 mmol), the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was diluted with water, and is extracted with CH ₂ Cl _2. The organic layer with saturated aqueous sodium chloride (brine), dried (MgSO _4), solvent was removed in vacuo. The residue was purified by EtOAc (EtOAc) MS: [M+H] ⁺ 359

Step SGE

Step SGE1-imidazo[1,2-a]pyridine-7-carboxylic acid decylamine (Imidazo[1,2-a]pyridine-7-carboxylic acid amide)

Step SGA1, using 2-aminoisonicotinamide MS: [M+H] ⁺ 162.

Step SGE2-imidazo[1,2-a1pyridine-7-cyano (Imidazo[1,2-a]pyridine-7-carbonitrile)

Add dropwise trifluoroacetic anhydride (0.39, 2.83 mmol) to imidazo[1,2-a]pyridine-7-carboxylic acid decylamine (Imidazo [1,2-] dissolved in CH ₂ Cl ₂ (5 ml) a] pyridine-7-carboxylic acid amide, 38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol). The reaction mixture was stirred for 2 hours at room temperature prior to loading the crude mixture to SCX SPE cartridge, washed with MeOH and eluting with 2M NH ₃ / MeOH. The solvent was removed in vacuo to give the compound (32 mg). MS: [M+H] ⁺ 144.

Step SGE3-3-iodo-imidazo[1,2-a]pyridine-7-cyano (3-Iodo-imidazo[1,2-a]pyridine-7-carbonitrile)

Step SGA2, using Imidazo[1,2-a]pyridine-7-carbonitrile. MS: [M+H] ⁺ 270.

Step SGE4-1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

Prepared as in the procedure of Step A3a, but using 3-iodo-imidazo[1,2-a]pyridine-7-earbonitrile. Purification was carried out using reverse phase HPLC to give a white solid product. MS: [M+H] ⁺ 360.

Step SGF:

Step SGF1-Methylimidazo-[1,2-a]pyridine-7-carboxylate (Methyl imidazo[1,2-a]pyridine-7-carboxylate)

Prepared as in the method of step SGA1, but using methyl-2-aminopyridine-4-carboxylate: NaHCO ₃ (11.1 g, 132 mmol, 2.0 equivalents) was added. Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol, 1.0 eq.) in EtOH (150 ml), followed by chloroacetaldehyde (chloroacetaldehyde, 13.0 ml, 99 mmol, 1.5 equivalents). 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 in Et ₂ O and MeOH / Et ₂ O to afford 8.4 g crystalline product. MS: [M+H] ⁺ 177

Step SGF2-2-imidazo[1,2-a]pyridin-7-yl-propan-2-ol (2-Imidazo[1,2-a]pyridin-7-yl-propan-2-ol)

A solution of 1.6 M MeLi in Et ₂ O (5.3 ml) was added to methylimidazo[1,2-a]pyridine-7-carboxylate ( Methyl imidazo ) dissolved in THF (20 ml) at -78 °C. In [1,2-a]pyridine-7-carboxylate, 0.50 g, 2.84 mmol), the reaction was then warmed to room temperature. The reaction was stopped with water and then layered. Followed by a water layer was extracted with Et ₂ O, and the organic layer was concentrated, dried (MgSO _4), filtered, and the solvent removed in vacuo to afford the product (0.38g). MS: [M+H] ⁺ 177

Step SGF3-2-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-propan-2-ol (2-(3-Iodo-imidazo[1,2-a]pyridin-7-yl)-propan-2-ol)

Prepared as in step SGA2, but using 2-imidazo[1,2-a]pyridin-7-yl-propan-2-ol (2-Imidazo[1,2-a]pyridin-7-yl-propan -2-ol). MS: [M+H] ⁺ 303.

Step SGF4-1-{3-[7-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2, 2,2-trifluoro-ethyl)-urea (1-{3-[7-(1-Hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

Prepared as in the method of step SGA3a, but using 2-(3-iodo-imidazo[1,2-a]pyridin-7-yl)-propan-2-ol (2-(3-Iodo-imidazo[1, 2-a]pyridin-7-yl)-propan-2-ol). Purification by reverse phase HPLC gave the product. MS: [M+H] ⁺ 393.

Step SGG

Step SGG1:1-[3-(7-Mercapto-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl) -urea (1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

0 ℃ conditions will TPAP (0.14g, 0.38mmol) was dissolved was added to CH ₂ Cl ₂ (30ml) 1- [3- (7-hydroxymethyl - imidazo [1,2-a] pyridin-3 -yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Hydroxymethyl-imidazo[1,2-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, 11.7mmol) in solution containing sieve (3g) . 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 H ₂ O (x2) washed, dried (MgSO _4), and the solvent removed in vacuo. The residue was purified by silica column chromatography silica column chromatography _{(0-60% MeOH in Et 2 O} ) to afford the product (0.2g). MS: [M+H] ⁺ 363

Step SGG2(E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine- 7-yl)-ethyl acrylate ((E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-acrylic Acid ethyl ester)

Triethylphosphonoacetate (99 μl, 0.5 mmol) and lithium chloride (21 mg, 0.5 mmol) were dissolved in MeCN (5 ml) and stirred. DBU (62 μl, 0.41 mmol) was added, and 1-[3-(7-methylindolyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2, 2-Trifluoro-ethyl)-urea (1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-) The reaction mixture was stirred for a further 15 minutes before ethyl)-urea). Prior with EtOAc and H ₂ O which is isolated, and the mixture was stirred for another hour. Aqueous layer was extracted with EtOAc, the organic layer was concentrated, dried (MgSO ₄₎ and solvent was removed in vacuo. The residue was triturated in Et ₂ O to give the product as a yellow solid. MS: [M+H] ⁺ 433.

Step SGG3(E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine- 7-base)-acrylic acid ((E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-acrylic Acid)

Add 1 M Na ₂ CO ₃ (4 ml) to (E)-3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido] dissolved in EtOH (10 ml) -phenyl}-imidazo[1,2-a]pyridin-7-yl)-ethyl acrylate ((E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl) -ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-acrylic acid ethyl ester, 83 mg, 0.19 mmol) and the reaction was heated to 80 ° C for 1.5 hours. The reaction was neutralized with 1 M HCl and concentrated. The residue was taken up in hot EtOH, filtered and solvent was evaporated in vacuo to afford product. MS: [M+H] ⁺ 405

Step SGG4(E)-N-Alkyl-3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2 -a]pyridine-7-yl)-acrylamide ((E)-N-alkyl-3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7- Yl)-acryl amide)

Add TBTU (1.5 equivalents) and HOBt (1.5 equivalents) to (E)-3-(3-{3-[3-(2,2,2-trifluoro-ethyl)-urea}benzene dissolved in DMF —(I)Imidazo[1,2-a]pyridin-7-yl)-acrylic acid ((E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]- In phenyl}-imidazo[1,2-a]pyridin-7-yl)-acrylic acid, the reaction mixture was stirred for 15 minutes. Amine (2 equivalents) was added and the reaction mixture was stirred for 2 h. The crude material was placed into a SCX SPE cartridge, and the cartridge in MeOH (x2 column volumes (column volume)) washing, and eluting with 2M NH ₃ / MeOH (1 column volume). After the solvent was removed in vacuo, the desired product was obtained.

Step SGH

Step SGH1

7-Bromo-imidazo[1,2-a]pyrdine

Prepared as in the method of step A1, but using 4-bromo-pyridin-2-ylamine.

Step SGH2-7-cyclopropyl-imidazo[1,2-a]pyridine (7-Cyclopropyl-imidazo[1,2-a]pyrdine)

Pd(OAc) ₂ (0.03 g) was added to 7-bromo-imidazo[1,2-a]pyridine (7-Bromo-imidazo) dissolved in deoxytoluene (11.36 ml) and H ₂ O (0.57 ml). [1,2-a]pyridine, 0.5 g, 2.53 mmol), cyclopropylboronic acid (0.29 g, 3.29 mmol), K ₃ PO ₄ (1.79 g, 8.88 mmol), Pcy ₃ (0.07 g, 10) Mol%) in solution. The reaction mixture was heated to 100 ° C for 18 hours before it was separated with EtOAc and H ₂ O. Aqueous layer was washed with EtOAc, and the organic layer was concentrated, dried (MgSO _4), and the solvent removed in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) MS: [M+H] ⁺ =159

Step SGH3-7-cyclopropyl-3-iodo-imidazo[1,2-a]pyridine (7-Cyclopropyl-3-iodo-imidazo[1,2-a]pyridine)

Prepared as in the step SGA2 to give the product as a yellow oil. MS: [M+H] ⁺ =285

Step SGH4-1-[3-(7-Cyclopropyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl) -urea (1-[3-(7-Cyclopropyl-imidazo[1,2-a]pyridin-3-yl)-pheyl]-3-(2,2,2-trifluoro-ethyl)-urea)

The product was obtained as in the step in SGA3a. MS: [M+H] ⁺ =375

Step SGI: 1-{3-[7-(hydroxyimino-methyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1-{3-[7-(Hydroxyimino-methyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea0

Hydroxyamine hydrochloride (11 mg, 0.15 mmol) and triethylamine (21 μl, 0.15 mmol) were added to 1-[3-(7-methylindolyl-imidazo[1, 2-a]pyridin-3-yl)-phenyl]-3-(2,2,2,-trifluoro-ethyl)-urea (50 mg, 0.14 mmol). The reaction mixture was stirred for 10 minutes, then p-toluic acid (3 mg, &lt;RTI ID=0.0&gt; The precipitate was filtered off and washed in Et ₂ O to afford product (23mg). MS: [M+H] ⁺ 378.

1-{3-[7-(methoxyimino-methyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-tri Fluoro-ethyl)-urea (1-{3-[7-(Methoxyimino-methyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea)

The same procedure as above was followed except that hydroxylamine hydrochloride was replaced with methoxy amine hydrochloride. MS: [M+H] ⁺ 392.

Examples 1 to 59

The compounds of Examples 1 to 59 shown in the following Table were prepared by the methods described above.

Example 59A 1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-B Base)-urea salt-acid (1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea Hydrochloride).

Step (a): 1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea)

3-Bromophenyl isocyanate (21.12 g, 107 mmol) was slowly added to a stirred 2,2,2-trifluoroethylamine (2,2,2) at 0 ° C under nitrogen. -trifluoroethyl amine, 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). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (1H, s), 7.80 (1H, t), 7.31-7.24 (1H, m), 7.20 (1H, t), 7.16-7.08 (1H, m ), 6.83 (1H, bt), 3.98-3.85 (2H, m).

Step (b): 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2) , 2,2-trifluoro-ethyl)-urea (1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-phenyl)-3-(2,2,2-trifluoro) -ethyl)-urea) (31.6 g, 106 mmol), bis(pinacolato diboron, 54 g, 212 mmol) and KOAc (31.3 g, 319 mmol) dissolved in dry DMSO (110 mL) And deoxygenated (x3) via vacuum/re-nitrogenation. PdCl ₂ ddpf (7.78 g, 10.6 mmol) was added, and the mixture was again deoxygenated (x3) and stirred, and heated to 100 ° C for 100 minutes under nitrogen. The reaction was cooled to room temperature, diluted with water (EtOAc) The collected organic extracts were washed with water (320 mL), saturated brine (320 mL) washed, dried (MgSO _4), filtered and evaporated. The residue was triturated in petroleum to give a solid compound (37.4 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (1H, s), 7.58 (1H, d), 7.46 (1H, d), 7.34 (1H, t), 6.65 (1H, brs), 5.21. Brs), 3.99-3.86 (2H, m), 1.33 (12H, s).

Step (c): 7-Chloro-imidazo[1,2-a]pyridine (7-Chloro-imidazo[1,2-a]pyridine)

Add NaHCO ₃ (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). A solution of 50% chloroacetaldehyde dissolved in water (37 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 organic layer was concentrated with saturated brine (50 mL) washed, dried (MgSO _4), and concentrated under reduced pressure to give 7-chloro - imidazo [1,2-a] pyridine (32.7 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d), 7.64 (2H, d), 7.56 (1H, s), 6.79 (1H, dd).

Step (d): 7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine (7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine)

7-Chloro-imidazo[1,2-a]pyridine (15.0 g, 98.6 mmol), 4-fluorophenylboronic acid (16.55 g, 118.3 mmol), potassium carbonate (81.5 g, 590 mmol) dissolved in toluene-methanol - ethanol-water (1:1:1:1, 800 mL), filled with nitrogen to remove the gas, and added bis(tri-tert-butylphosphine)palladium (0) ((bis(tri-tert-butylphosphine)palladium) (400 mg). After degassing the mixture, it was added to 80 ° C for 18 hours. The mixture was then cooled to ambient temperature, transferred to a separating funnel and layered. The organic portion was reduced under reduced pressure and the residue was extracted with dichloromethane. the dichloromethane extracts were washed with water, dried (MgSO _4), filtered, and concentrated under reduced pressure to give the title as shown in the compound ^{17.3 g (83%). 1} H NMR ( 400 MHz, CDCl ₃ ) δ 8.22 (1H, d), 7.87 (1H, s), 7.71 (1H, s), 7.69-7.58 (3H, m), 7.20 (2H, t), 7.11 (1H, d) .

Step (e): 7-(4-Fluoro-phenyl)-3-iodo-imidazole [1,2-a]pyridine (7-(4-Fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine)

Add N-iodosuccinimide (14.5 g, 64.4 mmol) to 7-(4-fluoro-phenyl)-imidazole [1,2-a]pyridine (7-(4- Fluoro-phenyl)-imidazo[1,2-a]pyridine) (13.0 g, 61.3 mmol) in N,N-dimethylformamide (100 mL) was 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, washed with water, and placed on a filter paper to be dried in the air. The solid was triturated in diethyl ether, collected by filtration and dried in vacuo. The resulting solid was separated by water and EtOAc. The organic layer was washed with saturated brine, dried (MgSO _4), filtered, and concentrated under reduced pressure. The solid obtained was partitioned with aqueous sodium thiosulfate and EtOAc. The organic layer was washed with saturated brine, dried (MgSO _4), and concentrated under reduced pressure. The product was triturated in EtOAc, EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ) 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.

Step (f): 1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2 -trifluoro-ethyl)-urea (1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea )

7-(4-Fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine (7-(4-Fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine) (10.1 g, 29.8 mmol), 1-(3-bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-Bromo-phenyl)-3-( 2,2,2-trifluoro-ethyl)-urea) (12.3 g, 35.8 mmol) and 2M sodium carbonate (120 mL) dissolved in dimethoxyethane (595 mL) and vacuum/refilled with nitrogen (x3) Deoxygenation. Tetrakis(triphenylphosphine)palladium (1.72 g, 1.49 mmol) was added, and the mixture was again deoxygenated (x3) and heated to 80 ° 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 (100 mL), EtOAc (100 mL) andEtOAc. After the obtained slurry was filtered, EtOAc was evaporated. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.98 (1H, s), 8.61 (1H, d), 7.99 (1H, s), 7.96-7.87 (2H, m), 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): 1-{3-[7-(4F-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl-}-3-(2,2,2 -trifluoro-ethyl)-urea hydrochloride (1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea Hydrochlori-de salt)

Add 4M hydrogen chloride / dioxane (10 mL) to 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea, 9.8 g) and a solution of methanol (100 mL). The solution was stirred at room temperature for 90 minutes, then concentrated under reduced pressure to give compound (1l. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.47 (1H, s), 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(2H,m), 7.50-7.39(3H,m),7.37-7.28(1H,m),7.14(1H,t),4.03-3.42(7H,m), 3.17 (3H, s).

Examples 60 to 110

The compounds of Examples 60 to 110 shown in the following Table were prepared by the methods described above.

Examples 111 to 116

The pyrazolo[1,5-a]pyrimidine compounds of Examples 111 to 114 shown in the following Table were prepared by the methods described above.

Example 117 N-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazin-3-yl]-phenyl}-acetamide (N-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazin-3-yl]-phenyl}-acetamide) Step 1: 2-Bromo-5-trimethyldecylamine acetylene-pyrazine (2-Bromo-5-trimethylsilanylethynyl-pyrazine)

2-bromo-5-iodo-pyrazine (1.14 g, 4.0 mmol) and cuprous iodide (copper(I) iodide, 80 mg, 0.42 mmol) were dissolved in DMF/Et ₃ N (2:1, 24 ml), deoxygenated via vacuum/re-nitrogenation (x3). After adding ethyne-trimethyl-silane (680 μl, 4.8 mmol), Pd(PPh ₃ ) ₄ (230 mg, 0.2 mmol) was added thereto, and the mixture was again deoxygenated (x1). The reaction was stirred at room temperature for 16 hours and then isolated in Et ₂ O / H ₂ O. The organic layer was with water (x1), saturated brine (x1) washed, dried (MgSO _4), filtered and evaporated. The residue was purified by silica gel chromatography _{(2 → 4% Et 2 O} / Petrol) to to give the compound as shown in the title (850 mg of, a wax-like solid) as a ~ 3: 1 mixture of single coupling ratio of the coupling of the bis . ¹ H NMR (400 MHz, CDCl ₃ ): 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-trimethylguanamine-pyrazolo[1,5-a]pyrazine (6-Bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine)

O-(Mesitylenesulfonylhydroxylamine, 680 mg, 3.2 mmol) was added in one portion to 0 ° C, and 2-bromo-5 was dissolved in CH ₂ Cl ₂ (3 ml) with stirring. a solution of 2-bromo-5-trimethylsilanylethynyl-pyrazine (step 1, 3 mmol). The mixture was stirred at 0 ° C for 30 minutes, at room temperature for 4 hours, and then evaporated. The N-amino adduct can be used without further processing.

K ₂ CO ₃ (410 mg, 3 mmol) was added to a solution of the above-mentioned N-aminopyrazine dissolved in dry DMF (5 ml) under stirring at room temperature. After 6 hours, the mixture was separated in EtOAc / H ₂ O. The organic layer was washed with saturated brine (x2) and then evaporated. The residue was taken up in CH ₂ Cl ₂ and passed through a phase. The filtrate was evaporated, and the residue was purified mjjjjjjjjjjjj MS: [M+H] ⁺ 270/272.

Step 3: 6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazine (6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazine)

6-bromo-2-trimethylguanamine-pyrazolo[1,5-a]pyrazine (6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine in a microwaveable bottle , 60 mg, 0.23 mmol), 4-fluorophenylboronic acid (40 mg, 0.29 mmol), and PdCl ₂ dppf (10 mg, 0.014 mmol) in CH ₃ CN (1 ml) and 2N Na ₂ CO ₃ (aq, 1 ml). The oxygen was removed by charging a nitrogen gas bubble for 20 seconds. The bottle was sealed, stirred and heated in a microwave for 150 ° C for 20 minutes. After cooling, the reaction mixture was separated with CH ₂ Cl ₂ /H ₂ O. The mixture was passed through a phase separation. The organic layer was evaporated, and the residue was purified (5 → 20% EtOAc / Petrol ) to silica column chromatography to give the compound as shown in the title ^{(14mg, oil) 1 H NMR} (400 MHz, CDCl 3): 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-Fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrazine (6-(4-Fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrazine)

N-iodosuccinimide (13 mg, 0.06 mmol) was added to a stirred solution at room temperature under a nitrogen atmosphere in dry DMF (0.5 ml). a solution of -phenyl)-pyrazolo[1,5-a]pyrazine (6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrazine, 11 mg, 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). 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 aqueous sodium thiosulfate / saturated NaHCO ₃ (1: 1,1ml) is stopped. The mixture was stirred at room temperature for 1 hour and then separated with CH ₂ Cl ₂ /H ₂ O. The mixture was passed through a phase separation. The organic layer was evaporated to give the title compound (13 mg, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 9.01 (1H, d), 8.69 (1H, d), 8.05 (1H, s), 8.00-7.90 (2H, m), 7.24 - 7.14 (2H, m).

Step 5: N-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazin-3-yl]-phenyl}-acetamide (N-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrazin-3-yl]-phenyl}-acetamide)

In a microwaveable bottle, 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrazine (6-(4-fluoro-phenyl)-3-iodo- Pyrazolo[1,5-a]pyrazine, 13 mg, 0.04 mmol), 3-acetamidophenylboronic acid (14 mg, 0.08 mmol) and PdCl ₂ dppf (3 mg) dissolved in CH ₃ CN (1 ml) and 2N Na ₂ CO ₃ (aq, 1 ml), and deoxidized by bubbling with nitrogen gas for 20 seconds. The bottle was sealed, stirred and microwaved at 150 ° C for 30 minutes. After cooling, the reaction mixture was separated with CH ₂ Cl ₂ /H ₂ O. The mixture was passed through a phase separation. The organic layer was evaporated, and the residue was purified with ethylamine to afford compound (6 mg, solid). ¹ H NMR (400 MHz, Me-d _{3 -} 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).

Example 118 3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenylamine (3-[6-(4-Fluoro-phenyl)-pyrazolo[ 1,5-a]pyridin-3-yl]-phenyl amine) Step 1: 3-(4-Fluoro-phenyl)-pyridine (3-(4-Fluoro-phenyl)-pyridine)

A solution of 3-bromopyridine (2.5 g, 15.8 mmol) and 4-fluorophenylboronic acid (2.8 g, 20.0 mmol) in DME (20 mL) and 2N Na ₂ CO ₃ (aq, 20 mL) Nitrogen (x2) deoxygenation. PdCl ₂ dppf (600 mg, 0.8 mmol) was added and the mixture was again deoxygenated (x3). After the reaction was heated under nitrogen to a state 80 ℃, 16 hours, cooled to room temperature, the mixture was separated in EtOAc / H ₂ O. The aqueous layer was extracted with EtOAc (×2). Concentrated extract was washed with brine (x1) washed, dried (Na ₂ SO _4), filtered and evaporated. . The residue was purified by silica gel chromatography (10 → 40% EtOAc / Petrol ) to to give the compound as shown in the title ^{(3.0g, oil) 1 H NMR} (400 MHz, CDCl 3): 8.83 (1H, brs) , 8.61 (1H, brs), 7.85 (1H, d), 7.54 (2H, dd), 7.39 (1H, brs), 7.18 (2H, t).

Step 2: 6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic Acid methyl ester)

O-(Mesitylenesulfonyl)hydroxylamine (O-(Mesitylenesulfonyl)hydroxylamine, 3.5 g, 16.2 mmol), 0 ° C, under nitrogen, one time added to the stirred solution of dry CH ₂ Cl ₂ -(4-fluoro-phenyl)-pyridine (3-(4-fluoro-phenyl)-pyridine, 2.8 g, 16 mmol) solution. After 30 minutes, the ice bath was removed and the reaction was stirred at room temperature for 16 h. The volatiles are removed in vacuo and the N-aminopyridine can be used directly without further purification.

K ₂ CO ₃ (4.4 g, 32 mmol) was added to the stirred N-aminopyridine (~16 mmol) solution at room temperature under nitrogen, followed by 2- dissolved in dry DMF (48 mL) A solution of 2-benzenesulfonyl-3-dimethylamino-acrylic acid 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 in EtOAc / H ₂ O. The aqueous layer was extracted with EtOAc (x2). The extract was concentrated to water (x1), saturated brine (x1) washed, dried (MgSO _4), filtered and evaporated. The residue was purified by trituration in CH ₂ Cl ₂ /EtOAc to afford compound (2.7 g, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 8.68 (1H, s), 8.42 (1H, s), 8.22 (1H, d), 7.63 (1H, dd), 7.60-7.51 (2H, m), 7.23 7.14 (2H, m), 3.94 (3H, s).

Step 3: 6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridine (6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridine)

6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (6-(4-fluoro-phenyl)-pyrazolo[1,5-a] A mixed solution of pyridine-3-carboxylic acid methyl ester, 1.08 g, 4 mmol) and aqueous NaOH (2N, 4 ml) and EtOH (16 ml) was stirred and heated to 85 ° C for 30 hours under nitrogen. The reaction was cooled to room temperature then ice bath. 2N hydrochloric acid (5 ml) was added slowly. The solid was filtered to collect, and washed in Et ₂ O, and dried in vacuo. The acid can be used directly without further processing. .

The above acid was suspended in polyphosphoric acid (~15 ml) under nitrogen atmosphere and stirred, and heated to 150 °C. After 3 hours, the reaction was cooled to room temperature and poured carefully into ice water. The solid was separated by filtration, and dissolved in CH ₂ Cl _2. The solution was passed through a phase-by-phase phase and then evaporated to give the title compound ( 582 mg, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 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-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (6-(4-Fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine)

N-iodosuccinimide (630 mg, 2.8 mmol) was added to a stirred 6-(4-fluoro-phenyl)-pyrazole at room temperature under nitrogen atmosphere. A solution of [1,5-a]pyridine (6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine, 500 mg, 2.4 mmol) in dry DMF (6 mL). After 45 minutes, the reaction with saturated aqueous sodium thiosulfate / saturated NaHCO ₃ (1: 1,40ml) was stopped. The mixture was stirred at room temperature for 15 minutes, followed by EtOAc / H ₂ O to separate. The organic layer was with water (x1), saturated brine (x1) washed, dried (MgSO _4), filtered and evaporated. The residue was purified by trituration in petroleum to give compound ( 635 mg, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (1H, dd), 7.22-7.13 (2H, m).

Step 5: 3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenylamine (3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenyl amine)

6-(4-Fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a] Pyridine, 140 mg, 0.41 mmol) and a mixture of 3-aminophenylboronic acid pinacol ester (120 mg, 0.5 mmol) dissolved in DME (2 ml) and 2N Na ₂ CO ₃ (aq, 2 ml) In solution, deoxygenate via vacuum/re-nitrogenation (x3). After the addition of PdCl ₂ ddpf (15 mg, 0.02 mmol), the mixture was again deoxygenated (x2). The reaction was stirred and heated to 90 ° C for 24 hours under nitrogen. After cooling to room temperature, the mixture was separated with CH ₂ Cl ₂ /H ₂ O. Use a split phase to layer. The organic layer was evaporated and the residue was purified mjjjjjjjjjjj

Example 119 1-ethyl-3-{3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenyl}-urea (1-Ethyl-3-{3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenyl}-urea)

3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenylamine (3-[6-(4-fluoro-phenyl)-pyrazolo [1,5-a]pyridin-3-yl]-phenyl amine) (Example 118, 50 mg, 0.16 mmol), Et ₃ N (45 μL, 0.32 mmol), and ethyl isocyanate (26) μL, 0.32 mmol) was dissolved in dry DME (2 mL) and stirred and heated to 60 ° C for 24 hours under nitrogen [7 h, then ethyl isocyanate (30 μL) was added]. The reaction mixture was evaporated and dried <RTI ID=0.0> ¹ H NMR (400 MHz, DMSO-d6): 9.09 (1H, s), 8.53 (1H, s), 8. s (1H, s), 8.02 (1H, d), 7.93-7.83 (3H, m), 7.72 (1H, dd), 7.38-7.29 (3H, m), 7.27-7.22 (2H, m), 6.15 (1H, t), 3.19-3.09 (2H, m), 1.08 (3H, t).

Examples 120 to 328

The compounds of Examples 120 to 328 shown in the following Table were prepared by the methods described above.

Example 329 1-{3-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-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]pyridin-3-yl]-phenyl}-3-(2 ,2,2-trifluoro-ethyl)-urea) Step (a): Methylimidazo[1,2-a]pyridine-7-carboxylate (Methyl Imidazo[1,2-a]pyridine-7-carboxylate)

Add NaHCO ₃ (11.1 g, 132 mmol, 2.0 equiv) to methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol, 1.0 equiv) 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 separated with water and EtOAc. And the resulting precipitate was washed in Et ₂ O, and in MeOH / Et ₂ O as recrystallized to give 8.4 g of product. 1H NMR (400 MHz, DMSO-d ⁶ ): 8.66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7.33 (1H, d), 3.90 (3H, s). MS: M+H] ⁺ 177.

Step (b) Methyl 3-iodo-imidazo[1,2-a]pyridine-7-carboxylate (Methyl 3-iodo-imidazo[1,2-a]pyridine-7-carboxylate)

N-iodosuccinimide (5.8 g, 26 mmol, 1.2 equiv) was added to methylimidazo[1,2-a]pyridine-7-carboxylate (Methyl imidazo[1] , 2-a]pyridine-7-carboxylate, 3.8 g, 21.6 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-d ^{3 -} OD): 8.44 (1H, d), 8.25 (1H, s), 7.78 (1H, s), 7.61 (1H, dd ), 3.95 (3H, s).

Step (c) 3-iodo-imidazo[1,2-a]pyridine-7-carboxylate (3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide)

Add hydrazine hydrate (0.25 ml, 5.28 mmol) to methyl-3-iodo-imidazo[1,2-a]pyridine-7-carboxylate (Methyl-3-Iodo-imidazo[1,2-a] Pyridine-7-carboxylate, 0.4 g, 1.32 mmol) was dissolved in MeOH (6 mL). The mixture was refluxed for 4 hrs, then hydrazine hydrate (0.25 ml, 5.28 mmol). The solid was filtered off and washed with MeOH and dried to give 0.36 g. MS: [M+H] ⁺ 303.

Step (d) 3-iodo-7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridine (3-Iodo-7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridine)

3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide, 0.18 g, 0.59 mmol, Triethyl orthoacetate (3 ml) and concentrated H ₂ SO ₄ (1 drop) were treated. The mixture was heated to 80 ° C o / n. After cooling, the solid was filtered and washed with EtOH, and dried to give 0.165 g of product. MS: [M+H] ⁺ 327

Step (e) 1-{3-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-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]pyridin-3-yl]-phenyl}-3-(2 ,2,2-trifluoro-ethyl)-urea)

1-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaoxyborolan-2-yl)-phenyl]-3-(2,2, 2-Trifluoro-ethyl)-urea (I6)(1-[3-(4,4,5,5-Tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-3- (2,2,2-trifluoro-ethyl)-urea (I6), 0.226 g, 0.65 mmol) and 2M Na ₂ CO ₃ (3.4 ml) were added to 3-iodo-7-(5-methyl-[1, 3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridine (3-Iodo-7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo [1,2-a]pyridine, 0.165 g, 0.5 mmol) in a solution of DME (10 ml) [to remove the reaction by nitrogen], followed by tetrakis(triphenylphosphine)palladium(0) (45 Mg, 0.039 mmol). The mixture was heated to 80 &lt;0&gt;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-d ^{3 -} 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).

Example 330 1-[3-(7-[1,3,4]oxadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-benzene 3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,3,4]Oxadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro -ethyl)-urea)

In the same manner as in Example 329, 1-[3-(7-[1,3,4]oxadiazol-2-yl-imidazo[1,2-a] was prepared using triethyl orthoformate in step d. Pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,3,4]Oxadiazol-2-yl) -imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea).

MS: [M+H] ⁺ 403

1H NMR (400 MHz, Me-d ^{3 -} 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).

Example 331 1-{3-[7-(5-ethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Ethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 ,2,2-trifluoro-ethyl)-urea)

1-{3-[7-(5-(Ethyl-[1,3,4]oxadiazole-2-) was prepared in the same manner as in Example 329 using triethylorthopropionate in the step d. Imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-( 5-Ethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)- Urea).

MS: [M+H] ⁺ 431

1H NMR (400 MHz, DMSO-d ⁶ ): 8.98 (1H, s), 8.72 (1H, 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 1-{3-[7-(4-methyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-imidazo[1,2- a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) Step (a) 1-[3-(7-Mercaptocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl --Urea (1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea)

Prepared as described in B3a.

Step (b) 1-{3-[7-(4-Methyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin- 3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea)

1-[3-(7-Mercaptocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea, 90 mg, 0.23 mmol And methyl isothiocyanate (17 mg, 0.23 mmol) was 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: [M+H] ⁺ 447

1H NMR (400 MHz, DMSO- d 6): 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).

Examples 333 to 400

The compounds of Examples 333 to 400 shown in the following Table were prepared by the methods described above.

Examples 401-418

Examples 401-118 can be prepared using methods as follows:

Example 401 1-(3-{7-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)- 3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-( 2,2,2-trifluoro-ethyl)-urea)

The compound as indicated in the heading can be subjected to the method of the general formula A, steps A1 to A3, and the step A3b, using I6[3-(4,4,5,5-tetramethyl-[1,3,2]dimer Oxaloborane-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (I6[3-(4,4,5,5-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), step E2 and step 2-3 using 2-(4-bromo-1H-pyrazole- 1-(4-bromo-1H-pyrazol-1-yl)ethanol was prepared.

Example 402 1-(3-{7-[1-(2-Amino-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridyl Pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[1-(2-Amino-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-( 2,2,2-trifluoro-ethyl)-urea)

The compound as indicated in the heading can be passed through the same general procedure as in steps A1-A3, but in step A3b, I6[3-(4,4,5,5-tetramethyl-[1,3,2]di Oxaloborane-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (I6[3-(4,4,5,5-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), step E2 and step 2-3 using 2-(4-bromo-pyrazole-1- Prepared by 2-(4-bromo-pyrazol-1-yl)-ethyl amine.

Example 403 1-{3-[7-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]- Phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}- 3-(2,2,2-trifluoro-ethyl)-urea)

The compound as indicated in the heading can be subjected to the method of the general formula A, steps A1 to A3, and the step A3b, using I6[3-(4,4,5,5-tetramethyl-[1,3,2]dimer Oxaloborane-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (I6[3-(4,4,5,5-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), step E2 and step 3-3 using 3-halo-4,5-dimethyl- Prepared by 4H-[1,2,4]triazole (3-halo-4,5-dimethyl-4H-[1,2,4]triazole).

Using commercially available 3-chloro-5-methyl-4H-[1,2,4]triazole (3-chloro-5-methyl-4H-[1,2,4]triazole) 3-halo-4,5-dimethyl-4H-[1,2,4]triazole (3-Halo-4,5-dimethyl-4H-[1,2,4]triazole).

In addition, the compound as indicated in the heading can be permeable to 1-{3-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a] Pyridin-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]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) is reacted with methylamine .

Example 404 1-{3-[7-(5-methyl-oxazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2 -trifluoro-ethyl)-urea (1-{3-[7-(5-Methyl-oxazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

The compound as indicated in the heading can be passed through the same general procedure as in steps A1-A3, but in step A3b, I6[3-(4,4,5,5-tetramethyl-[1,3,2]di Oxaloborane-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (I6[3-(4,4,5,5-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), step E2 and step 2-3 using 2-chloro-5-methyl-oxazole ( 2-chloro-5-methyl-oxazole) was prepared.

Example 405 1-{3-[7-(4-methyl-oxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2 -trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-oxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

Compounds as indicated by the headings can be prepared via the same formula AB, but must be replaced by Me-TosMIC (as described in Bioorg. Med. Chem. Lett. 12 2002 1323).

Example 406 1-{3-[7-(4-methyl-oxazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2 -trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-oxazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

As the compound shown in the title, imidazo[1,2-a]pyridine-7-carboxylic acid amide can be used, as in the method of step Aca. The chloroacetone reaction is prepared (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.

Furthermore, compounds as indicated by the headings can be obtained by Stille Type coupling reactions as described in Synthesis 1987 , 8 , 693.

Example 407 1-{5-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-pyridine-3- }}-3-(2,2,2-trifluoro-ethyl)-urea (1-{5-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-pyridin-3-yl}- 3-(2,2,2-trifluoro-ethyl)-urea)

The compound as indicated in the title can be subjected to the method described in Example 329, in step e, as I28 1-[5-(4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)-pyridin-3-yl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[5-(4,4,5,5) -tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-3-(2,2,2-trifluoro-ethyl)-urea) was replaced.

Example 408 1-[3-(7-cyclopropylacetylene)-imidazo[1,2-a]pyridin-3-yl]-phenyl-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Cyclopropylethynyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl-3-(2,2,2-trifluoro-ethyl)-urea)

The compound as indicated in the heading can be processed by the general formula SGD. The procedure SGD4a is prepared using commercially available cyclopropyl acetylene.

Example 409 1-{3-[7-(4,5-Dimethyl-isoxazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 , 2,2-trifluoro-ethyl)-urea (1-{3-[7-(4,5-Dimethyl-isoxazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea)

The methyl ketone can be prepared via a Stille coupling reaction. Further, it can be reacted with a base and 3-bromo-2-butanone to prepare a 1,3-dicarbonyl group as described in J. Med. Chem., 2004 , 47(4) , 792. As described in Tetrahedron, 2006 , 62(18) , 4430, reaction with hydroxylamine produces an oxazole which can be iodized and reacted under Suzuki coupling conditions, as in general formula B, step 2 And 3 is shown.

Example 410 1-{3-[7-(2,4-dimethyl-isoxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 , 2,2-trifluoro-ethyl)-urea (1-{3-[7-(2,4-Dimethyl-isoxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea)

An aldehyde prepared by the step AB, as described in Bioorg. Med. Chem. Lett., 2003 , 13 , 2059, can be treated with 2-acetamidoacrylic acid to produce dimethyl oxalate. Dimrthyloxadiazole.

Example 411 1-{3-[7-(2-methyl-isoxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2, 2-trifluoro-ethyl)-urea (1-{3-[7-(2-Methyl-isoxazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

An aldehyde prepared by the step AB can be used in an alkaline environment (as described in J. Het. Chem., 1981 , 18(6) , 1133), with N-(toluene-4-sulfonylmethyl) - N-(toluene-4-sulfonylmethyl)-acetimidic acid methyl ester is treated (eg J. Het. Chem., 1981 , 18(6) , 1127) to produce the corresponding Oxazole.

Further, the above methyl ketone is brominated under photochemical conditions (as described in J. Org. Chem., 2005 , 70(7) , 2720). Its bromo group can be substituted in an alkaline environment to produce the corresponding acetamide. This reaction can be reacted with a Burgess reagent under microwave conditions to form an oxazole as described in Synlett, 1999 , 1642. The compound can be iodinated 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-1H-imidazol-4-yl)-imidazo[1,2 , a]pyridin-3-yl]-phenyl}-urea (1-(2,2,2-Trifluoro-ethyl)-3-{3-[7-(1,2,5-trimethyl-1H-imidazol-4-yl)-imidazo[1,2,a]pyridine -3-yl]-phenyl}-urea)

4-Bromo-1,2,5-trimethyl-1H-imidazole (4-Bromo-1,2,5-trimethyl-1H-imidazole) via 2,4-dibromo-1,5-dimethyl 2,4-dibromo-1,5-dimethyl-1H-imidazole is obtained by treatment with n-butyllithium and methyl iodide as described in J. Org. Chem., 1994 , 59 , 5524. The method described. According to step E3, this compound can be combined with 1-[3-(7-boronic acid-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro- Ethyl)-urea (1-[3-(7-boronic acid-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea ) Coupling.

Example 413 1-{3-[7-(4-methyl-5-oxy-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a Pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-imdazo[1,2-a]pyridin-3- Yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea)

its Oxadiazolone can be prepared using the procedure described in Step AP (Example 377) and can be methylated under Mitsunobu conditions. Using the general formula B, the methods of steps 2 and 3 for iodination and the Suzuki coupling reaction, the desired product can be produced.

Example 414 1-{3-[7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl }-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3- (2,2,2-trifluoro-ethyl)-urea)

Under the catalysis of copper, 7-Bromo-imidazo[1,2-a]pyridine can be combined with 3,5-dimethyl-[1,2, 4]-Triazole (3,5-dimethyl-[1,2,4]-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.

Example 415 1-{3-[7-(3-Methyl-[1,2,4]triazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3 -(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(3-Methyl-[1,2,4]triazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2 ,2,2-trifluoro-ethyl)-urea)

Under the catalysis of copper, 7-bromo-imidazo[1,2-a]pyridine and 3-methyl-[1,2,4]-triazole (3-methyl-[1,2,4]- 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.

Example 416 1-{3-[7-(4-Methyl-imidazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl-imidazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

Under the catalysis of copper, 7-bromo-imidazo[1,2-a]pyridine can be coupled with 4-methyl-1H-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-[7-(3,5-Dimethylpyrazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2 , 2-trifluoro-ethyl)-urea (1-{3-[7-(3,5-Dimethylpyrazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

Under the catalysis of copper, 7-bromo-imidazo[1,2-a]pyridine and 3,5-dimethyl-[1,2,4]-triazole (3,5-dimethyl-[1, 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.

Example 418 1-{3-[7-(5-Methyl-pyrazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-benzene }}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(5-Methyl-pyrazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea)

Catalyzed by copper, 7-bromo-imidazo[1,2-a]pyridine and 3-methyl-[1,2,4]-triazole (3-methyl-[1,2,4]-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 for inhibition of FGFR3 and PDGFR kinase activity

The enzyme (purchased from Upstate) was formulated into a final concentration of 2x (as described below) in a 1x enzyme assay buffer. 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 (PDGFR-beta) followed by 20 μl, 35 mM EDTA, pH 8 (FGFR3) The reaction was terminated by 55 mM EDTA, pH 8 (PDGFR-beta). Add 20 μl of 5x test mixture (50 mM HEPES pH 7.5, 0.1% BSA, 2nM Eu-anti-pY (PY20) (PerkinElmer) 15nM SA-XL665 (Cisbio) used in FGFR3, and PDGFR-beta 50 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.

Enzyme buffer solution:

A: 50 mM HEPES pH 7.5, 6 mM MnCl ₂ , 1 mM DTT, 0.1% Triton X-100

B: 20 mM MOPS pH 7.0, 10 mM MnCl ₂ , 0.01% Triton X-100, 1 mM DTT, 0.1 mM [normal] sodium vanadate (Sodium orthovanadate)

The compounds of the invention (except for Examples 75 and 192) have IC50 values of less than 10 μM or at least 50% inhibition of FGFR3 activity at concentrations of 10 μM. In the FGFR3 assay, the compounds of the invention preferably have an IC50 value of less than 1 μM.

In vitro test for inhibition of VEGFR2 kinase activity

Preparation of a VEGFR 2 enzyme in a ratio of 4:1 in the presence of a compound in a buffer solution of 50 mM HEPES, pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% Triton X-100, 5 μM ATP (2.8 Ci/mmol) (purchased from Upstate) and 250 μM Poly (Glu, Tyr) (CisBio) for testing. After the reaction was carried out for 15 minutes, the reaction was stopped by adding an excess of phosphoric 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.

Inhibition of FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3 kinase activity in vitro

Inhibition against FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3 activity can be measured by Upstate Discovery Ltd. The enzyme is formulated into 10x in an enzyme buffer solution (20 mM MOPS, pH 7.0, 1 mM EDTA, 0.1% B-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/ml BSA). The final concentration. The enzyme was then mixed with various receptors and ³³ P-ATP (~500 cpm/pmol) 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 at room temperature for 40 minutes and the reaction was stopped with 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction mixture was placed in a filter A (filter mat A) or P30 filter, and washed three times with 75 mM phosphoric acid, once with methanol, and then dried for calculation by a scintillation counter.

The concentration of the recorded compound at the time of the test and the relative control group inhibited the activity of all the kinases. And determine the level of inhibition and its IC ₅₀ value.

Enzyme buffer solution A: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM magnesium acetate

Enzyme buffer solution B: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnCl2, 10 mM magnesium acetate

Enzyme buffer solution C: 8 mM Mops, H 7.0, 0.2 mM EDTA, 10 mM MnCl2, 10 mM magnesium acetate

Cell-based pERK ELISA Method

The LP-1 or JIM-1 multiple myeloma cells (multiple myeloma cells) to 1x10 ⁶ cells / ml, the amount of implanted in every hole 200ul serum-free medium. HUVEC cells at 2.5x10 ⁵ cells / ml of the implantation conditions and recovery (recover) 24 hours, followed by serum-free medium and then placed. 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% DMSO. After 30 minutes of this, a mixture of FGF-1/Heparin (FGF-1 100 ng/ml final concentration of FGF-1 and 100 ug/ml Heparin) or VEGF ¹⁶⁵ (100 ug/ml) was added to each well, and then Leave for 5 minutes. The medium was removed and 50 ul 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 standards were based on the DuoSet protocols standard and the amount of pERK relative to 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 (DSMZ no.: ACC 41) 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 μM, 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, 114, 115, and 123) more than 1 IC50 value of μM.

HUVEC cell selectivity test

HUVEC cells were seeded in medium 6, following / condition of each medium recovery 1x10 ⁶ cells for 24 hours. The assay was again placed in serum-free medium for 16 hours and then treated 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 VEGF ¹⁶⁵ (100 ng/ml) for 5 minutes. After the medium was removed, it was washed with ice-cold PBS and lysed in 100 ul of TG lysis buffer (20 mM Tris, 130 nM NaCl, 1% Triton-X-100, 10% Glycerol, protease and phosphatase inhibitors, pH 7.5). 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 phosphorylation-ERK1/2.

Blood pressure test in vivo

Take some animal samples and measure the effects of small molecule inhibitors on their blood pressure. It can be divided into two types: indirect and direct measurements. 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 observe.

The direct method includes a method of connecting to an external detector using a wireless telemetry technique or 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 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 et al (2005), Hypertension. 45 , 299-310.

The above-mentioned embodiments are merely examples for convenience of description, and the scope of the claims is intended to be limited to the above embodiments.

Claims (40)

A compound of the formula (I): Wherein X ₁ is carbon; each of X ₂ and X ₃ is independently selected from carbon or nitrogen, at least one of X ₁ to X ₃ is nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is Is CR ⁶ , nitrogen or C=O; no more than three of nitrogen in X ₁ to X ₅ ; Is a single bond or a double bond, at least one of the five-membered rings is bonded to a double bond; R ³ is hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, cyano, halo C _1-6 alkyl, halo C _1-6 alkoxy or =O A is an aromatic or non-aromatic carbocyclic or heterocyclic group having 5 or 6 members, and the carbocyclic and heterocyclic groups are optionally substituted by 1, 2 or 3 R ^a groups; ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-(CH ₂ ) _n -CONR ⁴ R ⁵ , -NH-CO-(CH ₂ ) _n -COOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , or -NHCSNR ⁴ R ⁵ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _2-6 olefin , C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkanol, halogen C _1-6 alkyl, -(CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _s -COOR ^z , -(CH ₂ ) _n -O-(CH ₂ ) _m -OH, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -O-aryl , -(CH ₂ ) _n -heterocyclyl or -(CH ₂ ) _n -O-heterocyclyl, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _{3 -8} cycloalkyl, C _3-8 cycloalkenyl group, aryl group and heterocyclic group optionally 1, 2, or 3 substituents R ^a; R ^x, R ^y and R ^z are each independently a hydrogen based, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkanol, -COOC _1-6 alkyl, hydroxyoxy, C _1-6 alkoxy, halo C _1-6 alkyl, -CO-(CH ₂ ) _n -C _1-6 alkoxy, C _{a 1-6} alkylamino group, a C _3-8 cycloalkyl group or a C _3-8 cycloalkenyl group; each of R ² and R ⁶ is independently halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -NHSO ₂ R ^w , -CH=N-OR ^w , aromatic Or a heterocyclic group, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, aryl group and heterocyclic group are optionally substituted by one or more R ^b groups, and R ² and R ^{6 are} not hydrogen at the same time; R ^w is hydrogen or C _1-6 alkyl; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -(CH ₂ ) _n -OC _1-6 alkyl, -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 Alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, =O, =S, nitro, Si(R ^x ) ₄ , -(CH ₂ ) _s -CN, -SR ^x , -SO -R ^x , -SO ₂ -R ^x , -COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -(CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^y -(CH ₂ ) _t -OR ^z or -(CH ₂ ) _{s ^{-SO 2 NR x R y; R}} b or R ^a system is a carbocyclic group or a -Y- -Z- heterocyclyl, wherein the carbocyclyl and heterocyclyl optionally substituted with 1, 2 or 3 Each of the R ^a groups is substituted; the Y and Z systems are each independently a bond, -CO-(CH ₂ ) _s -, -COO-, -(CH ₂ ) _n -, NR ^x -(CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -O -(CH ₂ ) _s -, -(CH ₂ ) _s -O-, S-, -SO- or -(CH ₂ ) _s -SO ₂ -; 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 salt thereof, but the compound of formula (I) is not: N-(4-{6-[3-(4- Fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl}phenyl)methylsulfonamide (N-(4-{6-[3-( 4-fluorophenyl)-1H-4-pyrazolyl]imidazo[1,2-a]-pyridin-3-yl}phenyl)methane sulfonamide); N-(4-{6-[3-(4-fluorophenyl) -1 -trityl-1H-4-pyrazolyl]-imidazo[1,2-a]-pyridin-3-yl}phenyl)methylsulfonamide (N-(4-{6-[3 -(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-imidazo[1,2-a]pyridin-3-yl}phenyl)methane sulfonamide); N-cyclohexyl-N'-{2-fluoro 4-[6-(1-tritylmethyl-1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}urea (N-cyclohexyl-N'-{ 2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)i midazo[1,2-a]pyridin-3-yl]phenyl}urea);N-{2-fluoro-4-[ 6-(1-tritylmethyl-1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}-N'-isopropylurea (N-{2- Fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo[1,2-a]pyridine-3-yl]phenyl}-N'-isopropyl urea); N-cyclohexyl-N'- {2-Fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}urea (N-cyclohexyl-N'-{2-fluoro -4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}urea); or N-12-fluoro-4-[6-(1H-4-pyridyl) Azyl)imidazo[1,2-a]pyridin-3-yl]phenyl}-N'-isopropylurea (N-12-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[ 1,2-a]pyridin-3-yl]phenyl)-N'-isopropylurea). The compound of claim 1, wherein R ¹ represents -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO-(CH _{2 n} -COOR ⁴ , -NHSO ₂ R ⁴ , or -NHCSNR ⁴ R ⁵ . The compound of claim 1, wherein X ₁ is carbon; each of X ₂ and X ₃ is independently selected from carbon or nitrogen, and at least one of X ₁ to X ₃ is nitrogen; X ₄ is CR ³ or nitrogen; X ₅ is CH, nitrogen or C=O; and no more than three of X ₁ to X ₅ are nitrogen; Is a single bond or a double bond; R ³ is hydrogen or =0; A is a 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic group, the carbocyclic ring and heterocyclic group Optionally substituted by 1, 2 or 3 R ^a groups; R ¹ is -NHCONR ⁴ R ⁵ , -NHCOOR ⁴ , -NH-CO-(CH ₂ ) _n -NR ⁴ R ⁵ , -NH-CO -(CH ₂ ) _n -COOR ⁴ , -NHSO ₂ R ⁴ , or -NHCSNR ⁴ R ⁵ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkanol, -( CH ₂ ) _n -NR ^x R ^y , -(CH ₂ ) _n -aryl or halogen C _1-6 alkyl; R ^x , R ^y and R ^z are each independently hydrogen, C _1-6 alkyl, C _1-6 alkanol, hydroxyl, C _1-6 alkoxy, halo C _1-6 alkyl or -CO-(CH ₂ ) _n -C _1-6 alkoxy; R ² is an aryl group Or a heterocyclic group, the aryl or heterocyclic group may be optionally substituted by one or more R ^b groups; R ^a is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O-(CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy Base, C _1-6 alkanol, =O, =S, nitro, -(CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , -( CR ^x R ^y ) _s -COOR ^z , -(CH ₂ ) _s -CONR ^x R ^y , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -NR ^x COR ^y , -(CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , -(CH ₂ ) _s -NR ^x CO ₂ R ^y , -O-(CH ₂ ) _s -CR ^x R ^y -(CH ₂ ) _t -OR ^z or -(CH ₂ ) _s -SO ₂ NR ^x R ^y ; R ^b is a 1-Y-aryl or -Z-heterocyclic group, wherein the aryl and heterocyclic groups are optionally substituted by 1, 2 or 3 R ^a groups; but when the R ² is a non-hydrogen functional group When X ₅ is CH or C=O; Y and Z are each independently a bond, CO, -(CH ₂ ) _n -, -NR ^x -(CH ₂ ) _n -, -O-or-O- (CH ₂ ) _s -; m and n are each independently an integer from 1 to 4; s and t are each independently an integer from 0 to 4; the aryl is a carbocyclic ring; and the heterocyclic group is one. Heterocyclic. The compound of claim 1, wherein A is a phenyl or pyridyl group which is optionally substituted by 1, 2 or 3 R ^a groups. The compound of claim 1, wherein A is a phenyl or pyridyl group substituted with a R ¹ group at the 5-position and optionally substituted with a R ^a group at the 3-position. The compound of claim 5, wherein A is an unsubstituted phenyl group. The application of the compound of item 1 patentable scope, in which R ¹ is based -NHCONR ⁴ R ⁵ or -NHCSNR ⁴ R ^5. The compound of claim 7, wherein R ¹ is -NHCONR ⁴ R ⁵ . The compound of claim 8, wherein R ¹ is -NHCONHCH ₂ CF ₃ or -NHCONHCH ₂ CH ₃ . The compound of claim 9, wherein R ¹ is -NHCONHCH ₂ CF ₃ . The compound of claim 1, wherein R ² is an aryl or heterocyclic group which is optionally substituted by one or more R ^a groups. The compound of claim 1, wherein R ² is an aryl group which is optionally substituted by a halogen, a -Z-heterocyclic group or -(CR ^x R ^y ) _s -COOR ^z Substituting wherein the heterocyclic group is optionally substituted by a C _1-6 alkyl group or -(CR ^x R ^y ) _s -COOR ^z . The compound of claim 12, wherein R ² is a phenyl group which is optionally substituted by an R ^b group. The compound of claim 13, wherein R ² is a phenyl group which is optionally substituted by a fluorine atom. The compound of claim 14, wherein the R ² is 4-fluorobenzene. The compound of claim 1, wherein R ² is a heterocyclic group, which may be optionally mono-Z-heterocyclic or -(CH ₂ ) _s -NR ^x R ^y Substituted by the base. The compound of claim 1, wherein R ² is a heterocyclic group, and the heterocyclic group is optionally substituted with an R ^b group. The compound of claim 17, wherein R ² is a heterocyclic group which is optionally substituted by a =O, =S, halogen, C _1-6 alkyl, halogen C _{1 -6} alkyl, C _3-8 cycloalkyl, -(CH ₂ ) _s -NR ^x R ^y , -OR ^x , -(CH ₂ ) _n -OC _1-6 alkyl, -COR ^x , -(CR ^x R ^y ) _s -COOR ^z , -SR ^x , -SO ₂ -R ^x , -(CH ₂ ) _s -NR ^x R ^y , -(CH ₂ ) _s -SO ₂ NR ^x R ^y or C _1-6 Substituted by an alkanol group. The compound of claim 18, wherein R ² is a 5-membered heterocyclic group. The compound of claim 19, wherein the R ² is oxazole, oxadiazole, triazole, tetrazole, thiadiazole or evil. Oxadithiadiazole. The compound of claim 20, wherein R ² is an oxazole or oxadiazole which is optionally substituted by one or more methyl, ethyl or -S-methyl groups. Oxadiazole), triazole, tetrazole, thiadiazole or oxathiadiazole. The compound of claim 21, wherein R ² is an oxadiazole, tetrazole or a tetrazole which is optionally substituted with a methyl group, an ethyl group or a -S-methyl group. Thiadiazole. The compound of claim 1, wherein R ² is pyridyl optionally substituted with an NH ₂ group. The compound of claim 1, wherein the Y and Z systems are each independently a bond, CO, -CH ₂ -, -(CH ₂ ) ₂ , -(CH ₂ ) ₃ or -O-. The compound of claim 24, wherein the Z system is a bond or -CH ₂ -. The compound of claim 1, wherein X ₁ to X ₅ have a ring structure as shown below: The compound of claim 26, wherein X ₁ to X ₅ have the ring structure shown below: The compound of claim 27, wherein X ₁ to X ₅ have the ring structure shown below: The compound as described in claim 1 is a compound selected from the group consisting of: 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl] -phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3 -yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(5-methyl-[1,3,4]-thiadiazole- 2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7- (5-Methyl-[1,3,4]-thiadiazol-2-yl)-imidazo[1,2-a]pyridin-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]pyridin-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]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(5-methylsulfonate) -[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro- Ethyl)-urea (1-{3-[7-(5-Methylsulfanyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a Pyridin-3-yl]-benzene -3-}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2-a ]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(1,5-dimethyl-1H-imidazole-4 -yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7- (1,5-Dimethyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) , 1-{3-[7-(1-methyl-1H-imidazole1-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2, 2-trifluoro-ethyl)-urea (1-{3-[7-(1-Methyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} -3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(1,5-dimethyl-1H-[1,2,3]triazol-4-yl )-Imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-ureacarboxylate (1-{3-[7- (1,5-Dimethyl-1H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2- Trifluoro-ethyl)-ureaformate), 1-[3-(7-[1,3,4]thiadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]- 3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-[1,3,4] Thiadiazol-2-yl-imidazo[1,2-a]pyridin-3 -yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), 1-[3-(7-1-propynyl-imidazo[1,2-a]pyridine-3- -phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[3-(7-Prop-1-ynyl-imidazo[1,2-a]pyridin-3) -yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea), 1-{3-[7-(3-methyl-[1,2,4]thiadiazole-5 -yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-( 3-Methyl-[1,2,4]thiadiazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3- (2,2,2-trifluoro-ethyl)-urea), 1-(3-{7-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-imidazo[1, 2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[1-(2-Hydroxy-ethyl) )-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea), 1-(3) -{7-[1-(2-Amino-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-( 2,2,2-trifluoro-ethyl)-urea (1-(3-{7-[1-(2-Amino-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-( 2,2,2-trifluoro-ethyl)-urea), 1-{5-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2 -a]pyridin-3-yl]-pyridin-3-yl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{5-[7-(5-Methyl-[1 ,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-pyridin-3-yl}-3-(2,2,2-trifluoro-ethyl)-urea) , 1-(2,2,2-trifluoro-ethyl)-3-{3-[7-(1,2,5-trimethyl-1H-imidazol-4-yl)-imidazo[1, 2, a]pyridin-3-yl]-phenyl}-urea (1-(2,2,2-Trifluoro-ethyl)-3-{3-[7-(1,2,5-trimethyl-1H- Imidazol-4-yl)-imidazo[1,2,a]pyridine-3-yl]-phenyl}-urea), and 1-{3-[7-(4-methyl-imidazol-1-yl)- Imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-Methyl) -imidazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea), or a pharmaceutically acceptable Its salts. The compound of claim 29, wherein the compound is 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzene -3-}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl ]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) or a pharmaceutically acceptable salt thereof or a solvate thereof, or 1-[3-(7-[1,3, 4] thiadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1-[ 3-(7-[1,3,4]Thiadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)- Urea) or a pharmaceutically acceptable salt thereof. The compound according to claim 29, wherein the compound represented by the formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a Pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (1-{3-[7-(4-fluoro-phenyl)-imidazo[1, 2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea) or a pharmaceutically acceptable salt thereof. The compound according to claim 29, wherein the compound represented by the formula (I) is 1-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a] Pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride (1-{3-[7-(4-fluoro-phenyl)-imidazo[1, 2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea hydrochloride). A compound of the formula (Id): Wherein R ^a , R ² , and R ⁵ are as defined in claim 1 of the patent application, and q is an integer from 0 to 3, and each of J and L is independently selected from the group consisting of carbon or nitrogen. A compound according to claim 1, which is in the form of a free base. A method for preparing a compound as shown in the chemical formula (I) in the first aspect of the patent application, comprising the steps of: (i) in carbonyl diimidazole (CDI), as in the chemical formula (XX) or (XXI) ) the compound shown: 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 acetaldehyde or ketone; or (iii) a compound of the formula (XX) or (XXI): Wherein X _1-5 , A and R ₂ are as defined in claim 1; or a protected form thereof, reacted with an appropriately substituted carboxylic acid or a reactive derivative; or (iv) A compound represented by the formula (V) and a compound represented by the formula (VI): as well as And removing any of the protecting groups present after the reaction; and selectively converting a compound of the formula (I) to another compound of the formula (I). A pharmaceutical composition comprising a compound of the formula (I) as in any one of claims 1 to 31 of the patent application. A compound according to any one of claims 1 to 34 for use in the treatment of a disease. A compound according to any one of claims 1 to 34 for use in the prevention or treatment of a disease or a condition caused by a fibroblast growth factor receptor enzyme. A use of a compound according to any one of claims 1 to 34 for the manufacture of a medicament for treating a disease or a condition caused by a fibroblast growth factor receptor enzyme. A use of a compound according to any one of claims 1 to 34 for the manufacture of a medicament for the treatment of cancer.