FGFR INHIBITOR COMPOUND AND USE THEREOF

Abstract

The present disclosure relates to FGFR inhibitor compounds and its use. Specifically, the present disclosure discloses a compound represented by formula (I), isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. The present disclosure also relates to use of the above compound in medicine.

##STR00001##

Claims

1. A compound of Formula (I) ##STR00081## or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein A is selected from C.sub.5-8 aryl, C.sub.7-11 bicycloaryl, 5-7 membered heteroaryl, 7-11 membered bicycloheteroaryl, C.sub.3-8 cycloalkyl, and 4-8 membered heterocycloalkyl; and R.sup.1 and R.sup.2 are each independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl, and 4-6 membered heterocycloalkyl; and R.sup.3 and R.sup.4 are each independently selected from H, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl, and 4-6 membered heterocycloalkyl; and 0, 1, 2, 3, 4, 5, 6, 7, or 8 R.sup.8(s) are present, and each R.sup.5 is independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C.sub.8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C.sub.5-8 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), —C.sub.1-4 alkyl-(C.sub.6-12 bicycloalkyl), —C.sub.1-4 alkyl-(6-12 membered bicycloheteroalkyl), —C.sub.1-4 alkyl-(C.sub.8-15-tricycloalkyl), —C.sub.1-4 alkyl-(8-15 membered tricycloheteroalkyl), —N(R.sup.7)(R.sup.8), —N(R.sup.7)(C(═O)R.sup.8), —N(R.sup.7)(C(═O)—OR.sup.8), —N(R.sup.7)(C(═O)—N(R.sup.8)(R.sup.9)), —C(═O)—N(R.sup.7)(R.sup.8), —C(═O)—R.sup.7, —C(═O)—OR.sup.7, —OC(═O)R.sup.7, —N(R.sup.7)(S(═O).sub.2R.sup.8), —S(═O).sub.2—N(R.sup.7)(R.sup.8), —SR.sup.7, and —OR.sup.7, wherein the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C.sub.8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C.sub.5-8 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), —C.sub.1-4 alkyl-(C.sub.6-12 bicycloalkyl), —C.sub.1-4 alkyl-(6-12 membered bicycloheteroalkyl), —C.sub.1-4 alkyl-(C.sub.8-15 tricycloalkyl), and —C.sub.1-4 alkyl-(8-15 membered tricycloheteroalkyl) are each optionally substituted with 0, 1, 2, 3 or 4 R.sup.5a; R.sup.5a is independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C.sub.8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C.sub.5-8 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), —C.sub.1-4 alkyl-(C.sub.6-12 bicycloalkyl), —C.sub.1-4 alkyl-(6-12 membered bicycloheteroalkyl), —N(R.sup.7)(R.sup.8), —N(R.sup.7)(C(═O)R.sup.8), —N(R.sup.7)(C(═O)—OR.sup.8), —N(R.sup.7)(C(═O)—N(R.sup.8)(R.sup.9)), —C(═O)—N(R.sup.7)(R.sup.8), —C(═O)—R.sup.7, —C(═O)—OR.sup.7, —OC(═O)R.sup.7, —N(R.sup.7)(S(═O).sub.2R.sup.8), —S(═O).sub.2—N(R.sup.7)(R.sup.8), —SR.sup.7, and —OR.sup.7, wherein the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C.sub.8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C.sub.5-8 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), —C.sub.1-4 alkyl-(C.sub.6-12 bicycloalkyl) and —C.sub.1-4 alkyl-(6-12 membered bicycloheteroalkyl) are each optionally substituted with 0, 1, 2, 3 or 4 R.sup.5b; R.sup.5b is independently selected from H, halogen, —OH, —CN, —NO.sub.2, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), —N(R.sup.7)(R.sup.8), —N(R.sup.7)(C(═O)R.sup.8), —N(R.sup.7)(C(═O)—OR.sup.8), —N(R.sup.7)(C(═O)—N(R.sup.8)(R.sup.9)), —C(═O)—N(R.sup.7)(R.sup.8), —C(═O)—R.sup.7, —C(═O)—OR.sup.7, —OC(═O)R.sup.7, —N(R.sup.7)(S(═O).sub.2R.sup.8), and —S(═O).sub.2—N(R.sup.7)(R.sup.8), wherein the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), and —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl) are each optionally substituted with 0, 1, 2, 3 or 4 substitutes each independently selected from a group consisting of halogen, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, —NO.sub.2, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; and 0, 1, 2, or 3 R.sup.6(s) are present, and each R.sup.6 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, and R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are each are each independently selected from a group consisting of: H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, (C.sub.3-7 cycloalkyl)-C.sub.1-4 alkyl-, (3-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl- and (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, wherein each substituent listed in the group is optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from a group consisting of: halogen, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, —NO.sub.2, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; or R.sup.7, R.sup.8, and the atoms attached thereto together form a 3-14-membered ring; or R.sup.8, R.sup.9, and the atoms attached thereto together form a 3-14-membered ring.

2. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein 0, 1, 2, 3, 4, 5, 6, 7, 8 or more R.sup.5(s) are present and each R.sup.5 is independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —N(R.sup.7)(R.sup.8), —N(R.sup.7)(C(═O)R.sup.8), —C(═O)—N(R.sup.8)(R.sup.9)), —C(═O)—R.sup.7, —C(═O)—OR.sup.7, —OC(═O)R.sup.7, —N(R.sup.7)(S(═O).sub.2R.sup.8), —S(═O).sub.2—N(R.sup.7)(R.sup.8), —SR.sup.7, and —OR.sup.7, wherein the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, —C.sub.1-4 alkyl-(C.sub.3-7 cycloalkyl), —C.sub.1-4 alkyl-(3-10 membered heterocycloalkyl), C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicycloaryl, 7-11 membered bicycloheteroaryl are each optionally substituted with 0, 1, 2, 3 or 4 substituents each independent selected from halogen, —CN, —OH, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, —N(R.sup.7)(R.sup.8), —N(R.sup.7)(C(═O)R.sup.8), —C(═O)—N(R.sup.7)(R.sup.8), —C(═O)—R.sup.7, —C(═O)—OR.sup.7, —OC(═O)R.sup.7, —N(R.sup.7)(S(═O).sub.2R.sup.8), —S(═O).sub.2—N(R.sup.7)(R.sup.8), —SR.sup.7, and —OR.sup.7; and 0, 1, 2 or 3 R.sup.6(s) are present and each R.sup.6 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkoxy, C.sub.3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, R.sup.7 and R.sup.8, at each occurrence, are each are each independently selected from a group consisting of: H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, (C.sub.3-7 cycloalkyl)-C.sub.1-4 alkyl-, (3-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl- and (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, wherein each substituent listed in the group is optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from a group consisting of: halogen, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, —NO.sub.2, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; or R.sup.7, R.sup.8, and the atoms attached thereto together form a 3-14-membered ring.

3. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.3 is methyl.

4. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.1 is Cl.

5. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.2 is Cl.

6. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein A is selected from phenyl, pyridinyl, pyridazinyl and pyrazolyl.

7. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, which is a compound selected from formula (II), formula (III), formula (IV) and formula (V), or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, ##STR00082## wherein R.sup.4, R.sup.5 and R.sup.6 are defined in claim 1 and X.sub.1 and X.sub.2 are each independently selected from —CH, N and C in the case of being directly connected with R.sup.5.

8. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.6 is H.

9. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.4 is H.

10. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein R.sup.5 is selected from halogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and 3-10 membered heterocycloalkyl, wherein the C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and 3-10 membered heterocycloalkyl are each optionally substituted with 0, 1, 2, 3 or 4 substituents each independently selected from a group consisting of: halogen, —CN, —OH, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl.

11. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein H is optionally replaced by D at each occurrence.

12. The compound according to claim 1 or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound is selected from: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3, 5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide, N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3 S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3, 5-dimethylpiperazin-1-yl) pyridin-3-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3, 5-dimethylpiperazin-1-yl) pyridin-2-yl)-1H-indazole-3-carboxamide, 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, N-(1-cyclobutyl-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(morpholinomethyl)phenyl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((S)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((R)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, and (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide.

13. A pharmaceutical composition comprising the compound according to claim 1, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients.

14. A method for the treatment of diseases or conditions associated with FGFR, the method comprising administering a patient in need of a therapeutically effective amount of the compounds according to claim 1, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

15. The method according to claim 14, wherein the diseases or conditions associated with FGFR are selected from cancers, skeletal disorders or chondrocyte disorders, hypophosphatemia disorders and fibrotic diseases.

16. The method according to claim 14, wherein the diseases or conditions associated with FGFR are selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, membrane adenocarcinoma, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

17. The method according to claim 14, wherein the diseases or conditions associated with FGFR are diseases and conditions that are resistant to FGFR inhibitors that do not target gatekeeper mutants of FGFR due to gatekeeper mutations in FGFR.

18. A method for the treatment of diseases or conditions associated with FGFR, the method comprising administering a patient in need of a therapeutically effective amount of A the pharmaceutical composition according to claim 13.

19. The method according to claim 18, wherein the diseases or conditions associated with FGFR are selected from cancers, skeletal disorders or chondrocyte disorders, hypophosphatemia disorders and fibrotic diseases.

20. The method according to claim 18, wherein the diseases or conditions associated with FGFR are diseases and conditions that are resistant to FGFR inhibitors that do not target gatekeeper mutants of FGFR due to gatekeeper mutations in FGFR.

Description

EXAMPLES

[0209] The following examples set forth herein are for illustrative purposes only, to exemplify aspects of the invention and the manner in which they are to be carried out, and are not intended to limit in any way the scope of protection as claimed.

[0210] Unless otherwise stated, all reactants were obtained from commercial sources. The instruments and equipment used in the synthesis experiments and product analysis are all conventional instruments and equipment normally used in organic synthesis.

Example 1: synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide (1)

[0211] ##STR00005##

Synthetic Route of Compound 1:

[0212] ##STR00006##

Synthesis Method:

Synthesis of Intermediate 1-1: 1H-indole-5-acetate

[0213] 5-hydroxyindole (240.0 mg, 1.80 mmol) was dissolved in 20 ml of pyridine, to which acetic anhydride (202.4 mg, 1.98 mmol) was added dropwise and the resulting mixture was stirred for 16 h at room temperature. Water was added to the reaction solution, and the resulting mixture was extracted twice with ethyl acetate. The resulting organic phases were combined, washed with saturated salt water, dried with anhydrous sodium sulfate, and concentrated to afford 276.6 mg of the crude intermediate 111 with a yield of 87.4%.

Synthesis of Intermediate 1-2: 3-formyl-1H-indazole-5-acetate

[0214] Sodium nitrite (157.5 mg, 2.28 mmol) was dissolved in 10 ml of water, to which 10 ml of DMF was added, and 3M HCl (0.7 ml, 2.05 mmol) was added dropwise at 0 degree. The resulting mixture was stirred for 10 min. To the reaction solution, 1H-indole-5-acetate (50.0 mg, 0.29 mmol) in DMF (10 ml) was added and reacted for 3 h at room temperature. Water was added to the reaction solution, and the resulting mixture was extracted twice with ethyl acetate. The resulting organic phases were combined, washed with saturated salt water, dried with anhydrous sodium sulfate, concentrated and purified by silica gel column to give 37.6 mg of Intermediates 1-2 with a yield of 63.5%.

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.25 (s, 1H), 8.01 (s, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 2.36 (s, 3H).

Synthesis of Intermediate 1-3: 3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-acetate

[0216] 1-2 (190.0 mg, 0.93 mmol) was dissolved in 20 ml of DCM, to which p-toluenesulfonic acid (177.0 mg, 0.93 mmol) was added, and the mixture was stirred for 2 min. To the reaction solution, 3,4-dihydro-2H-pyran (117.4 mg, 1.40 mmol) in DCM (3 ml) was added and the reaction was carried out at room temperature for 1 h. Water was added to the reaction solution, and the resulting mixture was extracted twice with DCM. The resulting organic phases were combined, washed with saturated sodium bicarbonate solution and saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 160.2 mg of Intermediate 1-3 with a yield of 59.6%.

Synthesis of Intermediate 1-4: 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0217] 1-3 (160.2 mg, 0.56 mmol) was dissolved in 20 ml of methanol, to which potassium carbonate (115.1 mg, 0.83 mmol) was added. The reaction was carried out at room temperature for 30 min. The reaction solution was filtered and the filtrate was concentrated to afford 130.5 mg of crude intermediate 1-4 with a yield of 95.1%.

Synthesis of Intermediate 1-5: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0218] 1-(3,5-dichloropyridin-4-yl)ethan-1-ol (93.6 mg, 0.49 mmol) and triethylamine (148.6 mg, 1.47 mmol) were dissolved in 20 ml DCM, to which methanesulfonyl chloride (57.3 mg, 0.50 mmol) was added dropwise at 0° C. The reaction was carried out for 1 h at room temperature. The reaction solution was quenched with water, and extracted twice with dichloromethane, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. 1-4 (100.0 mg, 0.41 mmol) and the concentrate were dissolved in 20 ml DMF, to which cesium carbonate (264.6 mg, 0.82 mmol) was added, and the reaction was carried out at 60 degrees for 16 hours. To the reaction solution water was added and the resulting mixture was extracted with ethyl acetate twice. The resulting organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 64.3 mg of Intermediate 1-5 with a yield of 37.5%.

[0219] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.16 (s, 1H), 8.42 (s, 2H), 7.59-7.53 (m, 2H), 7.18-7.15 (m, 1H), 6.11 (q, J=6.7 Hz, 1H), 5.77-5.72 (m, 1H), 4.01-3.94 (m, 1H), 3.77-3.70 (m, 1H), 2.54-2.46 (m, 1H), 2.22-2.06 (m, 2H), 1.81 (d, J=6.7 Hz, 3H), 1.76-1.68 (m, 3H).

Synthesis of Intermediate 1-6: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0220] (24.0 mg, 0.06 mmol) was dissolved in 12 ml of acetonitrile and 4 ml of water, to which potassium permanganate (18.1 mg, 0.12 mmol) was added and the reaction was carried out for 16 h at room temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was adjusted to pH 3 with 3M hydrochloric acid, and extracted twice with dichloromethane. The resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to give 16.3 mg of Intermediate 1-6 with a yield of 64.2%.

[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (s, 2H), 7.60-7.57 (m, 1H), 7.50 (s, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.11 (q, J=6.7 Hz, 1H), 5.77-5.72 (m, 1H), 4.01-3.98 (m, 1H), 3.74-3.71 (m, 1H), 2.54-2.46 (m, 1H), 2.07-2.04 (m, 2H), 1.82 (d, J=6.7 Hz, 3H), 1.76-1.66 (m, 3H).

Synthesis of compound 1: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0222] 1-6 (20.0 mg, 0.05 mmol) and 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (11.3 mg, 0.06 mmol) were dissolved in 10 ml DMF, to which HATU (20.9 mg, 0.06 mmol) and DIPEA (17.8 mg, 0.12 mmol) were added and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution and the resulting mixture was extracted twice with ethyl acetate. The resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 6 ml of methanol, to which 3 ml of concentrated hydrochloric acid was added, and it was allowed to react at 50 degrees for 1 h. The reaction solution was concentrated, and dissolved in 5 ml of methanol, to which 0.5 ml of ammonia was added, and the resulting mixture was concentrated, and purified by a preparative plate to afford 1.2 mg of the final product, with a yield of 50.8%.

[0223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.65 (s, 1H), 10.04 (s, 1H), 8.60 (s, 2H), 7.73-7.70 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.17-7.14 (m, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.07 (q, J=6.6 Hz, 1H), 3.78 (d, J=12.7 Hz, 2H), 3.31 (s, 2H), 2.67-2.58 (m, 2H), 1.75 (d, J=6.6 Hz, 3H), 1.27-1.23 (m, 6H).

Example 2: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (2)

[0224] ##STR00007##

[0225] Synthesis Method:

[0226] Synthetic Route of Compound 2:

##STR00008##

Synthesis of Intermediate 2-1: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole

[0227] 4-Nitro-1H-pyrazole (200 mg, 1.77 mmol) was dissolved in 25 ml of acetonitrile, to which potassium carbonate (733 mg, 5.31 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (508 mg, 2.12 mmol) were added. The resulting mixture was heated to 80 degrees to allow the reaction to proceed. After the reaction was completed, 50 ml of water was added to the system, and the reaction solution was extracted with ethyl acetate (EA), and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 470 mg of Intermediate 2-1 with a yield of 97.9%.

[0228] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (s, 1H), 8.07 (s, 1H), 4.24 (t, J=4.9 Hz, 2H), 3.95 (t, J=4.9 Hz, 2H), 0.83 (s, 9H), −0.04 (s, 6H).

Synthesis of Intermediate 2-2: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-amine

[0229] Intermediate 2-1 (450 mg, 1.66 mmol) was dissolved in 10 ml of methanol, to which 10% Pd/C (45 mg) was added, and the atmosphere was replaced with hydrogen gas three times. It was allowed to react at room temperature. After the reaction was completed, the system was filtered and concentrated to give 390 mg of intermediate 2-2 with a yield of 97.4%.

Synthesis of compound 2: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0230] Intermediate 1-6 (30.0 mg, 0.069 mmol) was dissolved in 4 ml DMF, to which HATU (28.8 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added and the resulting mixture was stirred for one hour at room temperature. And then, to the system, the intermediate 2-2 (16.7 mg, 0.069 mmol) was added. After the addition was completed, it was allowed to react at room temperature. After the reaction was completed, the system was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved with 4 ml of methanol, then 2 ml of concentrated hydrochloric acid was added and it was allowed to react at 50° C. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was dissolved with 2 ml of methanol and neutralized with 0.5 ml of ammonia. After the neutralization was completed, the compound was purified by column chromatography to afford 14.0 mg of compound 2 with a yield of 44.1%.

[0231] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.62 (s, 1H), 10.42 (s, 1H), 8.60 (s, 2H), 8.06 (s, 1H), 7.66 (s, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.54 (s, 1H), 7.15 (dd, J=2.3, 9.1 Hz, 1H), 6.09 (q, J=6.6 Hz, 1H), 4.12 (t, J=5.6 Hz, 2H), 3.95 (t, J=5.6 Hz, 2H), 1.76 (d, J=6.6 Hz, 3H).

Example 3: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide (3)

[0232] ##STR00009##

[0233] Synthetic Route of Compound 3:

##STR00010##

[0234] Synthesis Method:

Synthesis of compound 3: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0235] 1-6 (25.0 mg, 0.06 mmol) and (R)-4-(3-((tert-butyldimethylsilyl)oxy) pyrrolidin-1-yl)aniline (25.2 mg, 0.09 mmol) were dissolved in 10 ml DMF, then HATU (32.7 mg, 0.09 mmol) and DIPEA (22.2 mg, 0.17 mmol) were added to the solution and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 6 ml of methanol, to which 3 ml of concentrated hydrochloric acid was added, it was allowed to react at 50° C. for 1 h, and the reaction solution was concentrated. The concentrate was dissolved in 5 ml of methanol, neutralized with 0.5 ml of ammonia, concentrated, and purified by a preparative plate to afford 11.5 mg of the final product with a yield of 63.8%.

[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.57 (s, 1H), 9.83 (s, 1H), 8.60 (s, 2H), 7.62-7.50 (m, 4H), 7.15-7.13 (m, 1H), 6.51-6.49 (m, 2H), 6.07 (q, J=6.6 Hz, 1H), 4.41 (s, 1H), 3.43-3.23 (m, 3H), 3.08-3.05 (m, 1H), 2.09-1.95 (m, 1H), 1.92-1.86 (m, 1H), 1.75 (d, J=6.6 Hz, 3H).

Example 4: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide (4)

[0237] ##STR00011##

[0238] Synthetic Route of Compound 4:

##STR00012##

[0239] Synthesis Method:

Synthesis of compound 4: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide

[0240] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (20.0 mg, 0.05 mmol) and 6-morpholinopyridin-3-amine (10.8 mg, 0.06 mmol) were dissolved in 5 ml DMF, then HATU (20.9 mg, 0.06 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added to the solution and it was allowed to react for 3 h at room temperature. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate twice. The resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated, and the resulting solid was dissolved in 4 ml of methanol, to which 2 ml of concentrated hydrochloric acid was added, it was allowed to react at 50° C. for 1 h, and the reaction solution was concentrated. The concentrate was dissolved in 5 ml of methanol, neutralized with 0.5 ml of ammonia, concentrated, and purified by a preparative plate to afford 6.4 mg of the final product with a total yield of 19.6% in two steps.

[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.68 (s, 1H), 10.18 (s, 1H), 8.60 (s, 2H), 8.56 (d, J=4.0 Hz, 1H), 8.01 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=4.0 Hz, 1H), 7.16 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.90 (d, J=12.0 Hz, 1H), 6.07 (q, J=6.6 Hz, 1H), 3.73-3.71 (m, 4H), 3.42-3.39 (m, 4H), 1.75 (d, J=8.0 Hz, 3H).

Example 5: Synthesis of N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide (5)

[0242] ##STR00013##

[0243] Synthetic Route of Compound 5:

##STR00014##

[0244] Synthesis Method:

Synthesis of Intermediate 5-1: 3-(4-amino-1H-pyrazol-1-yl)butanenitrile

[0245] 4-nitro-1H-pyrazole (25 mg, 0.22 mmol) and 3-bromobutyronitrile (42.5 mg, 0.29 mmol) were dissolved in 5 ml of acetonitrile, potassium carbonate (92.1 mg, 0.66 mmol) was added to the solution and it was allowed to react at 80° C. for 3 hours. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate twice. The resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. To the resulting residue, 3 ml of methanol and 2.5 mg of palladium carbon were added and the atmosphere was replaced by hydrogen gas. It was allowed to react at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated and purified on silica gel plate to afford 20 mg of Intermediate 5-1 with a yield of 60.24%.

[0246] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.27 (s, 1H), 8.15 (s, 1H), 4.66-4.71 (m, 1H), 2.99-3.01 (m, 2H), 1.75 (d, J=8 Hz, 3H).

Synthesis of compound 5: N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide

[0247] Intermediate 5-1 (20 mg, 0.13 mmol) and Intermediate 1-6 (52.8 mg, 0.12 mmol) were dissolved in DMF (3 ml), then HATU (50.6 mg, 0.13 mmol) and DIPEA (31.2 mg, 0.24 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 2 ml methanol and 1 ml concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml methanol, neutralized with 0.5 ml ammonia, concentrated, and purified by a preparative plate to afford 9 mg of final product with a yield of 15.5%.

[0248] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.46 (s, 2H), 8.08 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=4 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 6.14-6.19 (m, 1H), 3.64 (m, 1H), 2.96-3.02 (m, 1H), 2.82-2.87 (m, 1H), 1.82 (d, J=4 Hz, 3H), 1.55 (d, J=8 Hz, 3H). LC-MS: C.sub.22H.sub.20C.sub.12N.sub.7O.sub.2 [M+H].sup.+ m/z calculated as 484.1, detected as 484.1.

Example 6: Synthesis of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide (6)

[0249] ##STR00015##

[0250] Synthetic Route of Compound 6:

##STR00016##

[0251] Synthesis Method:

Synthesis of Intermediate 6-1: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxaldehyde

[0252] (S)-1-(3,5-dichloropyridin-4-yl)ethan-1-ol (200.0 mg, 1.05 mmol) and triethylamine (317.6 mg, 3.14 mmol) were dissolved in 20 ml DCM and methanesulfonyl chloride (131.9 mg, 1.15 mmol) was added dropwise to the reaction solution at 0° C. The reaction was carried out at room temperature for 1 h. The reaction solution was quenched with water, and extracted twice with dichloromethane, and the resulting organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. 1-4 (270.0 mg, 1.09 mmol) and the concentrate were dissolved in 20 ml DMF, to which cesium carbonate (684.2 mg, 2.10 mmol) was added, and it was allowed to react at 60° C. for 16 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 289.3 mg of Intermediate 6-1 with a yield of 65.5%.

[0253] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.16 (s, 1H), 8.42 (s, 2H), 7.59-7.53 (m, 2H), 7.18-7.15 (m, 1H), 6.11 (q, J=6.7 Hz, 1H), 5.77-5.72 (m, 1H), 4.01-3.94 (m, 1H), 3.77-3.70 (m, 1H), 2.54-2.46 (m, 1H), 2.22-2.06 (m, 2H), 1.81 (d, J=6.7 Hz, 3H), 1.76-1.68 (m, 3H).

Synthesis of Intermediate 6-2: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0254] 6-1 (289.3 mg, 0.69 mmol) was dissolved in 12 ml of acetonitrile and 4 ml of water, potassium permanganate (218.1 mg, 1.38 mmol) was added and the reaction was carried out for 16 h at room temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was adjusted to pH 3 with 3M hydrochloric acid, and extracted twice with dichloromethane, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to give 246.5 mg of Intermediate 6-2 with a yield of 81.8%.

[0255] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (s, 2H), 7.60-7.57 (m, 1H), 7.50 (s, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.11 (q, J=6.7 Hz, 1H), 5.77-5.72 (m, 1H), 4.01-3.98 (m, 1H), 3.74-3.71 (m, 1H), 2.54-2.46 (m, 1H), 2.07-2.04 (m, 2H), 1.82 (d, J=6.7 Hz, 3H), 1.76-1.66 (m, 3H).

Synthesis of compound 6: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0256] 6-2 (40.0 mg, 0.09 mmol) and 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (22.5 mg, 0.12 mmol) were dissolved in 10 ml DMF, then HATU (41.8 mg, 0.12 mmol) and DIPEA (35.6 mg, 0.26 mmol) were added to the solution and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, it was allowed to react at 50° C. for 1 h, and the reaction solution was concentrated. The concentrate was dissolved in 5 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to give 37.2 mg of the final product with a yield of 76.3%.

[0257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.66 (s, 1H), 10.00 (s, 1H), 8.59 (s, 2H), 7.70 (d, J=8.6 Hz, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.16-7.13 (m, 1H), 6.98 (d, J=8.7 Hz, 2H), 6.07 (q, J=6.6 Hz, 1H), 3.73 (d, J=12.7 Hz, 2H), 3.26-3.17 (m, 2H), 2.57-2.54 (m, 2H), 1.75 (d, J=6.6 Hz, 3H), 1.26-1.23 (m, 6H).

Example 7: Synthesis of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (7)

[0258] ##STR00017##

[0259] Synthetic Route of Compound 7:

##STR00018##

[0260] Synthesis Method:

Synthesis of compound 7: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0261] 6-2 (40.0 mg, 0.09 mmol) and 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-amine (24.4 mg, 0.10 mmol) were dissolved in 10 ml DMF, then HATU (41.8 mg, 0.12 mmol) and DIPEA (35.6 mg, 0.26 mmol) were added to the solution and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, it was allowed to react at 50° C. for 1 h, and the reaction solution was concentrated. The concentrate was dissolved in 5 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to afford 17.6 mg of the final product with a yield of 42.4%.

[0262] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.60 (s, 1H), 10.39 (s, 1H), 8.60 (s, 2H), 8.05 (s, 1H), 7.66 (s, 1H), 7.56-7.53 (s, 2H), 7.16-7.13 (m, 1H), 6.08 (q, J=6.6 Hz, 1H), 4.88 (t, J=5.3 Hz, 1H), 4.12 (t, J=5.7 Hz, 2H), 3.72 (q, J=5.6 Hz, 2H), 1.76 (d, J=6.6 Hz, 3H).

Example 8: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S, 5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide (8)

[0263] ##STR00019##

[0264] Synthetic Route of Compound 8:

##STR00020##

[0265] Synthesis Method:

Synthesis of Intermediate 8-1: 6-((3S, 5R)-3,5-dimethylpiperazin-1-yl) pyridine-3-amine

[0266] 2-fluoro-5-nitropyridine (20 mg, 0.14 mmol) and (2S, 6R)-2,6-dimethyl piperazine (24.1 mg, 0.21 mmol) were dissolved in 3 ml DMSO, potassium carbonate (39.1 mg, 0.28 mmol) was added to the solution and it was allowed to react at 40° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. To the resulting residue, 3 ml of methanol and 2.5 mg of 10% palladium carbon were added, and the atmosphere was replaced by hydrogen three times, and it was allowed to react at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated, and purified on silica gel plate to afford 20 mg of Intermediate 8-1 with a yield of 68.9%.

[0267] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (s, 1H), 6.99 (d, J=8 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 3.93-4.01 (m, 2H), 3.08-3.18 (m, 2H), 2.51-2.62 (m, 2H), 1.29-1.35 (m, 6H).

Synthesis of compound 8: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide

[0268] Intermediate 8-1 (20 mg, 0.10 mmol) and Intermediate 1-6 (38.5 mg, 0.09 mmol) were dissolved in DMF (3 ml), then HATU (33.5 mg, 0.09 mmol) and DIPEA (22.74 mg, 0.18 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to afford 8 mg of the final product with a yield of 15.3%.

[0269] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.45 (s, 3H), 7.93 (d, J=8 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J=12 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 6.12-6.17 (m, 1H), 4.16 (d, J=12 Hz, 2H), 2.95-3.01 (m, 2H), 2.42-2.48 (m, 2H), 1.81 (d, J=4 Hz, 3H), 1.20 (d, J=4 Hz, 6H).

Example 9: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide (9)

[0270] ##STR00021##

[0271] Synthetic Route of Compound 9:

##STR00022##

[0272] Synthesis Method:

Synthesis of Intermediate 9-1: 4-(4-methylpiperazin-1-yl)aniline

[0273] 4-nitrofluorobenzene (25 mg, 0.18 mmol) and 1-methylpiperazine (26.6 mg, 0.27 mmol) were dissolved in 3 ml DMSO, potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and it was allowed to react at 40° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. To the resulting residue, 3 ml of methanol and 2.5 mg of palladium carbon were added, the atmosphere was replaced by hydrogen gas and the reaction was carried out at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated and purified on silica gel plate to afford 20 mg of Intermediate 9-1 with a yield of 73.8%.

[0274] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.82 (d, J=8 Hz, 2H), 6.65 (d, J=8 Hz, 2H), 3.08-3.10 (m, 4H), 2.60-2.63 (m, 4H), 2.37 (s, 3H).

Synthesis of compound 9: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0275] Intermediate 9-1 (20 mg, 0.10 mmol) and Intermediate 1-6 (41.5 mg, 0.09 mmol) were dissolved in DMF (3 ml), HATU (36.1 mg, 0.09 mmol) and DIPEA (24.5 mg, 0.19 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to afford 10 mg of the final product with a yield of 18.2%.

[0276] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.60 (s, 1H), 9.94 (s, 1H), 8.59 (s, 2H), 7.66 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 1H), 7.50 (d, J=4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 2H), 6.04-6.09 (m, 1H), 3.10-3.13 (m, 4H), 2.49-2.52 (m, 4H), 2.26 (s, 3H), 1.75 (d, J=4 Hz, 3H).

Example 10: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide (10)

[0277] ##STR00023##

[0278] Synthetic Route of Compound 10:

##STR00024##

[0279] Synthesis Method

Synthesis of intermediate 10-1: 4-(4-ethylpiperazin-1-yl)aniline

[0280] 4-nitrofluorobenzene (25 mg, 0.18 mmol) and 1-ethylpiperazine (30.4 mg, 0.27 mmol) were dissolved in 3 ml DMSO, potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and it was allowed to react at 40° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. To the resulting residue, 3 ml of methanol and 2.5 mg of palladium carbon were added, the atmosphere was replaced by hydrogen gas three times and the reaction was carried out at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated and purified on silica gel plate to afford 20 mg of intermediate 10-1 with a yield of 68.7%.

[0281] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.82 (d, J=8 Hz, 2H), 6.65 (d, J=8 Hz, 2H), 3.09-3.12 (m, 4H), 2.64-2.66 (m, 4H), 2.48-2.54 (m, 2H), 1.15 (t, J=8 Hz, 3H).

Synthesis of compound 10: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0282] Intermediate 10-1 (20 mg, 0.10 mmol) and Intermediate 1-6 (38.6 mg, 0.09 mmol) were dissolved in DMF (3 ml), HATU (33.7 mg, 0.09 mmol) and DIPEA (22.9 mg, 0.18 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to afford 12 mg of the final product with a yield of 22.8%.

[0283] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.60 (s, 1H), 9.95 (s, 1H), 8.59 (s, 2H), 7.66 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 1H), 7.50 (d, J=4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 2H), 6.04-6.09 (m, 1H), 3.09-3.14 (m, 4H), 2.51-2.55 (m, 4H), 2.41-2.44 (m, 2H), 1.75 (d, J=4 Hz, 3H), 1.06 (t, J=4 Hz, 3H).

Example 11: Synthesis of N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide (11)

[0284] ##STR00025##

[0285] Synthetic Route of Compound 11:

##STR00026##

[0286] Synthesis Method:

Synthesis of intermediate 11-1: 3-(4-nitro-1H-pyrazol-1-yl)propanenitrile

[0287] 4-Nitro-1H-pyrazole (200 mg, 1.77 mmol) was dissolved in 25 ml of acetonitrile, potassium carbonate (733 mg, 5.31 mmol) and bromopropionitrile (284 mg, 2.12 mmol) were added to the reaction solution, and the reaction was heated to 80° C. after the addition was completed. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with EA, and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 270 mg of Intermediate 11-1 with a yield of 91.9%.

[0288] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (s, 1H), 8.15 (s, 1H), 4.44 (t, J=6.5 Hz, 2H), 3.04 (t, J=6.5 Hz, 2H).

Synthesis of Intermediate 11-2: 3-(4-amino-1H-pyrazol-1-yl) propanenitrile

[0289] Intermediate 11-1 (200 mg, 1.20 mmol) was dissolved in 10 ml of methanol and 10% Pd/C (20 mg) was added to the system, which was replaced with hydrogen gas three times and then it was allowed to react at room temperature. After the reaction was completed, the system was filtered and concentrated to give 156 mg of intermediate 11-2 with a yield of 95.4%.

Synthesis of compound 11: N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide

[0290] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30.0 mg, 0.069 mmol) was dissolved in 4 ml DMF, HATU (28.8 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added to the system and the mixture was stirred for one hour at room temperature. Then Intermediate 15-2 (9.37 mg, 0.069 mmol) was added to the system and it was allowed to react at room temperature after the addition was completed. After the reaction was completed, the system was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 4 ml of methanol, then 2 ml of concentrated hydrochloric acid was added, and it was allowed to react at 50° C. After the reaction was completed, the reaction solution was evaporated under reduced pressure, the residue was dissolved in 2 ml of methanol, and neutralized by adding 0.5 ml of ammonia. After the neutralization, it was concentrated and purified by column chromatography to give 5.3 mg of compound 11 with a yield of 18.4%.

[0291] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.26 (s, 1H), 8.63 (s, 1H), 8.42 (s, 2H), 8.09 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.57 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.17 (dd, J=2.3, 9.0 Hz, 1H), 6.14 (q, J=6.7 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 1.76 (d, J=6.7 Hz, 3H). LC-MS: C.sub.21H.sub.18Cl.sub.2N.sub.7O.sub.2 [M+H].sup.+ m/z calculated as 470.1, detected as 470.1.

Example 12: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (12)

[0292] ##STR00027##

[0293] Synthetic Route of Compound 12:

##STR00028##

[0294] Synthesis Method:

Synthesis of intermediate 12-1: 1-(3-((tert-butyldimethylsilyl)oxy) cyclobutyl)-4-nitro-1H-pyrazole

[0295] 4-Nitro-1H-pyrazole (149 mg, 1.32 mmol) was dissolved in 25 ml of acetonitrile, potassium phosphate (839 mg, 3.95 mmol) and cyclobutyl 3-((tert-butyldimethylsilyl)oxy)4-methylbenzenesulfonate (470 mg, 1.32 mmol) were added to the reaction solution and it was allowed to react at 80° C. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with EA, and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated by column chromatography to give 223 mg of Intermediate 12-1 with a yield of 56.8%.

[0296] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.07 (s, 1H), 8.04 (s, 1H), 4.86-4.79 (m, 1H), 4.64-4.58 (m, 1H), 2.75-2.69 (m, 2H), 2.52-2.45 (m, 2H), 0.84 (s, 9H), 0.02 (s, 6H).

Synthesis of Intermediate 12-2: 1-(3-((tert-butyldimethylsilyl)oxy) cyclobutyl)-1H-pyrazol-4-amine

[0297] Intermediate 12-1 (50 mg, 0.168 mmol) was dissolved in 5 ml of methanol, 10% Pd/C (5 mg) was added to the system, the atmosphere was replaced with hydrogen three times and then the reaction was carried out at room temperature. After the reaction was completed, the reaction system was filtered and concentrated to give 43 mg of intermediate 12-2 with a yield of 95.6%.

Synthesis of compound 12: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0298] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (36.0 mg, 0.082 mmol) was dissolved in 4 ml DMF, HATU (34.4 mg, 0.091 mmol) and DIPEA (21.2 mg, 0.165 mmol) were added to the system and the mixture was stirred for one hour at room temperature. Then Intermediate 12-2 (22.0 mg, 0.082 mmol) was added to the system and it was allowed to react at room temperature after the addition was completed. After the reaction was completed, the system was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 4 ml of methanol, then 2 ml of concentrated hydrochloric acid was added, and it was allowed to react at 50° C. After the reaction was completed, the reaction solution was evaporated under reduced pressure, the residue was dissolved in 2 ml of methanol, and neutralized by adding 0.5 ml of ammonia. After the neutralization, it was concentrated and purified by column chromatography to give 16.0 mg of compound 12 with a yield of 42.3%.

[0299] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.46 (s, 2H), 8.09 (s, 1H), 7.73 (s, 1H), 7.58 (d, J=2.2 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.16 (dd, J=2.3, 9.0 Hz, 1H), 6.16 (q, J=6.7 Hz, 1H), 5.02-4.94 (m, 1H), 4.62-4.56 (m, 1H), 2.82-2.75 (m, 2H), 2.54-2.47 (m, 2H), 1.81 (d, J=6.7 Hz, 3H).

Example 13: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide (13)

[0300] ##STR00029##

[0301] Synthetic Route of Compound 13:

##STR00030##

[0302] Synthesis Method:

Synthesis of Intermediate 13-1: 1-(4-aminophenyl)piperidin-4-ol

[0303] 4-nitrofluorobenzene (25 mg, 0.18 mmol) and piperidin-4-ol (26.9 mg, 0.27 mmol) were dissolved in 3 ml DMSO, potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and it was allowed to react at 40° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. To the resulting residue, 3 ml of methanol and 2.5 mg of palladium carbon were added, the atmosphere was replaced by hydrogen gas three times and the reaction was carried out at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated and purified on silica gel plate to afford 20 mg of intermediate 13-1 with a yield of 73.4%.

[0304] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.85 (d, J=8 Hz, 2H), 6.64 (d, J=8 Hz, 2H), 3.79-3.83 (m, 1H), 3.33-3.39 (m, 2H), 2.77-2.83 (m, 2H), 2.01-2.05 (m, 2H), 1.68-1.77 (m, 2H).

Synthesis of compound 13: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0305] Intermediate 13-1 (20 mg, 0.10 mmol) and Intermediate 1-=(41.3 mg, 0.09 mmol) were dissolved in DMF (3 ml), HATU (35.9 mg, 0.09 mmol) and DIPEA (24.4 mg, 0.18 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting mixture was concentrated and purified by a preparative plate to afford 8 mg of the final product with a yield of 14.60%.

[0306] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.58 (s, 1H), 9.92 (s, 1H), 8.59 (s, 2H), 7.63 (d, J=12 Hz, 2H), 7.55 (d, J=8 Hz, 1H), 7.50 (d, J=4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.90 (d, J=12 Hz, 2H), 6.04-6.09 (m, 1H), 4.63-4.65 (m, 1H), 3.61-3.63 (m, 1H), 3.47-3.50 (m, 2H), 2.77-2.83 (m, 2H), 1.81-1.84 (m, 2H), 1.75 (d, J=4 Hz, 3H), 1.48-1.52 (m, 2H).

Example 14: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (14)

[0307] ##STR00031##

[0308] Synthetic Route of Compound 14

##STR00032##

[0309] Synthesis Method:

Synthesis of Intermediate 14-1: 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine

[0310] 4-nitro-1H-pyrazole (100 mg, 0.884 mmol) was dissolved in 20 ml of acetonitrile, and potassium phosphate (563 mg, 2.65 mmol) and 1-methylpiperidin-4-yl-4-methylbenzenesulfonate (238 mg, 0.884 mmol) were added to the reaction solution, and it was allowed to react at 80° C. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with EA, and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated by column chromatography to give 112 mg of Intermediate 14-1 with a yield of 60.1%.

[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (s, 1H), 8.08 (s, 1H), 4.18-4.10 (m, 1H), 3.02-2.98 (m, 2H), 2.51 (s, 3H), 2.22-2.13 (m, 4H), 2.09-1.99 (m, 2H).

Synthesis of Intermediate 14-2: 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine

[0312] Intermediate 14-1 (50.0 mg, 0.238 mmol) was dissolved in 5 ml of methanol and 10% Pd/C (5 mg) was added to the system, the atmosphere was replaced with hydrogen three times and then the reaction was carried out at room temperature. After the reaction was completed, the system was filtered and concentrated to give 37.0 mg of intermediate 14-2 with a yield of 86.3%.

Synthesis of compound 14: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0313] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30.0 mg, 0.069 mmol) was dissolved in 4 ml DMF, HATU (28.7 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added to the system and the mixture was stirred for one hour at room temperature. Then Intermediate 14-2 (12.4 mg, 0.069 mmol) was added to the system and it was allowed to react at room temperature after the addition was completed. After the reaction was completed, the system was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 4 ml of methanol, then 2 ml of concentrated hydrochloric acid was added, and it was allowed to react at 50° C. After the reaction was completed, the reaction solution was evaporated under reduced pressure, the residue was dissolved in 2 ml of methanol, and neutralized by adding 0.5 ml of ammonia. After the neutralization, it was concentrated and purified by column chromatography to give 14.0 mg of compound 14 with a yield of 39.6%.

[0314] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.45 (s, 2H), 8.10 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.16 (dd, J=2.4, 9.1 Hz, 1H), 6.16 (q, J=6.7 Hz, 1H), 4.23-4.03 (m, 1H), 3.08-2.99 (m, 2H), 2.37 (s, 3H), 2.33-2.26 (m, 2H), 2.19-2.05 (m, 4H), 1.81 (d, J=6.7 Hz, 3H).

Example 15: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-methylamide (15)

[0315] ##STR00033##

[0316] Synthetic Route of Compound 15:

##STR00034##

[0317] Synthesis Method:

Synthesis of Intermediate 15-1: 1-(2-bromoethyl)cyclopropan-1-ol

[0318] Methyl 3-bromopropionate (1 g, 5.99 mmol) and tetraisopropyl titanate (170.2 mg, 0.60 mmol) were dissolved in 30 ml THE (dry). The atmosphere was replaced by nitrogen, and the system was cooled down to 0° C. Ethylmagnesium bromide (13.2 ml, 1 mol/L) was added dropwise to the solution, and it was allowed to react for 2 h at room temperature. To the reaction solution, saturated ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography to afford 230 mg of Intermediate 15-1 with a yield of 23.3%.

[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.62 (t, J=6 Hz, 2H), 2.13 (t, J=8 Hz, 2H), 0.81-0.84 (m, 2H), 0.54-0.57 (m, 2H).

Synthesis of Intermediate 15-2: 1-(2-(4-amino-1H-pyrazol-1-yl)ethyl) cyclopropan-1-ol

[0320] 4-nitro-1H-pyrazole (100 mg, 0.88 mmol) was dissolved in 15 ml acetonitrile, cesium carbonate (864.9 mg, 2.65 mmol) and Intermediate 15-1 (230 mg, 1.39 mmol) were added to the reaction solution, and it was allowed to react at 60° C. 3 hours later, 30 ml of water was added to the system, the mixture was extracted with EA, and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated by column chromatography to give 100 mg of product. The product was dissolved in 5 ml of methanol, 10 mg of palladium carbon was added, the atmosphere was replaced by hydrogen, and the reaction was carried out for 1 h at room temperature. After the reaction was completed, the reaction mixture was filtered, concentrated and purified by column chromatography to afford 60 mg of intermediate 15-2 with a yield of 40.6%.

[0321] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.16 (s, 1H), 7.03 (s, 1H), 4.26 (t, J=6 Hz, 2H), 1.95 (t, J=6 Hz, 2H), 0.67-0.70 (m, 2H), 0.27-0.30 (m, 2H).

Synthesis of compound 15: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0322] Intermediate 1-6 (50 mg, 0.11 mmol) was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, and it was allowed to react at 50° C. for 3 h. The reaction solution was concentrated, 3 ml of methanol and 0.5 ml of ammonia were added, and the resulting mixture was concentrated and purified by column chromatography. The resulting product and Intermediate 15-2 (14.2 mg, 0.08 mmol) were dissolved in DMF (3 ml), HATU (38.8 mg, 0.10 mmol) and DIPEA (22.0 mg, 0.17 mmol) were added, and it was allowed to react at room temperature for 2 h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to afford 2.8 mg of the final product with a yield of 7%.

[0323] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.61 (s, 1H), 10.39 (s, 1H), 8.60 (s, 2H), 8.05 (s, 1H), 7.64 (s, 1H), 7.54-7.56 (m, 2H), 7.15 (d, J=8 Hz, 1H), 6.06-6.11 (m, 1H), 4.25 (t, J=6 Hz, 2H), 1.94 (t, J=6 Hz, 2H), 1.76 (d, J=8 Hz, 3H), 0.50-0.53 (m, 2H), 0.25-0.28 (m, 2H).

Example 16: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide (16)

[0324] ##STR00035##

[0325] Synthetic Route of Compound 16:

##STR00036##

[0326] Synthesis Method:

Synthesis of Intermediate 16-1: (3S, 5R)-3, 5-dimethyl-1-(6-nitropyridin-3-yl)piperazine

[0327] 5-Fluoro-2-nitropyridine (100 mg, 0.70 mmol) and (2S, 6R)-2, 6-dimethylpiperazine (88.4 mg, 0.77 mmol) were dissolved in 2 ml DMF, DIPEA (181.6 mg, 1.41 mmol) was added to the solution and it was allowed to react at 50° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated to afford 155 mg of Intermediate 16-1 with a yield of 93.2%.

[0328] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16-8.12 (m, 2H), 7.20-7.17 (m, 1H), 3.76-3.72 (m, 2H), 3.04-2.99 (m, 2H), 2.60-2.54 (m, 2H), 0.90 (dd, J=4 Hz, J=8 Hz, 6H).

Synthetic Intermediate 16-2: 5-((3S, 5R)-3, 5-dimethylpiperazin-1-yl) pyridin-2-amine

[0329] Intermediate 16-1 (155 mg, 0.66 mmol) was dissolved in 10 ml methanol, 20 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen 3 times, and the reaction was carried out at room temperature for 2 h. The mixture was filtered and concentrated to give 130 mg of Intermediate 16-2 with a yield of 96.1%.

Synthesis of compound 16: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide

[0330] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 16-2 (15.6 mg, 0.08 mmol) were dissolved in DMF (1 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 4 mg of the final product with a total yield of 10.8% in two steps.

[0331] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.45 (s, 1H), 8.60 (s, 2H), 8.05-8.03 (m, 2H), 7.59 (d, J=8 Hz, 1H), 7.49-7.46 (m, 2H), 7.18 (dd, J=4 Hz, J=8 Hz, 1H), 6.11-6.06 (m, 1H), 3.56-3.51 (m, 2H), 2.90-2.85 (m, 2H), 2.18-2.12 (m, 2H), 1.77 (d, J=8 Hz, 3H), 1.04 (d, J=4 Hz, 6H).

Example 17: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide (17)

[0332] ##STR00037##

[0333] Synthetic Route of Compound 17:

##STR00038##

[0334] Synthesis Method:

Synthesis of Intermediate 17-1: 4-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)-3-fluoroaniline

[0335] 1, 2-difluoro-4-nitrobenzene (50 mg, 0.31 mmol) and (2S, 6R)-2, 6-dimethylpiperazine (39.5 mg, 0.34 mmol) were dissolved in 5 ml of acetonitrile, DIPEA (81.1 mg, 0.63 mmol) was added to the solution and it was allowed to react at 80° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. To the resulting residue, 3 ml of methanol and 5 mg of 10% palladium carbon were added, the atmosphere was replaced by hydrogen three times and the reaction was carried out at 40° C. for 1 h. After the reaction was completed, the reaction mixture was filtered, concentrated and purified on silica gel plate to afford 44 mg of intermediate 17-1 with a yield of 62.7%.

[0336] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.79 (t, J=8 Hz, 1H), 6.37-6.43 (m, 2H), 3.07-3.16 (m, 4H), 2.26 (t, J=10 Hz, 2H), 1.10 (d, J=8 Hz, 6H).

Synthesis of compound 17: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide

[0337] Intermediate 17-1 (18.4 mg, 0.08 mmol) and Intermediate 1-6 (30 mg, 0.06 mmol) were dissolved in DMF (3 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 10 mg of the final product with a yield of 26.1%.

[0338] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.48 (s, 1H), 8.71 (s, 1H), 8.43 (s, 2H), 7.77 (s, 1H), 7.67 (d, J=12 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.16-7.24 (m, 2H), 6.94 (t, J=10 Hz, 1H), 6.13-6.18 (m, 1H), 3.28-3.31 (m, 2H), 3.16-3.20 (m, 2H), 2.40 (m, 2H), 1.81 (d, J=8 Hz, 3H), 1.18 (d, J=4 Hz, 6H).

Example 18: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide (18)

[0339] ##STR00039##

[0340] Synthetic Route of Compound 18:

##STR00040##

[0341] Synthesis Method:

Synthesis of Intermediate 18-1: 1-ethyl-4-phenylpiperidine

[0342] 4-Phenylpiperidine (100 mg, 0.62 mmol) and triethylamine (188.4 mg, 1.86 mmol) were dissolved in 10 ml of dichloromethane and acetyl chloride (58.4 mg, 0.74 mmol) was added dropwise to the solution and the reaction was carried out at room temperature for 1 hour. Water was added to the reaction solution, the reaction solution was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was dissolved in dry THF, and cooled to 0° C. Lithium tetrahydroaluminum (61.7 mg, 1.62 mmol) was added and it was allowed to react at room temperature for 3 h. The reaction was quenched by adding a small amount of water, and anhydrous sodium sulfate was added while stirring for 20 min. The resulting mixture was filtered and concentrated to give 96 mg of Intermediate 18-1 with a total yield of 82.1% in two steps.

[0343] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.32-7.19 (m, 5H), 3.11-3.06 (m, 2H), 2.50-2.42 (m, 3H), 2.05-2.01 (m, 2H), 1.99-1.79 (m, 4H), 1.11 (t, J=8 Hz, 3H).

Synthetic intermediate 18-2: 1-ethyl-4-(4-nitrophenyl)piperidine

[0344] Intermediate 18-1 (96 mg, 0.51 mmol) was dissolved in 196 mg concentrated sulfuric acid, and cooled to 0° C., to which concentrated nitric acid (56.7 mg, 0.90 mmol) was added dropwise, and it was allowed to react overnight at room temperature. Water was added to the reaction solution and the mixture was adjusted to pH=8 with sodium hydroxide solution. The resulting solution was extracted with ethyl acetate, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated to give 83 mg of Intermediate 18-2 with a yield of 70.9% N.

[0345] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (d, J=8 Hz, 2H), 7.39 (d, J=8 Hz, 2H), 3.13-3.10 (m, 2H), 2.64-2.60 (m, 1H), 2.50-2.45 (m, 2H), 2.07-2.01 (m, 2H), 1.89-1.81 (m, 4H), 1.13 (t, J=8 Hz, 3H).

Synthetic intermediate 18-3: 4-(1-ethylpiperidin-4-yl)aniline

[0346] Intermediate 18-2 (83 mg, 0.35 mmol) was dissolved in 10 ml of methanol, 8 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen 3 times, and the reaction was carried out at room temperature for 2 h. The reaction mixture was filtered and concentrated to give 49 mg of Intermediate 18-3 with a yield of 67.7%.

Synthesis of compound 18: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide

[0347] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 18-3 (15.5 mg, 0.08 mmol) were dissolved in DMF (1 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 11 mg of the final product with a total yield of 29.7% in two steps.

[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.65 (s, 1H), 10.10 (s, 1H), 8.60 (s, 2H), 7.74 (d, J=8 Hz, 2H), 7.58 (d, J=8 Hz, 1H), 7.51 (d, J=4 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 7.17-7.14 (m, 1H), 6.10-6.07 (m, 1H), 3.00-2.97 (m, 2H), 2.50-2.46 (m, 1H), 2.37-2.33 (m, 2H), 2.01-1.94 (m, 3H), 1.77 (d, J=8 Hz, 3H), 1.68-1.63 (m, 3H), 1.04 (t, J=8 Hz, 3H).

Example 19: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (19)

[0349] ##STR00041##

[0350] Synthetic Route of Compound 19:

##STR00042##

[0351] Synthesis Method:

Synthesis of Intermediate 19-1: 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl) morpholine

[0352] 4-Nitro-1H-pyrazole (70 mg, 0.62 mmol) was dissolved in 10 ml of acetonitrile and potassium carbonate (256.7 mg, 1.86 mmol) and 4-(2-bromoethyl)morpholine hydrobromide (187.7 mg, 0.68 mmol) were added to the reaction solution and it was allowed to react at 80° C. for 4 hours. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated by column chromatography to give 103 mg of Intermediate 19-1 with a yield of 73.5%.

[0353] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (s, 1H), 8.08 (s, 1H), 4.27 (t, J=8 Hz, 2H), 3.73-3.71 (m, 4H), 2.84 (t, J=8 Hz, 2H), 2.52-2.50 (m, 4H).

Synthesis of Intermediate 19-2: 1-(2-morpholinoethyl)-1H-pyrazol-4-amine

[0354] Intermediate 19-1 (103 mg, 0.46 mmol) was dissolved in 10 ml of methanol, 10 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen 3 times, the reaction was carried out at room temperature for 2 h. The reaction mixture was filtered and concentrated to give 92 mg of Intermediate 19-2 with a yield of 91.8%.

Synthesis of compound 19: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0355] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 19-2 (16.2 mg, 0.08 mmol) were dissolved in DMF (1 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 23 mg of the final product with a total yield of 63.0% in two steps.

[0356] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.48 (s, 2H), 8.17 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=4 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.20 (dd, J=4 Hz, J=8 Hz, 1H), 6.21-6.16 (m, 1H), 4.31 (t, J=4 Hz, 2H), 3.74-3.71 (m, 4H), 2.84 (t, J=8 Hz, 2H), 2.55-2.52 (m, 4H), 1.83 (d, J=4 Hz, 3H).

Example 20: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (20)

[0357] ##STR00043##

[0358] Synthetic Route of Compound 20:

##STR00044##

[0359] Synthesis Method:

Synthesis of Intermediate 20-1: 1-ethyl-4-nitro-1H-pyrazole

[0360] 4-Nitro-1H-pyrazole (100 mg, 0.88 mmol) was dissolved in 15 ml of acetonitrile and potassium carbonate (366.7 mg, 2.65 mmol) and bromoethane (217.6 mg, 1.77 mmol) were added to the reaction solution and it was allowed to react at 80° C. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 110 mg of Intermediate 20-1 with a yield of 88.1%.

[0361] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (s, 1H), 8.10 (s, 1H), 4.27 (dd, J=8 Hz, J=12 Hz, 2H), 1.59-1.56 (m, 3H).

Synthetic Intermediate 20-2: 1-ethyl-1H-pyrazol-4-amine

[0362] Intermediate 20-1 (110 mg, 0.78 mmol) was dissolved in 10 ml of methanol, 20 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen three times, and the reaction was carried out at room temperature for 2 h. The reaction mixture was filtered and concentrated to give 73 mg of intermediate 20-2 with a yield of 84.3%.

Synthesis of compound 20: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0363] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 2 (8.4 mg, 0.08 mmol) were dissolved in DMF (1 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 19 mg of the final product with a total yield of 62.0% in two steps.

[0364] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.48 (s, 2H), 8.08 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=4 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.20 (dd, J=4 Hz, J=8 Hz, 1H), 6.21-6.16 (m, 1H), 4.24 (dd, J=8 Hz, J=16 Hz, 2H), 1.85 (d, J=8 Hz, 3H), 1.52 (t, J=8 Hz, 3H).

Example 21: Synthesis of 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (21)

[0365] ##STR00045##

[0366] Synthetic Route of Compound 21:

##STR00046##

[0367] Synthesis Method.

Synthesis of Intermediate 21-1: tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate

[0368] 4-Nitro-1H-pyrazole (230 mg, 2.04 mmol) was dissolved in 4 ml DMF, cesium carbonate (1.33 g, 4.08 mmol) and tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (614.4 mg, 2.45 mmol) were added to the reaction solution and it was allowed to react at 100° C. overnight. After the reaction was completed, 50 ml of water was added to the system, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 480 mg of Intermediate 21-1 with a yield of 87.6%.

[0369] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.30 (s, 1H), 8.18 (s, 1H), 5.09-5.05 (m, 1H), 4.47-4.42 (m, 2H), 4.36-4.33 (m, 2H), 1.46 (s, 9H).

Synthetic intermediate 21-2: 1-(1-methylazetidin-3-yl)-4-nitro-1H-pyrazole

[0370] Intermediate 21-1 (460 mg, 1.72 mmol) was dissolved in 10 ml of dichloromethane, 2.5 ml of trifluoroacetic acid was added and it was allowed to react at room temperature for 0.5 h. The reaction solution was concentrated, and the resulting residue was dissolved with dichloromethane, adjusted to pH=8 with saturated sodium bicarbonate solution, and extracted three times with dichloromethane. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained product (83 mg, 0.49 mmol) was dissolved with dichloromethane, aqueous formaldehyde solution (0.12 ml, 1.48 mmol) was added, and the mixture was stirred for 20 min at room temperature. NaBH(OAc).sub.3 (627.9 mg, 2.96 mmol) was added, and the mixture was stirred for 2 h at room temperature and extracted with water, dried over anhydrous sodium sulfate and concentrated to give Intermediate 21-2 of 42 mg in a total yield of 13.5% in two steps.

[0371] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (s, 1H), 8.13 (s, 1H), 4.97-4.90 (m, 1H), 3.83-3.79 (m, 2H), 3.58-3.54 (m, 2H), 2.47 (s, 3H).

Synthesis of Intermediate 21-3: 1-(1-methylazetidin-3-yl)-1H-pyrazol-4-amine

[0372] Intermediate 21-2 (42 mg, 0.23 mmol) was dissolved in 5 ml methanol, 5 mg 10% palladium carbon was added, the atmosphere was replaced with hydrogen 3 times, and the reaction was carried out at room temperature for 2 h. The reaction mixture was filtered and concentrated to give 29 mg of Intermediate 21-3 with a yield of 82.9%.

Synthesis of compound 21: 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0373] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 21-3 (12.6 mg, 0.08 mmol) were dissolved in DMF (1 ml), HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 3.6 mg of the final product with a total yield of 10.8% in two steps.

[0374] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.48 (s, 2H), 8.19 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=4 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.20 (dd, J=4 Hz, J=8 Hz, 1H), 6.21-6.16 (m, 1H), 5.06-5.02 (m, 1H), 3.94-3.90 (m, 2H), 3.68-3.65 (m, 2H), 2.52 (s, 3H), 1.52 (d, J=4 Hz, 3H). LC-MS: C.sub.22H.sub.22Cl.sub.2N.sub.7O.sub.2 [M+H].sup.+ m/z calculated as 486.1, detected as 486.1.

Example 22: Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (22)

[0375] ##STR00047##

[0376] Synthetic Route of Compound 22:

##STR00048##

[0377] Synthesis Method:

Synthesis of intermediate 22-1: tert-butyl 4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0378] Tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (130.0 mg, 0.47 mmol) and 4-nitro-1H-pyrazole (48.0 mg, 0.42 mmol) were dissolved in 20 ml of acetonitrile, cesium carbonate (276.8 mg, 0.85 mmol) was added to the reaction solution and it was allowed to react at 80° C. for 2 hours. After the reaction was completed, water was added to the system, the system was extracted with ethyl acetate, and partitioned, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to afford 130.3 mg of Intermediate 22-1 with a yield of 98.6%.

Synthesis Intermediate 22-2: 1-methyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine

[0379] Intermediate 22-1 (130.3 mg, 0.41 mmol) was dissolved in 10 ml of dichloromethane, 2 ml of trifluoroacetic acid was added to the solution, and it was allowed to react for 30 minutes at room temperature. The reaction solution was concentrated, the concentrate was dissolved in 10 ml of dichloromethane, aqueous formaldehyde solution (0.10 ml, 1.25 mmol) was added, and the mixture was stirred for 20 min at room temperature. NaBH(OAc).sub.3 (265.1 mg, 1.25 mmol) was added, and the mixture was stirred for 2 h at room temperature, extracted with water, dried over anhydrous sodium sulfate and concentrated to give 90.2 mg of Intermediate 22-2 with a yield of 95.8%.

[0380] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.61 (s, 1H), 8.14 (s, 1H), 4.14 (d, J=7.2 Hz, 2H), 3.09-3.04 (m, 2H), 2.44 (s, 3H), 2.32-2.21 (m, 2H), 2.08-2.01 (m, 1H), 1.71-1.66 (m, 2H), 1.48-1.40 (m, 2H).

Synthesis of compound 22-3: 1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-amine

[0381] Intermediate 22-2 (50.0 mg, 0.22 mmol) was dissolved in 5 ml of methanol, 5 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen three times and the reaction was carried out at room temperature for 2 h. The reaction solution was filtered and the filtrate was concentrated to give 42.9 mg of Intermediate 22-3 with a yield of 99.2%.

Synthesis of compound 22: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0382] Intermediate 5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and Intermediate 22-3 (14.7 mg, 0.08 mmol) were dissolved in 5 ml DMF, HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 7.6 mg of the final product with a total yield of 35.2% in two steps.

[0383] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.47 (s, 2H), 8.08 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.50 (d, J=9.1 Hz, 1H), 7.18 (dd, J=9.1 Hz, 2.4 Hz, 1H), 6.18 (q, J=6.6 Hz, 1H), 4.06 (d, J=7.2 Hz, 2H), 2.94 (d, J=11.7 Hz, 2H), 2.32 (s, 3H), 2.09 (t, J=11.3 Hz, 2H), 2.00-1.89 (m, 1H), 1.83 (d, J=6.7 Hz, 3H), 1.64 (d, J=13.1 Hz, 2H), 1.44-1.37 (m, 2H).

Example 23: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0384] ##STR00049##

[0385] Synthetic Route of Compound 23:

##STR00050##

[0386] Synthesis Method:

Synthesis of Intermediate 23-1: 2-(4-amino-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

[0387] 2-(4-Nitro-1H-pyrazol-1-yl)acetic acid (50 mg, 0.29 mmol) and pyrrolidine (24.9 mg, 0.35 mmol) were dissolved in DMF, HATU (133.3 mg, 0.35 mmol) and DIPEA (75.4 mg, 0.58 mmol) were added to the solution, and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel plate. The resulting product was dissolved in 3 ml of methanol, 5 mg of 10% palladium carbon was added, the atmosphere was replaced with hydrogen, and the reaction was carried out at 40° C. for 1 h. After the reaction was completed, the product was filtered, concentrated and purified on silica gel plate to afford 40 mg of Intermediate 23-1 with a yield of 70.4%.

[0388] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.17 (d, J=4 Hz, 2H), 4.78 (s, 2H), 3.42-3.50 (m, 4H), 2.00-1.93 (m, 2H), 1.88-1.81 (m, 2H).

Synthesis of compound 23: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0389] Intermediate 23-1 (16.0 mg, 0.08 mmol) and Intermediate 1-6 (30 mg, 0.07 mmol) were dissolved in DMF (3 ml), HATU (31.3 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol) were added, and it was allowed to react at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 6 mg of the final product with a yield of 16.5%.

[0390] .sup.1H NMR (400 MHz, DMSO) δ 13.62 (s, 1H), 10.45 (s, 1H), 8.60 (s, 2H), 8.03 (s, 1H), 7.66 (s, 1H), 7.57-7.54 (m, 2H), 7.17-7.14 (m, 1H), 6.11-6.06 (m, 1H), 5.01 (s, 2H), 3.49 (t, J=8 Hz, 2H), 3.36-3.34 (m, 2H), 1.96-1.89 (m, 2H), 1.83-1.76 (m, 5H).

Examples 24 to 30

[0391] Each compound shown in the table below was prepared via a synthetic route and method similar to that of Example 23 by varying the starting materials, and their .sup.1H NMR and/or mass spectrometry data were measured.

TABLE-US-00001 LC-MS Theoretical LC-MS Calculated Measured .sup.1HNMR(400 values values Examples MHz) (M + 1).sup.+ (M + 1).sup.+ [00051]   Example 24: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(1-(2-(dimethylamino)-2- oxoethyl)-1H-pyrazol-4-yl)-1H-indazole-3- carboxamide (MeOD)δ 8.47 (s, 2H), 8.11 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.19- 7.17 (m, 1H), 6.20-6.15 (m, 1H), 5.15 (s, 2H), 3.15 (s, 3H), 3.01 (s, 3H), 1.83 (d, J = 8.0 Hz, 3H). [00052]   Example 25: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(1-(2-(pyrrolidin-1-yl)ethyl)- 1H-pyrazol-4-yl)-1H-indazole-3- carboxamide 514.1 514.1 [00053]   Example 26: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(1-isopropyl-1H-pyrazol-4- yl)-1H-indazole-3-carboxainide 459.1 459.1 [00054]   Example 27: N-(1-cyclobutyl-1H-pyrazol-4- yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazole-3-carboxamide 471.1 471.1 [00055]   Example 28: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(1-(2,2,2-trifluoroethyl)-1H- pyrazol-4-yl)-1H-indazole-3-carboxamide 499.1 499.0 [00056]   Example 29: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(1-(3-hydroxypropyl)-1H- pyrazol-4-yl)-1H-indazole-3-carboxamide 475.1 475.1 [00057]   Example 30: 5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-N-(4-(morpholinomethyl) phenyl)-1H-indazole-3-carboxamide 526.1 526.1

Example 31: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethyl-azetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0392] ##STR00058##

[0393] Synthetic Route of Compound 31

##STR00059##

[0394] Synthesis Method:

Synthesis of Intermediate 31-1: 1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-amine

[0395] 4-Nitro-1H-pyrazole (50 mg, 0.44 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (114.8 mg, 0.47 mmol) were dissolved in DMF, K.sub.2CO.sub.3 (184.4 mg, 1.33 mmol) was added to the solution and it was allowed to react at 80° C. for 4 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate and the resulting organic phases were combined, washed with water twice, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated and purified by silica gel plate. The obtained product was dissolved in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated. The obtained product was dissolved in 5 ml of dichloromethane, acetaldehyde (21.4 mg, 0.49 mmol) was added to the solution and the mixture was stirred at room temperature for half an hour. Sodium triacetylborohydride (186.5 mg, 0.88 mmol) was added and it was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to the reaction solution, the reaction solution was extracted twice with dichloromethane, and the resulting organic phases were combined, concentrated, purified on silica gel plate. The resulting product was dissolved in 5 ml of methanol, 5 mg of palladium carbon was added, the atmosphere was replaced with hydrogen, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the product was filtered and concentrated to afford 29 mg of Intermediate 31-1 with a yield of 39.5%.

[0396] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (s, 1H), 8.13 (s, 1H), 4.98-4.96 (m, 1H), 3.82-3.79 (m, 2H), 3.53-3.50 (m, 2H), 2.64-2.62 (m, 2H), 1.05 (t, J=8 Hz, 3H).

Synthesis of compound 31: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethyl-azetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0397] Intermediate 31-1 (13.7 mg, 0.08 mmol) and Intermediate 6-2 (30 mg, 0.07 mmol) were dissolved in DMF (3 ml), HATU (31.3 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol) were added, and the reaction was carried out at room temperature for 3 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column. The resulting product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, it was allowed to react at 50° C. for 2 h, and the reaction solution was concentrated. The concentrate was dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and the resulting solution was concentrated and purified by a preparative plate to afford 12 mg of the final product with a yield of 34.9%.

[0398] 1H NMR (400 MHz, MeOD) δ 8.47 (s, 2H), 8.20 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 6.20-6.15 (m, 1H), 5.13-5.05 (m, 1H), 3.98-3.93 (m, 2H), 3.70-3.35 (m, 2H), 2.80-2.75 (m, 2H), 1.83 (d, J=8 Hz, 3H), 1.09 (t, J=8 Hz, 3H).

Examples 32-46 and Examples 47-51

[0399] Each compound shown in the table below was prepared via a synthetic route and method similar to that of Example 31 by varying the starting materials, and their .sup.1H NMR and/or mass spectrometry data were measured.

TABLE-US-00002 LC-MS Theoretical LC-MS Calculated Measured values values Examples .sup.1HNMR(400 MHz) (M + 1).sup.+ (M + 1).sup.+ [00060]   Example 32: 5-((R)-1-(3,5-dichloropyridin- 4-yl)ethoxy)-N-(1-((S)-2-hydroxypropyl)- 1H-pyrazol-4-yl)-1H-indazole-3- carboxamide (MeOD) δ 8.48 (s, 2H), 8.10 (s, 1H), 7.73 (s, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22- 7.15 (m, 1H), 6.18 (q, J = 4.0 Hz, 1H), 4.22- 4.04 (m, 3H), 1.83 (d, J = 8.0 Hz, 3H), 1.20 (d, J = 4.0 Hz, 3H). [00061]   Example 33: 5-((R)-1-(3,5-dichloropyridin- 4-yl)ethoxy)-N-(1-((R)-2-hydroxypropyl)- 1H-pyrazol-4-yl)-1H-indazole-3- carboxamide (MeOD) δ 8.47 (s, 2H), 8.10 (s, 1H), 7.73 (s, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.20- 7.16 (m, 1H), 6.18 (q, J = 8.0 Hz, 1H), 4.21- 4.04 (m, 3H), 1.83 (d, J = 8.0 Hz, 3H), 1.20 (d, J = 4.0 Hz, 3H). [00062]   Example 34: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-ethyl- 1H-pyrazol-4-yl)-1H-indazole-3- carboxamide (MeOD) δ 8.49 (s, 2H), 8.08 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 4 Hz, 1H), 7.50 (d, J = 8 Hz, 1H), 7.18 (dd, J = 8.4 Hz, 1H), 6.20- 6.17 (m, 1H), 4.24- 4.18 (m, 2H), 1.83 (d, J = 4 Hz, 3H), 1.50 (t, J = 8 Hz, 3H). [00063]   Example 35: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(3- hydroxycyclobutyl)-1H-py razol-4-yl)-1H- indazole-3-carboxamide (DMSO)δ 13.63 (s, 1H), 10.42 (s, 1H), 8.60 (s, 2H), 8.06 (s, 1H), 7.70 (s, 1H), 7.63- 7.49 (m, 2H), 7.21- 7.11 (m, 1H), 6.15- 6.03 (m, 1H), 5.21 (d, J = 4.0 Hz, 1H), 4.98- 4.89 (m, 1H), 4.51- 4.41 (m, 1H), 2.69- 2.57 (m, 2H), 2.42- 2.27 (m, 2H), 1.75 (d, J = 8.0 Hz, 3H). [00064]   Example 36: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(2- (dimethylamino)ethyl)-1H-pyrazol-4-yl)- 1H-indazole-3-carboxamide (MeOD) δ 8.47 (s, 2H), 8.13 (s, 1H), 7.72 (s, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.51-7.48 (m, 1H), 7.17 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 6.17 (q, J = 6.7 Hz, 1H), 4.30 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.32 (s, 6H), 1.82 (d, J = 6.6 Hz, 3H). [00065]   Example 37: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1H- indazole-3-carboxamide (MeOD) δ 8.48 (s, 2H), 8.17 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 2.4, 9.0 Hz, 1H), 6.18 (q, J = 6.7 Hz, 1H), 4.31 (t, J = 6.5 Hz, 2H), 3.73- 3.71 (m, 4H), 2.85 (t, J = 6.5 Hz, 2H), 2.56- 2.53 (m, 4H), 1.83 (d, J = 6.7 Hz, 3H). [00066]   Example 38: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-1H-indazole-3-carboxamide (MeOD) δ 8.48 (s, 2H), 8.12 (s, 1H), 7.72 (s, 1H), 7.59 (d, J = 2.5 Hz,1H), 7.51-7.49 (m, 1H), 7.18 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 6.18 (q, J = 6.6 Hz, 1H), 4.12 (s, 2H), 1.83 (d, J = 6.6 Hz, 3H), 1.22 (s, 6H). [00067]   Example 39: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- ethyl-azetidin-3-yl)methyl)-1H-pyrazol-4- yl)-1H-indazole-3-carboxamide (MeOD) δ 8.48 (s, 2H), 8.10 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 2.4 Hz,1H), 7.51-7.49 (m, 1H), 7.18 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 6.18 (q, J = 6.7 Hz, 1H), 4.34 (d, J = 7.1 Hz, 2H), 3.52-3.48 (m, 2H), 3.16-3.12 (m, 2H), 3.09-3.00 (m, 1H), 2.57 (q, J = 7.2 Hz, 2H), 1.83 (d, J = 6.7 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). [00068]   Example 40: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- ethylpiperidin-4-yl)methyl)-1H-pyrazol-4- yl)-1H-indazole-3-carboxamide (MeOD) δ 8.48 (s, 2H), 8.08 (s, 1H), 7.72 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.51-7.49 (m, 1H), 7.18 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 6.18 (q, J = 6.7 Hz, 1H), 4.06 (d, J = 7.2 Hz, 2H), 3.04 (d, J = 11.7 Hz, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.07-1.94 (m, 3H), 1.83 (d, J = 6.7 Hz, 3H), 1.65 (d, J = 12.2 Hz, 2H), 1.44- 1.34 (m,2H), 1.13 (t, J = 7.2 Hz, 3H). [00069]   Example 41: 5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- methylpyrrolidin-3-yl)methyl)-1H-pyrazol- 4-yl)-1H-indazole-3-carboxamide 514.1 514.1 [00070]   Example 42: 5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-N- (methylpyrrolidin-2-yl)methyl)-1H-pyrazol- 4-yl)-1H-indazole-3-carboxamide 514.1 514.1 [00071]   Example 43: 5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(1- methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)- 1H-indazole-3-carboxamide 500.1 500.1 [00072]   Example 44: 5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- methylpiperidin-3-yl)methyl)-1H-pyrazol- 4-yl)-1H-indazole-3-carboxamide 528.1 528.1 [00073]   Example 45: 5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- methylpiperidin-2-yl)methyl)-1H-pyrazol- 4-yl)-1H-indazole-3-carboxamide 528.1 528.1 [00074]   Example 47: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)-1H-indazole-3-carboxamide (CDCl3)δ 10.56 (s, 1H), 8.74 (s, 1H), 8.44 (s, 2H), 8.17 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J= 12.0 Hz, 1H), 7.19 (d, J = 10.0 Hz, 1H), 6.19-6.14 (m, 1H), 4.40-4.32 (m, 1H), 4.17-4.13 (m, 2H), 3.61-3.54 (m, 2H), 2.18-2.12 (m, 4H), 1.83 (d, J = 8.0 Hz, 3H). [00075]   Example 48: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-(4- hydroxycyclohexyl)-1H-pyrazol-4-yl)-1H- indazole-3-carboxamide (MeOD) δ 8.48 (s, 2H), 8.09 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.51- 7.49 (m, 1H), 7.18 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 6.18 (q, J = 6.7 Hz, 1H), 4.21- 4.14 (m, 1H), 3 .73- 3.66 (m, 1H), 2.28- 2.10 (m, 4H), 1.97- 1.87 (m, 2H), 1.83 (d, J = 6.7 Hz, 3H), 1.55- 1.46(m, 2H). [00076]   Example 49: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1- (pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H- indazole-3-carboxamide (MeOD) δ 8.53-8.50 (m, 2H), 8.47 (s, 2H), 8.24 (s, 1H), 7.78- 7.76 (m, 2H), 7.58 (d, J = 2.4 Hz, 1H), 7.51- 7.44 (m, 2H), 7.18 (dd, J = 9.1Hz, 2.4 Hz, 1H), 6.17 (q, J = 6.7 Hz, 1H), 5.44 (s, 2H), 1.83 (d, J = 6.6 Hz, 3H). [00077]   Example 50: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1- (pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H- indazole-3-carboxamide (MeOD) δ 8.53-8.52 (m, 2H), 8.47 (s, 2H), 8.26 (s, 1H), 7.80 (s, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.51-7.49 (m, 1H), 7.24 (d, J = 5.2 Hz, 2H), 7.18 (dd, J = 9.1Hz, 2.5 Hz, 1H), 6.17 (q, J = 6.6 Hz, 1H), 5.47 (s, 2H), 1.83 (d, J = 6.5 Hz, 3H). [00078]   Example 51: (R)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-N-(1-((1- methylazetidin-3-yl)methyl)-1H-pyrazol-4- yl)-1H-indazole-3-carboxamide 500.1 500.1

Example 46: 5-(1-3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0400] ##STR00079##

[0401] Synthetic Route of Compound 46:

##STR00080##

[0402] Synthesis Method:

Synthesis of Intermediate 46-1: 1-(3,5-dichloropyridin-4-yl)propan-1-ol

[0403] DIEA (6.35 g, 0.049 mol) was dissolved in 20 ml THF, the atmosphere was replaced with nitrogen, and the solution was cooled down to below −50° C. N-butyllithium (20 ml, 0.049 mol) was added dropwise and it was allowed to react for 10 min. The temperature was controlled in the range of −70° C. to −50° C. 3,5-Dichloropyridine (6.0 g, 0.041 mol) dissolved in THE was added dropwise and it was allowed to react for 20 min. Finally, anhydrous propionaldehyde (4.7 g, 0.082 mol) was added dropwise and the reaction was carried out at −50° C. for 2 h, then the reaction system was allowed to naturally return to room temperature and monitored by LCMS whether the reaction was completed. To the reaction solution, 30 ml of ammonium chloride solution was added, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to afford 7.8 g of intermediate 46-1 with a yield of 93.9%.

Synthesis of Intermediate 46-2: 1-(3,5-dichloropyridin-4-yl)propyl 4-methylbenzenesulfonate

[0404] Intermediate 46-1 (7.8 g, 0.038 mol) and TEA (11.5 g, 0.114 mol) were dissolved in 20 ml DCM, and the reaction was cooled down to 0° C. p-Toluenesulfonyl chloride (8.7 g, 0.045 mol) and DMAP (0.48 g, 0.0038 mol) were added, and it was allowed to react at room temperature overnight. The reaction solution was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate and concentrated to afford 10.3 g of crude Intermediate 46-2 with a yield of 75.7%.

Synthesis of Intermediate 46-3: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1H-indole

[0405] Intermediate 46-2 (10.3 g, 0.028 mol) and 5-hydroxyindole (4.6 g, 0.034 mol) were dissolved in 20 ml DMF, cesium carbonate (28.0 g, 0.086 mol) was added, and it was allowed to react at 60° C. for 2 h. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 4.51 g of intermediate 46-3 with a yield of 49.1%. LC-MS m/z (ESI) [M+H].sup.+ for C.sub.15H.sub.13Cl.sub.2N.sub.3O was calculated as: 322.04; measured as: 322.04.

Synthesis of Intermediate 46-4: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1H-indazole-3-carbaldehyde

[0406] Sodium nitrite (8.1 g, 0.117 mol) was dissolved in 20 ml of water, 20 ml of DMF was added, and the reaction was cooled down to 0° C. 3M HCl (24 ml, 0.073 mol) was added dropwise, and then the cooling batch was removed after addition was completed. The mixture was stirred for 10 min at room temperature. Intermediate 46-3 (4.51 g, 0.015 mol) dissolved in 20 ml of DMF was added dropwise, and it was allowed to react for 3 h at room temperature. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated to afford 4.63 g of crude intermediate 46-4 with a yield of 94.3%. LC-MS m/z (ESI) [M+H].sup.+ for C.sub.15H.sub.12Cl.sub.2N.sub.4O.sub.2 was calculated as: 351.03; measured as: 351.03.

Synthesis of Intermediate 46-5: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0407] 46-4 (4.63 g, 0.013 mol) was dissolved in 20 ml DCM, p-toluenesulfonic acid (2.26 g, 0.013 mol) was added, and the mixture was stirred for 2 min. 3,4-dihydro-2H-pyran (1.32 g, 0.015 mol) in DCM (5 ml) was added to the reaction solution and it was allowed to react for 2 h at room temperature. Water was added to the reaction solution, the mixture was extracted twice with DCM, and the resulting organic phases were combined, washed with saturated sodium bicarbonate solution and saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 2.61 g of Intermediate 46-5 with a yield of 45.6%. LC-MS m/z (ESI) LC-MS [M+H].sup.+ for C.sub.20H.sub.20N.sub.4O.sub.3 was calculated as: 435.09; measured as: 435.09.

Synthesis of Intermediate 46-6: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0408] 46-5 (100.0 mg, 0.221 mmol) was dissolved in 24 ml of acetonitrile and 8 ml of water, potassium permanganate (87.1 mg, 0.442 mmol) was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was adjusted to pH 3 with 3M hydrochloric acid, and extracted twice with dichloromethane, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 91 mg of Intermediate 46-6 with a yield of 88.1%. LC-MS m/z (ESI) [M+H].sup.+ for C.sub.20H.sub.20N.sub.4O.sub.4 was calculated as: 451.09; measured as: 451.09.

Synthesis of compound 46: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0409] Intermediate 46-6 (40.0 mg, 0.088 mmol) was dissolved in 5 ml DMF, HATU (40.5 mg, 0.11 mmol) and DIPEA (16.1 mg, 0.12 mmol) were added to the system and the mixture was stirred for one hour at room temperature. Then 1-methyl-1H-pyrazol-4-amine (8.6 mg. 0.088 mmol) was added to the system. After the addition was completed, it was allowed to react for 1 hour at room temperature. After the reaction was completed, the system was quenched with water, and extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in 4 ml of methanol, then 2 ml of concentrated hydrochloric acid was added and it was allowed to react at 50° C. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was dissolved in 2 ml of methanol, and neutralized with 0.5 mmol of ammonia. After neutralization, the product was concentrate and purified by a preparative plate to afford 6.0 mg of the final product with a yield of 15.4%. LC-MS m/z (ESI) [M+H].sup.+ for C.sub.20H.sub.18Cl.sub.2N.sub.6O.sub.2 was calculated as: 445.09; measured as: 445.09.

[0410] Assay I: Determination of Inhibitory Activity Against FGFR Mutants

[0411] 1. Reagents and Equipment

TABLE-US-00003 Materials and reagents Manufacturer Cat. No. HTRF KinEASE-TK kit Cisbio 62TK0PEC FGFR1 V561M Signalchem F04-13G FGFR2 V564F Signalchem F05-12FG VEGFR2 Carna 08-191 FGFR3 V555M Signalchem F06-12GG MgCl2 Sigma M1028 ATP Promega V910B DTT Sigma D0632 DMSO Sigma D8418-1L Infigratinib (NVP-BGJ398) MCE HY-13311 Nintedanib MCE HY-50904 Cat. No. or Instruments and Equipment Manufacturer Model No. 384-well plate, white, low Greiner September 20, 4046 volume, round-bottom 96-well polypropylene plate Nunc April 26, 2584 Microplate low-speed centrifuge Xiang Zhi TD5B Biotek Enzyme Labeler Biotek Synergy 4

[0412] 2. Experimental Steps

[0413] 2.1 Preparation of 1×Kinase Reaction Buffer:

[0414] 1×Kinase reaction buffer was formulated with 1×volume of 5×kinase reaction buffer and 4×volume of water; 5 mM MgCl.sub.2; and 1 mM DTT.

TABLE-US-00004 2.2 Reaction conditions ATP working ATP concentration Substrate Kinase Km[μM] [μM] TK[μM] FGFR1 V561M 4.24 5 1 FGFR2 V564F 13.81 10 1 FGFR3 K650E 45.58 50 1 FGFR3 V555M 18.02 20 1 VEGFR2 5.92 5 1

[0415] 2.3 Screening of Compounds:

[0416] 1. Diluting a compound 4-fold in a dilution plate with DMSO, with a starting compound concentration of 2 mM (4 mM for Nentedanib).

[0417] 2. Diluting the compound 40-fold into 1×kinase reaction buffer and shaking it on a shaker for 20 minutes.

[0418] 3. Formulating 2×FGFR1 V561M/FGFR2 V564F/FGFR3 K650E/VEGFR2 with 1× of enzyme reaction buffer.

[0419] 4. Adding 2 μl FGFR1 V561M/FGFR2 V564F/FGFR3 K650E/VEGFR2 kinase (formulated in step 3) to each well of the reaction plate.

[0420] 5. Adding 1 μl of the compound diluted in buffer to each well, sealing the plate with a sealing membrane and centrifuging the plate at 1000 g for 30 seconds and leaving it at room temperature for 10 minutes.

[0421] 6. Formulating 2.5×TK-substrate-biotin and ATP mixture with 1×enzyme reaction buffer and adding 2 μl of K-substrate-biotin/ATP mixture to the reaction plate.

[0422] 7. Sealing the plate with a sealing membrane and centrifuging the plate at 1000 g for 30 seconds and allowing it to react at room temperature for 50 minutes.

[0423] 8. Formulating 4×Sa-XL 665 (250 nM) with HTRF assay buffer.

[0424] 9. Adding 5 μl Sa-XL 665 and 5 μl TK-Antibody-Cryptate to each well, centrifuging it at 1000 g for 30 seconds, and allowing it to react for 1 hour at room temperature.

[0425] 10. Reading fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) with Biotek.

[0426] 3. Data Analysis

[0427] 3.1 Calculation of the ratio for each well: the ratio was calculated as 665/615 nm.

[0428] 3.2 The inhibition rate was calculated as follows: inhibition rate of compound (% inh)=100%−(compound−positive control)/(negative control−positive control)*100%. The positive control was 20,000 nM Nintedanib or Infigratinib, and the negative control was 0.5% DMSO.

[0429] 3.3 Calculation of IC50 and plotting of inhibition curves for the compounds.

[0430] The IC50 (half inhibition concentration) of a compound was obtained using the following non-linear fitting equation, wherein data analysis was performed using Graphpad 6.0 software.

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC50−X)*Hill Slope))

[0431] X: log value of compound concentration; and Y: inhibition rate (% inh)

[0432] 3.4 Validation of Results

[0433] Data were exported from Envision and analyzed manually. The ratios were converted to inhibition rates and IC50 was calculated by Prism GraphPad 6.0 from the inhibition rates. IC50 was calculated again by the ratios to verify accuracy of the results.

[0434] 3.5 Quality Control

[0435] Z-factor>0.5; and S/B>2

[0436] Positive control IC50 was within 3 times of the average value

[0437] 4. Results

TABLE-US-00005 TABLE 1 Inhibition of FGFR mutants by compounds of Examples 1-22 IC.sub.50 (nM) FGFR1 FGFR2 FGFR3 FGFR3 Compounds V561M V564F K650E V555M VEGFR2 Infigratinib 26.6 691 Not 129 Not measured measured Nintedanib 166.4 19.4 16.7 Not 1.8 measured 1 6.3 2.3 26.8 8.6 Not measured 2 7.0 2.0 30   2.2 176 3 69.7 22.1 Not Not >10000 measured measured 4 95.1 9.5 Not Not 1586 measured measured 5 7.2 2.4 33.4 4.6 Not measured 6 2.3 0.66 Not 0.94 84.1 measured 7 5.2 0.42 Not 0.73 97.6 measured 8 2.3 4.0 Not 2.6 224 measured 9 1.0 0.94 Not 1.1 152 measured 10 1.7 3.2 Not 2.0 1387 measured 11 5.6 1.1 Not 1.7 230 measured 12 1.9 0.48 Not 0.74 208 measured 13 6.8 8.9 Not 5.9 >10000 measured 14 0.47 0.14 Not 0.27 24.7 measured 15 2.2 0.84 Not 2.1 66.2 measured 16 22.8 34.1 Not 41.7 1209 measured 17 8.6 2.3 Not 6.9 173 measured 18 1.6 0.63 Not 1.1 141 measured 19 0.35 0.24 Not 0.27 63.4 measured 20 9.1 0.82 Not 0.88 327 measured 21 0.27 0.09 Not 0.15 39.4 measured 22 0.91 0.6 Not 0.79 179 measured

[0438] Each example compound being tested above showed good inhibitory activity against FGFR1 V561M/FGFR2 V564F/FGFR3 V555M, while exhibiting relatively weak inhibitory activity against VEGFR2.

[0439] Assay II: Determination of inhibitory activity against wild-type FGFR

[0440] 1. Reagents and Equipment

TABLE-US-00006 Materials and reagents Manufacturer Cat. No. HTRF KinEASE-TK kit Cisbio 62TK0PEC FGFR1 Carna 08-133 FGFR2 Carna 08-134 FGFR3 Carna 08-135 MgCl2 Sigma M1028 ATP Promega V910B DTT Sigma D0632 DMSO Sigma D8418-1L Nintedanib MCE HY-50904 Cat. No. or Instruments and Equipment Manufacturer Model No. 384-well plate, white, low Greiner September 20, 4046 volume, round-bottom 96-well polypropylene plate Nunc April 26, 2584 Microplate low-speed centrifuge Xiang Zhi TD5B Biotek Enzyme Labeler Biotek Synergy 4

[0441] 2. Experimental Steps

[0442] 2.1 Preparation of 1×Kinase Reaction Buffer:

[0443] 1×Kinase reaction buffer was formulated with 1×volume of 5×kinase reaction buffer and 4×volume of water; 5 mM MgCl.sub.2; and 1 mM DTT.

TABLE-US-00007 2.2 Reaction conditions ATP working ATP concentration Substrate Kinase Km[μM] [μM] TK[μM] FGFR1 28.3 50 1 FGFR2 36.47 50 1 FGFR3 67.28 50 1

[0444] 2.3 Screening of Compounds:

[0445] 1. Diluting a compound 4-fold in a dilution plate with DMSO, with a starting compound concentration of 2 mM (4 mM for Nentedanib).

[0446] 2. Diluting the compound 40-fold into 1×kinase reaction buffer and shaking it on a shaker for 20 minutes.

[0447] 3. Formulating 2×FGFR1/FGFR2/FGFR3 with 1× of enzyme reaction buffer.

[0448] 4. Adding 2 μl FGFR1/FGFR2/FGFR3 kinase (formulated in step 3) to each well of the reaction plate.

[0449] 5. Adding 1 μl of the compound diluted in buffer to each well, sealing the plate with a sealing membrane and centrifuging the plate at 1000 g for 30 seconds and leaving it at room temperature for 10 minutes.

[0450] 6. Formulating 2.5×TK-substrate-biotin and ATP mixture with 1×enzyme reaction buffer and adding 2 μl of K-substrate-biotin/ATP mixture to the reaction plate.

[0451] 7. Sealing the plate with a sealing membrane and centrifuging the plate at 1000 g for 30 seconds and allowing it to react at room temperature for 50 minutes.

[0452] 8. Formulating 4×Sa-XL 665 (250 nM) with HTRF assay buffer.

[0453] 9. Adding 5 μl Sa-XL 665 and 5 μl TK-Antibody-Cryptate to each well, centrifuging it at 1000 g for 30 seconds, and allowing it to react for 1 hour at room temperature.

[0454] 10. Reading fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) with Biotek.

[0455] 3. Data Analysis

[0456] 3.1 Calculation of the ratio for each well: the ratio was calculated as 665/615 nm.

[0457] 3.2 The inhibition rate was calculated as follows: inhibition rate of compound (% inh)=100%−(compound−positive control)/(negative control−positive control)*100%. The positive control was 20,000 nM Nintedanib, and the negative control was 0.5% DMSO.

[0458] 3.3 Calculation of IC50 and plotting of inhibition curves for the compounds.

[0459] The IC50 (half inhibition concentration) of a compound was obtained using the following non-linear fitting equation, wherein data analysis was performed using Graphpad 6.0 software.

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC50−X)*Hill Slope))

[0460] X: log value of compound concentration; and Y: inhibition rate (% inh)

[0461] 3.4 Validation of Results

[0462] Data were exported from Envision and analyzed manually. The ratios were converted to inhibition rates and IC50 was calculated by Prism GraphPad 6.0 from the inhibition rates. IC50 was calculated again by the ratios to verify accuracy of the results.

[0463] 3.5 Quality Control

[0464] Z-factor>0.5; and S/B>2

[0465] Positive control IC50 was within 3 times of the average value

[0466] 4. Results

TABLE-US-00008 TABLE 2 Inhibition of wild FGFR by compounds IC.sub.50 (nM) Compounds FGFR1 FGFR2 FGFR3 Nintedanib 35.2 55.9 130.6 6 27.7 21.3 52.2 7 27.5 7.6 42.6 8 69.7 58.6 106 9 61.0 48.7 102 10 64.5 48 98.8 12 45.1 24.5 42.9 14 11.1 9.5 19.2

[0467] Each example compound being tested above showed similar or better inhibitory activity against wild-type FGFR1/FGFR2/FGFR3 compared with Nintedanib.

[0468] Assay III: Determination of Inhibitory Activity Against FGFR Mutants

[0469] The inhibitory activities of the compounds of examples 23-50 and the control compound Infigratinib against various FGFR mutants were measured using the same test method and equipment as described in “Assay I: Determination of Inhibitory Activity against FGFR Mutants”, but by a different experimental operator, and the results are shown in Table 3 below.

TABLE-US-00009 TABLE 3 Inhibition of FGFR mutants by compounds of Examples 23-50 IC.sub.50 (nM) FGFR1 FGFR2 FGFR3 Compounds V561M V564F V555M VEGFR2 Infigratinib 67.5 1128 69.6 73 23 2.2 0.47 0.92 114 24 3.3 0.43 1.3 201 25 3.6 0.26 0.21 145 26 11.4 1.8 2.9 255 27 20 2.1 7.3 581 28 11 2.6 3.0 68 29 2.3 0.93 0.25 144 30 36 3.7 7.6 729 31 0.93 0.11 0.07 54 32 0.3 0.37 0.26 86 33 1.0 0.33 0.39 99 34 0.24 0.06 0.75 61 35 0.29 0.16 0.27 89 36 0.88 0.07 0.11 41 37 1.6 0.44 0.16 79 38 3.7 0.40 0.59 61 39 0.35 0.05 0.05 30 40 0.42 1.3 0.02 33 41 0.37 0.18 0.22 84 42 1.1 0.43 0.44 169 43 0.38 0.15 0.14 62 44 1.1 0.39 0.55 145 45 0.34 0.10 0.14 62 46 3.4 1.0 2.1 184 47 2.3 1.2 2.1 194 48 1.0 0.31 0.82 115 49 0.51 0.55 1.4 110 50 1.7 0.37 0.64 152

[0470] It can be seen from the above table that each example compound being tested showed good inhibitory activity against FGFR1 V561M/FGFR2 V564F/FGFR3 V555M, while exhibiting relatively weak inhibitory activity against VEGFR2.

[0471] Although specific embodiments of the present disclosure have been illustrated and described, it does not mean that these embodiments illustrate and describe all possible implementation forms of the present disclosure. More precisely, the language used in this specification are only descriptive words and not restrictive. It will be obvious to those skilled in the art that various kinds of changes and modifications can be made without departing from the general scope of the present disclosure. Therefore, the appended claims are intended to include all these changes and modifications within the scope of the present disclosure.